Use of cerebral state index to predict long-term unconsciousness in patients after elective craniotomy with delay recovery
Use of cerebral state index to predict long-term unconsciousness in patients after elective craniotomy with delay recovery
Ming Xu 0
Yan-Ni Lei 0
Jian-Xin Zhou 0
0 Department of Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University , No 6, Tiantan Xili, Chongwenqu, Beijing, 100050 , China
Background: The major difficulty in postoperative care in patients after craniotomy is to distinguish the intracranial deficits from the residual effect of general anesthesia. In present study, we used cerebral state index (CSI) monitoring in patients after craniotomy with delayed recovery, and evaluated the prediction probability of CSI for long-term postoperative unconsciousness. Methods: We enrolled 57 consecutive adult patients admitted to neurosurgical intensive care unit (NICU) after elective craniotomy with delayed recovery. CSI was continuously monitored for 6 hours after admission. Patient's level of consciousness was followed up for 24 hours. According to whether obeyed verbal command, patients were divided into awaken group and non-awaken group. CSI values were compared between the two groups. Prediction probability (PK) was calculated to determine the probability of CSI in predicting unconsciousness 24 hours after operation. Results: In awaken group (n = 51), CSI increased significantly after the 2nd NICU admitted hour (P < 0.05). At each time point, CSI values in awaken group were significantly higher than those in non-awaken group (n = 6) (P < 0.05). The values of PK (SE) for CSI in the first 6 admitted hours ranged from 0.94 (0.06) to 0.99 (0.02). Conclusions: In patients after craniotomy with delayed recovery, CSI monitoring in early postoperative hours had high prediction probability for long-term unconsciousness. CSI monitoring may be a reliable objective method to predict level of consciousness after elective craniotomy.
The most feared complications after craniotomy are
formation of intracranial hematoma and major brain
swelling. Although rapid emergence from general anesthesia
is desirable in the majority of neurosurgical patients, in
certain cases whose systemic or brain homeostasis is
impaired, delayed recovery may be a better choice .
However, delayed recovery usually prevents the timely
diagnosis of cerebral complications after craniotomy.
Therefore, one of the main issues in postoperative care
in delayed recovery is to distinguish the unresponsive
state that is indicative of intracranial reasons from the
residual effects of general anesthesia . In clinical
practice, evaluation of consciousness is largely based on
subjective neurological examination, such as Glasgow
Coma Scale and pupil size and reaction to light.
Although many efforts have been made, it is still
difficult to measure consciousness by objective instruments.
In order to monitor the depth of anesthesia objectively
and quantitatively, several processed
electroencephalogram (EEG) algorithms have been designed and studied
extensively in operating room, but to a much lesser
degree, in postoperative care and brain injury . In
2004, the cerebral state index (CSI) monitor (Danmeter,
Odense, Denmark) was launched as a new processed
EEG monitor for measuring hypnotic depth . Up to
now, clinical studies of CSI monitoring in postoperative
care are limited, especially for neurosurgical patients.
In present study, CSI monitoring was used in patients
after elective craniotomy with delayed recovery from
general anesthesia. The aim of this study was to test
whether CSI monitoring in early postoperative recovery
The study protocol was reviewed and approved by
Research Ethic Committee in Beijing Tiantan Hospital,
Capital Medical University (Beijing, China). Written
informed consent was obtained from patients or their
The study was carried out in a neurosurgical intensive
care unit (NICU) of a 1000-bed university hospital over
a 3 month period, from November 2007 to January
2008. Our NICU is open to neurosurgical patients
24 hrs per day, 7 days per week, and all craniotomy
patients are admitted to NICU for postoperative care.
During the study, routine practices of anesthesia and
postoperative care were followed, and no attempt was
made to change or influence the standard practices.
In our hospital, all craniotomy were performed under
general anesthesia. Typically, anesthesia was induced
with propofol, 2 mg/kg IV, and sufentanil, 1-2 g/kg IV,
and tracheal intubation was facilitated with vecuronium,
0.1 mg/kg IV. Anesthesia was maintained by sevoflurane
in oxygen (with end-tidal concentration of 1.5%-2%),
and sufentanil (infusion rate of 0.2-0.5 g/kg/hr),
titrated to keep mean blood pressure within 30% of
preoperative values. Vecuronium (bolus of 0.05 mg/kg) was
administered according to train of four monitoring. At
the time of dural closure, sufentanil infusion was
discontinued. Sevoflurane was discontinued during skin
closure. Anesthesiologists and Neurosurgeons discussed
patients status, and made the decision of recovery.
