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Surgical Neurology International

Editor-in-Chief: Nancy E. Epstein, MD, Clinical Professor of Neurological Surgery, School of
Medicine, State U. of NY at Stony Brook.
SNI: Trauma Editor
 Roy Daniel
 Lausanne University Hospital, Lausanne, Switzerland
Open Access

Review Article

Initial neurocritical care of severe traumatic brain

injury: New paradigms and old challenges
Seif Tarek El-Swaify1 , Menna Kamel2, Sara Hassan Ali2 , Bassem Bahaa3 , Mazen Ahmed Refaat3 , Abdelrahman Amir2,
Abdelrahman Abdelrazek2, Pavly Wagih Beshay2 , Ahmed Kamel Mohamed Moner Basha4
Department of Neurosurgery, Faculty of Medicine, Ain Shams University, 2School of Medicine, Faculty of Medicine, Ain Shams University, 3Faculty of
1

Medicine, Ain Shams University, 4 Department of Neurosurgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
E-mail: Seif Tarek El-Swaify - emp14.seif.t.elswaify@gmail.com; Menna Kamel - emp14060@med.asu.edu.eg;
Sara Hassan Ali - emp14108@med.asu.edu.eg; Bassem Bahaa - bassembbb@gmail.com; Mazen Ahmed Refaat - emp14.mazen.a.ibrahim@gmail.com;
Abdelrahman Amir - emp14.abdelrahman.amir.abu3la@gmail.com; Abdelrahman Abdelrazek - emp14.abdelrahman.e.abdelrazek@gmail.com;
Pavly Wagih Beshay - emp14123@med.asu.edu.eg; *Ahmed Kamel Mohamed Moner Basha - ahmedbasha@med.asu.edu.eg

ABSTRACT
Background: Early neurocritical care aims to ameliorate secondary traumatic brain injury (TBI) and
improve neural salvage. Increased engagement of neurosurgeons in neurocritical care is warranted as daily
briefings between the intensivist and the neurosurgeon are considered a quality indicator for TBI care. Hence,
neurosurgeons should be aware of the latest evidence in the neurocritical care of severe TBI (sTBI).
*Corresponding author: Methods: We conducted a narrative literature review of bibliographic databases (PubMed and Scopus) to examine
Ahmed Kamel Mohamed recent research of sTBI.
Moner Basha,
Results: This review has several take-away messages. The concept of critical neuroworsening and its possible
Department of Neurosurgery,
causes is discussed. Static thresholds of intracranial pressure (ICP) and cerebral perfusion pressure may not be
Faculty of Medicine, Ain Shams
optimal for all patients. The use of dynamic cerebrovascular reactivity indices such as the pressure reactivity index
University, Cairo, Egypt. can facilitate individualized treatment decisions. The use of ICP monitoring to tailor treatment of intracranial
ahmedbasha@med.asu.edu.eg hypertension (IHT) is not routinely feasible. Different guidelines have been formulated for different scenarios.
Accordingly, we propose an integrated algorithm for ICP management in sTBI patients in different resource
settings. Although hyperosmolar therapy and decompressive craniectomy are standard treatments for IHT, there
Received : 08 July 2022 is a lack high-quality evidence on how to use them. A discussion of the advantages and disadvantages of invasive
Accepted : 29 August 2022 ICP monitoring is included in the study. Addition of beta-blocker, anti-seizure, and anticoagulant medications to
Published : 23 September 2022 standardized management protocols (SMPs) should be considered with careful patient selection.

DOI Conclusion: Despite consolidated research efforts in the refinement of SMPs, there are still many unanswered
10.25259/SNI_609_2022 questions and novel research opportunities for sTBI care.

Keywords: Intracranial hypertension, Intracranial pressure monitoring, Neurocritical care, Neurotrauma,

Quick Response Code:
Thromboembolism prophylaxis, Traumatic brain injury

INTRODUCTION
Every 21 seconds, a traumatic brain injury (TBI) occurs in the USA.[93] Low- and middle-income
countries (LMICs) are disproportionately affected; disparities in the delivery of neurosurgical

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Surgical Neurology International • 2022 • 13(431) | 1

