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© 2018 EDIZIONI MINERVA MEDICA Journal of Neurosurgical Sciences 2018 October;62(5):542-8

Online version at http://www.minervamedica.it DOI: 10.23736/S0390-5616.18.04501-0

REVIEW
S E V E R E T R A U M AT I C B R A I N I N J U R Y

Pathophysiology of severe traumatic brain injury

Ruth A. O’LEARY 1, Alistair D. NICHOL 1, 2, 3 *

1Department of Intensive Care Medicine, Alfred Hospital, Melbourne, Australia; 2Australia and New Zealand Intensive Care-Research
Center, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia; 3University College Dublin Clinical
Research Centre, St Vincent’s University Hospital, Dublin, Ireland
*Corresponding author: Alistair D. Nichol, Department of Intensive Care Medicine, Alfred Hospital, Melbourne, Australia.
E-mail: alistair.nichol@monash.edu

A B S T RAC T
Traumatic brain injury is a leading cause of morbidity and mortality globally, particularly among young people, with significant social and
economic effects. The World Health Organization (WHO) estimates that more than five million people die each year from traumatic injuries
worldwide. While public health initiatives such as seatbelts and airbags have had a major impact, it will be impossible to prevent traumatic brain
injury.Therefore, it is important that we understand the pathophysiology of secondary brain injury to be able to effectively treat our patient and
also to develop novel targets of future interventions. The mechanisms of secondary brain injury are complex involving alterations in cerebral
perfusion, activation of inflammatory cytokines and excitotoxicity. While our understanding of these mechanisms has advanced greatly over
the last decade, there is still much to learn and great uncertainty at the bedside. There has been some recent success with the discovery of some
simple interventions that can reduce secondary brain injury and improve outcomes in patients after traumatic brain injury. In this review we
summarize the current understanding of mechanisms and pathophysiology of primary and secondary brain injury, the goals for current treatment
and potential targets for future therapy.
(Cite this article as: O’Leary RA, Nichol AD. Pathophysiology of severe traumatic brain injury. J Neurosurg Sci 2018;62:542-8. DOI: 10.23736/
S0390-5616.18.04501-0)
Key words: Traumatic brain injuries - Pathophysiology - Cerebrovascular circulation - Neurogenic inflammation.

T he World Health Organization (WHO) estimates that

more than five million people die each year from
traumatic injuries worldwide.1 These represent 9% of all
Classification of traumatic brain injury

TBI may be classified in a number of different ways. It was

deaths and are 1.7 times the number of fatalities that re-
sult from HIV/AIDS, tuberculosis and malaria combined.1
Over 1.3 million of these deaths are a result of road trauma:
by 2020 this is projected to increase to over 2 million.2
Traumatic brain injury (TBI) is the leading cause of mor-
tality in young people and as a result it has significant so-
cial and economic impact: globally the estimated annual
cost of road trauma alone is estimated to be in excess of $
500 billion.3 We summarize the current understanding of
mechanisms and pathophysiology of primary and second-
ary brain injury, the goals for current treatment and poten-
tial targets for future therapy.
initially understood in terms of its effect on level of con-
sciousness and clinical scores were used to classify TBI on
this basis. The Glasgow Coma Scale (GCS) has been used
to classify TBIs according to severity — mild (GCS 14-15),
moderate (GCS 9-13), or severe (GCS 3-8).4 This scale is
made up of verbal, eye and motor responses to increasing
stimulus and has been in use for more than forty years and
still appears to have adequate reliability to determine long
term outcome.5 For accurate assessment the components of
the scale should be reported separately rather than as a sum
score. This is because the sum score is less reliable than the
component scores5 and also because the motor component

