Intensive Care Med (2002) 28:419–425

DOI 10.1007/s00134-002-1219-4 ORIGINAL

Benoit Vivien Detection of brain death onset using

Xavier Paqueron
Philippe Le Cosquer the bispectral index in severely comatose
Olivier Langeron
Pierre Coriat patients
Bruno Riou

Received: 10 September 2001
Accepted: 2 January 2002
Published online: 19 March 2002
© Springer-Verlag 2002
B. Vivien (✉) · X. Paqueron
P. Le Cosquer · O. Langeron · P. Coriat
B. Riou
Département d’Anesthésie-Réanimation,
Groupe Hospitalier Pitié Salpêtrière,
47-83 Boulevard de l’Hôpital, 75013 Paris,
France
e-mail: benoit.vivien@psl.ap-hop-paris.fr
Tel.: +33-1-42162251
Fax: +33-1-42162269
B. Riou
Service d’Accueil des Urgences,
Groupe Hospitalier Pitié Salpêtrière, Paris,
France
Abstract Objectives: To evaluate
the accuracy of bispectral index
(BIS) monitoring for the diagnosis of
brain death in severely comatose pa-
tients. Design: A prospective study
in an intensive care unit of a univer-
sity hospital. Population: Fifty-six
severely comatose patients (Glasgow
Coma Score ≤5) admitted to the ICU
mainly because of intracerebral hem-
orrhage, head injury, or postanoxic
coma. Methods: BIS was recorded
continuously during the hospitaliza-
tion in the ICU. Where necessary,
clinical brain death was confirmed
by EEG or cerebral angiography.
Measurements and results: Twelve
patients were already clinically brain
dead at the time of admission, and
their individual BIS values were 0.
In each of these 12 patients brain
death was thereafter confirmed by
EEG or cerebral angiography. Forty-
four patients were not clinically
brain-dead at the time of admission,
and their individual BIS values were
between 20 and 79. Twenty-seven of
these patients became brain-dead,
and their individual BIS values
dropped to 0 in a few hours to a few
days. In these 27 patients EEG or ce-
rebral angiography was performed
after the BIS value decreased to 0
and confirmed brain death in all
cases. Seventeen patients who did
not become brain dead during their
hospitalization in the ICU had per-
sistent electrocerebral activity on
EEG, and their average BIS values
remained above 35. Conclusion: BIS
can be used in severely comatose pa-
tients as an assessment of brain
death onset, enabling appropriate
scheduling of either EEG or cerebral
angiography to confirm brain death.
Keywords Bispectral index · Brain
death