 El-Swaify, et al. Initial neurocritical care for severe TBI

care in LMICs result in a 2- to 3-fold increase in mortality

Table 1: Definition and etiology of critical neuroworsening.
rates after severe TBI (sTBI).[23] The limitations of the
Glasgow Coma Scale (GCS), which has been the standard Definition • Any of the following:
measure for TBI classification, have driven clinicians to • Spontaneous decrease in GCS motor score ≥1 point
develop more comprehensive classification systems.[39,94] • New decrease in pupillary reactivity
• New pupillary asymmetry ≥2 mm/bilateral mydriasis
Regardless of the classification used, for many patients, TBI
• New focal motor deficit
extends beyond being an acute event and evolves into a
• Herniation syndrome (e.g., Cushing’s triad)
chronic disability that has long-term consequences.[46,102] Any Etiology • Neurological
TBI initiates a heterogeneous cascade of pathophysiological • Elevated ICP
events that lead to a potentially preventable secondary injury • Expanding intracranial lesion
following the irreversible primary injury.[72] The central • Cerebral edema
dogma of TBI management is to target the secondary injury • Seizures or postictal state
affecting susceptible neural tissue.[35] • Stroke
• CNS infection
With the majority of sTBI patients being admitted to trauma, • Systemic
general, and surgical intensive care units (ICUs), standardized • Hypotension
management protocols (SMPs) for sTBI may improve clinical • Hypoxemia
outcomes regardless of where patients are admitted.[6,68] • Hyper or hypothermia
The observed lower mortality and improved neurological • Dehydration
outcomes in dedicated neurocritical care units are possibly • Infection or sepsis
attributed to greater adherence to SMPs and differences in • Impaired renal function
use and interpretation of neuromonitoring data.[51] Increased • Impaired hepatic function
engagement of neurosurgeons is warranted as neurocritical • Other medical comorbidities
• Metabolic
care should not be limited to neurointensivists. In fact, a
• Electrolyte disturbance
daily briefing between the intensivist and the neurosurgeon (e.g., hyponatremia, hypernatremia, etc.)
is considered a clinical quality indicator for TBI care.[44] • Hypoglycemia
Consequently, all neurosurgeons should be minded with the • Miscellaneous
broad lines of TBI neurocritical care and its recent advances. • Drug induced
Neurotrauma is a rapidly evolving field. Knowledge of the • Substance withdrawal
latest evidence may not directly change treatment decisions, CNS: Central nervous system, GCS: Glasgow Coma Scale,
ICP: Intracranial pressure
but it will definitely guide future research initiatives. We are
writing this review to highlight some recent advances and
ongoing challenges in the early neurocritical care of sTBI benefit ratio is unclear, physicians should refer to decision-
since the publication of the 2017 Brain Trauma Foundation’s support matrices designed by the 2019 Seattle International
(BTF) guidelines.[17] These advances and challenges may Severe TBI Consensus Conference (SIBICC).[40]
influence the management decisions of all health-care
Multimodality neuromonitoring [Table 2] is a less
practitioners involved in the critical care of sTBI patients.
preferable alternative available for unstable patients with
contraindications to NWT to detect neurophysiologic
IDENTIFYING NEUROWORSENING worsening.[55,61,91] Unfortunately, such a scenario is
Any sTBI patient should be considered a critical patient increasingly being observed in severely brain injured patients
with the potential risk of further deterioration beyond who are susceptible to developing multiple organ dysfunction
the initial insult, especially within the first 48 h. Critical syndrome (MODS). MODS, which has been estimated to
neuroworsening is defined as a deterioration in the occur in more than two-thirds of sTBI patients, can lead to
neurological status of the neurologically debilitated several contraindications to NWT.[52,65] Neuromonitoring
patient necessitating early recognition along with prompt can indirectly detect neuroworsening through evaluating
evaluation and management.[21,40] The criteria and possible the physiologic state of brain tissue in some of these difficult
etiologies of neuroworsening are shown in Table 1. Repeated scenarios.[19,57] In particular, recent evidence has pointed
clinical examination is the mainstay of prompt detection to a survival benefit of using brain tissue oxygen (BtpO2)
of neuroworsening. However, severely injured patients are monitoring. The randomized Phase II BOOST-2 trial (brain
usually sedated in ICUs. To avoid fallacies, evaluation of oxygen optimization in severe TBI) compared combined
deeply sedated patients requires a neurological wake-up test BtpO2 and intracranial pressure (ICP) monitoring versus ICP
(NWT) which poses the risk of inducing a stress response in monitoring alone. The investigators found a nonsignificant
sTBI patients. For uncertain clinical scenarios when the risk/ 9% decrease in mortality and 11% increase in favorable

Surgical Neurology International • 2022 • 13(431) | 2

 Table 2: Techniques for multimodality neuromonitoring.
Modality Application method Variable Significance Global Time span Invasiveness Derived indices Values and Limitations
monitored or focal thresholds
measure
Invasive ICP Intraparenchymal ICP Recommended to Focal Continuous Yes Intracranial ICP threshold EVD insertion
monitoring fiber‑optic monitor reduce in‑hospital Global compliance < 22 mmHg in compressed
(IPPM) and 2‑week CPP Normal or displaced
Ventricular catheter mortality PRx CPP = 50‑70 ventricles can
(Gold standard ICP mmHg PRx be difficult Risk
monitor for global > 0.2: Impaired of infection/
ICP) autoregulation hemorrhage
Others Transducer
should be
maintained at a
fixed reference
point relative to
the patient’s head
IPPM requires
placement to be
close to the area at
risk IPPM is costly
With IPPM, there
is no recalibration
of measurements
which drift with
time
Cerebral O2
monitoring
(Indicated for
patients with/at risk
for cerebral ischemia
El-Swaify, et al. Initial neurocritical care for severe TBI

and/or hypoxia)
PbtO2 measurement Flexible microcatheter Partial Most accurate Focal Continuous Yes O2 diffusion Normal Variable
(Gold standard) placed in white matter pressure of method Balance between PbtO2= 40 placement
of nontraumatized O2 in brain Uncertain effect on O2 supply and mmHg Low sensitivity
tissue as assessed on tissue outcomes demand Threshold: for detection
CT scan Can aid in titrating Adults: of cerebral
O2 in the cerebral hyperventilation ≤ 15–20 mmHg vasospasm after
interstitium is Paediatric: SAH
measured using ≤ 10 mmHg Requires 1 h run
optical luminescence in period
or polarographic

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techniques depending

|
on the type of

3
microcatheter
(Contd...)
 Table 2: (Continued).
Modality Application method Variable Significance Global Time span Invasiveness Derived indices Values and Limitations
monitored or focal thresholds
measure
SJVO2 Placement of a O2 Can aid in titrating Global Intermittent No Cerebral AVDO2 SJVO2= Technique is
measurement catheter/fiber‑optic saturation hyperventilation Continuous 55%‑69% prone to artifact
oximeter retrograde of jugular Desaturation with Ischemic Inherent risks
into the jugular bulb venous that is sustained fiber‑optic threshold: SjvO2 associated with
Catheter tip at the blood (> 10 min) catheters <50% for at least central catheter
level of the bodies of portends poor 10 min placement and
C1/C2 on lateral neck outcome in TBI maintenance,
radiograph suggests for example,
correct placement infection,
misplacement,

