Bi-frontal pneumocephalus is an independent risk factor for early postoperative agitation in adult patients admitted to intensive care unit after elective craniotomy for brain tumor: A prospective cohort study
Bi-frontal pneumocephalus is an independent risk factor for early postoperative agitation in adult patients admitted to intensive care unit after elective craniotomy for brain tumor: A prospective cohort study
Hua-Wei Huang 0 3
Li-Mei Yan 0 1 3
Yan-Lin Yang 0 3
Xuan He 0 3
Xiu-Mei Sun 0 3
Yu-Mei Wang 0 3
Guo-Bin Zhang 2 3
Jian-Xin Zhou 0 3
0 Department of Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University , Beijing , China
1 Department of Critical Care Medicine, Inner Mongolia People's Hospital , Hohhot, Inner Mongolia , China
2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University , Beijing , China
3 Editor: JianJun Yang, Jinling Clinical Medical College of Nanjing Medical University , CHINA
Postoperative agitation frequently occurs after general anesthesia and may be associated with serious consequences. However, studies in neurosurgical patients have been inadequate. We aimed to investigate the incidence and risk factors for early postoperative agitation in patients after craniotomy, specifically focusing on the association between postoperative pneumocephalus and agitation. Adult intensive care unit admitted patients after elective craniotomy under general anesthesia were consecutively enrolled. Patients were assessed using the Sedation-Agitation Scale during the first 24 hours after operation. The patients were divided into two groups based on their maximal Sedation-Agitation Scale: the agitation (Sedation-Agitation Scale 5) and non-agitation groups (Sedation-Agitation Scale 4). Preoperative baseline data, intraoperative and intensive care unit admission data were recorded and analyzed. Each patient's computed tomography scan obtained within six hours after operation was retrospectively reviewed. Modified Rankin Scale and hospital length of stay after the surgery were also collected. Of the 400 enrolled patients, agitation occurred in 13.0% (95% confidential interval: 9.7?16.3%). Body mass index, total intravenous anesthesia, intraoperative fluid intake, intraoperative bleeding and transfusion, consciousness after operation, endotracheal intubation kept at intensive care unit admission and mechanical ventilation, hyperglycemia without a history of diabetes, self-reported pain and postoperative bi-frontal pneumocephalus were used to build a multivariable model. Bifrontal pneumocephalus and delayed extubation after the operation were identified as independent risk factors for postoperative agitation. After adjustment for confounding, postoperative agitation was independently associated with worse neurologic outcome (odd ratio: 5.4, 95% confidential interval: 1.1?28.9, P = 0.048). Our results showed that early postoperative agitation was prevalent among post-craniotomy patients and was associated with adverse
study design, data collection and analysis, decision
to publish, or preparation of the manuscript.
Competing interests: The authors have declared
that no competing interests exist.
outcomes. Improvements in clinical strategies relevant to bi-frontal pneumocephalus should
Trial registration: ClinicalTrials.gov (NCT02318199).
Postoperative agitation after general anesthesia has been reported to occur in 3.7 to 29% of
patients and may be associated with serious consequences, such as unplanned extubation,
injuries and longer post-anesthesia care unit stay [1?7]. During the early stage of anesthesia
recovery, neurosurgical patients may be more vulnerable to stress caused by agitation [
Physiological fluctuations may result in edema, hemorrhage, and, ultimately, ischemia . In
our previous pilot study, which included 123 patients who underwent elective intracranial
operations, we found the incidence of agitation within 12 hours postoperatively to be 29%,
which was higher than that previously observed in other surgical populations [
investigations of this phenomenon in neurosurgical populations have been inadequate [1, 3,
The most commonly reported independent risk factors for postoperative agitation in
nonneurosurgical patients, including longer anesthesia duration, delayed extubation and pain,
have also been found to present in neurosurgical patients [
4, 8, 9
]. However, brain lesions and
intracranial manipulations in neurosurgical patients might affect the brain regions which
involves cognition and emotion, and are assumed to influence postoperative cognition [
Moreover, during our clinical work, we noticed that post-craniotomy frontal pneumocephalus
might also serve as a potential risk factor. Due to the preventable nature of pneumocephalus,
further investigation is needed to clarify its relationship with agitation. Therefore, we
conducted this prospective cohort study of adult patients who had undergone elective craniotomy
for brain tumors. Incidence and clinical consequences of early postoperative agitation were
documented. We aimed to investigate the risk factors for agitation, specifically focusing on the
association between postoperative pneumocephalus and agitation. The association of agitation
with long-term outcomes was also analyzed.