Introduction personnel and technology. In addition, to perform cere-

When brain death is clinically suspected, investigations
such as electroencephalography (EEG) and cerebral an-
giography are often mandatory, and are even required by
law in some countries, to definitely confirm the diagno-
sis [1]. Nevertheless, the time of brain death is some-
times clinically difficult to determine precisely [2]. On
the one hand, performing EEG or cerebral angiography
before this is of little value. On the other hand, perform-
ing these investigations presents several drawbacks, as
each is expensive because of the need for specialized
bral angiography the patient must be transported out of
the intensive care unit (ICU), with major medical risks,
and the use of contrast media can be detrimental for the
already compromised organs, such as kidneys [3].
For several years the bispectral index (BIS), a param-
eter derived from the EEG, has been reported as a qua-
ntifiable measure of the depth of sedation and degree of
awareness during and after general anesthesia [4] and the
depth of sedation in ICU [5, 6]. Good correlations have
been reported between BIS and neurological status in un-
sedated coma patients [7, 8]. It has also been recently
420
suggested that BIS, in association with the Glasgow
Coma Score (GCS), could be a good predictor of out-
come after head trauma [9]. However, BIS monitoring
during progression to brain death has been reported only
anecdotally [10, 11]. Therefore we investigated the accu-
racy of BIS monitoring for the diagnosis of brain death
in severely comatose patients.
Patients and methods
Study population
The study was approved by our local ethics committee (CCPPRB,
GH Pitié-Salpêtrière, Paris). Fifty-six consecutive patients were in-
vestigated prospectively over a 1-year period (Table 1). All of them
had been admitted to the ICU for severe coma (GCS ≤5) resulting
mainly from spontaneous intracranial hemorrhage, head injury, or
cerebral anoxia. The cause of coma was established for every pa-
tient. Reversible abnormalities (drug and metabolic intoxications,
hypothermia and shock) were excluded as the causes of coma. Be-
cause of the severity of their cerebral lesions at the time of admis-
sion into the ICU, all of these patients were potentially expected to
progress to brain death. Care of the patients conformed to standard
procedures in our ICU for severely comatose patients, with the ad-
ditional use of the noninvasive BIS monitoring for studied patients.
The skin was carefully cleaned before positioning the BIS sensor,
which was covered by a self-adhesive plastic film. Each BIS sensor
was used for a maximum of 72 h; nevertheless, in profusely sweat-
ing patients we sometimes had to change the BIS sensor every
24 h. We observed no skin breakdown after multiday recording. No
patient was excluded from the study because his forehead was to-
tally unavailable for positioning the BIS sensor.
Data collection
Demographic characteristics, cause of the coma, GCS, and neuro-
logical examination at the time of admission were recorded. Out-
come was recorded as one of the following: already brain dead on
admission to the ICU, progression to brain death, death from an ex-
tracerebral lesion, and alive at the time of discharge from the ICU.
Two periods were considered for the accuracy of BIS to detect
brain death: (a) initially, at the time of admission to the ICU, and
(b) at the time of death or discharge from the ICU. For each assess-
ment patients were classified in two groups: those who at the initial
assessment were brain dead (BDIni) and those who were not brain-
dead (NBDIni), and those who at the final assessment were brain-
dead (BDFin) and those who were not brain-dead (NBDFin).
Table 1 Clinical features of the
56 severely comatose patients Cerebral pathology
Intracerebral and/or subarachnoidal hemorrhage
Brain-stem hemorrhage
Head injury (blunt head trauma)
Cerebral gunshot injury
Cerebral anoxia (after cardiac arrest)
Cerebral ischemia (carotid embolism)
Cerebral air embolism
Meningitis
Total
BIS monitoring
BIS and electromyographic (EMG) activity were recorded contin-
uously using an A-2000 monitor (Aspect MS, Leiden, The Nether-
lands). Data were transferred and stored on a computer for off-line
analysis. Since it has been shown that many devices such as cardi-
ac pacing [12], forced-air warming systems [13], and radiofre-
quency noise in circumstances of extreme EEG suppression [14]
can interfere with BIS monitoring, all of these artifacts were sys-
tematically noted and removed from computer file recordings dur-
ing off-line analysis. Similarly, physical examination and care of
the patient were carefully noted, since these could markedly inter-
fere with BIS value either by neurological stimulation of the pa-
tient or by the production of artifacts.
Definition of brain death
Clinical diagnosis of brain death was defined as: (a) absence of
hypothermia (<35°) and drugs known to depress the central ner-
vous system; (b) neurological examination demonstrating the ab-
sence of brainstem reflexes; (c) absence of spontaneous ventila-
tion movement after 20 min of apnea, associated with an arterial
PCO2 higher than 60 mmHg. According to French law, the confir-
matory test of brain death was: (d) no electrical activity over a
30-min period of EEG recording with maximal amplification dur-
ing two consecutive examinations with at least 4 hours elapsed be-
tween the two recordings, or (e) absence of intracerebral blood
flow on four-vessel cerebral angiography.
Statistical analysis
Data are expressed as mean ±SD. Sensitivity, specificity, and posi-
tive and negative predictive values were defined for the accuracy
of BIS to detect brain death and were calculated by cumulating
both initial and final evaluations (112 assessments in 56 patients).
When the proportion was 100%, the 95% confidence interval was
calculated as previously reported [15].
Results
Progression to brain death
Twelve patients were already clinically brain dead at the
time of admission to the ICU (BDIni), and their individu-
al BIS values remained permanently 0 (Fig. 1a). In each
n Number of brain death
Initially Finally
26 6 22
6 0 1
12 3 8
3 1 3
6 0 2
1 0 1
1 1 1
1 1 1
56 12 39