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pneumothorax,

|
jugular vein

4
thrombosis, etc.
May miss critical
regional ischemia
as it is a global,
flow‑weighted
measure
Transcranial Using NIRS to O2 Least reliable Focal Continuous No Cerebral blood Normal value: Extracerebral
cerebral oximetry differentiate saturation When combined flow 60–80% distortion of
oxyhemoglobin from Relative with systemic Cerebral Threshold not signal
reduced hemoglobin blood blood pressure autoregulation clearly defined Inability to
volume and ICP monitors, distinguish
can potentially between
assess cerebral extracranial
autoregulation and intracranial
El-Swaify, et al. Initial neurocritical care for severe TBI

Screen for sources of O2

intracranial Ischemic
hematomas threshold not
in prehospital defined
environment
Electrical activity
monitoring
cEEG Electrodes affixed to Cortical Detect PTS Global Continuous No Seizure activity N/A cEEG is
the scalp electrical (majority are Abnormal patterns performed
activity nonconvulsive) for 48 h (as
intermittent
EEG monitoring
has a sensitivity
of only 50%)
(Contd...)
 Table 2: (Continued).
Modality Application method Variable Significance Global Time span Invasiveness Derived indices Values and Limitations
monitored or focal thresholds
measure
Electrocorticography Recording grids and Cortical More sensitive than Focal Continuous Yes Seizure activity N/A Requires specific
strips are laid on and depth EEG Spreading surgical
the cortical surface electrical Used for patients depolarization placement
intraoperatively activity with persistent (CSD)
and unexplained
alteration of mental
status
CBF monitoring
Intraparenchymal A probe with 2 CBF Quantitative Focal Continuous Yes Hypoperfusion or Ischemic Technical
thermal thermistors is estimate of CBF hyperperfusion threshold<18–25 limitations such
diffusion flowmetry inserted to measures mL/100 g/min as measurement
(TDF)/probe the tissue’s ability Irreversible drift Normal
(TDP) to dissipate heat. A damage <10 values in various
microprocessor then mL/100 g/min physiological
converts this into Normal CBF in conditions have
CBF in mL/100 g/ young adults: not been defined
min. 50 mL/100 g of Adverse
brain tissue/min effects of
(range temperature and
20–70 mL) hyperthermia
TCD Transducers placed Cerebral Qualitative Global Intermittent No Critical closing Mean flow Operator
directly on the blood estimate of CBF pressure velocity by dependent
patient’s skin with velocity Detection of Cerebral arterial TCD: Problems of
a small amount of vasospasm and impedance ECICA: 30 ± 9 probe fixation
gel facilitating the DCI in SAH, (away) to the head
ultrasound. differentiates MCA: 55 ± 12 and computer
El-Swaify, et al. Initial neurocritical care for severe TBI

The transducer hyperemia from cm/sec (toward) interfacing

is applied to the vasospasm ACA: 50 ± 11 Qualitative
patient’s temples, base cm/sec (away) estimate due to
of the skull at the PCA segment 1: small sample
back of the neck area 39 ± 11 cm/sec size (1 mm3)
or on closed eyelids. (toward) Relative than
It can also be done PCA segment 2: absolute values
through a burr hole 40 ± 10 cm/sec Failure in up to
in a surgical setting. (away) 10% of patients
BA: 41 ± 10 cm/ due to absent
sec (away) acoustic shadow

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VA: 38 ± 10 cm/

|
sec (away)

5
(Contd...)
 Table 2: (Continued).
Modality Application method Variable Significance Global Time span Invasiveness Derived indices Values and Limitations
monitored or focal thresholds
measure
Cerebral metabolism A flexible wire Brain Possible prognostic Focal Intermittent Yes Cerebral metabolism Physiological Focal
monitoring using with a 10 mm metabolites value for treatment, (LPR+Cerebral ranges: biochemical
microdialysis (CMD) semi‑membrane is and follow‑up, and glucose level) Lactate changes
inserted into the biomarkers mortality Cell injury 0.7–3.0 μmol/L occurring
white matter and a CMD can (Glutamate level) Glutamate elsewhere or
physiologic dialysate distinguish ischemic Cellular breakdown 2–10 μmol/L away from the
is constantly infused (strokes) from (Glycerol level) Glycerol catheter may be
nonischemic Adenosine, urea, 10–90 μmol/L different from
hypoxia amino acids, Thresholds: those occurring
Measurement of nitrate, and nitrite Glucose levels adjacent to the

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drug levels like concentrations < 0.7 mmol/L catheter

|
antibiotics or Other biomarkers of predict Labor intensive

6
anticonvulsants injury severity and metabolic crisis Requires at
Identify neuroinflammation LPR > 25‑40 least 1 h for
hyperglycolysis and Increased glutamate predicts poorer equilibration
increased glucose and lactate are outcome of cerebral
utilization post‑TBI earliest markers of Trend is more interstitial
(may be used ischemia followed useful than molecular
to guide insulin by increased glycerol absolute values markers and their
therapy while measurement
initiating enteral
feeds to avoid
hypoglycemia)
Temperature Intraparenchymal Brain The difference Focal Continuous Yes Gradient between N/A N/A
monitoring probe temperature between brain core and brain
temperature and core temperature
El-Swaify, et al. Initial neurocritical care for severe TBI