542 Journal of Neurosurgical Sciences October 2018

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PATHOPHYSIOLOGY OF SEVERE TBI O’LEARY
in its own right is a predictor of outcome in severe TBI.6
However, in the hospital setting clinical classification of
TBI may be of limited use due to confounding factors such
as sedation.7, 8 In view of this other means of classification
have become widely adopted in both research and clinical
practice over the last number of years.
Radiological classification is commonly used to aid in
the prediction of prognosis. The presence of a number of
individual features such as midline shift and subarachnoid
hemorrhage are predictive of outcome in severe TBI9 and
in addition to this a number of classification systems are in
use. The Marshall classification system10 has been widely
used for over 15 years. It divides TBI into six categories
— diffuse 1-4 with progressive amounts of compression,
midline shift and mixed-density lesions and mass lesions
either evacuated or non-evacuated. It is useful in that it
describes the injuries on the brain but it has a number of
limitations. Firstly, it cannot be used as a grading system
as mortality does not increase with each grade. Specifi-
cally the mortality for class 5 (an evacuated mass lesion)
is predictably lower than for class 6 (an unevacuated mass
lesion).11 In addition to this, it fails to differentiate between
different types of hematoma and discounts traumatic sub-
arachnoid hemorrhage entirely. Due to these shortcomings
the Rotterdam scoring system was developed — a linear
grading system that correlates with increasing mortality.12
Both scores correlate with mortality and with each other
and are used widely. Finally, a number of different prog-
nostic models have been developed based on admission
criteria. These have been developed from large patient
groups, such as those participating in the CRASH and IM-
PACT trial groups6, 13 and take into account demographic
data, clinical and radiological findings and the presence
of extracranial injuries. These models have found asso-
ciations between age, motor score and pupillary responses
and outcome at 6 months. The addition of CT findings,
specifically the presence of subarachnoid blood, hemato-
ma and mass lesion and compression of the basal cisterns,
improves the predictive power of the model.6 Although the
models developed from these large patient cohorts allow
classification by predicted outcome and may be of use on
an organizational level, they should be used to augment
rather than replace clinical judgement.14
Primary brain injury
Primary brain injury occurs when an external force results
in brain damage, which may be focal or diffuse. The pat-
tern of damage seen differs according to the mechanism of
Vol. 62 - No. 5 Journal of Neurosurgical Sciences 543
injury, although commonly focal and diffuse injuries co-
exist.15 Injuries resulting from a direct impact (e.g. closed
injury from focal blow or crush injury, penetrating wound)
are characteristically focal, presenting as contusions or
hematomas. Focal contusions are the most common pre-
senting lesion but intracranial hematomas may occur in up
to 35% of patients with severe TBI.4, 15 These are readily
visible on radiological imaging studies and may be graded
using the classification systems discussed above.10, 12 Ac-
celeration and deceleration injuries are associated with
more diffuse injuries related to rotational, shearing forc-
es.15 These may not manifest in radiological abnormalities
initially although there may be vascular damage at higher
shear rates, leading to microhemorrhages.4 Diffuse axonal
injuries may result from these acceleration/deceleration
injuries and are characterized by coma and poor outcome
despite benign radiological appearances.
Secondary brain injury
Secondary brain injury results from a complex cascade of
events. Alterations in cerebral blood flow and metabolic
dysfunction are associated with poor outcomes. In addi-
tion to this, TBI leads to immune activation with the re-
lease of excitatory neurotransmitters and inflammatory cy-
tokines. Our understanding of this complex interplay has
improved significantly since the start of the millennium
and the mechanisms detailed below have provided new
therapeutic targets.
Cerebral perfusion
Alterations in cerebral blood flow (CBF) are commonly
seen in the setting of traumatic brain injury. Inadequate
CBF leads to ischemia and consequently worse outcomes
with increased morbidity and mortality. These changes re-
sult from complex interactions between systemic hypoten-
sion, impaired autoregulation, raised intracranial pressure
(ICP) and vasospasm (Figure 1).16
