The Bispectral Index (BIS) is among the best-evaluated measures of sedation and anesthetic effect; it is largely derived from the bispectrum of the electroencephalogram (EEG) (1) that measures the effects of anesthetics on the brain. BIS is calculated from the voltage measured between a pair of electrodes placed near the center of the forehead and either the right or left temple. Although this voltage is predominantly EEG, potentials from other sources like muscular activity (i.e., electromyographic [EMG]) or electrode motion may comprise the measured signal. Because the frequency composition (i.e., spectra) of the EEG and EMG artifact overlap in the 30–50 Hz range, simple filtering will not completely remove EMG artifact from single-channel EEG recordings.
Substantial EEG power in the 30–50 Hz range is typically associated with awake or lightly sedated patients. Conversely, deeply unconscious patients generate little power in this range. From a spectral standpoint, EMG contamination in deeply unconscious patients may thus falsely mimic the EEG of awake subjects. Thus, there is considerable potential for EMG activity to contaminate, or even swamp, subtle EEG signals, thus falsely increasing BIS. Facial EMG has even been proposed as a measure of anesthetic depth (2,3). BIS electrodes are positioned on the forehead; paralysis may therefore reduce BIS by alleviating high-frequency muscle artifact.
However, there is a second mechanism by which muscle relaxation might reduce BIS: afferentation theory states that signals from muscle stretch receptors stimulate arousal centers in the brain (4). Under this hypothesis, BIS would decrease (appropriately) because of the relaxant’s indirect sedative effect. Consistent with this theory, neuromuscular block has been reported to reduce the minimum alveolar concentration (MAC) 25%(5,6), although subsequent studies failed to confirm that finding (7). We therefore studied the effect on BIS and EMG at different levels of neuromuscular blockade during propofol anesthesia to test the hypothesis that nondepolarizing neuromuscular blockade reduces BIS.
With approval from the Committee on Human Research at the University of California San Francisco and written informed consent, we studied 10 healthy young volunteers (3 women and 7 men). The average age was 28 ± 4 yr, height 172 ± 8 cm, and weight 70 ± 11 kg. None was obese, taking medication, or had a history of diseases affecting neuromuscular function.
The volunteers fasted for at least 8 h before the study. An IV cannula was inserted in the left antecubital vein. Anesthesia was induced and maintained by an IV infusion of propofol using a computer-controlled infusion system (STANpump, http://pkpd.icon.palo-alto.med.va.gov) to target effect-site concentrations between 3 and 5 μg/mL (average 3.8 ± 0.4 μg/mL), which produced a state of deep hypnosis (i.e., BIS <50) (8).
After loss of consciousness, a laryngeal mask was inserted to provide airway support. We confirmed that the mask was well positioned by demonstrating that an audible leak did not occur until airway pressure reached at least 20 cm H2O. The lungs were mechanically ventilated with a laryngeal mask to maintain end-tidal Pco2 between 35 and 40 mm Hg.
Neuromuscular block was monitored by response to super-maximal electrical stimulation of the ulnar nerve at the wrist. In a randomly-determined order, mivacurium was given by IV infusion until the first twitch (T1) in a train-of-four (TOF) was 80%, 30%, 20%, 15%, 10%, 5%, or 2% of preblock intensity. We also evaluated 0% T1, which we defined as fewer than three palpable posttetanic twitches. Each level of neuromuscular block was kept constant for a 10-min period. Between levels of neuromuscular block, the mivacurium infusion was stopped until T1 recovered to 90%–100%.
Core hypothermia reduces the metabolism of neuromuscular blocking drugs (9). Furthermore, local muscle temperature alters mechanical response to electrical nerve stimulation (10). Consequently, we kept the volunteers normothermic with forced-air (Augustine Medical, Inc., Eden Prairie, MN).
Core temperature was measured at the tympanic membrane using Mon-a-Therm® thermocouples (Tyco, Inc., St. Louis, MO). Noninvasive blood pressure, heart rate, oxygen saturation, and core temperature were recorded at 10-min intervals. We simultaneously recorded target effect-site propofol concentration and the mivacurium infusion rate.