Materials and methods
Study design, ethics and patient population
This prospective cohort study was approved by the Institutional Review Board of Beijing
Tiantan Hospital, Beijing, China (KY2014-034-01). Written informed consents were obtained from
study subjects or their pre-defined healthcare decision makers. The study protocol was
registered at ClinicalTrials.gov (NCT02318199; https://clinicaltrials.gov/ct2/show/NCT02318199).
Three authors (HWH, LMY and JXZ) had access to information that could identify individual
participants during and after data collection.
The study was conducted in a neurosurgical ICU of a University affiliated hospital (Beijing,
China) between Jan 1 and Aug 31, 2015. Patients admitted to the ICU after intracranial
operations under general anesthesia were consecutively screened for study eligibility. The inclusion
criterion was adult patients who had undergone elective craniotomy for brain tumors. The
exclusion criteria included: 1) aged under 18 or over 80 years; 2) preoperative impairment of
consciousness; 3) not following simple commands (lift hands or open mouth) during the first
24 hours after the operation; and 4) interval longer than 24 hours between the end of the
operation and ICU admission.
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Routine practices of neurosurgery, anesthesia and postoperative care
During the study, no attempts were made to change the standard of care, and routine practices
In our institute, all neurosurgeons had to undergo standard pre-job training for intracranial
operation, which included the instruction of adequate air removal via physical saline injection
prior to dural closure.
All intracranial surgeries were performed under general balanced anesthesia or total
intravenous anesthesia (TIVA). Anesthesia was induced with intravenous propofol and
sufentanil or remifentanil. Tracheal intubation was facilitated with intravenous rocuronium
or cisatracurium. Anesthesia was maintained with propofol and/or sevoflurane or isoflurane.
Sufentanil or remifentanil was administered intermittently or continuously, as needed.
Muscle relaxant was administered according to train-of-four monitoring. The choice of agents
was at the discretion of the anesthesiologist. For adult patients with brain tumors scheduled
elective operation, the anesthesiologist and the neurosurgeon discussed postoperative ICU
admission using criteria including, but were not limited to, age over 65 years, American
Society of Anesthesiology (ASA) classification III or higher, large tumor or located at the brain
stem, preoperative midline shift, preoperative consciousness impairment, anticipated
prolonged operation and anticipated delayed extubation. At the end of the operation, the
anesthesiologist and the neurosurgeon also discussed whether the patient had reasons for
unplanned ICU admission, mainly including unanticipated delayed extubation, major
intraoperative bleeding or brain swelling, injury to cranial nerve IX, X and XII, and severe
cardiorespiratory instability during the attempt of emergence. Approximately half of the
patients who had undergone elective craniotomy were admitted to the ICU for overnight
In the ICU, nurses evaluated the patients' Glasgow Coma Scale (GCS) scores and focal signs
and performed pupillary examinations hourly or as needed. Most patients received
patientcontrolled intravenous analgesia (PCIA), which was composed of sufentanil 100 ?g and
tropisetron 10 mg in 100 ml 0.9% sodium chloride solution. A basal PCIA infusion (2 ml/h) is
started after the confirmation of the patient's cardiorespiratory stability and recovery of
consciousness. A computed tomography (CT) scan was routinely performed within six hours
postoperatively. All extubated patients received supplemental oxygen by simple face mask at
flow of 3?6 L/min. In patients with delay extubation, oxygen was delivered by T tube.