Typically, delayed recovery was scheduled in patients
with following conditions: 1) emergency craniotomy in
traumatic brain injury and intracranial hematoma;
2) large or complicated arterio-venous malformation
resection; 3) large tumor resection with preoperative
midline shift; 4) major intraoperative bleeding or brain
swelling; 5) extensive posterior fossa operation involving
cranial nerves IX-XII; 6) impaired preoperative state of
consciousness; 7) intraoperative abnormal body
temperature, inadequate oxygenation, cardiovascular
instability, or coagulation disorder; 8) length of
operation longer than 6 hours.
For delayed recovery, patient was remained tracheal
intubated at the end of surgery and transported to
NICU with manual ventilation and supplemental
oxygen. On arrival to the NICU, mechanical ventilation and
standard clinical monitoring devices were applied
(including 5-lead continuous electrocardiogram, pulse
oximeter, noninvasive blood pressure, capnograph, and
rectal temperature). All patients were warmed during
NICU stay by using a forced-air warming blanket to
maintain rectal temperature above 36C. Criteria for
tracheal extubation included: 1) obey verbal command;
2) have adequate spontaneous breathing and
oxygenation; 3) possess an intact gag reflex. All extubated
patients were given supplemental oxygen by mask.
Postoperative sedation was not used deliberately. In patients
who exhibited agitation but did not meet the extubation
criteria, midazolam was IV infused for 2 hours (0.05-0.2
mg/kg/hr IV). The dose of midazolam was titrated to
obtain light sedation (patient unresponsive to verbal
command, but showing motor response to noxious
stimuli). Arterial blood gas, serum electrolytes, whole
blood counts, blood urea nitrogen, and blood glucose
analysis were performed during the first 2 postoperative
hours. Postoperative computed tomographic scan was
not used routinely, but was usually carried out in
patients who exhibited unexplained delayed awakening
or new neurological deficits.
During study period, adult patients (> 18 yrs of age)
after elective craniotomy with delayed recovery were
enrolled consecutively, excluding those with impaired
preoperative level of consciousness. Demographic data
were collected at patients admission, which included
age, sex, and length of operation. CSI monitoring was
set up within 30 min after patients arrival in NICU.
The skin was prepared by swabbing with alcohol and
then firmly rubbing with abrasive paper. Standard wet
gel ECG electrodes (SKINTACT, Leonhard Lang
GmbH, Innsbruck, Austria) were applied according to
the manufacturers instruction, with one on the
foreheads midline, one more laterally on the forehead, and
one on the mastoid process behind the ear. Electrodes
were attached to a handheld CSI monitor (Danmeter,
Odense, Denmark, SN 2006219982) by a snap
connector. After an initial control of electrode impedance, the
monitor displayed a numerical CSI from 0 to 100. CSI
was continuously monitored for 6 hours after NICU
admission. Glasgow coma scale was assessed every
1 hour for 6 hours. Because all enrolled patients had
endotracheal intubation at entry of the study, we only
documented the motor responses to external stimuli in
Glasgow coma scale (GCS-M) . Patients were given a
verbal command to open eyes or lift hands, first in a
normal voice, and then in a loud voice. If patients did
not respond to the loud verbal command, they were
given a light tap on the shoulder and verbal command
simultaneously. Obeying command in response to the
shoulder tap and verbal command was considered as a
positive response (GCS-M = 6). If there was still no
response, a painful stimulus of rubbing the sternum was
applied to differentiate pain localization (GCS-M = 5),
withdrawal flexion (GCS-M = 4), stereotyped flexion
(GCS-M = 3), stereotyped extension (GCS-M = 2), and
none response (GCS-M = 1). Immediately after each
hours verbal or painful stimulation in GCS-M
evaluation, CSI value was observed for 2 min by a nurse
(not involved in this study), and the maximal value was
documented manually. Use of sedatives during the CSI
monitoring was also recorded.
Patients were followed up at 24-hour after the end of
surgery, and level of consciousness was evaluated. In
patients under sedation, sedatives were stopped for at
least 1 hr to facilitate a reliable neurological assessment.
According to the results of follow-up, patients were
divided into two groups: awaken group (obey verbal
command evaluated as GCS-M = 6) and non-awaken
(GCS-M = 5 to 1).
Continuous variables (CSI, age, and length of
operation) were expressed as mean and SD, and ordinal
variables (GCS-M) were expressed as median and
interquartile range (IQR). For CSI and GCS-M data,
within-group comparisons across time points were
performed by non-repeated-measures of analysis of variance
with a post hoc Student-Newman-Keuls multiple
comparison test, and between-group comparisons in each
time points were performed by unpaired Students t test
for CSI and the Wilcoxon rank sum test for GCS-M.