Fig. 1a–c Typical bispectral index (BIS) and electromyographic
activity (EMG) course in severely comatose patients. a BIS and
EMG trend recordings in a 52-year-old brain-dead patient admit-
ted to the ICU for organ donation. Before these recordings brain
death was previously assessed by clinical examination and con-
firmed by cerebral angiography in another hospital. After family
authorization this patient was transferred into our ICU for organ
donation. As expected, upon arrival at the ICU the patient’s BIS
was permanently equal to 0, except some very small increases due
to environmental activity. The regular peaks in EMG activity (ver-
421
of these 12 patients brain death was then confirmed ei-
ther by EEG (n=7) or by cerebral angiography (n=5).
The 44 other patients were not clinically brain dead at
the time of admission (NBDIni), and their individual BIS
values were between 20 and 79. During a period of a few
hours to a few days (29±31 h) 27 of these patients pro-
gressed to brain death, and their individual BIS values
dropped to 0. In most of these cases brain death occurred
less than 24 h after admission to the ICU (minimal time
2.5 h; Fig. 1b). However, in some patients whose neuro-
logical status was apparently stabilized brain death onset
occurred only several days after admission to the ICU
(maximal time 115 h). In these cases the decrease in BIS
was a particularly useful signal of brain death, especially
when clinical changes in neurological status were mini-
mal. For 26 of these 27 patients who clinically evolved
to brain death after admission to the ICU either EEG
(n=24) or cerebral angiography (n=2) was performed af-
ter the BIS value decreased to 0 and confirmed brain
death in all cases. Clinical diagnosis of brain death could
not be confirmed in the 27th patient (cerebral gunshot in-
jury) because cardiac arrest occurred before any EEG re-
cording; nevertheless, since this patient fulfilled all clini-
cal criteria of brain death, he was classified as BDFin for
the final assessment. Elsewhere, in one clinically brain-
dead patient whose BIS values were still between 3 and
5, simultaneous EEG recording was not strictly isoelec-
tric, showing a residual cortical activity; 12 h later the
BIS values of this patient dropped to 0, and brain death
was confirmed by two successive isoelectric EEG re-
cordings. The total number of brain-dead patients at the
end of the study (BDFin) was therefore 39.
Finally, 17 patients who did not develop brain death
during their hospitalization in ICU (NBDFin) had persis-
tent activity on EEG, and their average BIS values re-
mained above 35 (Fig. 1c). Among these 17 patients who
did not progress to brain death, 9 died from extracerebral
lesions, and 8 partially recovered and were transferred to
a specialized neurological ICU. A summary of the
course in the 56 patients is shown in Fig. 2.
tical lines every 10 min) are linked to regular resets of the monitor
for EMG monitoring. No sedative drugs were used in this patient.
b BIS and EMG course in a 53-year-old patient admitted to the
ICU after spontaneous intracerebral hemorrhage. Approximately
2.5 h after admission the BIS value dropped to 0 within a few
minutes, simultaneously with clinical brain death and a slow de-
crease in EMG activity. Sedative drugs were stopped as soon as
neurological examination worsened. Two EEG performed 1 and
5 h later confirmed brain death, and the patient’s family allowed
organ donation. c BIS and EMG course in a 46-year-old patient
admitted to the ICU after spontaneous brainstem hemorrhage, with
an initial GCS of 3. Sedative drugs were used in this patient for
adaptation to ventilatory support. The BIS course showed slow
variations according to level of sedation during the 20 h of record-
ing. This patient partially recovered from his cerebral hemorrhage
and was transferred 4 days later into a specialized neurological
ICU
422

Fig. 2 Summary of the course

of the 56 severely comatose pa-
tients studied

Table 2 Overall accuracy of BIS monitoring to detect brain death. During progression to brain death the BIS sometimes
The overall number of evaluations for each group (brain dead and decreased to 0 a short time before complete clinical brain
not brain dead) was calculated by cumulating both initial (n=56)
and final (n=56) evaluations death. For example, in two patients, although the BIS
value had already dropped to 0 within a few minutes, the
BIS=0 BIS>0 Total cough response to bronchial suctioning was still present;
in less than 2 h it finally disappeared, enabling the clini-
Brain dead 51 0 51 cal diagnosis of brain death, which was thereafter con-
Not brain dead 0 61 61
Total 51 61 112 firmed by EEG.

