REVIEW ARTICLE

C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
CITE AS:
C O N T I N U U M ( M I N N E AP M I N N )
2 02 1 ; 27(5, NEUROCRITICAL CARE):
1278–1300.
Address correspondence to
Dr Christopher P. Robinson,
1149 Newell Dr, Gainesville,
FL 32610, christopher.robinson@
neurology.ufl.edu.
RELATIONSHIP DISCLOSURE:
Dr Robinson has provided legal
consulting for Thompson and
Evangelo PA.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Robinson reports no
disclosure.
© 2021 American Academy
of Neurology.
1278
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Moderate and Severe
Traumatic Brain Injury
By Christopher P. Robinson, DO, MS
ABSTRACT
PURPOSE OF REVIEW: Traumatic brain injury (TBI) encompasses a group of
heterogeneous manifestations of a disease process with high neurologic
morbidity and, for severe TBI, high probability of mortality and poor
neurologic outcomes. This article reviews TBI in neurocritical care, hence
focusing on moderate and severe TBI, and includes an up-to-date review
of the many variables to be considered in clinical care.
RECENT FINDINGS: With advances in medicine and biotechnology,
understanding of the impact of TBI has substantially elucidated the
distinction between primary and secondary brain injury. Consequently,
care of TBI is evolving, with intervention-based modalities targeting
multiple physiologic variables. Multimodality monitoring to assess
intracranial pressure, cerebral oxygenation, cerebral metabolism, cerebral
blood flow, and autoregulation is at the forefront of such advances.
SUMMARY: Understanding the anatomic and physiologic principles of acute
brain injury is necessary in managing moderate to severe TBI. Management
is based on the prevention of secondary brain injury from resultant
trauma. Care of patients with TBI should occur in a dedicated critical
care unit with subspecialty expertise. With the advent of multimodality
monitoring and targeted biomarkers in TBI, patient outcomes have a higher
probability of improving in the future.
INTRODUCTION
T
raumatic brain injury (TBI) is a leading cause of major disability and
death worldwide. In addition, the socioeconomic burden of TBI is
increasing substantially because of its large burden on the health care
system, including acute care, rehabilitation, and permanent
neurologic disability.1 The global incidence of TBI continues to
increase annually in both low- to middle-income countries and high-income
countries, with varying causation. Vehicular injury remains the largest causative
agent in lower-income countries, whereas falls are an ever-increasing etiology in
higher-income countries as populations age.2 TBI accounts for more than
2.5 million emergency department visits annually, with an average incidence of
242 per 100,000 to 317 per 100,000 per year.3,4 Worldwide, mild TBI accounts
for 81% of all cases, with the remaining 19% moderate and severe TBI.5 Case
fatality rates range from 0.9 per 100 to 7.6 per 100 persons overall, with fatality
rates ranging from 29 per 100 to 55 per 100 patients in severe TBI.3,6,7 TBI-related
OCTOBER 2021
disability accounts for the societal and economic burden of the disease, with KEY POINTS
nearly 12 million people affected in the United States and Europe.3
● Traumatic brain injury
TBI is an umbrella term for a heterogeneous group of disease processes with (TBI) is a leading cause of
multiple intracranial pathologies, including cerebral contusions, epidural death and disability
hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, skull fractures, worldwide.
diffuse axonal injury, and cerebral edema (FIGURE 4-1). It is these multiple
● The leading cause of TBI
pathologies that lead to the various sequelae of injury appreciated in TBI. This
in low- to middle-income
article discusses moderate and severe TBI, as they are most relevant to the countries is vehicular
neurologist in the acute and critical care setting, and includes an overview of the trauma, whereas the leading
pathology, presentation, management, prognostication, and pediatric cause of TBI in high-income
considerations. countries is falls.

● TBI is a heterogeneous
CLASSIFICATION OF TRAUMATIC BRAIN INJURY group of diseases with
The classification systems of TBI include the three broad categories of clinical, multiple chemical and
radiographic, and mechanistic domains aimed at providing prognostic guidance biomechanical pathologies.
in the acute care setting (CASE 4-1). The clinical classification system is the most
● Acute classifications for
well-known and commonly used diagnostic tool of TBI severity and is based moderate and severe TBI
on cumulative admission Glasgow Coma Scale (GCS) scoring using eye, motor, exist within the clinical,
and verbal scales (TABLE 4-1). Mild TBI is characterized by a GCS score of 13 to radiographic, and
mechanistic domains.
15, moderate TBI is characterized by a GCS score of 9 to 12, and severe TBI is
characterized by a GCS score of 8 or less. Both moderate and severe TBI are ● Clinical classification of
characterized as higher-grade injuries, typically requiring care in a specialized TBI describes mild,
neurocritical care unit.8 It should be noted, however, that the clinical moderate, and severe levels
of injury based on
presentation Glasgow Coma
Scale score.

FIGURE 4-1
Radiographic heterogeneity of traumatic brain injury on axial noncontrast head CTs. A, Right
parietal epidural hemorrhage and midline frontal contusion. B, Right frontal subdural
hemorrhage with subfalcine herniation. C, Diffuse cerebral edema with diffuse axonal injury.
D, Bifrontal contusions with left hemispheric subdural hematoma and midline shift.
E, Depressed skull fracture with pneumocephalus. F, Diffuse subarachnoid hemorrhage with
intraventricular hemorrhage and frontal contusions and right frontal skull fracture.

CONTINUUMJOURNAL.COM 1279

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MODERATE AND SEVERE TRAUMATIC BRAIN INJURY

CASE 4-1 An 18-year-old man with no significant past medical history was brought
to the emergency department as a Level 1 trauma alert. The report from
emergency providers revealed that the patient was swinging on a rope
swing when he slipped and fell 20 feet. He was found submerged face
first in the water among large tree roots.
On initial examination, the patient was noted to have a large head
laceration and an agonal breathing pattern. Clinical vital signs in the field
included blood pressure of 100/40 mm Hg and arterial oxygenation of
88%. The patient was emergently intubated, resuscitated with IV fluids,
and transferred to a tertiary trauma center for care.
Initial neurologic examination revealed a large left frontal laceration
with notable depression. The patient showed no eye opening or motor
movement in any extremity to central or localized noxious stimulus.
Pupillary examination revealed bilaterally fixed pupils, with the right
pupil measuring 8 mm and the left pupil measuring 6 mm. Corneal
reflexes were absent, as were cough and gag reflexes. Oculocephalic
reflexes were deferred because of cervical collar placement. A head CT
was obtained and showed evidence of a depressed skull fracture, left
temporal intracranial hemorrhage, and midline shift of 10 mm. (FIGURE 4-2).

FIGURE 4-2
Imaging of the patient in CASE 4-1. Axial noncontrast head CT shows severe traumatic brain
injury with tentorial subdural hemorrhage (A), cerebral edema and uncal herniation
(B, C), and depressed skull fracture with intracranial hemorrhage and midline shift (D).

COMMENT Clinical classification and early recognition of traumatic brain injury is

imperative. Classification systems rely on clinical, radiographic, and
mechanistic domains. In this case, the patient’s neurologic examination is
consistent with a Glasgow Coma Scale score of 3 T, with the T indicating
the patient was intubated (eyes, 1; voice, 1 T; motor, 1), classifying the injury
as severe. Radiographic Marshall CT classification of the lesion is
consistent with nonevacuated mass lesion VI. The mechanistic
classification of the injury is described as penetrating based on imaging
and mechanism of injury. Classification of such lesions allows for early and
acute management and provides objective data to aid in prognosis for the
practitioner.

1280 OCTOBER 2021

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

classification system has limitations because of medical confounders in acute
resuscitation, such as paralytics, anesthetics, and sedatives.
Radiographic classification schemes (such as the Marshall and Rotterdam CT
classification of traumatic brain injury scores) apply descriptive radiographic
CT findings, including appearance of the basal cisterns, degree of midline shift,
and intracranial mass lesions, to predict 6-month outcomes (TABLE 4-2, TABLE 4-3,
and TABLE 4-4).9,10 Limitations of these classification systems include broad
categorization of intracranial lesions (hemorrhage versus axonal injury) and
prognostication based upon a snapshot in time. Such limitations should be
considered when using these tools.
The mechanistic classification scheme describes various etiologies of TBI,
including closed head injury, penetrating head injury, crash injury (vehicular
injury), or blast injury (militarized injury). Descriptive analysis of the
mechanistic cause of TBI can provide valuable prognostic information as it
relates to mortality and outcomes.11 Several validated prognostic tools using large
patient samples, such as the Corticosteroid Randomisation After Significant
Head Injury (CRASH) and International Mission on Prognosis and Analysis of
Clinical Trials (IMPACT) prognostic models, are available for objective
assessment and prognostication.12
A final and important consideration in the acute classification of TBI should be
the impact of extracranial or systemic traumatic injuries, as such pathologies may
result in worsening hypoxemia, coagulopathy, hypotension, and secondary
brain injury.