Mechanical ventilation was initiated when the patient could not maintain adequate spontaneous
breathing or the pulse oxygenation saturation (SpO2) below 90%. Dexmedetomidine was
continuously infused (0.4 ?g/kg/h) in mechanically ventilated patients until they were weaned off
the ventilator [
]. The presence of agitation and depth of sedation were evaluated using the
Sedation-Agitation Scale (SAS) [
], which had been incorporated into clinical practice at our
facility for more than three years [
]. All ICU physicians and nurses were trained to perform
SAS assessment. Both nurses and physicians carefully evaluated patients with agitation (SAS
score from 5 to 7) and excluded the possibility of organic causes of agitation, including pain,
acute deterioration of cardiorespiratory function, a new neurologic event and hypoglycemia.
When patients complained of pain, an intravenous bolus of fentanyl (25 ?g) was administered.
An intermittent or continuous intravenous infusion of midazolam was used for agitated
patients, and the level of sedation was titrated until a SAS score of 3 to 4 was achieved. In
patients with delayed extubation, after recovery from anesthesia, the ICU physician evaluated
the patient's reliability for extubation by a screening checklist, including assessments of
consciousness, cardiorespiratory status, muscle strength recovery, gag reflex and cough function
. When each item in the checklist was passed, endotracheal extubation was performed by
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registered ICU nurses. Most patients were discharged from the ICU in the next morning after
achieving normal neurological, hemodynamic and respiratory statuses.
Agitation assessment and definition
During the study period, four trained investigators took turns screening and evaluating the
SAS scores of the patients. The SAS score of each eligible patient was evaluated hourly until the
patient was capable of following commands (SAS 3). After enrolment, SAS scores were
assessed every four hours or as needed until either 24 hours of evaluation or ICU discharge,
whichever occurred first. Agitation was defined as a SAS score ranging from 5 to 7 [
patients were divided into two groups based on their maximal SAS score: the agitation group
(maximal SAS 5) and the non-agitation group (maximal SAS 4).
Assessment of postoperative CT scans
Two attending neuroradiologists who were blinded to agitation status retrospectively
reviewed each patient's first postoperative CT scans. Bi-frontal subdural pneumocephalus
was defined by the following criteria: 1) subdural areas of hypoattenuation presenting
bilaterally in the frontal region; 2) low attenuation mass presence in at least four serial axial slices
(1 cm thickness); and 3) maximal displacement of the frontal lobe from the dura of more
than 1 cm in at least one slice (Fig 1A) [
]. A special type of bi-frontal pneumocephalus,
the ?Mount Fuji sign?, was characterized by bilateral subdural hypoattenuating collections,
collapsed frontal lobes and widening of the interhemispheric space between the tips of the
frontal lobes (Fig 1B) . The ?Mount Fuji sign? was deliberately inspected. Postoperative
hematomas, ischemia and midline shifts were also observed. Two neuroradiologists
independently reviewed the CT scans. Discrepancies were resolved by discussion until consensus
Fig 1. Example CT scans identified as bi-frontal pneumocephalus (A) and ?Mount Fuji sign? (B). Patients name and medical record number are masked. Bi-frontal
pneumocephalus (A) was defined as complying with all three: 1) subdural areas of hypoattenuation were bilaterally presented in frontal region; 2) low attenuation mass
existed in at least four serial axial slices (1 cm thickness); and 3) the maximal displacement of the frontal lobe from the dura was more than 1 cm at least in one slice.
?Mount Fuji sign? (B) was identified by bilateral subdural hypoattenuating collections, collapsed frontal lobes and widening of the interhemispheric space between the
tips of the frontal lobes.
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During the study period, the numbers of elective craniotomies performed for brain tumors
and patients transferred to the ICU and neurosurgical ward were documented. The time of
ICU admission and time interval between admission and enrolment were also recorded.
Baseline and preoperative data were extracted from hospital records, including the patients'
demographic characteristics, ASA classification, health history (comorbid diseases, smoking
and alcohol abuse, and long-term use of antidepressant drugs or benzodiazepines). The type of
tumor (glioma or non-glioma) was documented based on the postoperative pathological
reports issued during the follow-up period.
Intraoperative data were extracted from anesthesia and operation records, including tumor
location (supratentorial or infratentorial), surgical approach (frontal or non-frontal),
anesthesia duration and method (balanced anesthesia or TIVA), fluid balance, bleeding amount,
transfusion occurrence, mannitol and steroid use, and hypotension episode occurrence.