To monitor neuromuscular function, supramaximal stimuli (200-μs duration) in a TOF sequence at 2 Hz were applied via surface electrodes to the ulnar nerve at the wrist. Each TOF sequence was repeated every 10 s. The resulting integrated EMG of the adductor pollicis muscle was measured (Relaxograph; Datex Instrumentarium Inc., Helsinki, Finland). The thumb was abducted with 200–300 g of preload to minimize movement artifacts and to achieve stable responses. The first response in the TOF sequence was recorded and used as the control to which all subsequent T1 responses were compared.
EMG and mechanomyography are comparably reliable in patients without neuromuscular diseases (11), but EMG is easier to use. Because we were not interested in duration of action of neuromuscular blockade but in predetermined end points (first twitch in TOF as percentage of preblock intensity), we used EMG.
The forehead was cleaned with alcohol to remove surface oils, and then abraded with gauze to remove dead epidermal cells. Zipprep™ electrodes (Aspect Medical Systems, Inc., Newton, MA) were positioned according to the manufacturer’s recommendation. One active electrode was positioned 4 cm above the nasion, the other was situated midway between the preauricular point and outer malar bone of the right eye, and the ground electrode was positioned on the temple just above the right eye. The electrodes were depressed as necessary to maintain impedance <5000 Ohms. Depth of hypnosis, quantified by BIS (revision 3.3), and frontal-temporal EMG power (in dB relative to 0.0001 uV2) at 70–110 Hz were recorded continuously from an A1050 BIS Monitoring System (Aspect Medical Systems). BIS and frontal-temporal EMG were recorded before induction of anesthesia (baseline), after induction of anesthesia, and at each designated T1 twitch level.
Blood pressure, heart rate, oxygen saturation, and core temperature were first averaged over the anesthetic period in each volunteer. Subsequently, these values were averaged among the volunteers at each block level. Values at the designated T1 block levels were compared with analysis of variance.
BIS and frontal-temporal EMG intensity at baseline and after induction of anesthesia (but before mivacurium administration) were compared with two-tailed, paired Student’s t tests. Propofol target effect site concentration, BIS, and frontal-temporal EMG intensity were also compared at the designated T1 block levels with analysis of variance. A Scheffé F test was used for post hoc comparison among the T1 levels. Results are presented as mean ± sd;P < 0.05 was considered statistically significant.
There were no statistically significant differences in blood pressure, heart rate, oxygen saturation, or core temperature at the designated T1 block levels. Systolic arterial pressure was 144 ± 21 mm Hg, diastolic arterial pressure was 66 ± 9 mm Hg, heart rate was 72 ± 16 bpm, oxygen saturation was 99% ± 2%, and core temperature was 36.5 ± 0.3°C. Target propofol effect-site concentration averaged 3.8 ± 0.4 μg/mL during anesthesia; there were no statistically significant or clinically important differences in estimated propofol concentration at the designated block levels (Fig. 1).
BIS averaged 95 ± 4 before induction of anesthesia, and decreased significantly to 39 ± 4 after propofol administration. However, there were no statistically significant or clinically important differences at the designated block levels (Fig. 2). Frontal-temporal EMG intensity averaged 47 ± 3 dB before induction of anesthesia, and decreased significantly to 28 ± 1 dB after propofol administration. However, there were no statistically significant or clinically important differences at the designated block levels (Fig. 3).
The consequences of inadequate anesthesia include intraoperative awareness (12) and unexpected patient movement (13). Clinical evaluation of depth of anesthesia is difficult because hemodynamic responses correlates poorly with intraoperative memory or movement (14).
Proposed methods for evaluating anesthetic effect include spectral edge of the EEG (15), audio-evoked potentials (16), the pupillary light reflex (17), and esophageal contractility (18). However, BIS is probably the best evaluated measure of sedation and anesthetic effect (1).
