Eur J Anaesthesiol 2020; 37:14–24

ORIGINAL ARTICLE

Incidence and risk factors of postoperative delirium

in patients admitted to the ICU after elective
intracranial surgery
A prospective cohort study
Chun-Mei Wang, Hua-Wei Huang, Yu-Mei Wang, Xuan He, Xiu-Mei Sun, Yi-Min Zhou,
Guo-Bin Zhang, Hong-Qiu Gu and Jian-Xin Zhou
Downloaded from http://journals.lww.com/ejanaesthesiology by BhDMf5ePHKbH4TTImqenVJsWiCZ2rfmUZdOIL51rhpEpOOzu4v0FAoPQyjh4TYqR on 01/22/2020

BACKGROUND Postoperative delirium (POD) has been
confirmed as an important complication after major surgery.
However, neurosurgical patients have usually been excluded
in previous studies. To date, data on POD and risk factors in
patients after intracranial surgery are scarce.
OBJECTIVES To determine the incidence and risk factors of
POD in patients after intracranial surgery.
DESIGN Prospective cohort study.
SETTING A neurosurgical ICU of a university-affiliated hos-
pital, Beijing, China.
INTERVENTIONS Adult patients admitted to the ICU after
elective intracranial surgery under general anaesthesia were
consecutively enrolled between 1 March 2017 and 2 February
2018. Delirium was assessed using the Confusion Assess-
ment Method for the ICU. POD was diagnosed as Confusion
Assessment Method for the ICU positive on either postopera-
tive day 1 or day 3. Patients were classified into groups with or
without POD. Data were collected for univariate and multivari-
ate analyses to determine the risk factors for POD.
RESULTS A total of 800 patients were included. POD was
diagnosed in 157 patients (19.6%, 95% confidence interval
16.9 to 22.4%). Independent risk factors for POD included
age, nature of intracranial lesion, frontal approach craniotomy,
duration of surgery, presence of an episode of low pulse
oxygenation at ICU admission, presence of inadequate
emergence and emergence delirium, postoperative pain
and presence of immobilising events. POD was associated
with adverse outcomes and high costs.
CONCLUSION POD is prevalent in patients after elective
intracranial surgery. The identified risk factors for and the
potential association of POD with adverse outcomes sug-
gest that a comprehensive strategy involving screening for
predisposing factors and early prevention of modifiable
factors should be established in this population.
TRIAL REGISTRATION ClinicalTrials.gov NCT03087838.
Published online 28 August 2019

Introduction
Delirium is an important postoperative complication
which occurs in 11 to 51% of patients after major surgery.1
Recently, the Nomenclature Consensus Working Group
recommended that postoperative delirium (POD) is
included in peri-operative neurocognitive disorders.2
Investigations have shown that POD is associated with
greater lengths of ICU and hospital stays, mortality,
healthcare costs and worsened quality of life.3–5 In an
observational multicentre study, van den Boogaard et al.6
found that the admission category of neurosurgery was an
independent risk factor for the development of ICU
delirium. However, in the majority of clinical trials
investigating POD, neurosurgical patients were usually
excluded.3,7–11 To date, only a small number of POD

From the Department of Critical Care Medicine (C-MW, H-WH, Y-MW, XH, X-MS, Y-MZ, J-XZ), Department of Neurosurgery (G-BZ) and Clinical Trial and Research Center,
Beijing Tiantan Hospital, Capital Medical University, Beijing, China (H-QG)
Correspondence to Jian-Xin Zhou, Department of Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University, No 6, Tiantan Xili, Dongcheng District,
Beijing 100050, China
Tel: +86 10 67098019; fax: +86 10 67098019; e-mail: zhoujx.cn@icloud.com

0265-0215 Copyright ß 2019 European Society of Anaesthesiology. All rights reserved. DOI:10.1097/EJA.0000000000001074

Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.