PATHOLOGIC FEATURES OF TRAUMATIC BRAIN INJURY

Although TBI is classically described based on clinical severity, it is a
heterogeneous disease with multiple subtypes reliant on individualized
underlying pathology. In a broad sense, TBI is dichotomized pathologically into
primary and secondary injury. Primary injury results from an initial impact and

Clinical Classification Grading Scale for Traumatic Brain Injury TABLE 4-1

Mild

◆ Glasgow Coma Scale score = 14

OR
Glasgow Coma Scale score = 15 plus EITHER brief loss of consciousness (<5 minutes) OR
amnesia
Moderate
◆ Glasgow Coma Scale score = 8-13
OR
Loss of consciousness ≥5 minutes
OR
Focal neurologic deficit
Severe
◆ Glasgow Coma Scale score = 3-8

CONTINUUMJOURNAL.COM 1281

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MODERATE AND SEVERE TRAUMATIC BRAIN INJURY

direct traumatic injury to the skull or intracranial structures. Such injuries lead to
intracranial hemorrhage, focal contusions, cerebral edema, skull fractures, and
diffuse axonal injury. As a result of primary injury, diffuse activation of multiple
complex biochemical and cellular processes occurs, resulting in the pathologic
mechanisms and heterogeneity of secondary injury in TBI (FIGURE 4-3).13 Several
different types of head injury may result in moderate or severe TBI clinically;
however, the underlying secondary mechanisms of injury may vary widely in
pathology. Such pathologies include oxidative stress, free radical formation,
calcium-mediated damage, proapoptotic expression, and astrocytic
inflammation.8 For example, a patient with a focal cerebral contusion may
develop significant inflammation or apoptosis, whereas a patient with diffuse
axonal injury may develop significant calcium-related damage. Such effects
typically occur concomitantly and develop or intensify throughout the duration
of disease. It is these complex secondary reactions that lead to the potentiation
and worsening of elevated intracranial pressure (ICP), decreased cerebral blood
flow (CBF), cerebral hypoxemia, and cerebral edema.13

DIAGNOSIS OF TRAUMATIC BRAIN INJURY

The diagnosis of TBI is based on a set of clinical factors, including GCS score, loss
of consciousness, impaired short-term memory, and focal neurologic deficits.
Upon a patient’s arrival at the acute care setting, it is imperative that a brief
neurologic examination be performed concurrently with CT evaluation to assess
structural damage and the need for neurosurgical intervention. Neurologic
examination remains a cardinal feature in the diagnosis of TBI and is the
preferred method of assessment, in addition to radiographic findings, to
determine deterioration and the need for intervention. Rapid assessment should
include evaluation of pupillary function and other brainstem reflexes and a
motor examination of central and peripheral responses to pain with descriptive
documentation of findings related to the GCS score. An abnormal pupillary
examination or posturing related to rostrocaudal decompensation should be a
clue to the need for rapid intervention. CT is the preferred radiographic modality
for diagnosis based on its ultra-early ability to detect acute blood products and

TABLE 4-2 Marshall CT Classification Scale for Traumatic Brain Injurya

Category Definition 6-Month mortality

Diffuse injury I No visible intracranial pathology 10%

Diffuse injury II Cisterns patent; shift 0-5 mm and/or lesions present; no lesion >25 cm3 13%
3
Diffuse injury III Cisterns compressed or absent; shift 0-5 mm; no lesion >25 cm 33%

Diffuse injury IV Midline shift >5 mm; no lesion >25 cm3 56%

Evacuated mass lesion V Any lesion surgically evacuated 35%

Nonevacuated mass lesion VI High- or mixed-density lesion >25 cm3; not surgically evacuated 91%

CT = computed tomography.
a
Data from Marshall LF, et al, Lancet Neurol.9

1282 OCTOBER 2021

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

bony abnormalities. Intracranial mass lesions secondary to TBI occur quite
frequently in moderate to severe TBI but are also seen in up to 15% of patients
with a GCS score of 13 to 14.14 It is therefore recommended that all patients
presenting to the acute care setting with a GCS score of 14 or less should undergo
cranial imaging. After diagnosis and stabilization, a follow-up CT is recommended
6 hours later because of the risk of delayed progression of intracranial
hemorrhages.15 New intracranial lesions in an otherwise normal-appearing CT
can appear in up to 20% of patients,16,17 and between 25% and 45% of preexisting
intracranial lesions will enlarge on subsequent studies.18 CT angiography should
also be considered in patients with moderate or severe TBI, particularly when
due to blunt traumatic injury. MRI studies are not usually performed in the
acute care setting because of their complex setup and length and concerns of
hemodynamic instability and airway compromise. MRI is classically reserved for
the subacute setting when clinically relevant diffuse axonal injury is suspected.

INVASIVE INTRACRANIAL AND HEMODYNAMIC MONITORING

Conservation of cerebral homeostasis via assessment and management of cerebral
perfusion pressure (CPP) is a safe and effective strategy to reduce mortality
and improve outcome in TBI.19 Continuous invasive hemodynamic monitoring
should therefore be considered for all patients with moderate to severe TBI. CPP
is defined as the difference between the mean arterial pressure (MAP) and the
ICP and is the target variable for cerebral autoregulatory homeostasis.20 The

Rotterdam CT Classification Scorea TABLE 4-3

Score element Points

Basal cisterns

Normal 0

Compressed 1

Absent 2

Midline shift

No shift or shift ≤5 mm 0

Shift >5 mm 1

Epidural mass lesion

Present 0

Absent 1

Intraventricular blood or traumatic subarachnoid hemorrhage

Absent 0

Present 1

Sum score: calculate the sum of all variables and add 1 point to the total +1

a
Data from Maas AIR, et al, Neurosurgery.10

CONTINUUMJOURNAL.COM 1283

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MODERATE AND SEVERE TRAUMATIC BRAIN INJURY

generally accepted target CPP to provide value in outcome is between 60 mm Hg

and 70 mm Hg and is dependent on the patient’s autoregulatory function.21
The use of intracranial monitoring for elevations in ICP is typically reserved
for patients with severe TBI. Current guidelines recommend the placement of an
intracranial monitor in all patients with an abnormal CT scan and a GCS score
between 3 and 8 following resuscitation or, conversely, in patients with a similar
GCS score and a normal CT scan with two of the following characteristics: age
older than 40 years, systolic blood pressure less than 90 mm Hg, or motor
posturing on examination.21,22 The use of ICP monitoring and ICP-directed
therapy in this cohort is recommended to reduce early TBI-related mortality,
and the latest recommendations suggest an ICP threshold of 22 mm Hg.21,22
The duration of ICP elevation in the setting of TBI should also be an
important consideration for management, and it follows a heterogeneous
pattern similar to that of its underlying pathology. Patients with severe TBI
may display one of four distinct patterns in ICP elevation: early elevation
(<72 hours), late elevation (>72 hours), bimodal elevation (<72 and >72 hours),
or continuous elevation.23 These patterns allow for clinical distinction of
peak swelling times in individual patients. Such knowledge is imperative
for forming treatment algorithms and determining the duration of
monitoring.
The use of intracranial monitoring for decreases in brain tissue oxygen tension
(PbtO2) is an evolving concept in the management of TBI. Cerebral oxygenation
delivery and consumption relies on several factors, including the cerebral
metabolic rate of oxygen consumption (CMRO2) and cerebral oxygen
diffusion.24 Monitoring of PbtO2 requires invasive neuromonitoring much like
ICP. Current recommendations for target therapy suggest that a PbtO2 less than
20 mm Hg is correlative to the ischemic threshold of CBF at 18 mL/100 g/min.25
Attempts are therefore made to preserve cerebral oxygenation at greater than
20 mm Hg. At present, the literature suggests that monitoring of PbtO2 is safe.26
Its utility as an adjunctive treatment modality to improve outcomes is currently
being investigated in the multicenter BOOST3 (Brain Oxygen Optimization in
Severe TBI, Phase 3) trial.27 Although not validated in patients with moderate or

TABLE 4-4 Six-Month Mortality Based on Rotterdam CT Classification Scorea

Score Mortality

1 1%

2 2%

3 10%

4 57%

5 72%

6 80%

a
Data from Maas AIR, et al, Neurosurgery.10

1284 OCTOBER 2021

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

FIGURE 4-3
Pathologic heterogeneity of secondary brain injury in traumatic brain injury.
Data from Maas AIR, et al, Lancet Neurol.8

severe TBI, PbtO2 monitoring may be of use in the future, independent of ICP, as
small prospective studies have shown improvements in both mortality and
6-month outcomes.28
Other invasive intracranial measurements, including cerebral microdialysis,
jugular bulb arteriovenous oxygen content difference, and pressure-reactivity
index, exceed the scope of this article but are used at some centers in the
management of both moderate and severe TBI and likely will become more
developed concepts in the future.
With advances in bioinformatic and precision medicine, the use of
multimodality monitoring in the treatment of TBI has gained favor.
Multimodality monitoring includes the real-time monitoring of multiple
physiologic parameters, including ICP, CPP, CBF, PbtO2, cerebral
autoregulation, EEG, cerebral metabolism, cardiac output, and systemic
oxygenation. Formal guidelines currently exist for the implementation and use of
multimodality monitoring in the neurocritical care unit.29

CRITICAL CARE MANAGEMENT OF MODERATE AND SEVERE

TRAUMATIC BRAIN INJURY
Moderate and severe TBI are acute care diseases that require expert
multidisciplinary treatment within intensive care units (ICUs) equipped to
treat neurologic illness. Established in 1986, the Brain Trauma Foundation has