Transient false negatives

The overall accuracy of BIS monitoring to detect
brain death was calculated by cumulating both initial
(n=56) and final (n=56) evaluations (Table 2). Therefore
sensitivity, specificity, and positive and negative predic-
tive values were all equal to 100%. The 95% confidence
interval for sensitivity and specificity=100% was calcu-
lated as 99.7–100 [15].
Limitations of BIS monitoring
Transient false positives
The BIS value in one severely head injured patient tran-
siently decreased from 40 to 0 for a few minutes on the
third day after admission to the ICU while the oculocar-
diac reflex disappeared, and jugular venous saturation
markedly decreased (Fig. 3). After intravenous infusion
of mannitol the BIS returned to previous values as the
oculocardiac reflex reappeared, and jugular venous satu-
ration increased. Thereafter this patient never ap-
proached brain death during hospitalization in the ICU
but died from multiple organ failure 6 days later.
In some of our 39 clinically brain-dead patients, either
before or after confirmation of brain death by EEG or ce-
rebral angiography, the BIS values sometimes increased
for a few minutes, and afterwards decreased again to 0.
These increases, sometimes reaching a BIS value of 90,
were accompanied by simultaneous increases in EMG
activity recorded on the BIS monitor (Fig. 4a). Else-
where, in a few cases (5 of the 39 brain-dead patients),
BIS increased from 0 and remained stable at a high level
(up to 98) for a few hours. Again, in clinically brain-
dead patients these increases were associated with simul-
taneous increases in EMG activity recorded on the BIS
monitor. After intravenous administration of muscle re-
laxants the BIS quickly decreased again to 0 whereas
EMG activity was considerably reduced (Fig. 4b). These
overestimations of BIS because of important EMG activ-
ity were not specific to brain death. Indeed, in severely
comatose patients who never approached brain death the
administration of muscle relaxants was associated with a
significant decrease in BIS values during the period of
the paralysis; about 60 min later, as muscular paralysis
 423

Fig. 3 Bispectral index (BIS) and electromyographic activity

(EMG) course in a 34-year-old patient admitted to the ICU after
severe blunt head trauma. On day 3 after admission the BIS value
rapidly decreased to 0 during the night, while jugular venous oxy-
gen saturation (SjvO2) decreased and oculocardiac reflex disap-
peared. After intravenous administration of mannitol the BIS val-
ue increased again to previous values, while SjvO2 increased and
oculocardiac reflex reappeared

disappeared, both BIS and EMG activity increased to

previous values.
Finally, in one patient whose brain death was certified
by both clinical examination and cerebral angiography
BIS values increased from 0 to an average of 60
(Fig. 4c). After myorelaxant injection BIS values did not
decrease to 0 but only to 38 and remained fairly stable
around this level. This hemodynamically unstable patient
showed an important cardiovascular hyperpulsatility un-
der epinephrine, responsible for head and neck move-