ICU admission data were extracted from nursing records, including GCS (especially scores
on the motor response subscale), body temperature, endotracheal tube kept at ICU admission
and need for mechanical ventilation, central venous catheterization, external ventricular
drainage tube and PCIA device placement, SpO2 below 90% and serum glucose concentration
above 10 mmol/L (especially in patients without a history of diabetes). Complaints of pain
during screening period before the enrollment were also documented.
Patients were followed up until hospital discharge, death or 90 days after enrolment,
whichever occurred first. Following data were collected from ICU nursing and hospital records,
including self-extubation and accidental removal of catheter in the ICU, duration of
mechanical ventilation, time of endotracheal extubation, occurrence of reintubation and tracheotomy,
unexpected reoperation within 72 hours of surgery, and use of sedatives and fentanyl during
ICU stay. Long-term outcomes, including hospital LOS after the surgery and modified Rankin
Scale (mRS) scores, were collected at the end of follow-up. Poor neurologic outcome was
defined as a mRS score of 5 or 6 [
]. Results of the retrospective analyses of the first
postoperative CT scans were documented.
Categorical variables are expressed as counts (percentages), and continuous data are reported
as medians with interquartile ranges (IQRs). Missing data and loss to follow-up were
documented. The incidence of post-operative agitation and 95% confidential interval (CI) were
calculated. The agitation and non-agitation groups were univariably compared to screen for
potential confounding variables in a multivariable model predicting agitation. The associations
of preoperative baseline variables, intraoperative variables, ICU admission data and CT scan
data with the agitation were assessed. Categorical variables were compared using two-tailed
Pearson chi-square tests, and Fisher's exact tests were performed for variables with small cell
counts. Continuous variables were compared using the Mann-Whitney U test. The possible
interaction between variables was analyzed. Factors with P values < 0.05 in the univariable
analysis were entered into the multivariable analysis with stepwise backward logistic regression
to identify independent risk factors for agitation. Odds ratios (ORs) and 95% CIs were used to
assess the independent contributions of significant factors. The Hosmer-Lemeshow test was
used to determine whether the model fitted the data adequately well. The association of
agitation with hospital LOS after the surgery and poor neurologic outcome was analyzed using a
multivariable logistic regression analysis by confounding adjustment.
Statistical analyses were performed using SPSS 20.0 (SPSS Inc., Chicago, IL, USA). A P
value of less than 0.05 was considered statistically significant.
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According to standard recommendations, 10 cases of interest (agitation) would be required
for each degree of freedom in the multivariable model to reliably fit the model. Therefore, a
model with 4 degrees of freedom would require at least 40 patients with postoperative agitation
]. We anticipated an average incidence of agitation in the present cohort using data from
previous reports (11%) [1?7], and planned to enroll 400 cases to identify risk factors for
During the study period, 1281 patients underwent elective craniotomy for brain tumors, of
whom 784 returned to the neurosurgical ward and 497 were admitted to the ICU. After
excluding 97 patients, 400 patients were included (Fig 2). All patients were enrolled within six
Fig 2. The patients flow diagram. Abbreviations: ICU, intensive care unit; SAS, Sedation-Agitation Scale.
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hours of ICU admission, with 258/400 (64.5%) patients enrolled just after admission, 131/400
(32.8%) patients enrolled between one and three hours after admission and 11/400 (2.7%)
patients enrolled between four and six hours after admission. Three hundred sixty-one
patients (361/400, 90.3%) were discharged on postoperative day 1, and the remaining patients
(39/400, 9.7%) stayed in the ICU for longer than 24 hours.
Incidence of postoperative agitation
A total of 2019 SAS assessments were performed, with an average of five assessments per
patient. SAS scores were 5 on 89/2019 (4.4%, 95% CI: 3.5?5.3%) of these assessments.
According to the individual data, 300/400 (75.0%), 48/400 (12.0%), 21/400 (5.3%), 24/400
(6.0%) and 7/400 (1.8%) patients had a maximal SAS score of 3, 4, 5, 6 and 7, respectively.