CONTINUUMJOURNAL.COM 1285

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MODERATE AND SEVERE TRAUMATIC BRAIN INJURY

TABLE 4-5 Clinical Standardization Guidelines for Moderate to Severe Traumatic Brain
Injurya

Tier 0
◆ Maintain euvolemia
◆ Cerebral perfusion pressure >60 mm Hg
◆ PCO2 35-40 mm Hg
◆ SaO2 >90%
◆ Serum sodium >135 mmol/L
◆ Serum glucose >60 mg/dL and <180 mg/dL
◆ Hemoglobin >7 g/dL
◆ Normothermia
◆ Evacuate intracranial mass lesions
◆ Head of bed 30 degrees
Tier 1
◆ Adjust head of bed
◆ Ensure normothermia
◆ Titrate sedation to intracranial pressure
◆ Standard-dose hyperosmolar therapies
◆ CSF drainage if external ventricular drain available
◆ Consider EEG to rule out nonconvulsive seizures
◆ If intracranial pressure persistently >25 mm Hg, consider repeat CT
Tier 2
◆ High-dose hyperosmolar therapy
◆ Adjust PCO2 to 30-35 mm Hg
◆ Increased sedation to intracranial pressure target
◆ Vasopressor trial for increased cerebral perfusion pressure (70 mm Hg)
◆ Neuromuscular paralysis
◆ Consider EEG to rule out nonconvulsive seizures
◆ If intracranial pressure persistently >25 mm Hg, consider repeat CT
Tier 3
◆ Adjust temperature to 35 °C to 37 °C (95 °F to 98.6 °F)
◆ Sedative bolus dosing
◆ Decompressive craniectomy
◆ Barbiturate coma
◆ Consider EEG to rule out nonconvulsive seizures
◆ If intracranial pressure persistently >25 mm Hg, consider repeat CT

CSF = cerebrospinal fluid; CT = computed tomography; EEG = electroencephalogram.

a
Data from Carney N, et al, Neurosurgery.21

1286 OCTOBER 2021

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

developed evidence-based guidelines for the management of moderate to KEY POINTS
severe TBI.21 Extrapolated from these guidelines, a multitiered algorithmic
● Mechanistic classification
approach to patient care has been adopted to adequately minimize secondary of TBI includes closed head,
injury while reducing iatrogenic complications (TABLE 4-5) (CASE 4-2).30 penetrating head, crash, and
Tier 0 in the algorithm is aimed at primary prevention and prophylaxis of blast injuries.
secondary injury and is applied to all patients treated for TBI. Tiers 1 through 3
● Primary injury in TBI is
are aimed at interventions based on abnormalities in ICP, CPP, CBF, CMRO2,
defined as the initial
and cerebral autoregulation. The physiologic principles applied to the acute traumatic insult resulting in
management of TBI rely on underlying neuroanatomic knowledge, the hemorrhage, edema, and
principles of compartmentalization, and the Monro-Kellie doctrine. Specific axonal injury.
evidence for such interventions aimed at improving mortality and functional
● Secondary injury in TBI is
outcomes is discussed below. defined as injury related to
cellular and biochemical
Ventilator Management activation, including
Ventilator management in patients with moderate or severe TBI is an important inflammation, calcium
overload, free radical
physiologic concept that should be considered by all physicians. Intrathoracic formation, and blood-brain
pressure, oxygenation, and ventilation are all important for the neurologist to barrier breakdown.
understand as such factors have a direct role on ICP and CBF. It is common that
patients with higher-grade TBI have loss of airway reflexes and ventilatory drive. ● A severe TBI with Glasgow
Coma Scale score of 8 or
As such, the risk for aspiration with resulting hypoxia, and hyperventilation with
less with an abnormal CT
resulting hypercapnia, potentiates secondary brain injury. Ventilation in scan is an acute indication
particular is an important physiologic parameter used to augment CBF through for intracranial pressure
vasodilatory and constriction mechanisms in a direct fashion. As a result, monitoring.
decreases in ventilation produce hypercapnia and cerebral vasodilation with
● Neurocritical care for
subsequent increases in ICP. In the presence of mechanical ventilation with acute TBI follows a tiered
high-grade injuries, tight control of PCO2 within typical physiologic norms approach based on
(35 mm Hg to 45 mm Hg) is therefore necessary. The use of hyperventilation for consensus guidelines.
the treatment of acute elevations in ICP is, at times, appropriate in emergency
● Physiologic targets in the
situations; however, this should occur in a time-limited fashion so as not to risk
management of TBI include
cerebral ischemia from vasoconstriction and decreased CBF. In contrast, the use intracranial pressure,
of prophylactic hyperventilation in TBI with PCO2 targets less than 25 mm Hg is cerebral perfusion pressure,
not recommended because of this ischemic risk.21 Oxygenation targets with brain tissue oxygen tension,
and cerebral blood flow.
mechanical ventilation should remain within normal physiologic targets
(PaO2 >60 mm Hg) and, at times, can be augmented in specific patients with
intracranial PbtO2 monitoring. Finally, neurologists have a vital role in
determining long-term ventilatory strategies. Clinical acumen and objective
neurologic findings allow the clinician to assess anticipated neurologic burden
from the disease and assist in the decision for tracheostomy.

Hemodynamic Augmentation
CPP, CBF, and cerebral autoregulation play a critical role in the prevention of
secondary injury in patients with moderate and severe TBI. One singular isolated
episode of systolic hypotension (<90 mm Hg) in either the prehospital or acute
care setting is associated with worse functional outcomes and increased
mortality.31 Under normal physiologic circumstances, cerebral autoregulatory
mechanisms potentiate cerebral vasodilation or vasoconstriction to maintain an
adequate and constant CBF. In a patient with preserved autoregulation, CBF is
independent of systolic blood pressure and relies on cerebral myogenic,
neurogenic, and metabolic factors for maintenance. If such protective
autoregulatory mechanisms fail, CBF becomes completely dependent on systolic

CONTINUUMJOURNAL.COM 1287

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MODERATE AND SEVERE TRAUMATIC BRAIN INJURY

blood pressure and any elevation in ICP can be deleterious. Given this intricate
dependence of autoregulation for perfusion and its subsequent pathology with
autoregulatory failure, maintenance of tight systolic blood pressure and MAP
goals is essential in preventing secondary injury. Current recommendations
aimed at reducing secondary injury suggest that patients 50 to 69 years of age
should maintain a systolic blood pressure greater than 100 mm Hg, and patients
15 to 49 years of age or older than 70 years of age should maintain a systolic blood
pressure greater than 110 mm Hg at all times.21

Reversal of Coagulopathy
Acute coagulopathy is a common finding in moderate or severe TBI, found in
between 7% and 63% of patients.32 Etiologic considerations of coagulopathy include

CASE 4-2 A 22-year-old woman with a severe traumatic brain injury (TBI) secondary
to a motor vehicle accident was admitted to the intensive care unit. A
head CT was obtained and showed evidence of diffuse cerebral edema
and bifrontal contusions (FIGURE 4-4). Her Glasgow Coma Scale score on
admission was 5 T (eyes, 1; voice, 1 T; motor, 3, decorticate posturing).
An intracranial pressure (ICP) monitor was emergently placed.
In the 24 hours following admission, the patient’s ICP fluctuated
between 15 mm Hg and 20 mm Hg. Tier 0/1 TBI interventions were
performed, including normothermia, normonatremia, head of bed
elevation, sedation, and cerebral perfusion pressure (CPP) greater than
60 mm Hg. The neurointensivist was acutely called to the bedside
because of a newly discovered 5-minute episode of ICP elevation of
30 mm Hg. Mean arterial pressure (MAP) at this time was 70 mm Hg.
Emergent tier 2 interventions were indicated, so the patient was given
hypertonic saline, hyperventilated to a PCO2 of 30 mm Hg, and given bolus
dose sedation. Her ICP subsequently decreased to 25 mm Hg with a
decrease in the MAP to 65 mm Hg. The decision was made to
simultaneously administer vasopressors to support CPP, which resulted
in improvement to a MAP of 90 mm Hg; however, her ICP was also noted
to increase to 30 mm Hg. Neuromuscular paralysis was initiated and
improved ICP to 20 mm Hg. Given concerns for the acute rise in ICP with
relative refractory features, repeat imaging was obtained and showed an
acute epidural hemorrhage in the right frontal lobe. The patient was
emergently taken to the operating room for urgent decompressive
craniectomy and hematoma evacuation.

1288 OCTOBER 2021

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

anticoagulant or antiplatelet medications, endogenous anticoagulation, or coexistent
systemic trauma, which is its own independent risk factor for coagulopathy. Rapidly
progressive hemorrhagic deterioration, delayed deterioration, and progressive
intracranial hemorrhage are all associated with coagulopathy in the acute setting.33
Independent of clinical worsening, the presence of coagulopathy on admission is a
powerful prognostic predictor, with 9 times increased risk of mortality and 30 times
increased risk of unfavorable outcome.32 Treatment of coagulopathy in TBI should
consist of acute reversal mechanisms aimed at the underlying cause. Abrupt reversal
of systemic pharmacologic anticoagulation should be considered with either fresh
frozen plasma or prothrombin complex concentrates. The use of platelet transfusion
or desmopressin for patients on antiplatelet therapy is controversial; it has definite
risks, and no definitive mortality benefit has been shown.34

FIGURE 4-4
Imaging of the patient in CASE 4-2. Axial noncontrast head CT shows right temporal
contusion (A), diffuse cerebral edema and bifrontal contusions (B, C), and diffuse
traumatic subarachnoid hemorrhage (D).