Categorical variables were expressed as numbers and
percentages, and c2 test was used for comparison
between the two groups. Spearman rank-order
correlation analysis was used to evaluate the relationship
between GCS-M and CSI. For evaluating the probability
of CSI in predicting unconsciousness 24 hrs after
operation, we calculated the prediction probability (PK) as
described by Smith et al . PK was calculated as the
Somers d statistic using SPSS version 10.0, which was
then transformed from -1 to +1 range of Somers d to 0
to 1 range of PK by using the equation :
PK = 1 ( 1 | Somers d | ) / 2
Standard error (SE) of PK was calculated as the SE of
Somers d divided by 2. Best-fitting logistic curve
between CSI and the probability of unconsciousness was
plotted. The values of CSI associated with a probability
of 50% and 95% for unconsciousness at 24-hour after
operation (CSI50% and CSI95%) were estimated by using
logistic regression analysis, and 95% confidence limit
(95% CL) was calculated.
Statistical analysis was carried out by SPSS version
10.0 (SPSS, Chicago, IL, USA). A P-value less than 0.05
was considered statistically significant.
During the study period, 487 adult patients after elective
craniotomy were admitted in our NICU for
postoperative care. Among these patients, 62 were treated with
delayed recovery, of whom 57 were enrolled and 5 were
excluded due to decreased level of consciousness
preoperatively. Fifty-one patients obeyed verbal
command at the 24-hour postoperative follow-up (awaken
group), and 6 patients did not (non-awaken group). The
patients in the 2 groups were comparable as to
demographic characteristics (Table 1).
Figure 1 showed CSI data in the two groups for the
first 6 NICU admitted hours. In awaken group, CSI
value at the 1st hour of admission was 75 12. CSI
increased significantly at the 2nd admitted hour (P <
0.05), but there was no significant changes during the
2nd to 6th hours (85 12 to 88 7). There was no
significant change of CSI across different time points in
non-awaken group, ranging from 43 15 to 52 19
(P > 0.05). Inter-patient variability of CSI existed in each
group, which was demonstrated by a significant
difference in random factor of patient in
non-repeated-measures of analysis of variance (P < 0.05). At each time
point, CSI values in non-awaken group were
significantly lower than those in awaken group (P < 0.05,
GCS-M data were shown in Table 2. GCS-M
increased significantly during the early NICU admitted
hours. GCS-M in awaken group were significantly
higher than those in non-awaken group (P < 0.05). At
the first NICU admitted hour, no patient obeyed verbal
command in either group. At the 6th admitted hour,
88% of patients in awaken group obeyed verbal
command, but still no patient obeyed in non-awaken group
A significant correlation was found between CSI and
GCS-M from all data sets (Spearmans correlation
coefficient = 0.635, P < 0.05, Figure 2).
The values of PK (SE) for CSI in the first 6 NICU
admitted hours ranged from 0.94 (0.06) to 0.99 (0.02)
(Table 3). CSI50% and CSI95% were also shown in Table 3.
In present study, CSI monitoring was used in early
postoperative period in craniotomy patients with delayed
recovery. The main result of our study is that CSI values
were significantly different between patients who awake
and those who remained unconscious at 24-hour after
operation, and that CSI monitoring in early
postoperative hours had high prediction probability for long-term
The major difficulty in postoperative care in patients
after craniotomy, especially for the situation of delayed
recovery, is to distinguish the intracranial deficits from
the residual effect of general anaesthesia . Although
the bedside physical examination is the standard method
of assessment of consciousness in neurosurgical patients,
EEG is an objective tool that permits sensitive and
continuous monitoring of brain function. However, because
interpretation of the raw EEG signal requires
Table 1 Demographic characteristics of the patients
Awaken group (n = 51)
Non-awaken group (n = 6)
considerable expertise and specialised training, more
standardised and simpler measures of brain function are
desirable . In order to measure the depth of hypnotic
objectively and quantitatively, several processed EEG
algorithms, such as the bispectral index (BIS) , the
Narcotrend , the SNAP index , and more
recently, CSI [3,11], are designed. The CSI value is
passively derived from EEG signals and provides a
dimensionless number from 0 to 100. It uses a fuzzy logic
inference system based on power analysis of beta, alpha
and beta-alpha ratio with an estimation of burst
suppression ratio. Recent attempts have been made to
extend the use of BIS to brain-injured patients [12,13],
and the results of these studies indicate that BIS value
correlates with the severity of brain-injury. In present
study, we enrolled craniotomy patients with delayed
recovery, and performed CSI monitoring in early
postoperative period. The patients level of consciousness
was followed up at 24-hour after craniotomy to
excluding the residual effect of general anaesthesia. By this
study design, we could evaluate the predicting ability of
early postoperative CSI monitoring to long-term
neurological outcome. Early postoperative CSI values in
patients with long-term neurological deficits were
significantly lower than those recovered (Figure 1). The CSI
values in the first 6 NICU admitted hours ranged from
Figure 1 Cerebral state index (CSI) at the first to 6th neurosurgical intensive care unit (NICU) admitted hours in awaken and
nonawaken group. * P < 0.05 between the groups; # P < 0.05 compared to values at 2nd to 6th NICU admitted hour.
