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Anesth Analg 2000;91:1398-1403
© 2000 International Anesthesia Research Society

INTRAVENOUS ANESTHESIA

Auditory Steady-State Response and Bispectral Index for Assessing Level of Consciousness During Propofol Sedation and Hypnosis

Vincent Bonhomme, MD*, Gilles Plourde, MD, MSc*,{dagger}, Pascal Meuret, MD*, Pierre Fiset, MD*,{dagger}, and Steven B. Backman, MD, PhD*,{dagger}

*Department of Anesthesia, McGill University, and {dagger}Department of Anesthesia Royal Victoria Hospital, Montreal, Quebec, Canada

Address correspondence and reprint requests to Gilles Plourde, MD, MSc, Royal Victoria Hospital, Department of Anaesthesia, 687 Pine Ave. West, Room S5.05, Montreal, Quebec, Canada H3A 1A1. Address e-mail to mdgp{at}musica.mcgill.ca


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We assessed the effect of propofol on the auditory steady-state response (ASSR), bispectral (BIS) index, and level of consciousness in two experiments. In Experiment 1, propofol was infused in 11 subjects to obtain effect-site concentrations of 1, 2, 3, and 4 µg/mL. The ASSR and BIS index were recorded during baseline and at each concentration. The ASSR was evoked by monaural stimuli. Propofol caused a concentration-dependent decrease of the ASSR and BIS index values (r2 = 0.76 and 0.93, respectively; P < 0.0001). The prediction probability for loss of consciousness was 0.89, 0.96, and 0.94 for ASSR, BIS, and arterial blood concentration of propofol, respectively. In Experiment 2, we compared the effects of binaural versus monaural stimulus delivery on the ASSR in six subjects during awake baseline and propofol-induced unconsciousness. During baseline, the ASSR amplitude with binaural stimulation (0.47 ± 0.13 µV, mean ± SD) was significantly (P < 0.002) larger than with monaural stimulation (0.35 ± 0.11 µV). During unconsciousness, the amplitude was 0.09 ± 0.09 µV with monaural and 0.06 ± 0.04 µV with binaural stimulation (NS). The prediction probability for loss of consciousness was 0.97 (0.04 SE) for monaural and 1.00 (0.00 SE) for binaural delivery. We conclude that the ASSR and BIS index are attenuated in a concentration-dependent manner by propofol and provide a useful measure of its sedative and hypnotic effect. BIS was easier to use and slightly more sensitive. The ASSR should be recorded with binaural stimulation. The ASSR and BIS index are both useful for assessing the level of consciousness during sedation and hypnosis with propofol. However, the BIS index was simpler to use and provided a more sensitive measure of sedation.

Implications: We have compared two methods for predicting whether the amount of propofol given to a human subject is sufficient to cause unconsciousness, defined as failure to respond to a simple verbal command. The two methods studied are the auditory steady-state response, which measures the electrical response of the brain to sound, and the bispectral index, which is a number derived from the electroencephalogram. The results showed that both methods are very good predictors of the level of consciousness; however, bispectral was easier to use.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Loss of consciousness is an essential element of general anesthesia (1,2). Consciousness may be defined as "the fact or state of being mentally conscious or aware of anything" (3). In practice, responsiveness to verbal commands is the standard method to assess the level of consciousness (4). However, the level of consciousness cannot be reliably assessed in patients who are paralyzed by neuromuscular blocking drugs (5). There is, therefore, a need for a device that would provide an indication of the level of consciousness without requiring patient move-ment. The auditory steady-state response (ASSR) is a sensory-evoked potential proposed for that purpose (6–8).

The effect of a propofol bolus (1.5 mg/kg) on the ASSR has been previously described (9). Propofol caused a marked attenuation of the ASSR coinciding with loss of consciousness. During recovery from the effects of propofol, the ASSR often reappeared before the return of consciousness. This is different from isoflurane (6,8) and enflurane (10) for which the return of consciousness and reappearance of the ASSR coincided. This difference raises the possibility that the relationship between the ASSR and the level of consciousness may not be the same for propofol. It was, however, difficult to assess with confidence the relationship between the ASSR and consciousness during the propofol study because of the rapid changes in the level of consciousness and propofol concentration.