studies have included patients who have undergone
intracranial surgery and these studies have been hindered
by the methodological limitations of retrospective design
and small sample size.12–17 In brain injured patients,
although the attribution of altered consciousness entirely
to delirium might be erroneous without thoroughly con-
sidering the primary brain injury, the delirium in this
patient population might be a manifestation of secondary
brain injury superimposed on the major neurological
deficits of the primary injury.18
The causes of delirium are multifactorial. Several inde-
pendent risk factors for POD have been identified,
mainly including advanced age, comorbidities, the dura-
tion of surgery, intra-operative bleeding, postoperative
pain and delayed extubation.19 These factors also exist in
neurosurgical patients. In addition, a large proportion of
patients after craniotomy are admitted to the ICU for
postoperative care.20 Therefore, risk factors for ICU
delirium, such as mechanical ventilation, sedation, anal-
gesia and ICU environment,21 may further increase the
risk of POD in neurosurgical patients admitted to the
ICU. Moreover, the underlying brain lesions and intra-
cranial manipulations are assumed to influence postoper-
ative cognition.22 In light of the potential adverse
consequences of delirium in neurosurgical patients, fur-
ther study is needed to explore the incidence and risk
factors of POD in this population.
In this prospective cohort study, delirium was assessed in
adult patients admitted to the ICU after elective intra-
cranial surgery under general anaesthesia. We aimed to
determine the incidence and risk factors of POD in this
population. In accordance with our previous finding that
a high incidence of emergence agitation occurred in
patients after elective intracranial surgery,22 we
hypothesised that these patients were at a high risk of
developing POD. In addition, identifying disease-spe-
cific and modifiable risk factors could help to facilitate
the early detection and prevention of POD after
intracranial surgery.
Patients and methods
The study was approved by the Institutional Review
Board of Beijing Tiantan Hospital, Capital Medical
University, Beijing, China (KY2017-018-02). The study
was registered at ClinicalTrials.gov (NCT03087838).
Written informed consent was obtained from the patients
or their predefined healthcare decision makers. The study
protocol is shown in Supplemental Digital Content 1,
http://links.lww.com/EJA/A217.
This prospective cohort study was conducted in a 30-bed
neurosurgical ICU in Beijing Tiantan Hospital, Capital
Medical University, Beijing, China. The ICU is managed
by full-time ICU physicians with a 24-h/7-day on-duty rota,
and the nurse-to-bed ratio is 3 : 1. During the study, the
routine clinical practices of anaesthesia and postoperative
Eur J Anaesthesiol 2020; 37:14–24
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
Postoperative delirium in patients after intracranial surgery 15
care were followed, and no attempts were made to change or
influence the routine clinical management.22–24
In our institute, all intracranial operations are performed
under general balanced anaesthesia or total intravenous
anaesthesia. Bispectral index (BIS) is monitored and
anaesthesia is routinely titrated to main the BIS value
between 30 and 50. In our practice, we do not use awake
neurosurgery. Nevertheless, regarding intra-operative
neurofunctional brain assessment, multimodal neuro-
physiological monitoring is performed following recent
international recommendations.25 Anaesthesia is typi-
cally induced with intravenous propofol and sufentanil
or remifentanil. Tracheal intubation is facilitated by
intravenous rocuronium or cisatracurium. Anaesthesia
is maintained with propofol and/or sevoflurane or isoflur-
ane. Sufentanil, remifentanil or fentanyl are administered
intermittently or continuously, as needed. Muscle relax-
ants are administered according to train-of-four monitor-
ing. The choice of agents is at the discretion of
the anaesthesiologist.
Neurosurgeons decide the administration of osmotherapy
based on the patient’s brain tissue relaxation. The
patients receive either 20% mannitol or 3% NaCl in
5 ml kg1 doses over 15 min. Brain tissue relaxation is
assessed using a four-point scale reported previously.26
Intra-operative hypotension is defined as SBP below
95 mmHg, or in the case of a baseline SBP below
119 mmHg, a decrease of SBP by more than 20% of
baseline value. If hypotension is considered to be due
to hypovolaemia, 250 ml of 0.9% NaCl is infused intra-
venously over 15 min as a fluid challenge. If hypotension
persists for more than 10 min, a continuous infusion of
noradrenaline is initiated at a dose of 0.05 mg kg1 min1.
Then the dose of noradrenaline is adjusted to maintain
blood pressure (BP) within the target range.
For adult patients scheduled for elective surgery, the
anaesthesiologist and the neurosurgeon discuss postop-
erative ICU admission using criteria including, but not
limited to, an age over 65 years, an American Society of
Anesthesiologists’ physical status of at least three, the
presence of a large tumour or a lesion located in the brain
stem, a pre-operative midline shift, pre-operative con-
sciousness impairments, an anticipated prolonged proce-
dure and an anticipated delayed extubation. At the end of
surgery, the anaesthesiologist and the neurosurgeon also
discuss whether the patient may have reasons for
unplanned ICU admission, mainly including unantici-
pated delayed extubation, major intra-operative haemor-
rhage or brain swelling, injury to cranial nerve IX, X or
XII, or severe cardiorespiratory instability during the
attempt of emergence.
Patients admitted to the ICU are transferred directly to
the ICU. Although it is routine practice for many hospi-
tals to admit all patients after elective intracranial opera-
tions to the ICU, some researchers have recommended
 16 Wang et al.
that only high-risk patients should receive ICU-specific
monitoring and treatment.27 We adopt this selective ICU
admission strategy in our institution. Approximately one-
third of the patients who have undergone elective crani-
otomy are admitted to the ICU for postoperative care.
In the ICU, cardiorespiratory monitoring includes con-
tinuous electrocardiography, pulse oximetry and nonin-
vasive BP. An arterial blood sample is obtained to
perform blood gas assessment and to measure serum
concentrations of sodium, potassium, creatinine and albu-
min, as well as blood glucose and haematocrit. Neurolog-
ical examinations including the use of the Glasgow Coma
Score (GCS), pupillary examinations and evaluation of
focal signs are performed by nurses, hourly or as needed.
The Richmond Agitation-Sedation Scale (RASS) is eval-
uated by nurses every 4 h or as needed.
Most patients receive patient-controlled intravenous
analgesia (PCIA), which is composed of sufentanil
100 mg and tropisetron 10 mg in 100 ml of 0.9% NaCl
solution. A basal PCIA infusion (2 ml h1) is started after
the confirmation of the patient’s cardiorespiratory stabil-
ity and recovery of consciousness. When patients com-
plain of pain, an intravenous bolus of fentanyl (25 mg) is
administered. In patients with agitation (RASS scores of
þ2 to þ4), both the nurse and the physician carefully
evaluate and exclude possible organic causes of agitation,
including pain, acute deterioration of cardiorespiratory
function, a new neurological event or hypoglycaemia. If
necessary, propofol or midazolam is used, and the level of
sedation is titrated until a RASS score from 2 to þ1 is
achieved. Physical restraint is often required in patients
with an intracranial drainage tube and/or agitation.
All extubated patients receive standard oxygen by a
simple face mask at a flow rate of 3 to 6 l min1. In
patients with delayed extubation, oxygen is delivered
via a T-tube. Mechanical ventilation is initiated when the
patient cannot maintain adequate spontaneous breathing
and/or the oxygen saturation (SpO2) is less than 90%. In
patients with delayed extubation, the ICU physician
evaluates the patient’s readiness for extubation by a
screening checklist after recovery from anaesthesia,
including assessments of consciousness, cardiorespiratory
status, muscle strength recovery, gag reflex and cough
function.22 When each item in the checklist is satisfied,
tracheal extubation is performed by registered ICU
nurses. A computed tomography scan is performed within
6 h after surgery.
Before the initiation of the current study, we did not
incorporate a delirium assessment in our routine postop-
erative care. No standard operating procedures for delir-
ium prevention were used in our ICU.
Patients are discharged from the ICU the morning after
they achieve a normal neurological, haemodynamic and
respiratory status.
Eur J Anaesthesiol 2020; 37:14–24
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Participants
Adult patients who underwent elective intracranial sur-
gery under general anaesthesia were consecutively
screened at ICU admission. Their hospital records were
evaluated, and the exclusion criteria were as follows: age
younger than 18 years; non-Chinese speaker; transsphe-
noidal surgery, cerebrospinal fluid shunt and drainage
surgery, and deep brain stimulation surgery; pre-opera-
tive coma (GCS  8); pre-operative mental retardation
due to Parkinson’s disease or dementia; history of psy-
chosis; pregnant or lactating; moribund condition with a
low likelihood of survival for more than 24 h; and ICU
admission after 20:00 h.
Delirium assessments were initiated after written
informed consent had been obtained. All patient enrol-
ments were fulfilled within 2 h after ICU admission.
Delirium was evaluated by the Confusion Assessment
Method for the ICU (CAM-ICU).28 The Chinese version
of the CAM-ICU has been validated in an ICU setting in
mainland China.29 The delirium assessment was per-
formed in two steps. The arousal level was first assessed
by RASS.30 If the patient was not responsive to verbal
stimuli (i.e. RASS score 4), the remaining delirium
assessment was aborted, and the patient was recorded as
comatose. When the RASS score was greater than or
equal to 3, delirium was evaluated using the CAM-
ICU. The CAM-ICU consists of four key features: acute
onset of a change in mental status or a fluctuating level of
consciousness, inattention, disorganised thinking and an
altered level of consciousness. The patient was diagnosed
as delirious if both the first and second features were
present, and either the third or fourth was present.
Delirious patients were classified into three motor sub-
types: hyperactive delirium, which was defined as con-
sistently positive RASS scores (þ1 to þ4); hypoactive
delirium, which was defined as consistently neutral or
negative RASS scores (3 to 0); or mixed delirium, which
was defined as altered RASS scores between positive and
neutral or negative at different time points.31
Before the initiation of the study, four researchers (Y-
MW, XH, X-MS and Y-MZ) were trained to perform the
delirium assessment. They were clinical research fellows
and not involved in the clinical care of the patients. An
expert from the Department of Psychiatry was invited to
provide the training. The training course consists of four
phases: group training: information about delirium, RASS
scores and the CAM-ICU were provided, and a video
demonstrating the detailed conduction of the CAM-ICU
assessment was presented; one-on-one instruction at the
bedside; practice: trainees evaluated patients on their
own every day for 1 week, during which time the trainees
were able to contact the expert regarding any issues that
occurred with the evaluations; examination: each trainee
evaluated five patients who had been preassessed by the
expert. Different results in the delirium assessments