body temperature
may be associated
with changes in
cerebral perfusion
Noninvasive ICP Optic nerve sheath ONSD Novel noninvasive Global Intermittent No ICP N/A Operator
monitoring ultrasonography method to detect dependent
ICP Less accurate
compared
to invasive
monitoring
ACA: Anterior cerebral artery, AVDO2: Cerebral arteriovenous oxygen content difference, BA: Basilar artery, cEEG: Continuous electroencephalography, CBF: Cerebral blood flow, CPP: Cerebral
perfusion pressure, CSD: Cortical spreading depression, DCI: Delayed cerebral ischemia, ECICA: Extracranial internal carotid artery, ICP: Intracranial pressure, LPR: Lactate‑to‑pyruvate
ratio, MCA: Middle cerebral artery, N/A: Not applicable, NIRS: Near‑infrared spectroscopy, O2: Oxygen, ONSD: Optic nerve sheath diameter, PbtO2: Partial pressure of oxygen in brain tissue,
PCA: Posterior cerebral artery, PRx: Pressure reactivity index, PTS: Posttraumatic seizures, SAH: Subarachnoid hemorrhage, SJVO2: Jugular bulb venous oxygen saturation, TCD: Transcranial
Doppler, VA: Vertebral artery
 El-Swaify, et al. Initial neurocritical care for severe TBI

6-month neurologic outcomes.[73] Although promising results MANAGING INTRACRANIAL

have also been demonstrated in large observational studies, HYPERTENSION (IHT)
routine adoption of BtpO2 monitoring will likely be influenced
by the anticipated BOOST-3 trial (NCT03754114).[42,49] The initiation of ICP reducing measures is triggered when
patients meet certain criteria and exceed prespecified
DEFINING THRESHOLDS thresholds. Maintaining these thresholds is a challenging task
complicated by the lack of sufficient high-quality evidence
Most TBI patients are susceptible to altered cerebral as previously mentioned. The SIBICC adopted a consensus-
autoregulation and detrimental increases in ICP with based tier system to categorize the interventions commonly
resultant fluctuations in cerebral blood flow (CBF).[77] The employed to prevent and control secondary IHT in patients
latest BTF guidelines recommend, based on Class II evidence, with ICP monitors. Treatments within the same tier are
an ICP cutoff of 22 mmHg, and a cerebral perfusion pressure employed without a specific order and are based on individual
(CPP) threshold of 60–70 mmHg. The minimum value cases. Tier-zero, ideally initiated in the ICU, represents the
of CPP should be determined on a case-by-case basis with primary management of patients to stabilize the condition and
some authors suggesting different thresholds for different age achieve neuroprotection regardless of the eventual ICP reading.
groups.[9,103] However, it has been suggested that aggressive Beyond tier-zero, the tiers target lowering the ICP according to
treatments to maintain a high CPP increase the risk of the recommended thresholds by the BTF guidelines.[17,40]
acute respiratory distress syndrome in adults.[17] It is now For patients who do not undergo ICP monitoring, especially
well-known that the most important determinant of CPP in under-resourced LMICs, the Consensus Revised Imaging
is ICP and not mean arterial pressure (MAP). Therefore, and Clinical Examination (CREVICE) Protocol employs a
treatment is usually tailored according to the ICP. However, similar tier-based algorithm that is initiated based on major
one number does not fit all. Sorrentino et al. analyzed and minor criteria [Table 3].[21,66] The original ICE protocol
459 patients and found a lower ICP cutoff (18 mmHg) for
favorable neurological outcomes in patients above 55 years
Table 3: CREVICE protocol criteria for initiating therapy for
(χ2 = 5.14; P = 0.023) and females (χ2 = 8.23; P = 0.004).[88] intracranial hypertension.
Interestingly, the cutoff for mortality was 22 mmHg across all
subgroups. Other investigators suggested utilizing “patient- CREVICE
protocol criteria
specific” thresholds.[3,54,56]
Major criteria 1. CT Marshall Class III
The variability in defining optimum thresholds has ignited 2. CT Marshall Class IV
interest in pursuing patient-specific measurements based 3. CT Marshall Class VI
on the physiology of cerebral vascular reactivity instead of Minor criteria 1. GCS motor score ≤4
targeting static ICP and CPP thresholds.[38] The most basic 2. Pupillary asymmetry
yet most common continuous method for assessment is 3. Abnormal pupillary reactivity
4. CT Marshall Class II
the pressure reactivity index (PRx) which is a correlation
Marshall CT A. DI I
coefficient between MAP and ICP.[108] A negative correlation classification a. No visible intracranial pathology
between both indicates intact autoregulation. A PRx >0.20– B. DI II
0.25 is significantly associated with increased mortality and a. Midline shift 0–5 mm
worse neurological outcome. Therefore, the PRx can be used b. Basal cisterns visible
to guide treatment by targeting the optimal CPP and ICP with c. No high or mixed density lesions > 25 cm3
the lowest PRx.[48,50,54,56,71,81,88,107,110] Alternative cerebrovascular C. DI III
reactivity indices have shown superior predictive abilities a. Midline shift 0–5 mm
than PRx. These include the pulse amplitude index, which is b. Basal cisterns compressed or completely
effaced
a correlation coefficient between MAP and pulse amplitude
c. No high or mixed density lesions > 25 cm3
of ICP, and the regression coefficient between CPP and D. DI IV
pulse amplitude of ICP (RAC).[109] However, international a. Midline shift > 5 mm
experts could not reach a consensus on how to implement b. No high or mixed density lesions > 25 cm3
these indices, and a research agenda was accordingly E. EML V
proposed.[25] Other researchers have pursued noninvasive a. Any lesion evacuated surgically
methods altogether for real-time assessment of CPP such F. Non‑EML VI
as the transcranial Doppler. Varsos et al. estimated the CPP a. High or mixed density lesions > 25 cm3
using the critical closing pressure in a cohort of 280 patients; b. Not surgically evacuated
they found their model to be significantly predictive of low CT: Computed tomography, DI: Diffuse injury, EML: Evacuated mass
lesion, GCS: Glasgow Coma Scale
CPP values (90% diagnostic accuracy).[98]