Thus, at least one episode of agitation (SAS 5) occurred in 52/400 (13.0%, 95% CI: 9.7?
Risk factors for postoperative agitation
In the univariable analyses, compared with the non-agitation group, patients in the agitation
group had significantly higher body height and weight, intraoperative fluid intake, and amount
of bleeding (and hourly bleeding); a significantly lower GCS score at ICU admission; and
significantly more use of balanced anesthesia and higher occurrence of transfusion, endotracheal
tube kept at ICU admission, need for mechanical ventilation, serum glucose concentration
10 mmol/L in patients without a history of diabetes, complaint of pain during screening, and
bi-frontal pneumocephalus (Tables 1?3). The ?Mount Fuji sign? was identified in four cases
(4/400, 1.0%), all in the non-agitation group and responsive to conservative therapy without
operation. Bi-frontal pneumocephalus occurred more frequently in patients who underwent
frontal approach than non-frontal approach operations (57/159 [35.8%] versus 33/241
[13.7%], P < 0.001), and in patients who underwent surgery for supratentorial tumors than for
infratentorial tumors (58/209 [27.8%] versus 32/191 [16.8%], P = 0.009).
In the multivariable analyses, we combined body height and weight as body mass index
(Table 1, P = 0.064). We included the hourly amount of bleeding variable (Table 2, P = 0.018)
to avoid the influence of the anesthesia duration variable. To clarify the interaction between
bleeding and transfusion, we arbitrarily stratified patients into two clusters according to the
median of the hourly bleeding variable (71 ml/h) as having major (> 71 ml/h) and minor
intraoperative bleeding ( 71 ml/h). We then divided the patients into three classifications: 1)
minor bleeding; 2) major bleeding without transfusion; and 3) major bleeding with transfusion
(Table 4). By combining the endotracheal tube and mechanical ventilation variables, we
categorized patients into the following groups: 1) extubated in the operating room; 2) endotracheal
tube kept at ICU admission without the need for mechanical ventilation; and 3) endotracheal
tube kept at ICU admission with the need for mechanical ventilation (Table 4). The
classification of the intraoperative bleeding and transfusion as well as endotracheal tube and
mechanical ventilation variables were included as a categorical covariate in the multivariable models.
The results of the multivariable analysis showed that bi-frontal pneumocephalus and
endotracheal tube kept at ICU admission (either without or with the need for mechanical
ventilation) were independent risk factors for postoperative agitation (Table 5). The results of the
Hosmer-Lemeshow test showed the model fits the data adequately well (P = 0.782).
Patients were followed up at a median (IQR) of 10 (8?14) days after the operation. Follow-up
data are shown in Table 6. Multivariable logistic regression analysis revealed that after
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Abbreviations: ADD, antidepressant drugs; ASA, American Society of Anesthesiologist; BMI, body mass index; CAD, coronary artery disease; ICU, intensive care unit;
IQR, interquartile range.
adjusting for significant potential confounders, including GCS at ICU admission, endotracheal
tube kept at ICU admission, and serum glucose concentration 10 mmol/L in patients
without a history of diabetes, postoperative agitation was independently associated with
poorgrade mRS (OR: 5.4, 95% CI: 1.1?28.9, P = 0.048) (Table 7). However, after adjusting for
significant potential confounders, including GCS at ICU admission, motor function of GCS at
ICU admission and endotracheal tube kept at ICU admission, postoperative agitation was not
independently associated with longer hospital length of stay (LOS > 10 days) (OR: 1.4, 95%
CI: 0.7?2.8, P = 0.294) (Table 8).
Our main findings were: 1) early postoperative agitation was prevalent in adult patients who
had undergone elective craniotomy for brain tumors and was associated with adverse
neurological outcomes; and 2) independent risk factors for agitation included bi-frontal
pneumocephalus and delayed extubation, especially with the need for mechanical ventilation.