The patient in this case presented with an acute ICP crisis. Based on the COMMENT
guidelines for the management of an acute ICP crisis, a tiered approach to
treatment was initiated. As is standard, tier 0 and tier 1 interventions had
been employed before the time of crisis. With an acute rise in ICP,
determination of etiology and acute management to prevent secondary
injury are of vital importance. In this case, tier 2 interventions, including
hyperosmolar fluids, hyperventilation, and bolus dose sedation, were used.
Such interventions resulted in improvement of the ICP; however, the MAP
decreased, resulting in a decreased CPP, which was treated with
vasopressors with an improvement in perfusion pressures. However, the
increase in MAP also resulted in an increase in ICP, alerting the examiner to
impaired cerebral autoregulation. As CPP remained greater than 60 mm Hg
with vasopressor use, neuromuscular paralysis was instituted to reach the
target ICP of less than 22 mm Hg. As ICP goals were deemed appropriate,
etiologic concerns dictated repeat neuroimaging, which revealed acute
epidural hemorrhage. Emergent evacuation was indicated and performed.
The events related to acute ICP crisis in this case are common in the
neurocritical care unit, making it relatively clear that early recognition and
prompt management can decrease secondary brain injury.

CONTINUUMJOURNAL.COM 1289

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MODERATE AND SEVERE TRAUMATIC BRAIN INJURY

Sedatives and Paralytics

Analgesics, anesthetics, sedatives, and paralytics are common interventions in
moderate and severe TBI aimed at reducing secondary brain injury. Medications
including propofol, midazolam, fentanyl, ketamine, and vecuronium are
common. Prevention of secondary injury through the use of such medications is
accomplished through several means, including reduction in CMRO2, reduction
in stimulus-induced ICP increases (ie, coughing), and reduction in free radical
oxygen formation.35 Although an effective strategy for targeted ICP therapy in
attempts to curb mortality, no singular sedative agent is more efficacious than
another, and no effective benefit on outcomes has been seen.36 Neurologists
should be very aware of such interventions because of the vast side effect profiles
of these medications. Complications include systemic hypotension, pulmonary
shunting, and depressed cardiac output leading to decreased perfusion pressure,
which can potentiate secondary brain injury. Sedative recommendations should
occur in conjunction with neurologic consultation in patients with TBI to ensure
safety and preservation of neurologic function. The use of barbiturates is also
a long-debated topic in the treatment of ICP and acute brain injury in TBI.
Trials investigating the use of barbiturates in TBI have assessed effective ICP
control, mortality, and 12-month outcomes. Data suggest that the use of
barbiturates in moderate or severe TBI lowers ICP values, has no effect on
mortality or functional outcomes, and results in systemic hypotension and
increased ICU length of stay.37-39 Increased ICU-related complications, such
as pneumonia and ileus, have also been associated with their use. Based on
these findings, neurologists should reserve the use of barbiturates for patients
whose ICP remains refractory to maximal medical interventions.21 The use of
neuromuscular paralytics in TBI is reserved for cases of refractory ICP and aims
at reducing the effective CMRO2.

CSF Drainage
The use of an external ventricular drain (EVD) as a means for CSF diversion
to treat elevated ICP in TBI relies on the physiologic principles of the
Monro-Kellie doctrine. The intracranial vault contents, including the brain
parenchyma, CSF, and arterial and venous blood, create a transcortical
pressure gradient commonly referred to as ICP. Based on the Monro-Kellie
doctrine, the use of CSF drainage attempts to reduce the relative pressure
exerted by CSF within the vault, effectively lowering ICP. Evidence to support
the use of CSF drainage to improve mortality and functional outcomes in TBI
is limited and of low quality.40 Although the effects of CSF drainage on
outcomes are limited, sufficient evidence is available to support patient
improvements in ICP, CPP, PbtO2, and cerebral metabolism.41 Although
potentially beneficial in mitigating secondary brain injury, EVD placement
and use is not without risk. Neurologists should be aware of the risks of tract
hemorrhage associated with drain placement and be vigilant in the assessment
of ventriculitis with acute neurologic deterioration. Ventriculitis resulting from
an EVD can occur in more than 20% of patients.42 Because of inflammation
caused by the drain itself and existing blood products within the ventricular
system, objective assessment of ventriculitis can be difficult. Classic findings of
bacterial infection, including CSF cell count, have limited diagnostic value. More
recently, CSF lactate and IL-6 have shown promise for diagnosing ventriculitis
when used in conjunction with CSF cell count.43,44 If concern for ventriculitis

1290 OCTOBER 2021

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

exists, empiric antibiotics should be administered and CSF cultures should KEY POINT
be obtained.
● Acute coagulopathy in TBI
is a powerful predictor of
Decompressive Craniectomy outcome and prognosis.
The use of decompressive craniectomy for the management of TBI has classically
been reserved for acute surgical lesions and cases of refractory ICP elevations.
The rationale for its use lies within the predescribed principles of
compartmentalization, ICP elevation, reduced cerebral blood flow, and
secondary brain injury. Primary decompressive craniectomy involves the acute
or early management of surgical lesions requiring evacuation, including epidural
and subdural hematomas and refractory ICP. Secondary decompressive
craniectomy refers to the late or delayed management of ICP refractory to
medical management. Two landmark trials (DECRA [Early Decompressive
Craniectomy in Patients With Severe Traumatic Brain Injury] and RESCUEicp
[Randomised Evaluation of Surgery with Craniectomy for Uncontrollable
Elevation of Intracranial Pressure]) evaluated the effectiveness of decompressive
craniectomy in early and late ICP elevations in TBI and compared mortality and
outcomes in each group. Findings from the DECRA trial suggested that an early
large bifrontal temporoparietal decompressive craniectomy decreased ICP values
but had no effect on mortality and increased unfavorable outcomes (vegetative
state).45 Findings from the RESCUEicp trial suggested that a smaller and later
unilateral decompressive craniectomy decreased ICP values, decreased
mortality, and provided an increased chance for functional independence.46
Based on this body of evidence, the current guidelines recommend late
decompressive craniectomy for refractory ICP to improve outcomes,
recommend against early decompressive craniectomy because of worsening of
outcomes, and suggest that both early and late decompressive craniectomy are
satisfactory interventions to reduce overall ICP burden.47

Other Interventions
Several other interventions aimed at reducing ICP and improving outcomes in
TBI have been explored, including the use of hypothermia to treat refractory ICP
to reduce secondary injury. Several studies exploring both prophylactic and
interventional hypothermia at multiple target temperatures have been
conducted. The current body of evidence suggests that hypothermia effectively
reduces ICP but does not improve outcomes.48,49
The use of glucocorticoids to reduce secondary injury in moderate to severe
TBI has also been explored. In the CRASH trial, which enrolled 10,000 patients to
placebo or intervention within 8 hours of presentation, mortality was higher in
the steroid arm at both 2 weeks and 6 months.50

GENERAL NEUROLOGIC MANAGEMENT OF MODERATE AND SEVERE

TRAUMATIC BRAIN INJURY
The neurologic care of patients with moderate or severe TBI typically occurs in
conjunction with other specialized services. The role of the neurologist is to aid in
the acute and subacute management of TBI to reduce secondary injury and
cognitive-behavioral burden and improve rehabilitation potential. Specific
evidence for such interventions, including seizure prophylaxis and management;
hyperosmolar therapies; and agitation, delirium, and behavior control, is
discussed in the sections that follow.