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 El-Swaify, et al. Initial neurocritical care for severe TBI

followed a “tranquillity” approach that avoids potential potentially hard to replicate.[20,40] An integrated algorithm
neurotoxic ICP surges by keeping ICP levels at a presumed for the management of suspected IHT in different resource
minimum using fixed scheduled usage of ICP reducing settings is illustrated in Figure 1.
measures.[20] It is prudent to understand that despite showing Hyperosmolar therapy still has many controversies with no
comparable outcomes to an ICP monitoring protocol, the recommendations regarding the type of agent (hypertonic
CREVICE protocol should not replace monitoring when saline [HTS] vs. mannitol) or concentrations to be used.[18]
it is available. ICP monitoring allows a more personalized HTS-induced volume expansion may reduce ICP through
approach to patient care. Moreover, the patients in the ICE raising the CPP and causing cerebral vasoconstriction if
protocol were directly monitored by trained intensivists static pressure autoregulation is intact.[74,77] A MAP challenge
and neurosurgeons not nursing staff making their protocol can be performed to test autoregulation.[40,86] A meta-

Figure 1: Algorithmic approach to the management of raised intracranial pressure. BP: Blood pressure, CPP: Cerebral perfusion pressure,
CT: Computed tomography, EEG: Electroencephalogram, EVD: External ventricular drain, GCS: Glasgow Coma Scale, ICP: Intracranial
pressure, MAP: Mean arterial pressure, OR: Operating room. *A postoperative CT scan is obtained, and patients are reclassified using the
Marshall classification using a dual system. **Escalating treatment is defined as using another measure from the same tier of therapy or
upgrading to a higher tier. ^Refers to the dosing frequency of hyperosmolar therapy.

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 El-Swaify, et al. Initial neurocritical care for severe TBI

analysis of 12 randomized and controlled trials [RCTs] with DC for pediatric sTBI patients is still preliminary, and the
438 patients found no significant difference in terms of results of an ongoing RCT are anticipated (NCT03766087).[62]
functional outcomes or mortality. However, HTS was found
to be significantly more likely to achieve ICP control (risk SHOULD ICP BE INVASIVELY MONITORED?
ratio [RR], 1.06; 95% confidence interval [CI], 1.00–1.13)
and significantly more likely to increase serum sodium Elevated ICP is detrimental to cerebral physiology through
(mean difference [MD], 5.30; 95% CI, 4.37–6.22) and serum reduction of CBF and compression or herniation of cerebral
osmolality. Although these differences are likely not clinically structures. Invasive cerebral monitoring in general and ICP
significant, the sample size is insufficient to produce a valid monitoring in specific allow real-time assessment of cerebral
conclusion. In addition, trials lacked uniformity of dosing physiology and dynamic titration of treatment modalities
and concentrations; most studies used mannitol 20% and to optimize cerebral tissue conditions. Although ICP
HTS 3% or 7.5% in boluses of 2–5 mL/kg.[37] A recent case– monitoring should logically be used for critical patients when
control study found that the total duration of high ICP available, the previous indications for ICP monitoring are no
combined with low CPP was significantly lower with HTS longer supported by the 2017 BTF guidelines, especially since
prior guideline compliance was poor, and neither survival
(11.12 ± 14.11 vs. 30.56 ± 31.89 h).[63] Another potential
nor functional outcomes were significantly improved as
advantage of HTS is the ability to immediately wean patients
evidenced in the landmark BEST: TRIP RCT (Benchmark
when treatment is no longer required. On the other hand,
Evidence from South American Trials: Treatment of ICP).[1,17]
mannitol must be gradually tapered to avoid rebound
Cohort studies that had found better mortality rates at centers
cerebral edema and increased ICP.[21,36]
that utilize ICP monitoring found that ICP monitoring could
A small subset of sTBI patients with IHT develops refractory only explain 10–15% of the variability between institutions.[5]
IHT that is detrimental to cerebral physiology and disrupts A systematic review by Yuan et al. found no evidence that ICP
all homeostatic mechanisms.[28] Decompressive craniectomy monitoring reduces mortality rates (OR, 0.93; 95% CI, 0.77–
(DC) is the temporary surgical removal of a skull bone flap. 1.11). However, a separate analysis of seven studies published
It may be primary, when performed to evacuate a mass lesion after 2012, which included 12,944 patients, revealed a
and control postoperative ICP, or secondary when performed statistically significant decrease in mortality (OR, 0.56; 95%
as part of tiered therapy for refractory IHT (usually a tier- CI, 0.41–0.78).[106] These results imply that temporal changes
three measure).[21,40] It is an essential lifesaving option because in management strategies and technological advances in
it indirectly improves BtpO2 pressure through reduction monitoring devices may have a substantial impact on patient
of ICP.[60] The BTF updated their 2020 guidelines based on outcomes.[27] A more recent meta-analysis of 18 studies with
the results of two high-quality RCTs which investigated 25,229 patients found a significantly lower mortality rate with
secondary DC versus medical management outcomes within ICP monitoring (RR, 0.85; 95% CI, 0.73–0.98). Once again, a
a 12-month period in sTBI patients with refractory IHT. The
DECRA (DC in patients with severe TBI) study resorted to Table 4: Complication rates of intracranial pressure monitoring
early DC (within 72 h of admission) at a lower threshold devices.
(20 mmHg) in 73 patients whereas the Randomized
Complication EVD ICPM
Evaluation of Surgery with Craniectomy for Uncontrollable
Elevation of ICP (RESCUEicp) study used DC later (within Access site infections
Without antibiotic 7.3–10.4% 0.0–7.4%
10 days) at an ICP of >25 mmHg in 202 patients.[22,45]
prophylaxis
Despite the differences in the thresholds employed for AI‑EVDs 0.0–2.3% N/A
the intervention, both studies showed comparable results. Postprocedural hemorrhage 0.7–41.0% 0.025–0.900%
Secondary DC performed significantly better in the reduction 0.8–14.6% clinically
of ICP, reduction in use of ICP-lowering therapies, and significant
Misplacement
reduction of ICU length of stay (LOS). Only the RESCUEicp
Freehand technique 8.0– 45.0% N/A
study showed significantly lower 12-month mortality in the Bolt‑connected placement 6.5–30.9%
DC arm (30.4% vs. 52.0%). However, patients who survived Stereotactic image‑guided 5.3–5.9%
had an increased incidence of poor functional outcomes placement
in the DC group compared to the medical therapy group CT guided 0.0%
(DECRA = odds ratio [OR], 0.33; 95% CI 0.12–0.91). In Venous thromboembolism 9.2%
light of these findings, the current recommendations are to (OR, 1.75; 95% CI, 1.42–2.15)
perform secondary DC for late refractory ICP elevation to AI: Antibiotic impregnated, CI: Confidence interval, CT: Computed
improve mortality and functional outcomes (level IIA) but tomography, EVD: External ventricular drain, ICPM: Intracranial
pressure monitor, N/A: Not available, OR: Odds ratio
not for early refractory ICP elevation.[41] The role of secondary

