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Bis Index
Bis Index
The assessment of a patient’s brain state during surgery has long been an objective of research in the field of
automated electroencephalogram (EEG) analysis. Aspect Medical Systems has developed a processed EEG para -
meter, the Bispectral Index™ (BIS™), to measure the effects of anesthetic agents on the patient’s brain. The early
versions of the BIS were evaluated using prediction of movement to skin incision at the beginning of a surgical pro -
cedure. The movement response is considered by many researchers and clinicians to be a sign of inadequate anes -
thesia. While numerous individual studies showed these early versions of the BIS to be a good predictor of move -
ment response to incision 1,2 and hemodynamic response to incision3 and intubation 4 for the specific drug regimens
tested, it was not a good predictor of lack of movement across some commonly used drug combinations that include
the use of varying doses of opioids. The data supported the view that movement to skin incision is primarily an
indicator of inadequate analgesia and may not provide significant information about hypnosis when certain com -
binations of agents are used 5,6. It appears that the EEG primarily correlates with the patient’s hypnotic state and
provides less information about analgesia. Indeed, the BIS was shown to be well correlated with changes in the
level of hypnosis produced by anesthetics and sedatives.7 In response, Aspect Medical Systems redirected its
research with the objective of providing an improved means of quantifying the patient’s hypnotic state. The
Bispectral Index has been developed to monitor the effects of anesthetics and other pharmacological agents on the
hypnotic state of the brain.
Introduction
Clinicians administering anesthetics and sedatives ways to automate EEG analysis to create a measure (or
need to manage the hypnotic state of their patients. index) that is indicative of these changes. This paper
Hypnosis is defined as the impairment of consciousness describes the development of one such EEG measure,
and memory or oblivion to external stimuli. Patients the Bispectral Index, presents how the EEG and the
undergoing surgery or intensive therapy require an ade- index change with hypnotic/sedation state, and demon-
quate level of hypnosis to protect them from stress, strates how using the BIS to guide anesthetic titration
awareness and recall of traumatic interventions. It is not can provide clinical utility.
currently possible, however, to directly measure the
hypnotic state. At lighter levels, an indirect assessment
of the hypnotic state is performed clinically by observ- Changes in EEG with Increasing Sedation
ing physical signs and patient responsiveness to voice EEG sedation measures have been developed based
or touch. For example, sedation scales such as the on the observation that the EEG generally changes from
Ramsay Scale and the Modified Observer’s Assessment a low amplitude, high frequency signal while awake to
of Alertness/Sedation Scale have been used in pub- a large amplitude, low frequency signal when deeply
lished studies. Although this approach is adequate in anesthetized. The general, idealized pattern of changes
some situations, it has several significant limitations. that occur in the EEG as the level of hypnosis is
Assessment using patient responsiveness is not applic- increased is shown in Figure 1. These changes may be
able to patients who are incapable of responding. In described using the frequency bands in Table 1.