CONTINUUMJOURNAL.COM 1291

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MODERATE AND SEVERE TRAUMATIC BRAIN INJURY

Seizure Prophylaxis and Management

Symptomatic seizures are a frequent manifestation and common cause of
secondary brain injury in both moderate and severe TBI. These symptomatic
seizures are classified in dichotomous fashion as either early posttraumatic
seizures (<7 days) or late posttraumatic seizures (>7 days). The total prevalence
of clinical posttraumatic seizures ranges from 2% to 12% in patients with
moderate or severe TBI, with subclinical electrographic seizures occurring in up
to 30%.51,52 The presence of early posttraumatic seizures in TBI significantly
increases the probability of posttraumatic epilepsy and risks potentiation of
secondary brain injury due to physiologic abnormalities.53 To reduce this burden,
a 7-day course of a prophylactic antiseizure drug is recommended in all patients
with severe TBI.54,55 In addition, continuous EEG should be considered for up to
72 hours in all patients with moderate or severe TBI to monitor for subclinical
events that may worsen outcome or potentiate ICP. At present, in the absence of
seizure occurrence, no data support the use of prophylactic antiseizure drugs
after 7 days as no long-term benefit in late posttraumatic seizure reduction has
been seen and little is known about the progression of symptomatic seizures as
they relate to the ictal-interictal continuum.56

Hyperosmolar Therapies
The effect of hyperosmolar therapies on mortality and functional outcomes in
TBI has long been a controversial topic. The aim is to effectively reduce ICP with
attempts to maintain adequate CPP and CBF while avoiding iatrogenic
complications. The ultimate goal of such interventions is to drive acute osmolar
change rather than maintain hypertonicity to allow effective reductions in edema
during emergent situations. Mannitol and hypertonic saline are usually first-line
interventions in the management of acute deterioration; the use of each carries

TABLE 4-6 Blunt Cerebrovascular Injury Grading Scalea

Injury grade Vascular injury description

1 Vessel luminal irregularity
OR
dissection with <25% stenosis

2 Vessel dissection
OR
intramural thrombus with ≥25% stenosis

3 Dissecting
OR
pseudoaneurysm

4 Complete vascular occlusion

5 Complete vessel transection with contrast extravasation

a
Data from Biffl WL, et al, J Trauma.65

1292 OCTOBER 2021

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

the risk of adverse events, specifically, hypovolemia and osmotic nephropathy KEY POINT
with mannitol use and acute renal injury, metabolic acidosis, and pulmonary
● Treatments for refractory
edema with hypertonic saline. Evidence for the use of hyperosmolar therapies in intracranial pressure include
the management of TBI has classically focused on effective reduction of ICP with hyperosmolar fluids,
secondary outcomes focused on CPP, mortality, and functional improvement. To sedation, neuromuscular
date, studies have shown effective, yet isolated, reductions of ICP and paralysis, and surgical
decompression.
radiographic edema, with no evidence to support improvement in mortality or
neurologic outcomes.57-61 A 2020 study compared the effects of bolus dosing of
hypertonic saline and mannitol on elevated ICP burden and duration.62 The
findings showed superiority of hypertonic saline compared to mannitol in
reducing ICP burden and associated cerebral hypoperfusion. Outcome measures
for mortality and functional outcomes were not assessed. The recently published
COBI (Continuous Hyperosmolar Therapy for Brain-Injured Patients) trial
aimed to assess these differences and found no significant improvement in
6-month functional outcomes.63 At present, the use of hyperosmolar therapies in
moderate or severe TBI should be reserved for emergent settings of elevated ICP
or reduced CPP because of lack of evidence supporting improvement in outcome
and risk of adverse effects with their use.

Blunt Cerebrovascular Injury

Blunt cerebrovascular injury, or traumatic vascular injury, occurs in 9% to 17% of
severe TBI cases and has systemic implications based on severity of injury and
respective treatment modality.8,64 All patients presenting with moderate or
severe TBI should undergo CT angiography as a screening measure for diagnosis.
The severity of blunt cerebrovascular injury is graded on a scale of 1 to 5 from
dissection with luminal irregularity (1) to complete vessel transection (5)
(TABLE 4-6).65 The presence of blunt cerebrovascular injury in the acute setting
significantly increases the patient’s risk for stroke. Ischemic stroke occurs in 11%
of patients with blunt cerebrovascular injury, and such risks increase with the
level of injury severity.66 At present, guidelines suggest the use of antithrombotic
or antiplatelet medications, dependent on cerebrovascular injury severity, for
secondary stroke prophylaxis.67 Discussion among the neurologist and the
treatment team is imperative to ensure adequate selection of therapy.
Endovascular intervention for higher-grade lesions, including pseudoaneurysm
formation, may be necessary, and neurosurgical consultation should be
considered.

Cerebral Venous Sinus Thrombosis

Cerebral venous sinus thrombosis (CVST) is a common complication of
moderate and severe TBI. Thrombosis within venous structures typically
presents along fracture lines and occurs in up to 26% of patients with severe
TBI.68 Clinicians should have high suspicion of venous injury when patients have
multiple skull fractures. Diagnosis of CVST is typically made by CT venography;
however, frequent recognition is made during screening CT angiography for
blunt cerebrovascular injury. The presence of CVST in TBI significantly increases
the risk of in-hospital mortality by 10% and should be considered in diagnosis
when patients present with worsening cerebral edema or new intracranial
hemorrhage.69 The treatment of CVST in TBI remains controversial. Given the
common presence of intracranial hemorrhage in TBI, anticoagulation is
commonly contraindicated. Interventions such as antiplatelet therapy and deep

CONTINUUMJOURNAL.COM 1293

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MODERATE AND SEVERE TRAUMATIC BRAIN INJURY

venous thrombosis chemoprophylaxis can be considered, although no data exist

on their efficacy. In emergent situations, such as intracranial hemorrhage from
CVST, decompressive hemicraniectomy can be considered. Neurologists play a
vital role in this decision-making process and should weigh the potential risks
and benefits of any intervention for CVST in conjunction with the treatment
team.

Paroxysmal Sympathetic Hyperactivity

Paroxysmal sympathetic hyperactivity, defined as excessive sympathetic activity
after acute brain injury, includes paroxysms of symptoms such as tachycardia,
tachypnea, hyperthermia, hypertension, diaphoresis, and neurologic changes.70
Pathologically, paroxysmal sympathetic hyperactivity results from the loss of
inhibitory control of excitation, resulting in excessive sympathetic outflow.
Following TBI, paroxysmal sympathetic hyperactivity is a common occurrence,
with incidence between 8% and 10%.71 Although not an independent predictor of
morbidity or mortality, paroxysmal sympathetic hyperactivity is associated with
prolonged hospitalization and iatrogenic complications.72 Paroxysmal
sympathetic hyperactivity is often identified as “central fever” in patients with
TBI, and neurologists should be aware of this symptomatology as it manifests
with vital sign abnormalities but has its roots in a central neurologic disturbance.
The classic presentation of paroxysmal sympathetic hyperactivity occurs within 1
to 2 weeks following TBI, with paroxysms seen most commonly following
neurologic or noxious stimulation. The symptom-based Paroxysmal Sympathetic
Hyperactivity Assessment Measure is a tool that can be used to assess diagnostic
probability and for early identification of paroxysmal sympathetic
hyperactivity.73 The treatment of paroxysmal sympathetic hyperactivity
typically requires an individualized patient approach based on real-time
physiologic variables, including heart rate, respiratory rate, fever, and neurologic
examination, targeted at decreasing sympathetic drive. Multiple pharmacologic
agents are commonly needed to control paroxysms, including gabapentin,
bromocriptine, clonidine, propranolol, and opiates.74 The introduction of such
interventions should occur in a tiered manner with careful dose escalation and
assessment of response. For more information on paroxysmal sympathetic
hyperactivity, refer to the article “Autonomic Hyperactivity” by Alejandro A.
Rabinstein, MD, FAAN,75 in the February 2020 issue of Continuum.

Neurobehavioral Syndromes and Sleep-Wake Disorders

Neurobehavioral syndromes define a specific period of recovery following
moderate or severe TBI. Symptoms occur hours to weeks after emergence of
consciousness and include amnesia, agitation, impulsiveness, aggression,
delusions, and cognitive disturbance. The pathologic mechanisms behind such
disturbances relate to the secondary injurious effects of the catecholaminergic
and serotonergic systems in the brain.76 Several studies of pharmacologic efficacy
in neurobehavioral syndromes have been conducted, including the use of
propranolol, amantadine, sertraline, and atypical antipsychotics. Early initiation
of propranolol has shown improved survival and behavioral modification
following TBI, and the use of amantadine accelerates functional recovery,
reduces aggression, and improves cognitive outcomes.77,78 The use of sertraline
in neurobehavioral syndromes has been shown to reduce aggression, whereas the
use of neuroleptics such as olanzapine and quetiapine reduce the overall effects