between the trainee and the expert were discussed until
agreement was reached.
Screening, enrolment and patient grouping
Patients were screened at ICU admission by one of two
investigators (C-MW or H-WH). After confirming their
enrolment, one of the four trained researchers performed
the delirium assessment. During the study, delirium was
assessed in each patient at three time points: immediately
after enrolment; between 08:00 and 10:00 on postopera-
tive day 1 in the ICU; and between 08:00 and 10:00 on
postoperative day 3 in the ICU or in the neurosurgical
ward. Delirium assessments on postoperative day 2 were
omitted because of the research workload.
Patients who remained comatose (i.e. RASS score 4)
during the assessments on both postoperative day 1 and
day 3 were excluded. Patients who were unable to
communicate due to blindness, hearing loss or sensory
and mixed aphasia were also excluded.
The assessment performed immediately after enrolment
was used to diagnose emergence delirium, and the assess-
ments on postoperative day 1 and day 3 were used to
diagnose POD.32 The patients were assigned to the POD
group if delirium was diagnosed on postoperative day 1
and/or day 3, otherwise they were assigned to the non
POD group.
Immediately after POD assessment in each patient, the
level of pain and sleep quality were evaluated by
numerical rating scales (NRSs).33,34 Levels of environ-
mental noise and light were measured by a sound meter
(model GM1352, BENETECH, Shenzhen, China) and
a light detector (model GM1020, BENETECH, Shenz-
hen, China) that were positioned at the head of the
patient’s bed. The need for physical restraint was also
documented.
Patients were followed up until hospital discharge, death,
or 90 days after enrolment, whichever occurred first. Data
were collected using standard Case Report Forms.
Demographics and pre-operative data, anaesthesia-
related data, surgery-related data, data at the time of
ICU admission, data during the ICU stay before the POD
assessment on postoperative day 1, and follow-up data
were collected from the hospital records, anaesthesia
records, surgical records, ICU nursing records and hospi-
tal bills (details are shown in the Supplemental Digital
Content 1, http://links.lww.com/EJA/A217).
After completion of the study, we consulted the attend-
ing neurosurgeons and found that pre-operative cognition
assessment was performed only in patients with sus-
pected glioma using Mini-Mental State Examination or
Montreal Cognitive Assessment scales. We retrospec-
tively reviewed the hospital administration records of
enrolled patients and collected pre-operative cognition
assessments data.
Eur J Anaesthesiol 2020; 37:14–24
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Postoperative delirium in patients after intracranial surgery 17
Statistical analysis
According to standard recommendations, for a reliable fit,
10 cases of interest (POD) would be required for each
degree of freedom in the multivariate model.35 Given
that no study has been performed to investigate the
prevalence and risk factors of POD in patients after
intracranial surgery, we selected the low incidence of
POD (13%) reported in noncardiac postoperative
patients.19 With 10% compensation for possible missing
data, 800 cases would be sufficient to identify 10 risk
factors for POD in our cohort of patients.
Categorical variables are expressed as number (%). Con-
tinuous data were checked for normal distribution by the
Kolmogorov–Smirnov test and are reported as the
mean  SD or median [IQR]. The incidence of POD
and 95% confidence interval (CI) were calculated. Uni-
variate analyses between the POD and the non POD
group were performed. Categorical variables were ana-
lysed by the Pearson x2 test or Fisher’s exact test for
variables with small numbers. A comparison of continu-
ous data was performed by the unpaired t test for nor-
mally distributed variables and the Mann–Whitney U
test for nonnormally distributed variables.
The presence of an endotracheal tube, a central venous
catheter and intracranial drainage at ICU admission, and
the use of physical restraint or sedatives for controlling
agitation during the POD assessments were defined as
immobility-related events, which are often interrelated
and sometimes causal in the analysis of risk factors for
POD.36 Therefore, we established a score that included
the above events and named it the immobilising factor
score. Each item represented 1 point. Specifically, a score
of 0 indicates the existence of none, and a score of 5
indicates the existence of all five items.
Interactions between a history of diabetes mellitus and
blood glucose concentration at ICU admission and
between the hourly amount of haemorrhage and blood
transfusion during surgery were analysed and classified as
categorical variables.
Factors with P values less than 0.05 in the univariate
analyses and categorical analyses were entered into the
multivariate analysis with a stepwise backward logistic
regression to identify independent risk factors for POD.
Odds ratios (ORs) and their 95% CIs were used to assess
the independent contributions of significant factors. The
Hosmer–Lemeshow test was used to determine the
appropriateness of the model.
Statistical analyses were performed using SPSS 20.0
(SPSS Inc., Chicago, Illinois, USA). A P value of less
than 0.05 was considered statistically significant.
Results
Between 1 March and 1 November 2017, 1382 patients
who were admitted to the ICU after elective intracranial
 18 Wang et al.