GCS-M: the motor response to external stimuli in Glasgow Coma Scale; IQR: interquartile range; NICU: neurosurgical intensive care unit.
* P < 0.05 between the groups; | P < 0.05 compared to values of 2nd to 6th admitted hour; P < 0.05 compared to values of 3rd to 6th admitted hour; P <
0.05 compared to values of 5th and 6th admitted hour.
75 to 88 in awaken group, and 43 to 52 in non-awaken
group. For patients in awaken group, CSI values
remained relatively stable after the 2nd NICU admitted
hour (Figure 1). Further more, the PK statistic analysis
showed the good predictive ability of CSI for detecting
long-term postoperative unconsciousness (Table 3).
From 2nd to 6th NICU admitted hours, the CSI values
associated with probability of 50% and 95% for
longterm unconsciousness after craniotomy, which we
named as CSI50% and CSI95%, were 54 to 63 and 30 to
53, respectively (Table 3). Based on these results, it can
be said that those patients whose CSI values are lower
Figure 2 Correlation between the motor response to external stimuli in Glasgow Coma Scale (GCS-M) and cerebral state index (CSI).
To demonstrate the scatter of data, mean, standard deviation (SD), the minimum, and the maximum values of CSI are presented. Numbers of
data sets are also presented. Spearmans correlation coefficient was calculated from all individual data set.
CSI50% (95% CL) CSI95% (95% CL)
PK: prediction probability; CSI50% and CSI95%: the values of cerebral state index
associated with a probability of 50% and 95% for unconsciousness 24 hr after
craniotomy; NICU: neurosurgical intensive care unit.
than 54 to 63 in the first 6 postoperative hours have a
probability of long-term postoperative unconsciousness
higher than 50%, and those with CSI values lower than
30 to 53 have a probability higher than 95%. If CSI
monitoring shows a value below these borderlines,
physician should exam the patient carefully to exclude the
There are some limitations in our study. First, we did
not computerize CSI values recording, and therefore
our results may not accurately reflect rapid changes.
But the lack of such fast CSI data extractions may not
affect the clinical question, because majority of patients
in our study were relatively stable during the stay in
NICU. Second, because there was no attempt made to
change the standard practices, we did not control
postoperative sedation in our study. Midazolam was used
in 11 and 1 patients in awaken and non-awaken group,
respectively. When patients in awaken group were
stratified by the use of midazolam, it was interesting to
find that CSI values in patients under sedation were
not significantly different to those not receiving
sedatives, except for the values in the 1st admitted hour
(Table 4). After excluding the data from patients under
postoperative sedation, PK values for predicting
longterm unconsciousness after craniotomy were still
greater than 0.94 (data are not shown). Several studies
have carried out in intensive care unit patients under
sedation, and results showed that the verbal and
physical stimulations increased patient wakefulness with an
accompanying increase in BIS values [14,15]. In our
previous study, we found that CSI values increased
significantly after verbal or painful stimulation, and CSI
values after external stimulations were more reliable
than random baseline values for detecting purposeful
movement in response to external stimuli in
braininjured patients . In present study, the dose of
midazolam was titrated to obtain a light sedation level,
and we recorded the maximal CSI values immediately
after verbal or painful stimulation in GCS-M
evaluation. These external stimulations might increase the
CSI values. Third, we did not deliberately select the
side of CSI electrode placement according to the
location of operation. Previous study has found a very high
correlation in CSI derived simultaneously from the left
and right sides of the brain in patients without brain
injury . However, further studies are necessary to
determine the agreement in CSI readings between the
two sides in patients after craniotomy.
Results from present study suggest that CSI correlated
with postoperative unconsciousness in patients after
elective craniotomy with delayed recovery. More
importantly, CSI monitoring in early postoperative period had
high prediction probability for long-term postoperative
unconsciousness. These results would encourage
conducting clinical trials in greater populations.
The present study was supported by Beijing Municipal Health Bureau
(20093-28). The funding sources did not participate in the design or conduct of
the study; collection, management, analysis, or interpretation of the data; or
preparation, review, or approval of the manuscript.
MX and JXZ contributed to the study conception and design. MX and YNL
participated in recruitment of patients, performing CSI monitoring and
assessing Glasgow Coma Scale. YNL participated patients follow-up. YNL
and JXZ participated statistical analysis and drafting of the manuscript. All
authors read and approved the final manuscript.
Table 4 CSI values (mean SD) in patients under sedation or not.
NICU admitted hours
Under sedation (n = 11)
Not receiving sedatives (n = 40)
CSI: cerebral state index; NICU: neurosurgical intensive care unit.
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