1294 OCTOBER 2021

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

of neurobehavioral syndromes.79 α2-Adrenergic receptor agonists such as KEY POINTS
clonidine and dexmedetomidine have also been shown to reduce the severity of
● Early recognition and
neurobehavioral syndromes and provide neuroprotection in vitro.80,81 Further management of paroxysmal
prospective trials assessing the long-term benefit of these interventions are sympathetic hyperactivity
needed. following TBI can result in
Sleep-wake dysfunction is also a common sequela following TBI. Symptoms decreased length of stay
and decreased iatrogenic
such as insomnia and hypersomnia result from dysfunction within the reticulo-
complications.
hypothalamic-cortical system and can have lasting effects on functional quality
after injury. Insomnia and hypersomnias are reported in 30% to 60% of patients ● Management of
following TBI.82,83 Symptom-directed pharmacologic and cognitive-behavioral neurobehavioral syndromes
therapy are the mainstays of treatment for insomnia and parasomnias and following TBI is a key
component in improving
include the use of behavioral modifications and benzodiazepines.84 The use of long-term outcomes.
nonbenzodiazepines for the treatment of insomnia in TBI shows promise but
requires larger-scale studies to assess efficacy. The treatment of hypersomnias ● Determination of
following TBI includes the use of stimulants such as modafinil and prognosis of TBI is difficult
because of the
methylphenidate, which have shown significant improvements in daytime heterogeneity of the disease
sleepiness.84 and dynamic evolution of
pathologic processes.
PROGNOSIS IN TRAUMATIC BRAIN INJURY
● The management of
Prognostication in moderate and severe TBI remains difficult and complex.
refractory intracranial
Because of the heterogeneity and evolutionary pathology of TBI, creation of a pressure in pediatric
standardized approach to prognostication is difficult. In a 2019 study examining patients with TBI follows a
clinicians’ comfort with prognostication based on current TBI models, tiered approach similar to
assessments among neurologists, neurosurgeons, and intensivists were greatly that suggested for adult TBI,
with guidelines focused on
divided.85 At present, the CRASH and IMPACT models for prognostication in specific physiologic targets.
TBI are the most validated tools in the field. Each model aims to predict 6-month
outcomes following TBI based on objective data at a single point in time. The core
clinical predictors of outcome following admission for TBI in these models
include age, pupillary responses, and GCS motor score, which only accurately
predict 35% of all TBI outcomes.86 To attempt to reduce such variance, further
prognostic variables, including Marshall CT classification score, the presence of
subarachnoid hemorrhage, and laboratory values, were added to the outcome
prediction models. Although such objective measures improved the prediction
models, attempts to predict outcome at a single point in time remain difficult in
such a dynamic disease. Because of the risk of such confounding variables, the
recommended use of prognostic tools remains undefined in the current
guidelines. It is currently recommended that prognosis be attempted in the
context of real-time clinical care and objective data. At present, several clinical
validation studies into the use of biomarkers such as UCH-L1, S100B, and glial
fibrillary acidic protein (GFAP) for prognostication are ongoing.87 Further
research on models or data to support the dynamics of TBI are needed.

PEDIATRIC CONSIDERATIONS IN TRAUMATIC BRAIN INJURY

The worldwide incidence of pediatric TBI ranges between 47 per 100,000 and
280 per 100,000 children, with a similar pathologic distribution to the adult
population with 20% comprising moderate or severe TBI.88 The age of
distribution among the pediatric population follows a bimodal pattern (0 to
4 years and 15 to 18 years), with the leading injury mechanisms including motor
vehicle crashes, falls, and trauma.89 The acute care of pediatric patients with TBI
should include a dedicated pediatric ICU with dedicated specialists in brain

CONTINUUMJOURNAL.COM 1295

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MODERATE AND SEVERE TRAUMATIC BRAIN INJURY

injury. Similar to the adult TBI algorithm, physiologic management aimed at the
reduction of secondary brain injury is essential. Target variables such as ICP,
CPP, CBF, and PbtO2 are common in the pediatric literature. The current
guidelines for the management of moderate or severe pediatric TBI are published
by the Society of Critical Care Medicine and follow a tiered approach similar to
that suggested for the adult population, with slight alterations in physiologic
norms based on age and weight.90

CONCLUSION
Moderate and severe TBI are a heterogeneous, dynamic, and ever-evolving
group of diseases. Current clinical practice standards rely on a set of
evidence-based guidelines aimed at the reduction of secondary brain injury.
Early recognition, expedited resuscitation, physiologic stabilization, and
rehabilitation are the critical elements necessary in attempts to reduce mortality
and improve functional outcomes. Prognostic estimation in TBI remains difficult
and relies on objective data, clinical acumen, and expertise. Future directions in
TBI should include implementation of precision medicine, studies improving
functional outcomes, and development of individualized prognostic tools to
better serve the patient.

REFERENCES

1 Rubiano AM, Carney N, Chesnut R, Puyana JC.
Global neurotrauma research challenges and
opportunities. Nature 2015;527(7578):S193-S197.
doi:10.1038/nature16035
2 Iaccarino C, Carretta A, Nicolosi F, Morselli C.
Epidemiology of severe traumatic brain injury.
J Neurosurg Sci 2018;62(5):535-541. doi:10.23736/
S0390-5616.18.04532-0
3 Centers for Disease Control and Prevention.
Report to congress on traumatic brain injury in
the United States: epidemiology and
rehabilitation. Atlanta, GA: Division of
Unintentional Injury Prevention, National Center
for Injury Prevention and Control, 2015.
4 Nguyen R, Fiest KM, McChesney J, et al. The
international incidence of traumatic brain injury: a
systematic review and meta-analysis. Can J
Neurol Sci 2016;43(6):774-785. doi:10.1017/
cjn.2016.290
5 Capone-Neto A, Rizoli SB. Linking the chain of
survival: trauma as a traditional role model for
multisystem trauma and brain injury. Curr Opin
Crit Care 2009;15(4):290-294. doi:10.1097/
MCC.0b013e32832e383e
6 Peeters W, van den Brande R, Polinder S, et al.
Epidemiology of traumatic brain injury in Europe.
Acta Neurochir (Wien) 2015;157(10):1683-1696.
doi:10.1007/s00701-015-2512-7
7 Taylor CA, Bell JM, Breiding MJ, Xu L. Traumatic
brain injury-related emergency department
visits, hospitalizations, and deaths - United
States, 2007 and 2013. MMWR Surveill Summ
2017;66(9):1-16. doi:10.15585/mmwr.ss6609a1
8 Maas AIR, Stocchetti N, Bullock R. Moderate and
severe traumatic brain injury in adults. Lancet
Neurol 2008;7(8):728-741. doi:10.1016/S1474-
4422(08)70164-9
9 Marshall LF, Marshall SB, Klauber MR, et al. The
diagnosis of head injury requires a classification
based on computed axial tomography.
J Neurotrauma 1992;9(suppl 1):S287-S292.
10 Maas AIR, Hukkelhoven CWPM, Marshall LF,
Steyerberg EW. Prediction of outcome in
traumatic brain injury with computed
tomographic characteristics: a comparison
between the computed tomographic
classification and combinations of computed
tomographic predictors. Neurosurgery 2005;
57(6):1173-1182; discussion 1173-1182. doi:10.1227/
01.neu.0000186013.63046.6b
11 Butcher I, McHugh GS, Lu J, et al. Prognostic
value of cause of injury in traumatic brain injury:
results from the IMPACT study. J Neurotrauma
2007;24(2):281-286. doi:10.1089/neu.2006.0030