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 El-Swaify, et al. Initial neurocritical care for severe TBI

temporal change in trends was observed in a subanalysis of fluid drainage.[59] However, recent evidence has challenged
studies published after 2007 that showed an even larger effect this concept, and intraparenchymal monitors (IPMs) have
size for ICP monitoring (RR, 0.72; 95% CI, 0.63–0.83).[87] The emerged as a promising monitoring tool that is less invasive
findings of these meta-analyses are limited by the largely than EVDs with comparable outcomes.[2] In fact, Bales
observational nature of included studies and by significant et al. found that the in-hospital mortality (OR, 2.46; 95% CI,
heterogeneity of included studies. 1.20–5.05), Glasgow outcome scale-extended (GOS-E) at day
180 (weighted difference, −0.97; 95% CI, −1.58–−0.37), and
Several recent large cohort studies have shown significantly
neuropsychological performance at day 180 were all worse
lower mortality rates with ICP monitoring.[4,82,85,105] The
with EVDs placed within 6 h compared to IPMs.[13] A recent
recent international prospective cohort study by Robba
meta-analysis of six studies with 3968 patients compared
et al. analyzed 1287 TBI patients. They showed a significantly
the outcomes of EVDs and IPMs. They concluded that there
lower 6-month mortality (hazard ratio [HR], 0.31; 95% CI,
is no difference in mortality (RR, 0.90; 95% CI, 0.60–1.36)
0.20–0.47) and 6-month unfavorable neurological outcome
or functional outcomes (MD, 0.23; 95% CI, 0.67–1.13), but
(HR, 0.53; 95% CI, 0.30–0.93) in TBI patients undergoing
there is a higher rate of complications (RR, 2.56; 95% CI,
ICP monitoring with at least one unreactive pupil but
1.17–5.61), especially infections, associated with EVDs.[100]
not patients with bilaterally reactive pupils.[82] The largest
The risks of ICP monitoring recorded in the literature are
retrospective study to date included the data of 36,929
shown in Table 4.[8,92] The future research interests will
sTBI patients of which 6025 had an ICP monitor placed.
revolve around noninvasive modalities of ICP monitoring
When controlling for confounding factors (age, GCS, injury
that is considerably safer such as transcranial acoustic signal
severity score, and craniotomy), ICP monitoring was found
transmission, ultrasonographic assessment of optic nerve
to decrease in-hospital mortality by 25%. However, this
sheath diameter, and others (NCT04548596).[29,34,70,79,83,84,94]
was at the expense of increased ICU LOS (13.1 ± 11.6 days
vs. 6.0 ± 10.8 days; P < 0.0001).[4] However, a recent cohort The timing of ICP monitor placement is a matter of debate.
study analyzing trends of ICP monitoring in Level I trauma Early ICP monitor placement, defined as within 6 h of
centers in the USA has cast doubt over the benefits that admission, was not found to be associated with better
ICP monitoring offers. The authors analyzed 4880 patients mortality rates in neither adult nor pediatric patients.[12,43]
with sTBI while controlling for various confounders. The This could be explained by the early coagulopathy that usually
analysis revealed higher in-hospital mortality (OR, 1.63; 95% associates sTBI and may result in hemorrhagic complications
CI, 1.28–2.07) and decreased functional independence at during placement of invasive monitors. Another potential
discharge (OR, 1.71; 95% CI, 1.29–2.26).[75] In the pediatric confounder is the severity of patients’ injuries that necessitate
age group, ICP monitoring remains underutilized and has early ICP monitoring and could be the underlying cause of
an uncertain effect on pediatric TBI with some patients poor outcomes. However, other outcomes as LOS and days
having worse outcomes.[7,15,24] Further studies are still needed ventilated were significantly better in the early group; this is
to adequately define the pediatric population that stands to possibly the result of earlier detection and faster treatment
benefit from ICP monitoring. It must be noted that cohort of IHT. Robba et al. found that 80% of TBI patients had the
studies, although including large sample sizes, are susceptible ICP monitor placed on day 1 (ICU admission), and 60% of
to inherent selection bias. Patients who did not receive ICP patients had it placed in an operating room.[82]
monitoring could have been deemed, by either unreported
objective measures or subjective measures, too unstable by ANTI-SEIZURE PROPHYLAXIS AND
clinical assessment or neuroimaging. In addition, geographic NEUROPROTECTION
trends and hospital characteristics may influence the
selection of patients eligible for ICP monitoring.[96] To this Posttraumatic seizures (PTSs) can potentially worsen the
day, there have been no new RCTs of ICP monitoring. secondary brain injury by increasing cerebral metabolism and
inducing neural excitotoxicity. They are subdivided into early
PLACING THE ICP MONITOR PTS and late PTS. The incidence reaches 16.9% and 30.0%,
respectively.[31,33,99] The BTF guidelines recommend the use of
In the event that the neurocritical care team elects to phenytoin prophylaxis in the setting of TBI to decrease the
place an ICP monitor, they will still be faced with several rate of early PTS with no role in late PTS. However, a recent
decisional dilemmas. The optimal ICP monitoring systematic review displayed contradictory results with regard
modality is still unknown. Historically, the superiority of to sTBI. The subgroup analysis of observational studies
the external ventricular drain (EVD) as an ICP monitoring showed a protective effect of antiepileptic drugs (AEDs)
modality was related to its accuracy, ability to recalibrate, (mostly phenytoin) on early PTS (RR, 0.50; 95% CI, 0.28–
cost-effectiveness, and the fact that it could be used as a 0.87). On the other hand, results from the subgroup analysis
therapeutic modality to lower ICP through cerebrospinal of RCTs demonstrated high heterogeneity and showed that