those patients who are capable of responding, the stim- Sedatives may increase or decrease the activity in
ulation caused by the assessment itself may arouse the the high frequencies. In an alert subject, muscle activi-
patient. Also, this approach provides only a subjective, ty or “EMG” appears across frequency bands and
instantaneous assessment of the patient’s state. extends above 30Hz. Much of the decrease of activity
In response to these limitations, researchers have in the high frequency band seen with sedative doses is
sought an objective measurement of the hypnotic state a result of diminished EMG activity. Some sedative
that can be acquired continuously without disturbing doses may also increase medium/high frequency activ-
the patient. Because the spontaneous EEG shows ity or “beta activation”. As the doses increase and loss
changes with hypnotic state, scientists have examined of consciousness is approached, there is an increase in
70
60
Frequency Band Frequency Range 50
Awake
(Hz) 40 BIS=98
30
Very Low 20
10
Frequencies 0-4 Hz 0
(Delta) -10
-20
-30
Low Frequencies -40
(Theta) 4-8 Hz -50
-60
-70
Medium 0 2 4 6 8
Frequencies 8-14 Hz Time (seconds)
(Alpha) 70
60
High Frequencies 50
Light Hypnosis
(Beta) 14-30 Hz 40 BIS=67
30
20
10
Table 1: EEG Frequency Bands
0
-10
-20
the amplitude of low frequencies and the overall EEG -30
-40
amplitude is typically larger than awake. In deeper hyp- -50
notic states, beyond the loss of consciousness, the high- -60
er frequencies disappear entirely and the overall ampli- -70
0 2 4 6 8
tude is much larger than awake. At very high doses, all Time (seconds)
2
Hypnotic State/Sedation Level Score
parameters. Aspect Medical Systems has reduced the The Bispectral Index is computed real-time using a
complex data arrays generated from bispectral analysis combination of three analysis steps. The first step is an
using a sophisticated algorithm to generate a composite, EEG pre-processor, which breaks the EEG signal down
numerical Bispectral Index which tracks changes in the second by second and marks those segments containing
cerebral state. artifact that might arise from movement, EMG or elec-
trocautery equipment. Segments of suppressed EEG are
also identified. These segments are excluded from fur-
Bispectral Index Development ther processing. The second step is the calculation of
Over several years a large database of high fidelity the hypnosis/sedation index by combining selected
EEG recordings and clinical records was collected from EEG features using the algorithm which was developed
more than 2000 patients receiving a wide variety of as previously described. In the third step, the hypno-
anesthetic regimens. These regimens included the use sis/sedation index is modified to better reflect the level
of isoflurane, propofol, midazolam and sodium of suppression in the EEG. The suppression ratio (SR)
thiopental often supplemented with various opioids and is computed as the percentage of suppressed EEG in the
nitrous oxide. A subset of this data, the development non-artifact data.9
database, was used to develop and evaluate the index
using a learn and test approach. The development data-
base consisted of a segment of recorded EEG and an Results from Clinical Validation Studies
associated, clinically derived hypnotic state or sedation The Bispectral Index was developed using only
level. The criteria used to define the sedation level are segments of artifact-free, non-suppressed EEG. Figure
defined in Table 2. Figure 2 depicts an overview of the 3 depicts the distribution of the BIS at different clini-
index development process. The segments of EEG were cally assessed hypnotic states/sedation levels. Lower
used to compute a set of candidate bispectral and power numbered levels are deeper hypnotically, as defined in
spectral EEG features for evaluation. Those features Table 2.
best able to discriminate between different hypnotic The performance of the Bispectral Index was also
states/sedation levels were combined using multivariate evaluated on data more representative of the clinical
statistical modeling techniques to form a composite setting. This data consisted of recordings from more
index. This index was then prospectively tested on a than 400 patients totaling more than 1000 hours of EEG
different subset of Aspect’s larger database. data monitored intraoperatively during various anes-
3
Bispectral Index Development Process
Steps Output
Data Collection
Raw EEG Data/Artifact Rejected
& Clinical Endpoints
Spectral Calculations
Statistical Ranking
“Best” Variables
Multivariate Statistical
Models
Bispectral Index
Offline Prospective
Tests on Database
Real-time Validation
thetic techniques.7 Noise-corrupted and suppressed The relationship between the Bispectral Index and
EEG as well as artifact-free EEG were part of this data. the hypnotic effects provided by propofol, midazolam,
Key events were recorded by the clinician to assess the methohexitol, isoflurane and sevoflurane have also
level of hypnosis/sedation. Use of this data allowed the recently been described in a number of reports.7,11-16
full trend during a procedure to be analyzed. Figure 4 These studies concluded that the BIS provides a quan-
presents the range of BIS levels recorded during the tifiable measure of the effects of anesthetics on the
various periods of intraoperative procedures contained brain that correlates to the level of consciousness and
in the database. Data recordings started while the probability of recall. Values below 70 indicated a very
patients were still awake, but lightly sedated in some low probability of recall and values below 60 indicated
cases. Induction resulted in a rapid decrease in the unconsciousness. BIS was also found to be useful as an
index followed by intubation. The pre-incision period indication of return of consciousness during general
was classified as either light or deep hypnosis depend- anesthesia.17
ing on the level of effect-site drug concentration dur-
ing this time period. An effect-site drug concentration
is a hypothetical agent concentration at the site of Results from Clinical Utility Studies
agent action (e.g., the brain). It is computed based Findings from a randomized multicenter clinical
upon the pharmacokinetics and pharmacodynamics of trial conducted to evaluate the utility of BIS monitoring
a particular agent using a mathematical model. In cases as an adjunct to managing anesthetic drug delivery
where EEG suppression was present or during very showed more efficient drug utilization, faster emer-
deep anesthesia, as during cardiac procedures, the gence from anesthesia and improved patient recov-
index was very low. Awakening, or eyes open, ery.18-20
occurred at levels similar to initial baseline values. The goal of the study was to minimize the drug
delivered while maintaining an adequate hypnotic state.