1296 OCTOBER 2021

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

12 Roozenbeek B, Lingsma HF, Lecky FE, et al.
Prediction of outcome after moderate and
severe traumatic brain injury: external validation
of the International Mission on Prognosis and
Analysis of Clinical Trials (IMPACT) and Corticoid
Randomisation After Significant Head injury
(CRASH) prognostic models. Crit Care Med 2012;
40(5):1609-1617. doi:10.1097/CCM.
0b013e31824519ce
13 Corps KN, Roth TL, McGavern DB. Inflammation
and neuroprotection in traumatic brain injury.
JAMA Neurol 2015;72(3):355-362. doi:10.1001/
jamaneurol.2014.3558
14 Smits M, Dippel DWJ, Steyerberg EW, et al.
Predicting intracranial traumatic findings on
computed tomography in patients with minor
head injury: the CHIP prediction rule. Ann Intern
Med 2007;146(6):397-405. doi:10.7326/0003-
4819-146-6-200703200-00004
15 Narayan RK, Maas AIR, Servadei F, et al.
Progression of traumatic intracerebral hemorrhage:
a prospective observational study. J Neurotrauma
2008;25(6):629-639. doi:10.1089/neu.2007.0385
16 Kreitzer N, Lyons MS, Hart K, et al. Repeat
neuroimaging of mild traumatic brain-injured
patients with acute traumatic intracranial
hemorrhage: clinical outcomes and radiographic
features. Acad Emerg Med 2014;21(10):1083-1091.
doi:10.1111/acem.12479
17 Servadei F, Murray GD, Penny K, et al. The value
of the “worst” computed tomographic scan in
clinical studies of moderate and severe head
injury. European Brain Injury Consortium.
Neurosurgery 2000;46(1):70-75; discussion 75-77.
doi:10.1097/00006123-200001000-00014
18 Chang EF, Meeker M, Holland MC. Acute
traumatic intraparenchymal hemorrhage: risk
factors for progression in the early post-injury
period. Neurosurgery 2006;58(4):647-656;
discussion 647-656. doi:10.1227/01.
NEU.0000197101.68538.E6
19 Aries MJH, Czosnyka M, Budohoski KP, et al.
Continuous determination of optimal cerebral
perfusion pressure in traumatic brain injury. Crit
Care Med 2012;40(8):2456-2463. doi:10.1097/
CCM.0b013e3182514eb6
20 Rosner MJ, Rosner SD, Johnson AH. Cerebral
perfusion pressure: management protocol and
clinical results. J Neurosurg 1995;83(6):949-962.
doi:10.3171/jns.1995.83.6.0949
21 Carney N, Totten AM, O'Reilly C, et al. Guidelines
for the management of severe traumatic brain
injury, fourth edition. Neurosurgery 2017;80(1):
6-15. doi:10.1227/NEU.0000000000001432
22 Narayan RK, Becker DP. Selection of patients for
ICP monitoring. J Neurosurg 1985;62(4):624-625.
doi:10.3171/jns.1985.62.4.0624
23 O'Phelan KH, Park D, Efird JT, et al. Patterns of
increased intracranial pressure after severe
traumatic brain injury. Neurocrit Care 2009;10(3):
280-286. doi:10.1007/s12028-008-9183-7
CONTINUUMJOURNAL.COM
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
24 Menon DK, Coles JP, Gupta AK, et al. Diffusion
limited oxygen delivery following head injury. Crit
Care Med 2004;32(6):1384-1390. doi:10.1097/01.
ccm.0000127777.16609.08
25 Jaeger M, Soehle M, Schuhmann MU, et al.
Correlation of continuously monitored regional
cerebral blood flow and brain tissue oxygen.
Acta Neurochir (Wien) 2005;147(1):51-56;
discussion 56. doi:10.1007/s00701-004-0408-z
26 Okonkwo DO, Shutter LA, Moore C, et al. Brain
oxygen optimization in severe traumatic brain
injury phase-II: a phase II randomized trial. Crit
Care Med 2017;45(11):1907-1914. doi:10.1097/
CCM.0000000000002619
27 Brain oxygen optimization in severe TBI,
phase 3 (BOOST3). ClinicalTrials.gov identifier:
NCT03754114. Updated March 24, 2021. Accessed
June 17, 2021. clinicaltrials.gov/ct2/show/
NCT03754114
28 Lin C-M, Lin M-C, Huang S-J, et al. A prospective
randomized study of brain tissue oxygen
pressure-guided management in moderate and
severe traumatic brain injury patients. Biomed
Res Int 2015;2015:529580. doi:
10.1155/2015/529580
29 Le Roux P, Menon DK, Citerio G, et al. Consensus
summary statement of the International
Multidisciplinary Consensus Conference on
Multimodality Monitoring in Neurocritical Care: a
statement for healthcare professionals from the
Neurocritical Care Society and the European
Society of Intensive Care Medicine. Neurocrit
Care 2014;21(suppl 2):S1-S26. doi:10.1007/s12028-
014-0041-5
30 Hawryluk GWJ, Aguilera S, Buki A, et al. A
management algorithm for patients with
intracranial pressure monitoring: the Seattle
International Severe Traumatic Brain Injury
Consensus Conference (SIBICC). Intensive
Care Med 2019;45(12):1783-1794. doi:10.1007/
s00134-019-05805-9
31 Chesnut RM, Marshall LF, Klauber MR, et al. The
role of secondary brain injury in determining
outcome from severe head injury. J Trauma 1993;
34(2):216-222. doi:10.1097/00005373-199302000-
00006
32 Maegele M, Schöchl H, Menovsky T, et al.
Coagulopathy and haemorrhagic progression in
traumatic brain injury: advances in mechanisms,
diagnosis, and management. Lancet Neurol 2017;
16(8):630-647. doi:10.1016/S1474-4422(17)30197-7
33 Yuan Q, Sun YR, Wu X, et al. Coagulopathy in
traumatic brain injury and its correlation with
progressive hemorrhagic injury: a systematic
review and meta-analysis. J Neurotrauma 2016;
33(14):1279-1291. doi:10.1089/neu.2015.4205
34 Thorn S, Güting H, Mathes T, et al. The effect of
platelet transfusion in patients with traumatic
brain injury and concomitant antiplatelet use: a
systematic review and meta-analysis.
Transfusion 2019;59(11):3536-3544. doi:10.1111/
trf.15526
1297
MODERATE AND SEVERE TRAUMATIC BRAIN INJURY
35 Bilotta F, Gelb AW, Stazi E, et al. Pharmacological
perioperative brain neuroprotection: a
qualitative review of randomized clinical trials.
Br J Anaesth 2013;110(suppl 1):i113-i120.
doi:10.1093/bja/aet059
36 Roberts DJ, Hall RI, Kramer AH, et al. Sedation for
critically ill adults with severe traumatic brain
injury: a systematic review of randomized
controlled trials. Crit Care Med 2011;39(12):
2743-2751. doi:10.1097/CCM.0b013e318228236f
37 Ward JD, Becker DP, Miller JD, et al. Failure of
prophylactic barbiturate coma in the treatment
of severe head injury. J Neurosurg 1985;62(3):
383-388. doi:10.3171/jns.1985.62.3.0383
38 Eisenberg HM, Frankowski RF, Contant CF, et al.
High-dose barbiturate control of elevated
intracranial pressure in patients with severe head
injury. J Neurosurg 1988;69(1):15-23. doi:10.3171/
jns.1988.69.1.0015
39 Roberts I, Sydenham E. Barbiturates for acute
traumatic brain injury. Cochrane Database Syst
Rev 2012;12(12):CD000033. doi:10.1002/14651858.
CD000033.pub2
40 Chau CYC, Craven CL, Rubiano AM, et al. The
evolution of the role of external ventricular
drainage in traumatic brain injury. J Clin Med 2019;
8(9):1422. doi:10.3390/jcm8091422
41 Timofeev I, Dahyot-Fizelier C, Keong N, et al.
Ventriculostomy for control of raised ICP in
acute traumatic brain injury. Acta Neurochir
Suppl 2008;102:99-104. doi:10.1007/978-3-211-
85578-2_20
42 Dorresteijn KRIS, Jellema K, van de Beek D,
Brouwer MC. Factors and measures predicting
external CSF drain-associated ventriculitis: a
review and meta-analysis. Neurology 2019;93(22):
964-972. doi:10.1212/WNL.0000000000008552
43 Lenski M, Biczok A, Neufischer K, et al.
Significance of cerebrospinal fluid inflammatory
markers for diagnosing external ventricular
drain-associated ventriculitis in patients with
severe traumatic brain injury. Neurosurg Focus
2019;47(5):E15. doi:10.3171/2019.8.FOCUS19407
44 Hill E, Bleck TP, Singh K, et al. CSF lactate alone is
not a reliable indicator of bacterial ventriculitis in
patients with ventriculostomies. Clin Neurol
Neurosurg 2017;157:95-98. doi:10.1016/j.
clineuro.2017.03.021
45 Cooper DJ, Rosenfeld JV, Murray L, et al.
Decompressive craniectomy in diffuse traumatic
brain injury. N Engl J Med 2011;364(16):1493-1502.
doi:10.1056/NEJMoa1102077
46 Hutchinson PJ, Kolias AG, Timofeev IS, et al. Trial
of decompressive craniectomy for traumatic
intracranial hypertension. N Engl J Med 2016;
375(12):1119-1130. doi:10.1056/NEJMoa1605215
47 Hawryluk GWJ, Rubiano AM, Totten AM, et al.
Guidelines for the management of severe
traumatic brain injury: 2020 update of the
decompressive craniectomy recommendations.
Neurosurgery 2020;87(3):427-434. doi:10.1093/
neuros/nyaa278
1298
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
48 Clifton GL, Valadka A, Zygun D, et al. Very early
hypothermia induction in patients with severe
brain injury (the National Acute Brain Injury Study:
Hypothermia II): a randomised trial. Lancet
Neurol 2011;10(2):131-139. doi:10.1016/S1474-
4422(10)70300-8
49 Andrews PJD, Sinclair HL, Rodriguez A, et al.
Hypothermia for intracranial hypertension after
traumatic brain injury. N Engl J Med 2015;373(25):
2403-2412. doi:10.1056/NEJMoa1507581
50 Roberts I, Yates D, Sandercock P, et al. Effect of
intravenous corticosteroids on death within
14 days in 10008 adults with clinically significant
head injury (MRC CRASH trial): randomised
placebo-controlled trial. Lancet 2004;364(9442):
1321-1328. doi:10.1016/S0140-6736(04)17188-2
51 Annegers JF, Hauser WA, Coan SP, Rocca WA. A
population-based study of seizures after