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 El-Swaify, et al. Initial neurocritical care for severe TBI

the effect of AEDs was not statistically significant (RR, 0.58; treatment of posttraumatic hyperthermia which is believed
95% CI, 0.20–1.72).[101] These results demonstrate the lack to result from adrenergic overactivity as well. A retrospective
of definitive high-quality evidence on the prophylactic use cohort of 1544 patients by Asmar et al. showed that beta-
of AEDs, and therefore, the utmost need for adequately blockers significantly reduced febrile episodes (8 vs. 12;
designed future RCTs. The side effect profile of phenytoin P = 0.003), median maximum temperatures (38.0°C vs.
has prompted clinicians to explore the use of alternative 38.5°C; P = 0.025), and significantly prolonged median
AEDs. Fang et al. conducted a systematic review of AEDs time between febrile episodes (3 h vs. 1 h; P = 0.013). These
in neurocritical care and identified 10 studies comparing findings only translated to a shorter ICU stay and lower
levetiracetam to phenytoin in the prevention of PTS. They mortality in the subgroup of patients with head Abbreviated
found no significant difference between both AEDs (OR, Injury Scale ≥4.[10]
1.02; 95% CI, 0.72–1.45).[30] However, levetiracetam is A consolidated research effort is being put into the
still a popular AED because of a more favorable side effect development of effective neuroprotective agents that can
profile.[104] improve long-term outcomes after TBI. The discussion of
Paroxysmal sympathetic hyperactivity (PSH), an important the potential neuroprotective role of beta-blockers merits
differential of PTS, is an underdiagnosed syndrome a short discussion of another promising neuroprotective
of adrenergic surge with characteristic symptoms of agent: amantadine. Amantadine is an indirect dopamine
tachycardia, tachypnea, hypertension, hyperthermia, agonist and N-methyl-D-aspartate antagonist. It is believed
sweating, and posturing during paroxysmal episodes. Up to improve posttraumatic cognitive function and accelerate
to 80% of cases of PSH are due to TBI and around 10% functional recovery by replenishing depleted dopamine
of patients with TBI suffer from PSH. PSH portends an in neural circuits responsible for attentional and arousal
unfavorable prognosis up to death due to long ICU stays, functions (frontostriatal, nigrostriatal, and mesolimbic
longer mechanical ventilation time, increased infectious circuits). A recent meta-analysis of 20 studies found that
episodes, and worse GOS scores.[11,76] Adrenergic blockers can amantadine significantly improved cognitive function
potentially counteract this systemic dysregulation. Recent (standardized MD (SMD), 0.50; 95% CI, 0.33-0.66),
research, including a systematic review published in 2021, especially if administered in the 1st week (SMD, 0.97; 95%
strongly favors the routine administration of beta-blockers CI, 0.45–1.49) for <1 month (SMD, 0.83; 95% CI, 0.56–1.11).
(especially propranolol) as part of SMPs to ameliorate the The effect in sTBI specifically was still statistically significant
long-term (>6 months) functional outcomes (OR, 1.75; (SMD, 0.45; 95% CI, 0.11–0.78).[69]
95% CI, 1.09–2.80) and reduce the in-hospital mortality
rate (OR, 0.39; 95% CI, 0.30–0.51) of patient suffering from THROMBOEMBOLISM PROPHYLAXIS
TBI.[26,47] Another possible role for beta-blockers in sTBI is the
In general, trauma is a hypercoagulable state, and TBI
specifically leads to a systemic coagulopathy due to the
Table 5: Modified Berne‑Norwood criteria. release of procoagulant molecules and platelet-activating
Risk Criteria Proposed molecules in addition to prolonged immobilization.[32,53,80]
category management The current recommendations for venous thromboembolism
Low risk •N
 o moderate‑ or high‑risk • Anticoagulant (VTE) prophylaxis are to use anticoagulants in addition
criteria prophylaxis if to pneumatic compression stockings if the TBI is stable
CT stable at 24 h and after considering the risk-benefit ratio to avoid
Moderate • S ubdural or epidural hematoma • Anticoagulant resorting to therapeutic anticoagulation dosing.[17,58,67] Most
risk > 8 mm prophylaxis if centers use low-molecular-weight heparin as the primary
•C  ontusion or intraventricular CT stable at thromboprophylaxis agent for both adult and pediatric
hemorrhage > 2 cm 72 h patients.[14,97]
• Multiple contusions per lobe
• S ubarachnoid hemorrhage with Several systematic reviews have highlighted the safety of
abnormal CT angiogram early initiation of anticoagulants provided that repeat head
•E  vidence of progression on CT scans do not show progressive hemorrhagic injury (PHI)
imaging at 24 h within the first 24 h. Recently, Spano et al. systematically
High risk • E vidence of progression on • Consider IVC reviewed 17 studies and found the rates of PHI to vary
imaging at 72 h filter placement between 0% and 47%, but their recommendations are that
• Craniotomy anticoagulants reduce VTE without a corresponding increase
• ICP monitor placement in PHI. The majority of providers initiated anticoagulation
CT: Computed tomography, ICP: Intracranial pressure, IVC: Inferior within 24–72 h and a minority also initiated them within
vena cava
the first 24 h without demonstrating PHI.[64,89] Delaying