4
Bispectral Index vs. Sedation
(Mean +/- Std. Deviation)
100
90
80
70
60
50
40
30
0 1 2 3 4 5
No response to Loss of Awake/Alert
physical stimulus consciousness
80
Awake/Drowsy Agent Off
Deep Hypnosis
Intubation >0.65% Iso;
>2.5µg/ml propofol*
Awakening/
60 Eyes Open
40 Light Hypnosis
<0.65% Iso;
<2.5µg/ml propofol*
20
EEG Suppression or
Deep Cardiac Anesthesia
0
Induction Period Pre-Incision Period Emergence Period
Anesthetic Milestones
≈ 6mg/kg/hr infusion rate
*2.5µg/ml propofol effect-site concentration =
at steady state for a 50-year-old, 70kg patient
Figure 4: Level of the Bispectral Index at various intraoperative points
5
Utilizing a propofol/alfentanil/N2O technique, the emergence. The recording starts shortly after induction.
researchers documented that compared to standard The expired agent decreased significantly at around
practice, in the BIS managed patients: 10:30. This resulted in the patient’s hypnotic state
becoming gradually lighter as reflected by the BIS.
• 35-40% faster wake-up was obtained Monitoring this trend allows the clinician to anticipate
• 16% faster eligibility for PACU discharge when the patient will recover and hence, titrate drugs
was achieved better at the end of the procedure. It is also interesting
to compare this performance with the 95% SEF. The
• 13-23% less hypnotic drug was used
patient’s lightening hypnotic state is detected by the
• more patients were rated as “excellent-fully BIS trend at least fifteen minutes earlier than the 95%
oriented” on admission to the PACU, as noted in SEF.
Figure 5 (43% vs. 23%) Another important application of the BIS is the
ability to track patient arousals intraoperatively.
Arousals may be due to an inadequate amount of anes-
Figure 5: % of patients fully oriented on arrival
thesia as a result of drug delivery problems or changes
to PACU
in the patient’s drug requirements due to altered levels
50 of stimulation or metabolism. Figure 7 represents a case
where drug delivery was unintentionally interrupted.