Fig. 1

1382 patients admitted to the neurosurgical ICU

after elective craniotomy and screened
567 patients excluded
224 aged younger than 18 years
15 non-Chinese speaker
186 transsphenoidal surgery
25 CSF shunt and/or drainage surgery
56 DBS surgery
15 preoperative coma
13 preoperative mental retardation
5 history of psychosis
10 pregnant and lactating
18 ICU a dmission after 20:00
Delirium assessment attempted in 815 patients

Delirium assessment fulfilled in 788 patients on postoperative day one

Delirium assessment fulfilled in 795 patients on postoperative day three

15 patients excluded after assessments

on both postoperative day 1 and day 3
4 remained comatose
9 sensory and mixed aphasia
2 hearing loss

800 patients included for analysis

157 patients with 643 patients without

postoperative delirium postoperative delirium

800 patients followed-up until

hospital discharge, death, or 90 days after enrolment

Patient flow chart. CSF, cerebrospinal fluid; DBS, deep brain stimulation.

surgery were screened, and 567 patients were excluded According to the retrospective data analysis, 115
(Fig. 1). A delirium assessment was attempted in 815 patients with glioma (14% of all enrolled patients)
patients, of whom 15 were excluded after enrolment underwent pre-operative cognition assessment, 67 of
because they remained comatose (n ¼ 4), had hearing whom (58%) presented with pre-operative cognition
loss (n ¼ 2) or had sensory and mixed aphasia (n ¼ 9)
during the POD assessment on both postoperative day
Fig. 2
1 and day 3. Thus, 800 patients were included in the final
analysis, and the study was completed on 2 February 2018 20 Coma
with a 90-day follow-up. Hypoactive delirium
Hyperactive delirium
POD was diagnosed in 157 patients (19.6%, 95% CI 15
Incidence (%)

16.9 to 22.4), of whom 97 (61.8%), 33 (21.0%) and

27 (17.2%) were classified as hypoactive, hyperactive
10
or mixed subtypes, respectively. Incidences of
delirium at the three assessment time points are shown
in Fig. 2. 5

Results of univariate analyses between potential risk

factors are shown in Tables 1–4. The immobilising factor 0
Immediately On postoperative On postoperative
scores in the POD group were significantly higher than after enrolment day one day three
those in the non POD group (3 [2 to 3] vs. 1 [0 to 2],
P < 0.001). As the immobilising factor score increased, Incidence of coma, hypoactive delirium and hyperactive delirium during
the proportion of POD cases increased significantly assessments at different time points.
(P < 0.001, Fig. 3).