It is well-recognized that TBI frequently results in hy-
poperfusion leading to cerebral ischemia. This may be fo-
cal or global and has been established by multiple different
imaging modalities.17, 18 Cerebral ischemia in this setting
occurs due to a number of different mechanisms including
direct injury to vessels, mechanical compression, hypoten-
sion and reduced perfusion due to failure of autoregula-
tion.19 Of note ischemia occurs at a higher rate of CBF
than is found in ischemic stroke,20 even though cerebral
metabolic rate for oxygen is reduced after severe TBI.21-23
 ©
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cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
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O’LEARY PATHOPHYSIOLOGY OF SEVERE TBI
Intracranial pressure
Mass lesion size
Figure 1.—The Monro Kellie hypothesis: this schema describes the re-
lationship between the non-compressible components of the intracranial
volume. The skull is a rigid compartment so an increase in the volume
of brain tissue, CSF or blood must result either in a decrease in the other
two components or an increase in intracranial pressure.
In addition to hypoperfusion, patients with TBI may also
develop cerebral hyperperfusion, which is similarly detri-
mental. This leads to increased cerebral blood volume and
consequently increased ICP.24
CBF is normally tightly autoregulated — blood vessels
constrict or dilate to maintain a constant blood flow be-
tween mean arterial pressure ranges of 50-150 mmHg.25, 26
This autoregulation is impaired after TBI so CBF directly
correlates with MAP. As a result, patients are much more
susceptible to hypoperfusion after traumatic insults. Im-
pairment in autoregulation may occur immediately after
the event or it may develop over time and it may persist for
a variable amount of time. Autoregulation is more likely to
be impaired in response to decreased MAP, suggesting that
patients post TBI are less likely to tolerate hypotension.16
Cerebrovascular response to changes in CO2 is relatively
preserved even in severe TBI, suggesting it as a target for
ICP management. However, multiple studies have shown
that arterial vasoconstriction in response to hypocapnia leads
to worse outcomes due to cerebral hypoperfusion, rebound
intracranial hypertension on restoration of normocapnia and
N-methyl-D-aspartate-receptor-mediated neurotoxicity.27 In
view of this hypocapnia is recommended only as emergent
management of life-threatening ICP rises.
Vasospasm is well-described after subarachnoid hemor-
rhage and is associated with poor outcomes.28 A similar
picture is seen in TBI patients with vasospasm occurring
in up to 40% of patients.29, 30 However, vasospasm occurs
earlier in TBI patient, within 12 hours of injury and may
544 Journal of Neurosurgical Sciences October 2018
be difficult to assess due to the use of sedation. The mech-
anisms leading to vasospasm in this population include
chronic depolarization of vascular smooth muscle due to
reduced potassium channel activity16, 31 and reduced avail-
ability of smooth muscle relaxants such as nitric oxide and
cyclic GMP.32
Cerebral metabolism and oxygenation
In the immediate aftermath of a severe TBI there is an
increase in energy needs but a decrease in CRMO. This
leads to metabolic uncoupling and energy dysfunction.33
This dysfunction is associated with poor neurological
prognosis.21, 34 Lactate levels are commonly increased in
this setting and this has, in the past, been interpreted as
a marker of anaerobic metabolism and a potential target
for hyperoxic therapy.35 However, in this setting lactate
production may be due to hyperglycolysis in the absence
of ischemia33 and it may become an alternative substrate
to glucose for metabolism.36 Similarly, mitochondrial dys-
function is also seen in non-ischemic areas. These areas
with injury-induced mitochondrial dysfunction are associ-
ated with worse outcomes.37 Hyperoxia has been investi-
gated as a therapy for these metabolic derangements with
disappointing results.35
Oxidative stress and excitotoxicity
Oxidative stress plays a significant role in the development
of secondary injury after severe TBI. Reactive oxygen and
nitrogen species are formed when there is an imbalance be-
tween their production and the activity of antioxidants such
as glutathione peroxidase and superoxide dismutase.38 Su-
peroxide is the most common free radical seen after TBI39
and its production is associated with high intracellular cal-
cium levels.40 The proliferation in free radicals causes tis-
sue damage by promoting hydroxyl radicals and through
activation of matrix metalloproteinases (MMPs). MMPs
are responsible for extracellular matrix degradation of the