The incidence of agitation in our group of patients (13%) was within the range reported in
previous studies (3% to 22%) [1, 3, 5?7, 17?20] but markedly lower than that identified in our
previous study (29%) [
]. Several changes to clinical practice in our institution were
implemented after the completion of our previous studies. We have incorporated SAS assessment
into our daily clinical practice for more than three years [
]. Additionally, according to our
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(n = 400)
(n = 348)
previous investigation showing that prophylactic use of dexmedetomidine decreased the
incidence of agitation in patients with delayed extubation [
], we routinely initiated continuous
dexmedetomidine infusion at low dosage (0.4 ?g/kg/h) in mechanically ventilated patients.
However, whether these changes in our clinical strategies decreased the rate of agitation
requires further investigation.
Previous studies found that postoperative delirium, including agitation, was associated with
adverse outcomes [
]. We found that postoperative agitation was association with poor-grade
mRS even after controlling the potential confounders. The relatively high prevalence of
postoperative agitation and its association with adverse neurological outcome indicate the
importance of clinical attention to agitated patients who have undergone elective craniotomy.
A number of risk factors for postoperative agitation have been reported in
non-neurosurgical patients, including premedication, type of anesthesia, delayed extubation and pain [1, 3, 5?
7]. In the present study, we found that delayed extubation, especially when occurring in
combination with a need for mechanical ventilation, was associated with significantly increased
risk of agitation. Although fast track anesthesia has been increasingly used in neurosurgical
patients, delayed emergence is still advocated in patients with a high risk of postoperative
8, 9, 22, 23
]. In our cohort, the prevalence of delayed extubation was 25.5% in
patients who had been admitted to the ICU after elective craniotomy, and 40.8% in patients
who had undergone infratentorial craniotomy. These data were similar to the results of
previous studies [24?29]. Therefore, infratentorial tumors and delayed extubation were the major
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Abbreviations: CT, computed tomography; CVC, central venous catheter; EVD, external ventricular drainage; GCS, Glasgow Coma Scale; ICU, intensive care unit; IQR,
interquartile range; PCIA, patient-controlled intravenous analgesia; SpO2, pulse oxygenation saturation.
indications for postoperative ICU management, and clinical staff should be vigilant for the
occurrence of agitation in these patients.
Pneumocephalus has been found to commonly occur during the early stage after
craniotomy, but tension pneumocephalus requiring urgent surgical evacuation occurs rarely [30?34].
In our group of patients, the ?Mount Fuji sign? only occurred in 1.0% of study subjects and no
emergent operations were performed for intracranial air evacuation, a finding that was in
accordance with previous case reports [
]. Appropriate closure of the dura is important for
preventing pneumocephalus after craniotomy. The incidence of bi-frontal pneumocephalus
Data are shown as n (%).
Abbreviations: ICU, intensive care unit; MV, mechanical ventilation.
(n = 400)
PLOS ONE | https://doi.org/10.1371/journal.pone.0201064
Odd ratio (95% confidential
(22.5%) in our cohort was lower than previously reported incidence of moderate-to-large
pneumocephalus after craniotomy (approximately 50% to 70%) [
]. In our institute, all
neurosurgeons received standard pre-job training for intracranial operation, which included
the standard procedure for dural closure. However, our results showed that bi-frontal
pneumocephalus occurred more frequently in patients undergoing frontal approach (35.8%) and
surgery for supratentorial tumor (27.8%), which indeed indicated the margin for further
repeatedly reminding and training in dural closure technique.
Several case reports have suggested that agitation may occur in some patients with tension
]. As expected, bi-frontal pneumocephalus was found to be an
independent risk factor for postoperative agitation in our cohort of patients. In the supine position,
gas in the subdural space tends to gather in the frontal region. Because the executive function
of the frontal lobes involves cognition and emotion , stimulating the frontal lobes with a
large volume of gas may result in abrupt changes in behavior, including agitation. However,
this is only a presumptive mechanism and requires further investigation.
Given the preventable nature of large pneumocephalus after elective craniotomy and its
relationship with postoperative agitation, several strategies might be adopted into routine
Abbreviations: CVC, central venous catheter; ET, endotracheal tube; ICU, intensive care unit; IQR, interquartile range; MV, mechanical ventilation.