Eur J Anaesthesiol 2020; 37:14–24

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 Postoperative delirium in patients after intracranial surgery 19

Table 1 Univariate analyses for demographics and pre-operative data

All patients, Postoperative delirium Postoperative nondelirium

Variables n U 800 group, n U 157 group, n U 643 P
Male sex 328 (41%) 77 (49%) 251 (39%) 0.022
Age (years) 48 [35 to 58] 56 [46 to 64] 45 [34 to 55] <0.001
Weight (kg) 65 [57 to 75] 66 [58 to 75] 65 [56 to 75] 0.25
Height (cm) 165 [160 to 172] 165 [159 to 172] 165 [160 to 172] 0.84
BMI (kg m2) 24.3  3.8 24.6  3.7 24.2  3.9 0.24
Education level <0.001
8 years 391 (49%) 110 (70%) 281 (44%)
>8 years 409 (51%) 47 (30%) 362 (56%)
History of smoking 189 (24%) 41 (26%) 148 (23%) 0.41
History of alcohol abuse 162 (20%) 36 (23%) 126 (20%) 0.35
History of hypertension 191 (24%) 51 (33%) 140 (22%) 0.005
History of coronary artery disease 33 (4.1%) 9 (5.7%) 24 (3.7%) 0.26
History of diabetes mellitus 50 (6.2%) 18 (12%) 32 (5.0%) 0.003
History of ischaemic stroke 40 (5.0%) 13 (8.3%) 27 (4.2%) 0.035
History of hydrocephalus 42 (5.2%) 9 (5.7%) 33 (5.1%) 0.69
History of ADDs and/or benzodiazepine 8 (1.0%) 3 (1.9%) 5 (0.8%) 0.19
History of antiepileptic 19 (2.4%) 3 (1.9%) 16 (2.5%) >0.99
History of intracranial surgery 49 (6.1%) 12 (7.6%) 37 (5.8%) 0.48
ASA physical status <0.001
1 128 (16%) 12 (7.6%) 116 (18%)
2 642 (80%) 129 (82%) 513 (80%)
3 28 (3.5%) 15 (9.6%) 13 (2.0%)
4 2 (0.2%) 1 (0.6%) 1 (0.2%)

Data are shown as n (%), median [IQR] or mean  SD. ADDs, antidepressant drugs.

abnormality. The incidence of POD in the patients with
pre-operative cognitive abnormalities was significantly
higher than in the patients without (71 vs. 42%,
P < 0.001). Due to missing data for the majority of
enrolled patients and the retrospective nature of data
Table 2 Univariate analyses for anaesthesia-related and intra-operative data
collection, we did not add this variable to the multivari-
ate risk factors analysis.
The variables with P values less than 0.05 in the univariate
analyses (Tables 1–4) were used to build the multivariate

All patients, Postoperative delirium Postoperative nondelirium

Variables n U 800 group, n U 157 group, n U 643 P
Use of midazolam as premedicationa 793 (99.1%) 155 (98.7%) 638 (99.2%) 0.63
TIVA 186 (23%) 33 (21%) 153 (24%) 0.46
Duration of surgery (min) 261 [196 to 332] 295 [236 to 373] 253 [190 to 323] <0.001
Use of dexmedetomidine 110 (14%) 20 (13%) 90 (14%) 0.68
Use of only fentanyl for analgesia 47 (5.8%) 7 (4.5%) 40 (6.2%) 0.46
Use of anticholinergic 652 (82%) 122 (78%) 530 (82%) 0.17
Amount of bleeding per hour (ml) 62 [43 to 100] 79 [56 to 130] 59 [40 to 94] <0.001
Blood transfusion during operation 196 (25%) 57 (36%) 139 (22%) 0.001
Intra-operative bleeding and blood transfusion <0.001
Minor bleeding 396 (50%) 53 (34%) 343 (53%)
Major bleeding without transfusion 216 (27%) 50 (32%) 166 (26%)
Major bleeding with transfusion 188 (23%) 54 (34%) 134 (21%)
Fluid balance per hour (ml) 296 [191 to 418] 296 [204 to 423] 297 [190 to 415] 0.75
Episode of hypotension 128 (16%) 47 (30%) 81 (13%) <0.001
Surgical position <0.001
Supine 445 (56%) 109 (69%) 336 (52%)
Lateral 355 (44%) 48 (31%) 307 (48%)
Nature of the intracranial lesion <0.001
Benign tumour 500 (63%) 62 (40%) 438 (68%)
Malignant tumourb 180 (22%) 63 (40%) 117 (18%)
Cerebrovascular diseases 120 (15%) 32 (20%) 88 (14%)
Frontal approach craniotomy 271 (34%) 87 (55%) 184 (29%) <0.001
Location of the lesion <0.001
Frontal 154 (19%) 48 (31%) 106 (17%)
Limbic system 22 (2.8%) 13 (8.3%) 9 (1.4%)
Dominant hemisphere 174 (22%) 57 (36%) 117 (18%)
Multifocal 118 (15%) 39 (25%) 79 (12%)
Any of above 279 (35%) 88 (56%) 191 (30%)

Data are shown as n (%) or median [IQR]. TIVA, total intravenous anaesthesia. a Data were collected retrospectively. b In 180 patients with maligant tumours, there were
115 gliomas, 23 anaplastic meningiomas, 5 lymphomas, 8 chordomas, 5 medatloblastomas, 3 central neurocytomas, 14 brain metastatic tumours and 7 ependymomas.

Eur J Anaesthesiol 2020; 37:14–24

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 20 Wang et al.