blood brain barrier (BBB) and their inappropriate activa-
tion results in increased BBB permeability (Figure 2).41, 42
Oxygen free radicals may also lead to the activation of
nuclear factor-kappa B (NF-κB).43 NF-κB increases the
transcription of pro-inflammatory cytokines such as tu-
mor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).44
Although these mediators may be associated with normal
wound healing, inappropriate activation may be associat-
ed with secondary brain injury. These pathophysiological
changes are seen in other forms of brain injury, such as
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PATHOPHYSIOLOGY OF SEVERE TBI O’LEARY
Figure 2.—Schematic representation of oxidative stress-induced BBB
disruption and neuroinflammation in traumatic brain injury. Reactive
oxygen species (ROS) and reactive nitrogen species (RNS) are the
main sources of oxidative stress in brain injury. ROS include superox-
ide (O2−), hydroxyl radical (HO), hydrogen peroxide (H2O2), and hypo-
chlorous acid (HOCl). RNS refer to various nitric oxide (NO)-derived
compounds, such as peroxynitrite (ONOO–) and nitrogen dioxide (NO2).
O2− causes tissue damage by promoting hydroxyl radicals from H2O2
and ONOO– when combined with NO. ROS activate matrix metallo-
proteinases (MMPs) that further exacerbate the condition and lead to
BBB disruption via degradation of the extracellular matrix and tight
junction proteins. Further, MMPs are involved in degradation of vas-
cular endothelial growth factor (VEGFR) and lead to an increase in the
level of VEGF that in turn causes ROS and activates caspase-1/3, which
leads to cell death. At the same time, ROS or RNS also activate differ-
ent inflammatory cytokines and growth factors such as IL-1β, TNF-α,
and TGF-β, which cause BBB disruption and neuroinflammation (from
Abdul-Muneer et al.).39
neurodegenerative disease and alcohol abuse.45, 46 There
has been significant interest in the use of antioxidants to
reduce the impact of these free radicals, however to date
none have proven effective in phase III clinical trials.16, 47
Increased extracellular concentrations of the excitatory
neurotransmitter glutamate have been found after severe
TBI.40 This increase is multifactorial in nature. Disruption
of the BBB allows glutamate to move into the brain and
in addition to this extravasation of glutamate may occur
at the site of traumatic vascular damage.48, 49 Excessive
synaptic release of glutamate and impairment of glutamate
transporters compounds this increase in interstitial gluta-
mate.49 The result is overstimulation of glutamate recep-
tors leading to excitotoxicity. Glutamate mediates these
adverse effects through the stimulation of NMDA and
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
(AMPA) receptors.
NMDA receptors are coupled with the generation of re-
active oxygen and nitrogen species so their overstimula-
tion leads to the release of free radicals, in particular neu-
Vol. 62 - No. 5 Journal of Neurosurgical Sciences 545
ronal nitric oxide.40 This reacts with superoxide, discussed
above, to produce peroxynitrite, a highly reactive nitrating
free radical, which causes rapid cell death by a number of
processes.50, 51 The role of NMDA receptors in the devel-
opment of excitotoxicity has been confirmed by the obser-
vation that NMDA receptor agonists are more potent neu-
rotoxins than glutamate when delivered directly into the
brain.52 AMPA receptors are also found to be overactive
in the presence of neuronal injury, as seen after TBI. This
overactivity results in increased intracellular calcium, hy-
perexcitability and consequently cell damage and death.40
In view of these findings there is ongoing interest in target-
ing NMDA and AMPA receptors with the aim of mitigat-
ing glutamate associated neuroexcitotoxicity.
Calcium homeostasis
Abnormalities in calcium homeostasis play a critical role
in the development of secondary injury after TBI. As dis-
cussed above, increased intracellular free calcium levels
lead to neuroexcitotoxicity resulting in cell death through
activation of a number of enzymes. Mitochondrial swell-
ing occurs due to an increase in calcium sequestration and
this also leads to membrane depolarization with resultant
release of factors that initiate programmed cell death.53, 54
The resultant mitochondrial dysfunction leads to further
calcium influx. Increased axonal membrane permeability
also allows an influx of calcium.55 This leads to activation
of a family of enzymes, calpains, which target and degrade
key structural proteins.56 Ultimately these cascades lead to
axonal damage and disconnection.40
Neuroinflammation