Fig. 4a–c Bispectral index (BIS) and electromyographic activity

(EMG) trend recordings in patients for whom BIS values were
overestimated. a BIS and EMG course in a 46-year-old patient ad-
mitted to the ICU About 4 h after admission to the ICU, BIS de-
creased to 0, whereas clinical examination suggested brain death
onset. An EEG was immediately performed (time 100 min) and
confirmed brain death. Approximately 30 min later, spontaneous-
ly, while no body and no device were in contact with the patient,
EMG progressively increased, accompanied by significant in-
creases in the BIS value. The increase in EMG signal was proba-
bly linked to brain death (enhancement of EMG activity in brain-
dead patients) but was interpreted by the BIS monitor as EEG be-
cause of the absence of true EEG signal. b BIS and EMG course
in a 58-year-old brain-dead patient admitted to the ICU for organ
donation. Although brain death was confirmed by both clinical ex-
amination and cerebral angiography, BIS spontaneously increased
to 98, associated with an important EMG activity, while no body the ICU after head injury. Although brain death was already certi-
and no device were in contact to the patient. After intravenous in- fied by both clinical examination and cerebral angiography, BIS
jection of myorelaxant the EMG activity was dramatically reduced values increased from 0 to an average level of 50. Surprisingly, af-
in about 3 min, while BIS simultaneously dropped to 0. After- ter myorelaxant injection the BIS values decreased not to 0 but on-
wards BIS showed some small increases linked to patient care and ly to 38, and remained stable around this level. On the other hand,
physical examination. About 1 h later both signals recovered to after changing from epinephrine for norepinephrine to reduce car-
previous values, as the effect of myorelaxant disappeared. c BIS diovascular important hyperpulsatility the BIS values quickly de-
and EMG course in a 50-year-old brain-dead patient admitted to creased to 0
424
ments, and the real-time EEG waveform displayed regu-
lar oscillations at the same frequency as heart rate. To re-
duce this hyperpulsatility epinephrine was changed for
norepinephrine. Immediately after this switch the hyper-
pulsatility decreased, and the real-time EEG waveform
oscillations disappeared, while BIS values quickly de-
creased to 0. No other overestimation of BIS values only
due to cardiovascular hyperpulsatility was observed in
the 38 remaining brain-dead patients.
Discussion
This study shows that in the 56 severely comatose pa-
tients studied BIS values were 0 in patients already
brain-dead at the time of admission, and always de-
creased to 0 in the 37 patients who approached brain
death during hospitalization in ICU. Against this, aver-
age BIS values remained above 35 in the 17 patients who
never progressed to brain death during their hospitaliza-
tion in ICU, and who had persistent electrocortical activ-
ity detected by EEG. Nevertheless, two important limita-
tions of this monitoring were observed: (a) BIS could de-
crease to 0 before complete onset on brain death in pa-
tients with major intracranial hypertension, and (b) im-
portant EMG activity and cardiovascular hyperpulsatility
could falsely elevate the BIS.
In three patients the BIS decreased to 0 although
these patients were not clinically brain dead. In one of
them this decrease was accompanied by a worsening of
neurological status, which required administration of an
antiedematous treatment for correction. In the two other
patients the BIS decreased to 0 a short time (1 or 2 h) be-
fore all the criteria of brain death were fulfilled. Never-
theless, according to the major cerebral injuries of these
two patients, these decreases were interpreted as signal
of impending brain death, allowing the scheduling of
EEG or angiography and meeting with patients’ families.
Therefore continuous BIS monitoring in severely coma-
tose patients seems to be a very useful method for early
detection of neurological worsening. In our ICU, this is
particularly true for patients who have been hospitalized
for several days in ICU, and whose neurological status is
apparently stabilized, but who may be expected to deteri-
orate because of their cerebral injuries. Thus a decrease
in BIS values, for example, during the night, is some-
times the first signal of such a deterioration. Indeed,
good correlations between the BIS and neurological sta-
tus have been reported in unsedated ICU patients and in
neurosurgical ICU patients [8, 16]. Moreover, for refrac-
tory intracranial hypertension, Riker et al. [17] success-
fully used the BIS to titrate pentobarbital infusions.
EMG activity is undoubtedly the main pitfall of BIS
monitoring in severely comatose patients. While EEG
and EMG signals are conventionally considered to re-
main in the bands of 0.5–30 Hz and 30–300 Hz, respec-
tively, BIS uses EEG signals up to 47 Hz [18]. Indeed,
clinically, low-frequency EMG activity has already been
reported to falsely elevate BIS values in anesthetized pa-
tients without muscle relaxants [19]. Significant EMG
activity may be present in brain-dead patients [20], and
has been reported as a major artifact during EEG record-
ings for determining electrocortical silence [21, 22, 23].
Elsewhere, Mayr et al. [23], who reported “tetaniform”
muscle activity during EEG recording in five potential
organ donors, suggested that this enhanced EMG activity
could be due to hyperexcitability of the nerve membrane
caused by artificial hyperventilation in brain-dead pa-
tients. This interference between BIS and EMG activity
is an important pitfall for using BIS in severely comatose
and brain-dead patients. We hypothesize that this mis-
take is due in such patients to the very weak, or absence
of, EEG signal, as compared to the EMG activity. In
these cases the BIS monitor interprets EMG signals in
the 30- to 47-Hz band as EEG, especially when there is
no EEG signal in the 0.5–30 Hz band. Similarly, Mycha-
skiw et al. [14] have reported a case of falsely elevated
BIS during deep hypothermic circulatory arrest and pro-
pose that in such circumstances of extreme EEG sup-
pression electrical interferences from either EMG or ra-
diofrequency noise might be interpreted by the algorithm
as EEG activity and assigned a high BIS value.
This interference between EEG and EMG is also a
major pitfall for EEG recording, especially in brain-dead
patients for whom EMG activity may be enhanced [21,
22, 23]. Indeed, the administration of muscle relaxants is
generally necessary in brain-dead patients to obtain reli-
able isoelectric EEG recordings [20, 21]. In our clinical
practice we always consider EMG activity in interpreting
BIS values in severely comatose patients. Therefore, if
necessary, we recommend the administration of muscle
relaxants when high EMG activity could interfere with
BIS monitoring. In our opinion, this enables BIS to be-
come a reliable means for monitoring EEG activity in se-
verely comatose patients, especially when they are ex-
pected to progress to neurological worsening.
Nevertheless, it should be kept in mind that this inter-
ference between EEG and EMG during BIS monitoring
is not specific to severely comatose and brain-dead pa-
tients but has been previously reported to falsely elevate
BIS values in anesthetized patients without muscle relax-
ants [19]. Indeed, EMG activity is not specifically a pit-
fall for BIS monitoring, having been described 20 years
ago as a frequent contaminant of the EEG signal during
general anesthesia [24].
The results presented here should be interpreted with
caution. BIS monitoring in severely comatose patients is
a new concept [7, 8, 9], far from the initial purpose of
this monitor, and therefore new algorithms of analysis of
bispectral index should probably be developed for such
cases, especially in cases of very low EEG activity.
Nonetheless, BIS seems to be an interesting monitoring
 425