Table 3 Univariate analyses for data collected at ICU admission

All patients, Postoperative delirium Postoperative non delirium

Variables n U 800 group, n U 157 group, n U 643 P
GCS score 14 [6 to 14] 6 [3 to 14] 14 [10 to 14] <0.001
Temperature (8C) 36.4 [36 to 36.7] 36.5 [36 to 36.8] 36.4 [36 to 36.6] 0.66
Episode of SpO2 < 90% 10 (1.2%) 5 (3.2%) 5 (0.8%) 0.015
Blood glucose (mmol l1) 7.6 [6.2 to 9.3] 7.5 [6.1 to 8.9] 7.6 [6.3 to 9.3] 0.30
Episode of hyperglycaemia 140 (18%) 50 (32%) 90 (14%) <0.001
History of DM and BG at ICU admission <0.001
BG < 10 mmol l1 660 (82%) 107 (68%) 553 (86%)
BG  10 mmol l1 with DM history 30 (3.8%) 14 (8.9%) 16 (2.5%)
BG  10 mmol l1 without DM history 110 (14%) 36 (23%) 74 (11%)
Haematocrit (%) 37  5 37  5 37  5 0.61
Inadequate emergence and emergence delirium <0.001
None 591 (74%) 34 (22%) 557 (87%)
Inadequate emergence 47 (5.9%) 29 (18%) 18 (2.8%)
Hyperactive delirium 29 (3.6%) 17 (11%) 12 (1.9%)
Hypoactive delirium 133 (16%) 77 (49%) 56 (8.7%)

Data are shown as n (%), median [IQR] or mean  SD. BG, blood glucose; DM, diabetes mellitus; GCS, Glasgow Coma Scale; SpO2, pulse oxygen saturation

logistic regression model. The results of the multivariate
analysis are shown in Table 5. Independent risk factors
included the following: age, nature of the intracranial
lesion, frontal approach craniotomy, duration of surgery,
an episode of SpO2 below 90% at ICU admission, inade-
quate emergence and the presence of emergence delirium,
pain NRS and the immobilising factor score. The results of
the Hosmer–Lemeshow test showed that the model fitted
the data adequately well (P ¼ 0.843).
Compared with the non POD group, a lower incidence of
being discharged from the ICU on postoperative day 1,
higher incidence of accidental removal of tubes or cathe-
ters and unplanned re-operation within 72 h, longer post-
operative length of stay in the hospital, higher hospital
mortality and higher costs were found in patients with
POD (Table 6).
Discussion
In the current study, our main finding was that POD
occurred in approximately one fifth of adult patients
admitted to the ICU after elective intracranial surgery.
A number of risk factors previously reported in postoper-
ative patients were confirmed in our cohort, including
age, duration of surgery, an episode of hypoxaemia,

Table 4 Univariate analyses for data collected before and during postoperative delirium assessment

All patients, Postoperative delirium Postoperative nondelirium

Variables n U 800 group, n U 157 group, n U 643 P
Need for mechanical ventilation 18 (2.2%) 8 (5.1%) 10 (1.6%) 0.007
Use of PCIA 329 (41%) 45 (29%) 284 (44%) <0.001
Use of mannitol 652 (82%) 121 (77%) 531 (83%) 0.136
Use of nimodipine 186 (23%) 52 (33%) 134 (21%) 0.002
Use of steroid 583 (73%) 104 (66%) 479 (75%) 0.037
Prophylactic use of antiepileptic 490 (61%) 116 (74%) 374 (58%) <0.001
Presence of epilepsy 7 (0.9%) 3 (1.9%) 4 (0.6%) 0.14
Use of analgesics beside PCIA 29 (3.6%) 5 (3.2%) 24 (3.7%) >0.99
Fentanyl 14 (1.8%) 5 (3.2%) 9 (1.4%)
Flurbiprofen axetil 16 (2.0%) 0 16 (2.5%)
Serum sodium (mmol l1) 139 [137 to 141] 140 [138 to 142] 139 [137 to 141] 0.061
Serum potassium (mmol l1) 3.9 [3.6 to 4.1] 3.8 [3.5 to 4.1] 3.9 [3.6 to 4.1] 0.23
Serum creatinine (mmol l1) 57.8 [49.9 to 67.8] 61.2 [49.2 to 70.4] 57.3 [50.2 to 66.7] 0.063
Serum albumin (g l1) 35.9 [33.7 to 38.4] 35.9 [32 to 37.4] 35.9 [33.9 to 38.7] <0.001
Fluid balance (ml) 42  469 19  534 48  452 0.54
First postoperative CT scan <0.001
Haematoma 20 (2.5%) 10 (6.4%) 10 (1.6%)
Ischaemia 37 (4.6%) 18 (12%) 19 (3.0%)
Midline shift 96 (12%) 41 (26%) 55 (8.6%)
Bi-frontal pneumocephalus 277 (35%) 75 (48%) 202 (31%)
Any of above abnormalities 358 (45%) 105 (67%) 253 (40%)
Light (lux) 319 [266 to 381] 320 [279 to 378] 318 [262 to 383] 0.51
Noise (dB) 57  3 57  3 57  3 0.21
NRS for pain assessment 2 [1 to 3] 3 [2 to 4] 2 [1 to 3] <0.001
NRS for sleep quality assessment 2 [1 to 3] 1 [0 to 4] 2 [1 to 3] 0.53

Data are shown as n (%), median [IQR] or mean  SD. CT, computed tomography; NRS, numerical rating scale; PCIA, patient-controlled intravenous analgesia.