We have studied the effect of stable, propofol concentrations on the ASSR in two experiments. In the first experiment, we tested the hypothesis that the ASSR is attenuated in a concentration-dependent manner by propofol and that it provides a reliable indicator of the level of consciousness. The bispectral index (BIS) (11) was recorded for comparison. In the second experiment, we have tested the hypothesis that the ASSR evoked by binaural stimulation would be larger than that evoked by monaural stimulation during awake baseline but not during unconsciousness. We predicted that binaural stimulation would thus, increase the amplitude difference between baseline and unconsciousness and improve the performance of the ASSR.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Experiment 1
After approval of the Royal Victoria Hospital ethics board, we recruited 11 ASA physical status I, paid volunteers (six nonpregnant women) aged 20–31 (mean 25) yr. Subjects had no history of neurological or hearing disorders. They gave written consent, underwent a comprehensive medical evaluation, and had normal hearing based on pure tone audiometry.

Testing took place in the morning after an overnight fast. After placement of the electroencephalogram electrodes, we gave sodium citrate (30 mL orally) to reduce the acidity of gastric contents in the event of pulmonary aspiration. After local anesthesia we inserted a 18-gauge cannula in a vein of the right forearm for propofol administration and a 20-gauge cannula in the right radial artery for blood sampling of propofol concentration and for monitoring arterial pressure. Oxygen was given by face mask. Monitoring included three-lead electrocardiogram, pulse oximetry, and inspired and expired concentrations of oxygen and carbon dioxide of gas sampled from nasal prongs.

After baseline recordings of the ASSR and BIS, propofol was administered with a pump (Harvard 22; Harvard Apparatus, Southnatick, MA) driven by a personal computer running STANPUMP (S. L. Shafer, Stanford University, Stanford, CA) by using the kinetic variables of Tackley et al. (12). We targeted the following effect-site concentrations: 1, 2, 3, and 4 µg/mL, designated PRO_1, PRO_2, PRO_3 and PRO_4, respectively. After baseline recordings, the concentrations were targeted in the previously mentioned order until the subject showed no signs of responsiveness to commands and no spontaneous movements. We required absence of spontaneous movements because they make the assessment of the level of consciousness difficult.

To ensure equilibration between brain and blood concentrations, we delayed neurophysiological recordings for 5 min after obtaining the predicted effect-site concentration. At each concentration, an arterial blood sample was obtained before and after the neurophysiological recordings (duration 15–20 min) for determination of propofol concentration by high performance liquid chromatography (13).

Consciousness was defined as responsiveness to verbal commands ("open your eyes," "squeeze my finger") and was assessed every 2 min. The experimenter’s finger was placed in the subject’s hand at least 30 s before issuing the commands to distinguish reflex grasping after tactile stimulation from responsiveness to commands. The commands were spoken in a loud voice by the experimenter and were repeated up to three times, if the subject failed to respond. A subject who obeyed either command was considered conscious.

The procedures for recording the ASSR have been described in detail (8). Stimuli were 500 Hz tone bursts (10 ms, 82 dB PeSPL), delivered to the right ear via insert earphones at the rate of 34–44/sec. The electroencephalogram was recorded with gold cup electrodes from Cz (14) with reference to the right mastoid (impedance <3 k{Omega}; bandpass 0.1–100 Hz; digitization rate 1088–1410 Hz). Epochs contaminated by artifacts (±100 µV) were automatically rejected. For each period, we obtained 10 replicate averages of responses to 2,000 stimuli. Replicate averages judged deviant by visual inspection were excluded off-line before final averaging (exclusion rate 10.9%). The amplitude of the ASSR was measured by Fast Fourier Transform (15).

The BIS was recorded from C3 (14) with reference to right mastoid for 2 min before and after ASSR recordings with an monitor (A-1000; Aspect Medical Systems, Natick, MA) (version 3.12, bandpass 1.0–30 Hz). The mean of the two measures was used for analysis.

Procedures were performed with Statistica 4.1 for Macintosh (StatSoft, Tulsa, OK). We used logarithmic transformation of the ASSR for all procedures to meet the assumption of normal distribution (16). Differences among recording periods were evaluated with analysis of variance for repeated measures (with Geisser-Greenhouse adjustment of the degrees of freedom) and Tukey’s honestly significant difference post hoc test (17). Linear regression procedures also included a repeated measures design (18), where required.