traumatic brain injuries. N Engl J Med 1998;338(1):
20-24. doi:10.1056/NEJM199801013380104
52 Herman ST, Abend NS, Bleck TP, et al. Consensus
statement on continuous EEG in critically ill
adults and children, part I: indications. J Clin
Neurophysiol 2015;32(2):87-95. doi:10.1097/
WNP.0000000000000166
53 Ritter AC, Wagner AK, Fabio A, et al. Incidence
and risk factors of posttraumatic seizures
following traumatic brain injury: a traumatic brain
injury model systems study. Epilepsia 2016;57(12):
1968-1977. doi:10.1111/epi.13582
54 Temkin NR, Dikmen SS, Wilensky AJ, et al. A
randomized, double-blind study of phenytoin for
the prevention of post-traumatic seizures. N Engl
J Med 1990;323(8):497-502. doi:10.1056/
NEJM199008233230801
55 Inaba K, Menaker J, Branco BC, et al. A
prospective multicenter comparison of
levetiracetam versus phenytoin for early
posttraumatic seizure prophylaxis. J Trauma
Acute Care Surg 2013;74(3):766-773. doi:10.1097/
TA.0b013e3182826e847
56 Chang BS, Lowenstein DH. Practice parameter:
antiepileptic drug prophylaxis in severe
traumatic brain injury: report of the Quality
Standards Subcommittee of the American
Academy of Neurology. Neurology 2003;60(1):
10-16. doi:10.1212/01.wnl.0000031432.05543.14
57 Vialet R, Albanèse J, Thomachot L, et al.
Isovolume hypertonic solutes (sodium chloride
or mannitol) in the treatment of refractory
posttraumatic intracranial hypertension: 2 mL/kg
7.5% saline is more effective than 2 mL/kg 20%
mannitol. Crit Care Med 2003;31(6):1683-1687.
doi:10.1097/01.CCM.0000063268.91710.DF
58 Battison C, Andrews PJD, Graham C, Petty T.
Randomized, controlled trial on the effect of a
20% mannitol solution and a 7.5% saline/6%
dextran solution on increased intracranial
pressure after brain injury. Crit Care Med 2005;
33(1):196-202; discussion 257-258. doi:10.1097/01.
ccm.0000150269.65485.a6
OCTOBER 2021
59 Cottenceau V, Masson F, Mahamid E, et al.
Comparison of effects of equiosmolar doses of
mannitol and hypertonic saline on cerebral blood
flow and metabolism in traumatic brain injury.
J Neurotrauma 2011;28(10):2003-2012. doi:10.1089/
neu.2011.1929
60 Sakellaridis N, Pavlou E, Karatzas S, et al.
Comparison of mannitol and hypertonic saline in
the treatment of severe brain injuries.
J Neurosurg 2011;114(2):545-548. doi:
10.3171/2010.5.JNS091685
61 Oddo M, Levine JM, Frangos S, et al. Effect of
mannitol and hypertonic saline on cerebral
oxygenation in patients with severe traumatic
brain injury and refractory intracranial
hypertension. J Neurol Neurosurg Psychiatry
2009;80(8):916-920. doi:10.1136/jnnp.2008.156596
62 Mangat HS, Wu X, Gerber LM, et al. Hypertonic
saline is superior to mannitol for the combined
effect on intracranial pressure and cerebral
perfusion pressure burdens in patients with
severe traumatic brain injury. Neurosurgery 2020;
86(2):221-230. doi:10.1093/neuros/nyz046
63 Roquilly A, Moyer JD, Huet O, et al. Effect of
continuous infusion of hypertonic saline vs
standard care on 6-month neurological
outcomes in patients with traumatic brain injury:
the COBI randomized clinical trial. JAMA 2021;
325(20):2056-2066. doi:10.1001/jama.2021.5561
64 Esnault P, Cardinale M, Boret H, et al. Blunt
cerebrovascular injuries in severe traumatic brain
injury: incidence, risk factors, and evolution.
J Neurosurg 2017;127(1):16-22. doi:10.3171/2016.4.
JNS152600
65 Biffl WL, Moore EE, Offner PJ, et al. Blunt carotid
arterial injuries: implications of a new grading
scale. J Trauma 1999;47(5):845-853.
doi:10.1097/00005373-199911000-00004
66 Weber CD, Lefering R, Kobbe P, et al. Blunt
cerebrovascular artery injury and stroke in
severely injured patients: an international
multicenter analysis. World J Surg 2018;42(7):
2043-2053. doi:10.1007/s00268-017-4408-6
67 Cothren CC, Biffl WL, Moore EE, et al. Treatment
for blunt cerebrovascular injuries: equivalence of
anticoagulation and antiplatelet agents. Arch
Surg 2009;144(7):685-690. doi:10.1001/
archsurg.2009.111
68 Bokhari R, You E, Bakhaidar M, et al. Dural venous
sinus thrombosis in patients presenting with
blunt traumatic brain injuries and skull fractures:
a systematic review and meta-analysis. World
Neurosurg 2020;142:495.e3-505.e3. doi:10.1016/j.
wneu.2020.06.117
69 Qureshi AI, Sahito S, Liaqat J, et al. Traumatic
injury of major cerebral venous sinuses
associated with traumatic brain injury or head
and neck trauma: analysis of national trauma data
bank. J Vasc Interv Neurol 2020;11(1):27-33.
CONTINUUMJOURNAL.COM
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
70 Rabinstein AA. Paroxysmal sympathetic
hyperactivity in the neurological intensive care
unit. Neurol Res 2007;29(7):680-682. doi:
10.1179/016164107X240071
71 Fernandez-Ortega JF, Prieto-Palomino MA,
Garcia-Caballero M, et al. Paroxysmal
sympathetic hyperactivity after traumatic brain
injury: clinical and prognostic implications.
J Neurotrauma 2012;29(7):1364-1370. doi:10.1089/
neu.2011.2033
72 Perkes I, Baguley IJ, Nott MT, Menon DK. A review
of paroxysmal sympathetic hyperactivity after
acquired brain injury. Ann Neurol 2010;68(2):
126-135. doi:10.1002/ana.22066
73 Baguley IJ, Perkes IE, Fernandez-Ortega JF, et al.
Paroxysmal sympathetic hyperactivity after
acquired brain injury: consensus on conceptual
definition, nomenclature, and diagnostic criteria.
J Neurotrauma 2014;31(17):1515-1520. doi:10.1089/
neu.2013.3301
74 Zheng R-Z, Lei Z-Q, Yang R-Z, et al. Identification
and management of paroxysmal sympathetic
hyperactivity after traumatic brain injury. Front
Neurol 2020;11:81. doi:10.3389/fneur.2020.00081
75 Rabinstein AA. Autonomic hyperactivity.
Continuum (Minneap Minn) 2020;
26(1, Autonomic Disorders):138-153.
doi:10.1212/CON.0000000000000811
76 McAllister TW. Neurobehavioral sequelae of
traumatic brain injury: evaluation and
management. World Psychiatry 2008;7(1):3-10.
doi:10.1002/j.2051-5545.2008.tb00139.x
77 Ley EJ, Leonard SD, Barmparas G, et al. Beta
blockers in critically ill patients with traumatic
brain injury: results from a multicenter,
prospective, observational American Association
for the Surgery of Trauma study. J Trauma Acute
Care Surg 2018;84(2):234-244. doi:10.1097/
TA.0000000000001747
78 Giacino JT, Whyte J, Bagiella E, et al. Placebo-
controlled trial of amantadine for severe
traumatic brain injury. N Engl J Med 2012;366(9):
819-826. doi:10.1056/NEJMoa1102609
79 Hicks AJ, Clay FJ, Hopwood M, et al. The efficacy
and harms of pharmacological interventions for
aggression after traumatic brain
injury-systematic review. Front Neurol 2019;10:
1169. doi:10.3389/fneur.2019.01169
80 Meyfroidt G, Baguley IJ, Menon DK. Paroxysmal
sympathetic hyperactivity: the storm after acute
brain injury. Lancet Neurol 2017;16(9):721-729.
doi:10.1016/S1474-4422(17)30259-4
81 Schoeler M, Loetscher PD, Rossaint R, et al.
Dexmedetomidine is neuroprotective in an in
vitro model for traumatic brain injury.
BMC Neurol 2012;12:20. doi:10.1186/1471-
2377-12-20
82 Ouellet MC, Beaulieu-Bonneau S, Morin CM.
Insomnia in patients with traumatic brain injury:
frequency, characteristics, and risk factors.
J Head Trauma Rehabil 2006;21(3):199-212.
doi:10.1097/00001199-200605000-00001
1299
MODERATE AND SEVERE TRAUMATIC BRAIN INJURY
83 Imbach LL, Valko PO, Li T, et al. Increased sleep
need and daytime sleepiness 6 months after
traumatic brain injury: a prospective controlled
clinical trial. Brain 2015;138(pt 3):726-735. doi:
10.1093/brain/awu391
84 Sandsmark DK, Elliott JE, Lim MM. Sleep-wake
disturbances after traumatic brain injury:
synthesis of human and animal studies. Sleep
2017;40(5):zsx044. doi:10.1093/sleep/zsx044
85 Pratt AK, Chang JJ, Sederstrom NO. A fate worse
than death: prognostication of devastating brain
injury. Crit Care Med 2019;47(4):591-598. doi:
10.1097/CCM.0000000000003647
86 Dijkland SA, Foks KA, Polinder S, et al. Prognosis
in moderate and severe traumatic brain injury: a
systematic review of contemporary models and
validation studies. J Neurotrauma 2020;37(1):1-13.
doi:10.1089/neu.2019.6401
1300
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
87 Wang KK, Yang Z, Zhu T, et al. An update on
diagnostic and prognostic biomarkers for
traumatic brain injury. Expert Rev Mol Diagn 2018;
18(2):165-180. doi:10.1080/14737159.2018.1428089
88 Dewan MC, Mummareddy N, Wellons JC 3rd,
Bonfield CM. Epidemiology of global pediatric
traumatic brain injury: qualitative review. World
Neurosurg 2016;91:497.e1-509.e1. doi:10.1016/j.
wneu.2016.03.045
89 Majdan M, Mauritz W, Rusnak M, et al. Long-term
trends and patterns of fatal traumatic brain
injuries in the pediatric and adolescent
population of Austria in 1980-2012: analysis of
33 years. J Neurotrauma 2014;31(11):1046-1055.
doi:10.1089/neu.2013.3200
90 Kochanek PM, Tasker RC, Bell MJ, et al.
Management of pediatric severe traumatic brain
injury: 2019 consensus and guidelines-based
algorithm for first and second tier therapies.
Pediatr Crit Care Med 2019;20(3):269-279.
doi:10.1097/PCC.0000000000001737
OCTOBER 2021