Eur J Anaesthesiol 2020; 37:14–24

Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
 Postoperative delirium in patients after intracranial surgery 21

Fig. 3 lesion and a frontal approach craniotomy. The high inci-

dence of, the identified risk factors for and the potential
association of POD with adverse outcomes suggest that a
comprehensive strategy involving screening for predis-
100 posing factors and early prevention of modifiable factors
Incidence of postoperative

should be established in this population to minimise the

80 incidence of delirium.
delirium (%)

60 The previously reported incidence of POD after major

surgery varies widely (11 to 51%).1 The incidence of
40 POD in our cohort (19.6%) was comparable with the
results reported in an observational study (16%) and in
20 the control group of a randomised controlled trial (23%) of
postoperative patients admitted to the ICU, in which
0
neurosurgical patients were excluded.3,9 To date, only six
0 1 2 3 4 5 observational studies have investigated the occurrence of
Immobilising factor score POD in patients after intracranial surgery, with a total
Number of patients 227 178 180 166 43 6 sample size of 1240.12–17 The mean (95% CI) incidence
Postoperative delirium 6 29 40 53 23 6
of POD in these studies was 15.5 (13.5 to 17.5) % with a
range from 6.8 to 42.6%. These data, along with our
Incidence of postoperative delirium at different immobilising factor
scores. Values are mean. Bars indicate 95% confidence intervals. results, suggest that although intracranial surgery may
be a predisposing factor for delirium that cannot be
avoided, the impact of this on predictive models of
POD after intracranial surgery is an important issue.
postoperative pain, the presence of immobilising factors,
and the presence of inadequate emergence and emer- We selected postoperative days 1 and 3 as the POD
gence delirium. We also identified two intracranial sur- assessment time points to avoid the influence of inade-
gery-related risk factors: the nature of the intracranial quate recovery from general anaesthesia and emergence

Table 5 Independent risk factors for postoperative delirium

Variables Crude odds ratio (95% CI) Odds ratio (95% CI) P
Age (years) 1.05 (1.03 to 1.06) 1.04 (1.02 to 1.06) <0.001
Nature of the intracranial lesion
Benign tumour 1 (reference) 1 (reference) <0.001
Malignant tumour 3.80 (2.54 to 5.71) 2.82 (1.52 to 4.88) <0.001
Cerebrovascular diseases 2.57 (1.58 to 4.17) 3.20 (1.57 to 6.53) 0.001
Frontal approach craniotomy 3.10 (2.17 to 4.44) 3.01 (1.79 to 5.05) <0.001
Duration of surgery (min) 1.00 (1.00 to 1.01) 1.00 (1.00 to 1.01) 0.016
Episode of SpO2 < 90% at ICU admission 4.20 (1.20 to 14.68) 8.22 (1.38 to 48.92) 0.021
Inadequate emergence and emergence delirium
None 1 (reference) 1 (reference) <0.001
Inadequate emergence 26.39 (13.34 to 52.23) 11.15 (4.80 to 25.88) <0.001
Hyperactive delirium 23.21 (10.26 to 52.49) 14.60 (5.40 to 39.45) <0.001
Hypoactive delirium 22.53 (13.83 to 36.70) 11.64 (6.75 to 20.10) <0.001
NRS for pain assessment 1.36 (1.23 to 1.51) 1.19 (1.02 to 1.38) 0.028
Immobilising factor score 2.12 (1.81 to 2.48) 1.64 (1.30 to 2.08) <0.001

NRS, numerical rating scale; SpO2, pulse oxygenation saturation.

Table 6 Outcome data

All patients, Postoperative delirium Postoperative nondelirium

Variables n U 800 group, n U 157 group, n U 643 P
ICU discharge on postoperative day 1 728 (91%) 121 (77%) 607 (94%) <0.001
Accidental removal of tubes and catheters 10 (1.2%) 7 (4.5%) 3 (0.5%) <0.001
Tracheal tube 7 (0.9%) 5 (3.2%) 2 (0.3%) 0.004
Central venous catheter 3 (0.4%) 2 (1.3%) 1 (0.2%) 0.10
Unplanned re-operation within 72 h 3 (0.4%) 3 (1.9%) 0 0.007
Unplanned ICU readmission within 7 days 6 (0.8%) 3 (1.9%) 3 (0.5%) 0.094
Hospital mortality 11 (1.4%) 7 (4.5%) 4 (0.6%) 0.002
Postoperative length of hospital stay (days) 10 [8 to 14] 14 [11 to 20] 9 [8 to 13] <0.001
Hospital costs, Chinese Yuan/10 000 4.9 [4.1 to 6.7] 7.1 [5.4 to 10.4] 4.6 [4.0 to 5.9] <0.001

Data are shown as n (%) or median [IQR].