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 El-Swaify, et al. Initial neurocritical care for severe TBI

anticoagulation initiation beyond 72 h may put patients saline has theoretical advantages over mannitol as an ICP-
at a higher risk of VTE. The exception to these trends is lowering measure for IHT but supporting evidence is sparse.
sTBI patients who require neurosurgical intervention. Although DC can be used to lower mortality for refractory
A cohort study of 4951 patients undergoing neurosurgical IHT, poor functional outcomes limit its universal application
interventions by Byrne et al. found that although each day for all patients. ICP monitoring continues to be a standard
of prophylaxis delay after the first 24 h increased the odds of of care that likely improves outcomes. However, high-
VTE (OR, 1.08 per day; 95% CI, 1.04–1.12), it also decreased quality evidence should still be sought to define patients
the odds of repeat neurosurgical intervention during the first that stand to benefit most especially in pediatric age groups.
3 days (OR, 0.72 per day; 95% CI, 0.59–0.88). Prophylaxis The choice of device and timing of monitor placement are
delay also decreased odds of mortality in patients who a matter of debate. Prophylaxis against seizures and VTE
initially underwent intracranial monitor/drain insertion should be considered in SMPs but careful consideration is
(OR, 0.94 per day; 95% CI, 0.89–0.99).[16] needed in patient selection for anti-seizure and anticoagulant
prophylaxis. Beta-blockers can be added to SMPs to improve
The successful protocol by Tignanelli et al. stratified patients
outcomes through prevention of PSH and posttraumatic
according to their risk of TBI progression using the modified
hyperthermia. Amantadine is another promising
Berne-Norwood criteria and accordingly used prophylactic
neuroprotective agent that may improve cognitive recovery
anticoagulation for low- and medium-risk patients.[78,95] The
of sTBI patients. In spite of the consolidated research efforts
criteria are illustrated in Table 5. Their median time to VTE
in the refinement of SMPs, there are still many unanswered
prophylaxis initiation decreased from 140 to 59 h, and their
questions and novel research opportunities. We encourage
VTE rates decreased from 5.2% to 2.2%; both these results
future well-designed trials with clearly defined endpoints
were statistically significant. Patients considered at high risk
relevant to optimal patient care.
of brain injury progression and with concomitant high-risk
injuries are eligible for inferior vena cava filter placement.[78]
Authors’ contributions

LIMITATIONS OF THIS REVIEW STE conceived the idea and contributed to designing the
review. MK participated in data extraction from the literature
This is a narrative review intended to provide a qualitative and drafting the manuscript. SHA participated in data
overview of the literature. Based on their subjective extraction from the literature and drafting the manuscript. BB
evaluations, the authors reviewed the literature and cited participated in data extraction from the literature and drafting
relevant articles. Despite the fact that this method is the manuscript. MAR participated in data extraction from the
comprehensive, its nonsystematic nature is prone to bias. literature and critical review. AA participated in data extraction
Robust deductions are limited due to a lack of quantitative from the literature and critical review. AEMA participated in
synthesis of data from included studies. High-quality RCTs data extraction from the literature and critical review. PWB
and systematic reviews of sTBI neurocritical care are limited participated in data extraction from the literature and critical
in the literature. Due to the methodological limitations review. AKB designed the review and performed critical revision
of narrative reviews, readers should cautiously interpret of the manuscript. STE, MK, and AKB designed the algorithm.
the conclusions brought forward by the authors of this
study. Finally, although this review tackled several research Declaration of patient consent
questions that were proposed by the 2022 National Trauma
Research Action Plan Neurotrauma Research Panel Delphi Patient’s consent not required as there are no patients in this
Survey,[90] many controversial topics in sTBI care were study.
not sufficiently covered including the use of biomarkers,
neuroprognostication, and geriatric TBI. Financial support and sponsorship
Publication of this article was made possible by the James I.
CONCLUSION and Carolyn R. Ausman Educational Foundation
Severe TBI is a multifaceted disease process that requires
diligent critical care to improve outcomes. SMPs are Conflicts of interest
integral to achieve this. Repeated clinical examination There are no conflicts of interest.
should be used to detect critical neuroworsening, but
multimodality neuromonitoring may be needed in select
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