We calculated the prediction probability (Pk) (19,20) to quantify the efficiency of the ASSR and BIS and of the measured or targeted concentration of propofol to predict responsiveness to verbal commands. Pk is a nonparametric, rank-order measure of association ranging from 0.5 (chance level) to 1.0 (perfect concordance).

Logistic regression with maximal likelihood estimation (21) was used to estimate the probability of consciousness as a function of the ASSR, BIS, or pro-pofol concentration. Logistic regression was calculated on normalized data to facilitate comparison among ASSR, BIS, and concentration. Normalized ASSR values (Ni) were computed by using: Go


where Vi = raw values, MIN = lowest ASSR value, MAX = highest ASSR value, K = number of observations.

A similar process was used for BIS and concentration. Logistic regression by using the raw data yielded similar results. Only the normalized results will be reported. Results are expressed as mean ± SD and are based on 11 subjects unless indicated otherwise. The criterion for statistical significance was 0.05.

Experiment 2
We recruited six additional subjects (three women) aged 18–34 (mean 25) yr. The procedures were similar to those described in Experiment 1 except for the following: the target propofol concentration was first set at 2.0 µg/mL and increased by 0.5 µg/mL steps until loss of consciousness; and recordings of the ASSR were obtained during awake baseline and unconsciousness induced by propofol. For each condition, the ASSR was recorded with monaural (right ear) and binaural stimulation. In three subjects, monaural recordings were obtained first. In the other three subjects, binaural recordings were obtained first.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Experiment 1
The propofol concentrations measured at the beginning and end of each recording period were: 1.19 ± 0.30 and 1.03 ± 0.19 µg/mL for PRO_1; 2.31 ± 0.45 and 2.17 ± 0.66 µg/mL for PRO_2; 3.14 ± 0.82 and 3.17 ± 0.71 µg/mL for PRO_3 (n = 10); and 4.06 ± 0.46 and 3.42 ± 1.45 µg/mL for PRO_4 (n = 3). There were no significant differences between first and second measures (P > 0.10), which were averaged for subsequent analysis. Linear regression of the measured concentration of propofol (Cm) as a function to the target concentration (Ct) yielded [Cm = 1.03 · Ct + 0.06] (r2 = 0.94; P < 10-4).

All subjects remained conscious during baseline and PRO_1. During PRO_2, five subjects were unconscious, one subject was intermittently conscious (responsive on three of 10 assessments), and five subjects remained conscious. During PRO_3 (n = 10), seven subjects were unconscious, one subject was intermittently conscious (responsive on eight occasions), and two subjects remained conscious. During PRO_4 (n = 3), subjects were unconscious. Subjects intermittently conscious were considered conscious for subsequent analysis.

During PRO_2, four of the five unconscious subjects manifested frequent spontaneous movements, usually involving the lower limbs. During PRO_3 and PRO_4, no unconscious subjects showed persistent spontaneous movements.

The ASSR amplitude was 0.34 ± 0.24 µV during baseline, 0.35 ± 0.29 µV during PRO_1, 0.21 ± 0.22 µV during the PRO_2, 0.11 ± 0.12 µV during PRO_3 (n = 10), and 0.09 ± 0.07 µV during PRO_4 (n = 3). During the largest propofol concentration for each subject, the ASSR amplitude was 0.06 ± 0.04 µV. The amplitude during PRO_3 was significantly smaller than during all previous periods (P < 0.006). There were no other statistically significant differences. PRO_4 was not compared with the other periods because there were only three observations. Figure 1 shows grand-average traces that combine data from all subjects. There was a highly significant relationship between the concentration of propofol and the amplitude of the ASSR (Figure 2). Linear regression of the ASSR amplitude (A) (log transformed) as a function of measured concentration (Cm) of propofol yielded [A = - 0.18· Cm - 0.49] (r2 = 0.76; P < 10-4).