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clinical practice: 1) neurosurgeons should remain aware of the intricate processes involved
with closing the skull, including adequate air removal via physical saline injection before dural
closure and prior to carefully suturing the dura; 2) anesthesiologists should use nitrous oxide
cautiously, especially during reoperation; and 3) ICU physicians should differentiate between
agitation due to pneumocephalus and signs of elevated intracranial pressure. In addition to the
use of sedatives and analgesics to control agitation, neurological status should be carefully
monitored during the management of agitated patients with pneumocephalus to rule out or
confirm the occurrence of tension pneumocephalus.
Previous evidence demonstrated that severe intraoperative hyperglycemia was a predictor
of higher risk for postoperative infections in patients undergoing craniotomy [
]. In the
present study, we determined serum glucose at the ICU admission, which may partly reflect the
intraoperative hyperglycemia. We found that hyperglycemia during the early postoperative
period, especially in patients without a history of diabetes, occurred more in agitated patients.
Our data further enforced the alertness toward hyperglycemia in this population.There are
limitations to the present study. First, we only enrolled ICU admitted patients. When
compared with those directly returning to the neurosurgical ward, these patients might have had
relatively higher ASA classifications, tumors that were more frequently infratentorially located,
longer durations of anesthesia and greater amounts of bleeding during surgery. Thus, our
patients represented a population that was at high-risk of postoperative agitation, and our
results may limit the generalization to the entire population of patients undergoing craniotomy
for brain tumors. Second, although we focused on the association between bi-frontal
pneumocephalus and agitation, surgical factors potentially associated with pneumocephalus were not
collected, such as the opening of the basal cistern and closing of the dura mater. The influence
of these factors warrants further investigation. Third, we did not evaluate preoperatively
neurological disorders and visual or hearing impairments because it could not be determined in
advance which patients would be admitted to the ICU after surgery. Postoperative internal
environmental disturbances, such as sleep disorders due to light and noise in the ICU, were
not excluded. These factors may also be associated with postoperative agitation in the ICU
]. Therefore, we cannot rule out a potential bias introduced by these missing data. Fourth,
in the present study, we only evaluated postoperative agitation because there is no uniformly
accepted tool for assessing delirium in brain injured patients. However, the Confusion
Assessment Method (CAM) is increasingly employed in the neurological and neurosurgical patients
]. Additionally, previous reports have suggested that hypoactive delirium might be more
prevalent in the early period following general anesthesia [
]. In the present study, the
observation that patients with ?Mount Fuji sign? type of pneumocephalus were not agitated might
represent the occurrence of hypoactive delirium in this subgroup of patients. Therefore, we are
ongoing a study focusing on the postoperative delirium in adult patients after elective
intracranial operations to clarify the incidence and risk factors of delirium in this patient population
In conclusion, we found that early postoperative agitation was frequently identified in
patients who had undergone elective craniotomy for brain tumors and was associated with
adverse long-term neurological outcome. Risk factors for postoperative agitation included
bifrontal pneumocephalus and delayed extubation and mechanical ventilation. Improvements in
the clinical strategies relevant to these risk factors should be considered, and further studies
are needed to investigate the effect of such improvements on the occurrence of agitation and
S1 File. STROBE checklist.
Conceptualization: Hua-Wei Huang, Li-Mei Yan, Guo-Bin Zhang, Jian-Xin Zhou.
Data curation: Xuan He, Xiu-Mei Sun, Yu-Mei Wang.
Formal analysis: Yan-Lin Yang, Guo-Bin Zhang.
Funding acquisition: Jian-Xin Zhou.
Investigation: Hua-Wei Huang, Li-Mei Yan.
Methodology: Yan-Lin Yang, Guo-Bin Zhang, Jian-Xin Zhou.
Supervision: Jian-Xin Zhou.
Writing ? original draft: Hua-Wei Huang, Li-Mei Yan.
Writing ? review & editing: Yan-Lin Yang, Xuan He, Xiu-Mei Sun, Yu-Mei Wang, Guo-Bin
Zhang, Jian-Xin Zhou.
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