40
The graph shows the Bispectral Index, heart rate (HR)
30 and mean arterial pressure (MAP) over the entire pro-
20 cedure, a total abdominal hysterectomy. The case began
with induction at 8:03; the concomitant drop in the BIS
10
reflected the expected deepening of the patient’s hyp-
0 notic state. Intubation occurred at 8:07. The BIS subse-
BIS Directed Standard Practice quently increased to 80 and it was discovered that the
propofol infusion pump did not switch over to continu-
Case Reports ous infusion mode after the last bolus as expected. A
One important application of the BIS is the ability bolus of propofol was then administered and a constant
to consistently indicate the return of consciousness after infusion of propofol was initiated reducing the BIS to
a surgical procedure. 21,22 Figure 6 provides an example the 40’s range. The stimulation of incision and the
of how the Bispectral Index performs during a period of resultant lightening of the patient’s hypnotic state are
100 30
90
25
80
Expired agent decreasing Figure 6: Performance of
70 the Bispectral
20
Index vs. 95%
60
SEF during
50 15 emergence from
an intraopera-
40 tive procedure
10
30
20
5
10
0 0
8:36 8:51 9:06 9:21 9:36 9:51 10:06 10:21 10:36 10:51
Time
Bispectral Index
95% SEF 6
100 200
90
Infusion Infusion Pump Fails Eyes open
Turned On (battery change) 180
80
30 100
Incision
20
80
10
0 60
8:01 8:16 8:31 8:46 9:01 9:16 9:31 9:46 10:01 10:16
indicated by the rise in the BIS. In the middle of the hour intraoperative segment during which the patient
procedure the patient’s hypnotic state began to lighten. underwent a wake-up test during spinal surgery. At
This is clearly demonstrated by the increasing BIS 13:22, an attempt to wake the patient was initiated. The
trend after 8:46. Note that neither heart rate nor blood index increased to 95, reflecting the patient’s lightened
pressure indicated any clinically significant changes. hypnotic state, with wake-up occurring shortly there-
Based on this early indication of patient emergence, the after at 13:31.
anesthetist checked the infusion system and discovered
that it had stopped functioning. Replacing the batteries
and restoring the infusion returned the patient to deep- Conclusion
er hypnotic levels. At the end of the case, the index Aspect Medical Systems has developed a unique
increased rapidly prior to eye opening. processed EEG parameter, the Bispectral Index, that
monitors the effects of anesthetics and other pharmaco-
Another example of a patient regaining conscious-
logical agents on the hypnotic state of the brain. The
ness is shown in Figure 8. This graph depicts a one-
100
90
Wake-up
80 Occurred
70
60
50
40
5. Sebel, P.S., Lang, E., Rampil, I.J., White, P.F., Cork, R., Jopling, 22. Sawtelle, K., Rampil, I., “Bispectral EEG Index Predicts
M., Smith, N.T., Glass, P.S.A., Manberg, P., “A Multicenter Study of Awakening”, Anesthesiology, Vol. 81, No. 3A, A213, 1994.
Bispectral Electroencephalogram Analysis for Monitoring Anesthetic
Effect”, Anesthesia and Analgesia, Vol. 84, pp891-899, 1997.
6. Eger, E.I., Koblin, D.D., Harris, R.A., Kendig, J.J., Pohorille,
A., Halsey, M.J., Trudell, J.R., “Hypothesis: Inhaled Anesthetics
Produce Immobility and Amnesia by Different Mechanisms at Different Aspect Medical Systems, Inc.
Sites”, Anesthesia and Analgesia, Vol. 84, pp915-918, 1997. 2 Vision Drive
7. Glass, P.S., Bloom, M., Kearse, L., Rosow, C., Sebel, P., Natick, MA 01760-2059
Manberg, P., “Bispectral Analysis Measures Sedation and Memory
Effects of Propofol, Midazolam, Isoflurane and Alfentanil in Healthy
(888) BIS INDEX (508) 653-0603
Volunteers”, Anesthesiology, Vol. 86, No. 4, pp836-847, 1997. FAX: (508) 653-6788
8. Sigl, J.C., Chamoun, N.G., “An Introduction to Bispectral bis_info@aspectms.com
Analysis for the EEG”, Journal of Clinical Monitoring, Vol. 10, www.aspectms.com
pp392-404, 1994.
9. Sigl, J.C., Manberg P.J., Chamoun, N.G., Chiang, H.H., Devlin ©1997 Aspect Medical Systems, Inc. All rights reserved.
P., Rampil, I.J., “Quantification of EEG Suppression During Anesthesia:
Aspect, A-1000, A-1050, Bispectral Index, BIS and Zipprep are
Correlation with Isoflurane Dose and Patient Responsiveness”, trademarks of Aspect Medical Systems, Inc. 085-0014 2.0
Anesthesia and Analgesia, Vol. 80, S447, 1994.