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  		Figure 1. Grand-average auditory steady-state response waveforms where all subjects are pooled in a single trace for each period. Time scale normalized to a stimulus rate of 40/sec. The left panels show the raw data. The right panels show the best-fit 40 Hz sinusoid for each trace, which is analogous to measuring the amplitude by Fast Fourier Transform. Base = baseline; 1, 2, 3 and 4 µg refer to target propofol concentration; noi = residual electroencephalographic noise estimated from recordings obtained during baseline with no auditory stimuli. Upper panel; continuous line = baseline; dashed line = propofol 1 µg/mL; dotted line = propofol 2 µg/mL. Lower panel: continuous line = propofol 3 µg/mL; dashed line = propofol 4 µg/mL; dotted line = residual noise (noi) electroencephalographic noise.

 


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  		Figure 2. The auditory steady-state response amplitude (log scale) as a function of the measured concentration of propofol. Empty symbols indicate that subject was conscious; filled symbols that subject was unconscious. The lines connect points belonging to the same subject. The three subjects whose auditory steady-state response at onset of unconsciousness remained near baseline values are represented by squares and dotted lines. The other subjects are represented by circles and continuous lines. The triangles show an estimate of residual electroencephalographic noise obtained during baseline with the earphone disconnected. These triangles delimit the range of expected amplitudes, if the auditory steady-state response was abolished.

 
The BIS index value was 94 ± 2 during baseline, 87 ± 6 during PRO_1, 71 ± 8 during PRO_2, 56 ± 4 during PRO_3, and 53 ± 3 during PRO_4 (n = 3). During the largest propofol concentration for each subject, BIS was 51 ± 6. BIS during PRO_3 was significantly (P < 0.001) smaller than during all other periods. BIS during PRO_2 was significantly smaller than during baseline (P < 0.001) and PRO_1 (P < 0.005). The difference between baseline and PRO_1 was not statistically significant. There was a highly significant relationship between the concentration of propofol and BIS (Figure 3). Linear regression of BIS as a function of measured concentration (Cm) of propofol yielded [BIS = 10.9 · Cm + 86.9] (r2 = 0.93; P < 10-4).



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  		Figure 3. Bispectral index (BIS) as a function of measured concentration of propofol. Empty circles indicate that subject was conscious; filled circles indicate that subject was unconscious. The lines connect points belonging to the same subject.

 
When the ASSR amplitude was 0.08 µV or less, subjects were always unconscious (Figure 2). There were, however, six subjects whose ASSR remained >0.10 µV when consciousness was lost. For three of these subjects (represented by squares and dashed lines in Figure 2) ASSR at onset of unconsciousness was approximately the same as during baseline. These subjects had a low-amplitude awake baseline ASSR (between 0.10 and 0.12 µV) (Figure 2). When BIS was 60 or less, subjects were unconscious (Figure 3). During the period when unconsciousness occurred, BIS was lower than during the preceding period for all subjects.

The Pk was 0.888 (0.046 SE) for ASSR, 0.959 (0.028 SE) for BIS, 0.940 (0.035 SE) for measured concentration of propofol and 0.919 (0.036 SE) for target concentration. The results of the logistic regression are shown in Table 1 and the regression curves in Figure 4. The curves for ASSR and BIS are almost identical.


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  		Table 1. Logistic Regression
 


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  		Figure 4. Logistic regression for response to verbal commands. The top panel shows the quantal response for each independent variable: target propofol concentration (target conc.), measured propofol concentration (concentration), auditory steady-state response (ASSR) amplitude (log transformed) and BIS (bispectral index). Up and down ticks denote presence or absence of response, respectively. The bottom panel shows the probability of response based on logistic regression of the quantal response. The variables were scaled for 0 to 1 to facilitate comparisons. The scale for ASSR and BIS increases from left to right, whereas for concentrations, the scale decreases.

 
Experiment 2
The mean target propofol concentration for loss of consciousness was 3.08 ± 0.66 µg/mL. The concentration measured in arterial blood at the beginning and at the end of the recording period was 3.25 ± 0.54 and 3.09 ± 0.70 µg/mL (P > 0.10). The ASSR amplitude during baseline was 0.35 ± 0.11 µV and 0.47 ± 0.13 µV with monaural and binaural stimulation, respectively. During unconsciousness, the amplitude was 0.09 ± 0.09 µV and 0.06 ± 0.04 µV with monaural and binaural stimulation, respectively.