Traumatic brain injury results in an inflammatory response,
described as a sterile immune reaction.57 This reaction is
initiated by purinergic receptor signaling triggered by
ATP released by damaged cells58 and involves microglia,
monocytes and neutrophils.
Microglia are immune sentinels that reside in the CNS
and are first responders to inflammation.59 They may
transform into phagocytic cells in response to an injury
and their response appears to be neuroprotective.57, 59, 60
Microglia can respond to purinergic signals after cell death
and become phagocytes known as jellyfish microglia.57
These microglia can take the place of the dead cells and
thus seal gaps. As such they provide a dual role, remov-
ing the debris of dead cells and sealing gaps in the glial
limitans barrier. Monocytes are capable of differentiating
 ©
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This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
O’LEARY PATHOPHYSIOLOGY OF SEVERE TBI
into macrophages and dendritic cells in response to inflam-
mation or injury and their role appears to be destructive
after TBI. Meningeal macrophage death provides an early
source of reactive oxygen species after cortical injury.61
Subsequently monocytes cross the blood brain barrier
through the production of CCL2 by the choroid plexus.62
This response appears to be maladaptive with animal data
to suggest that outcomes are improved when this pathway
is blocked.63
Neutrophils are rapidly recruited to the site of injury af-
ter TBI and their involvement may be neuroprotective or
destructive. There is data to suggest that neutrophils are
neuroprotective in the meningeal space, interacting with
dead cells in the acute response to injury. However, they
may also release harmful mediators including reactive ox-
ygen species and metalloproteinases, which may result in
neurotoxicity and damage to the BBB.64
Targets for future therapy
At present therapy for TBI is limited to surgical manage-
ment of lesions and supportive care aimed at maintaining
adequate cerebral perfusion and oxygenation. However,
given our improved understanding of the pathophysiology
underpinning secondary brain injury, a number of phar-
macological targets have been identified. Unfortunately, to
date most studies have failed to demonstrate clinical ben-
efit in stage III trials.44 This may be due to the difficulties
in targeting one component of a complex cascade, as well
as the heterogeneity of this population.
Progesterone was up until recently regarded as a bio-
logically plausible therapy for TBI. It is known to inhibit
inflammatory cytokines and prevent excitotoxicity and va-
sogenic edema and two phase 2 trials showed a clinical
benefit in this population.65, 66 However, two recent phase
three trials67, 68 failed to show any benefit over placebo and
consequently a systematic review concluded that there was
no evidence of benefit.69 In contrast to the limited evidence
found for progesterone therapy, it has been demonstrated
that simple ICU interventions, such as the choice of resus-
citative fluid, or the decision to conduct surgery or not, can
reduce both mortality and severe disability in critically ill
trauma patients70, 71 with substantial healthcare cost sav-
ings of greater than $ 271 million independently reported.72
Prophylactic hypothermia is another therapy with prom-
ise. The POLAR study is examining the role of prophy-
lactic hypothermia to 33 °C initiated within three hours
of injury and maintained for 72 hours. Results from the
POLAR study will be published in late 2018.73
546 Journal of Neurosurgical Sciences October 2018
Conclusions
Management of traumatic brain injury remains a sig-
nificant challenge for clinicians. Public health initiatives
aimed at reducing rates of primary brain injury are of para-
mount importance,1 however therapies targeting second-
ary brain injury are also required. A clear understanding
of the complex pathophysiology of primary and secondary
brain injury is necessary to guide the development of new
therapies. Few therapies to date have demonstrated benefit
in clinical trials so ongoing research is needed to improve
outcomes in the future.
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COPYRIGHT 2018 EDIZIONI MINERVA MEDICA
cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.
This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically
to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove,
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Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.
Article first published online: May 22, 2018. - Manuscript accepted: May 8, 2018. - Manuscript received: May 3, 2018.

548 Journal of Neurosurgical Sciences October 2018