technique in severely comatose patients suffering from
cerebral injuries. Indeed, the decrease in BIS to 0 might
be used as an assessment of brain death onset, facilitat-
ing appropriate timing for either EEG or cerebral angiog-
raphy to confirm brain death. On the one hand, perform-
ing these examinations too early, before actual brain
death, is of limited value. Moreover, they should not be
repeated since they are expensive and, at least regarding
cerebral angiography, potentially deleterious. Against
this, brain death is characterized by a major hemody-
namic instability [2, 25], which is detrimental to the pa-
tient’s organs. This instability is one important limit to
organ donation, leading sometimes to a sudden and irre-
versible cardiac arrest, which prevents any organ dona-
tion [26]. Therefore the diagnosis of brain death should
be made required as soon as possible.
In conclusion, the decrease in BIS to 0 in severely co-
matose patients could be used as an assessment of brain
death onset, enabling scheduling of appropriate timing
for either EEG or cerebral angiography to confirm brain
death. Nevertheless, further studies are needed to deter-
mine whether BIS, which is a simple noninvasive moni-
toring of EEG, can improve the timely diagnosis of brain
death and therefore facilitate organ procurement for
transplantation.
Acknowledgements The writers are indebted to Dr. D.J. Baker,
(Département d’Anesthésie-Réanimation, Hôpital Necker, Paris,
France), for reviewing the present manuscript.

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