The analysis of variance yielded the following significant effects: level of consciousness (P < 0.001), stimulus condition (monaural vs binaural) (P < 0.002), and interaction (P < 0.02). The significant interaction confirmed that the effect of stimulus condition depends on the level of consciousness. Binaural stimulation increased the ASSR amplitude only during baseline. Unconsciousness was associated with a decrease in the amplitude of the ASSR for all subjects for binaural and monaural stimulation. The Pk was 0.972 (0.041 SE) for monaural delivery and 1.000 (0.000 SE) for the binaural delivery. For both modes of stimulus delivery an ASSR amplitude of 0.08 µV or less was associated with unconsciousness, as in Experiment 1.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The first experiment showed that the ASSR is attenuated in a concentration-dependent manner by propofol and that it provides a very good (Pk = 0.89) indicator of consciousness, defined as the ability to respond to verbal commands. An ASSR amplitude <0.08 µV was always associated with unconsciousness. There were, however, six subjects whose ASSR remained >0.10 µV when consciousness was lost. This finding confirms previous observations (9) that propofol-induced unconsciousness is not always associated with maximal suppression of the ASSR. An unexplained observation is that in three of these subjects, the amplitude of the ASSR when unconsciousness occurred was approximately the same as during baseline. These three subjects had baseline ASSR of low amplitude (0.10–0.12 µV).

The ASSR arises mainly from the primary auditory cortex (22–24) with a lesser contribution from subcortical generators in the thalamus or midbrain (25–27). The occasional observation of low amplitude ASSR in normal, awake subjects may be explained by a smaller contribution from the auditory cortex caused by incomplete activation (28) or by minor individual variations of its shape or orientation. In most subjects, the shape and orientation of the auditory cortex produces a maximal ASSR at Cz (28,29). Minor variations in the anatomy of the auditory cortex may alter the scalp topography of the ASSR with the consequence that the cortical contribution at Cz is reduced. The ASSR recorded at Cz would then predominantly arise from subcortical generators. Propofol predominantly acts at the cortical level with relative sparring of thalamic information transfer (30). This could explain why propofol has minimal affect on low amplitude ASSR. These speculations could be tested with methods of source localization of evoked potentials generators (31).

In Experiment 1, we presented stimuli only to the right ear. Because the amplitude of the ASSR increases with stimulus intensity in awake subjects (32), we expected that the ASSR would be larger with binaural stimulation during baseline. Based on our previous use of binaural stimulation (9), we expected no amplitude increase during unconsciousness. Experiment 2 confirmed these predictions. Because binaural stimuli increase the amplitude difference between baseline and unconsciousness, it is reasonable to expect that the performance of the ASSR as a measure of the consciousness level should be better with binaural stimuli. Confirmation of this would, however, require a new study.

The results for BIS confirmed published observations of a highly significant linear decrease with propofol concentration (33) or sedation intensity (34) and of an excellent ability (Pk = 0.96) to predict the level of consciousness. BIS was better than the ASSR at reflecting the graded effect of propofol. There was a significant difference between PRO_2 and PRO_1 only for BIS.

We conclude that the ASSR and BIS index are attenuated in a concentration-dependent manner by propofol and that they both provide a useful measure of its sedative and hypnotic effect. The ASSR should be recorded with binaural stimulation. BIS was easier to use and reflected the effects of small concentrations of propofol more precisely.


   Acknowledgments
 
Supported by grants from the International Anesthesia Research Society, the Canadian Anesthesiologists’ Society, the Association des Anesthésiste-Réanimateurs du Québec, the Royal Victoria Research Institute and from the Associated Anaesthetists Group. G. Plourde and V. Bonhomme were supported by scholarships from the Fond de la recherche en santé du Québec (FRSQ) and the CHU of Liège, Belgium, respectively.

We thank P. April for computer programming, F. Varin for the propofol assay, W. D. Smith for giving us the Excel macros for computation of Pk, F. Rouah for help with logistic regression, and the staff of the clinical investigation unit and of the recovery room for their generous collaboration. Zeneca Pharma, Mississauga, Ontario, kindly donated the propofol.


   Footnotes
 
Presented, in part, at the 27th Annual Meeting of the Society for Neuroscience in New Orleans, LA, 1997, and at the 55th Annual Meeting of the Canadian Anaesthetists’ Society in Toronto, Ontario, 1998.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication August 2, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press