Eur J Anaesthesiol 2020; 37:14–24

Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
 22 Wang et al.
delirium.32 In accordance with previous studies,9,37 we
also found that although the prevalence of POD
decreased over time, there was a substantial number of
patients (10.4%) who exhibited delirium on postoperative
day 3 (Fig. 2). Our data suggest that comprehensive
management of delirium, including screening vulnerable
patients, avoiding modifiable precipitating risk factors
and initiating prevention should be conducted early
and sustained until at least postoperative day 3.
Although the CAM-ICU has been recommended as a
delirium monitoring tool in adult postoperative patients
and ICU patients,19,21 to date there has been no study
specifically verifying its use in patients after intracranial
surgery. However, studies have shown that the CAM-
ICU is assessable in brain-injured patients, mainly in
those with stroke and traumatic brain injury.38–40 Taken
together, the strong and reproducible data on the validity
and reliability of the CAM-ICU in critically ill patients
and brain-injured patients lend support to the practice of
POD screening in patients admitted to the ICU after
intracranial surgery.
In the current study, we confirmed several independent
risk factors previously reported in nonneurosurgical
patients, including age, the duration of surgery, pain
and episodes of hypoxaemia.1,19 Meanwhile, in the uni-
variate analysis, we essentially found that the presence of
immobility-related events was significantly higher in the
POD group than in the non-POD group. It has been
considered that physical and chemical restraint predis-
pose patients to a greater risk of delirium.36 Obviously,
there were complex interactions among these events in
terms of the risk of POD. Therefore, we combined the
occurrence of these events into an immobilising factor
score for POD risk stratification. Unsurprisingly, our data
showed that the higher the score, the higher the risk of
occurrence of POD (Fig. 3). The immobilising factor
score was also an independent risk factor for POD in the
multivariate analysis, with a 64% increase in the OR for
POD with each one unit increase in the score (Table 5).
Our results suggest that further investigation aimed at
establishing a comprehensive POD prevention strategy,
including pharmacological and nonpharmacological pro-
tocols, is necessary in immobilised patients.
Emergence delirium, which occurred immediately after
general anaesthesia and usually resolved within several
hours, predicted POD in patients after major surgery.41
We confirmed this result in our cohort of patients who
underwent elective intracranial surgery. In our institu-
tion, patients who were admitted to the ICU were trans-
ferred directly from the operating room after intracranial
surgery. All the included patients were enrolled within
2 h after ICU admission. Thus, the first delirium assess-
ment in each patient was conducted within several hours
after surgery, which was defined as the time window for
the diagnosis of emergence delirium. Inadequate
32
Eur J Anaesthesiol 2020; 37:14–24
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
emergence and emergence delirium occurred in 5.9
and 20% of patients, respectively, which were within
the previously reported range.41 Of the 157 patients with
POD, 94 (60%) patients had preceding emergence delir-
ium. Compared with adequate recovery from anaesthesia,
inadequate emergence and emergence delirium
increased the OR for POD by approximately 11-fold to
15-fold (Table 5). Our data suggest that recognising
inadequate emergence and emergence delirium may
be important for identifying patients at high risk of
developing POD in the very early stage after surgery.
For these patients, the standard of care may need to
incorporate a reliable delirium screening and prevention
strategy. An ongoing retrospective study42 may provide
more information about emergence delirium and POD.
Two intracranial surgery-related risk factors were identi-
fied in our cohort: the nature of the intracranial lesion and a
frontal approach craniotomy. Compared with patients with
benign tumours, the ORs for POD were increased by
approximately three-fold in patients with malignant brain
tumours or cerebrovascular disease (Table 5). The concept
of ‘lesion momentum’ of neurocognitive function43 may
explain the high risk of POD in patients with malignant
brain tumours. Malignant brain tumours usually grow
faster than benign tumours and may allow less neuroplas-
ticity for nearby brain structures to reorganise, in other
words, these tumours have a higher ‘lesion momentum’.
Recent studies have shown that, compared with patients
with lower grade tumours, patients with higher grade
gliomas exhibit more severely impaired neurocognitive
function.44 However, an unambiguous conclusion in terms
of the effects of the nature of the tumour on POD needs
further investigation. Cognitive function may also be
affected by disruption of the blood–brain barrier which
may partly explain the increased risk of POD in patients
with cerebrovascular disease in the current study.45 Like-
wise, further investigation is needed to evaluate this.
In accordance with our previous study on risk factors for
emergence agitation after craniotomy,22 we also found that a
frontal approach craniotomy was an independent risk factor
for POD. Because the executive function of the frontal
lobes involves cognitive and emotional behaviours, damage
during a frontal approach for intracranial surgery may result
in abnormal behaviours.46 In addition, previous studies have
shown an association of neurotransmitter pathway targeting
the basal forebrain with altered states of consciousness.47
Furthermore, it has been demonstrated that there is a
relationship between the volume of grey matter at the
prefrontal area and the susceptibility of patients to hypnotic
agents.48 Our results suggest that patients undergoing intra-
cranial surgery via a frontal approach should be given more
attention in screening and prevention for POD.
Limitations
First, we only enrolled patients admitted to the ICU,
which may represent a population at high risk of POD.

Thus, our results may be limited for generalising to the
entire population of patients undergoing intracranial sur-
gery. Second, we did not evaluate neurocognitive func-
tion pre-operatively because it could not be determined
in advance which patients would be admitted to the ICU
after surgery. Pre-operative neurocognitive impairment,
which is an important predisposing factor for POD,1 is
common in patients with malignant glioma.44,49 There-
fore, we cannot rule out a potential bias introduced by
these missing data.
Third, we only investigated the relationship between the
intra-operative use of anaesthetics/analgesics and POD.
However, recent studies have shown that intra-operative
drug–brain interactions with disruption of some neuro-
transmitter pathways involved with altered consciousness
might be an important pathogenesis of POD.50 The
association of intra-operative electroencephalogram sig-
natures with postoperative delirium warrants further
research in future. Fourth, before the initiation of the
current study, we did not incorporate a delirium assess-
ment in our routine postoperative care, and no standar-
dised strategy was used for the comprehensive
prevention of delirium in our ICU. Although neurosurgi-
cal patients may present particular challenges in the
assessment and management of delirium,51 our data again
suggest that delirium assessment is assessable in this
population.33
Conclusion
In conclusion, we found a high incidence of POD in
patients admitted to the ICU after elective intracranial
surgery. Several previously reported risk factors were
confirmed in our cohort. In addition, patients with malig-
nant brain tumours and cerebrovascular disease, and
those undergoing surgery via a frontal approach, were
at higher risk of developing POD. Our data suggest that a
comprehensive strategy involving screening for predis-
posing factors and early prevention of modifiable factors
should be established in this population, and further
study is needed to validate this strategy.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: J-XZ has received a grant
(DFL20150502) from Beijing Municipal Administration of
Hospitals.
Conflicts of interest: none.
Presentation: preliminary data for this study were presented as a
poster presentation at the European Society of Intensive Care
Medicine, 20 to 24 October 2018, Paris.
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