BIS correlates well with anesthetic concentration of isoflurane, propofol, midazolam (8), and alfentanil (8), and return of consciousness during muscle relaxation (19). Changes in BIS in response to intraoperative stimulation are also inversely related to plasma remifentanil concentration (20) and thus reflect arousal responses to stimulation (21).
Bispectral EEG signal processing resolves the raw EEG signal into sinusoids using Fourier analysis. Bispectral analysis quantifies amplitude and phase relationships among the sinusoidal components that comprise the EEG. Power spectral analysis generates a histogram of power per frequency component. BIS was developed by identifying those bispectral and power spectral features that best correlated with hypnotic endpoints and drug effects measured under various anesthetic conditions.
As described above, the BIS is calculated from the voltage measured between a pair of electrodes placed near the center of the forehead and on either the right or left temple. Although this voltage is predominantly EEG, potentials from other sources (e.g., muscle contraction, eye motion, electrode motion) may contribute to the measured signal. Frequently the effects of these artifacts are diminished by attenuating by appropriate filtering. The ability to filter out artifacts, however, relates to both the relative strength (i.e., amplitude) and frequency composition (i.e., spectra) of the EEG and artifact. Because the frequency composition of EEG and EMG artifact overlap in the 30–50 Hz range, simple filtering will not completely remove EMG artifact from single-channel EEG recordings.
Consequently, when the strength of the EMG component is significant relative to the EEG component within the measured signal, EMG signal from the frontalis, temporoparietalis, and masseter muscles may interfere with the spectral and bispectral features used to make the BIS. EMG contamination in deeply unconscious patients may falsely mimic the EEG of awake subjects, and thus falsely increase BIS. However, our results indicate that mivacurium infusion did not alter EMG or BIS. These data thus indicate that the hypnotic level is unaltered by mivacurium administration, at least during propofol anesthesia in unstimulated subjects. We thus conclude that neuromuscular block does not alter anesthetic level as determined by BIS monitoring.
“Afferent muscle spindle theory,” was developed in the 1960s (22,23) and expanded by Lanier et al. (24) to explain their observation that paralysis diminishes EEG activity in dogs. This theory states that stretching or contracting muscle fibers provide important input to arousal centers in the brain. Muscle relaxation, hypothetically, would decrease arousal stimulation and potentially provide a sedative effect. This theory was consistent with reports that neuromuscular block reduces MAC 25% in humans (5,6), although subsequent studies failed to confirm that finding (7). It is also consistent with paralysis-induced enhancement of isoflurane action in dogs (25).
Considerable evidence thus suggests that paralysis reduces EEG activation and augments anesthetic effect. Nonetheless, we failed to demonstrate any effect of paralysis on alertness as measured by BIS—a result that clearly contrasts with previous reports in dogs. A species difference is of course possible and would be consistent with the fact that paralysis does not alter MAC in humans (7). An equally important consideration is that our study design was associated with minimal amount of background EMG activity. It is likely that EMG activity will be considerably greater in patients than volunteers, especially in patients undergoing stimulating procedures. Another factor to consider is that our volunteers were highly sedated. EMG activity may therefore be greater at lighter anesthetic planes, in which case paralysis may have a greater effect on EMG activity.
Because we used a computer-controlled infusion system to target effect-site concentrations, we refrained from direct measurement of plasma propofol levels. Actual blood and effect-site concentrations may thus have differed somewhat from our estimates. However, the target-controlled infusion system that we used is known to be reliable (26).
We conclude that neuromuscular block level does not alter BIS during propofol anesthesia, either via EMG artifact or by decreasing afferent neuronal input. These data suggest that the BIS will comparably estimate sedation during propofol anesthesia in unstimulated subjects who are paralyzed, partially paralyzed, or unparalyzed.
Augustine Medical, Inc. (Eden Prairie, MN) donated the forced-air blowers and covers, and Tyco, Inc. (St. Louis, MO) donated the thermocouples we used. The authors appreciate the assistance of Robert Fitzgerald, MD and Hank Bennett, PhD.
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