Biology Reference
In-Depth Information
unfavourable outcome at 12 months follow-up, with a mortality rate of 35%. Further-
more, 70% of severe TBI patients presented with evidence of diffuse injury
[4,5]
.
Perhaps the failure to translate preclinical therapies into the clinical setting is due to
the reliance on successful animal studies, most of which used models of focal TBI and
thus failed to mimic the diffuse injuries seen more commonly in clinical practice. It is
clear that future studies designed to improve outcomes and understand the mechanisms
of brain protection must examine more extensively the mechanisms of diffuse TBI.
10.2 Primary and Secondary Brain Injury
The pathophysiology of TBI can be divided into two temporal phases. Primary TBI
is induced at the time of the incident and is classified as focal or diffuse brain injury
depending on patterns of tissue damage.
Secondary brain injury
is defined as the
delayed degeneration of viable tissue surrounding the initial damage and is the result
of physiological, cellular, and molecular alterations. It is well established that sec-
ondary brain injury is the major cause of both mortality and physical and cognitive
impairments.
In clinical practice, classification of primary brain injury is determined by neu-
roimaging scans that reveal specific types of damage, including skull fractures, tissue
lacerations, subdural or epidural hemorrhages, and contusions, which constitute the
hallmarks of focal TBI. Alternatively, widespread swelling of and axonal damage at
the white matter and additional rupture of the cerebrovasculature presenting as pete-
chial hemorrhages are characteristic features of diffuse TBI
[6]
. Despite this clear
definition of two types of brain damage, in reality each patient presents with a unique
form of TBI in which a distribution of focal and diffuse injuries often coexists. In
the past decade, more emphasis has been placed on discerning the morphological
and molecular pathways specific to focal and diffuse brain trauma, as it has become
evident from human and animal studies that they differ significantly. Neurotrauma
research pursued over the past 20 years has focused mainly on focal (rather than dif-
fuse) TBI, and a variety of cerebral-contusion animal models have been developed to
explore the pathological sequelae leading to secondary brain damage. However, the
pathophysiology of diffuse brain injury remains less understood and more difficult to
reproduce in the laboratory using animal models.
Among the systemic events occurring after severe head trauma, respiratory dis-
tress or hypoxia and drop in systemic blood pressure (hypotension) further compro-
mise the injured brain by decreasing cerebral perfusion pressure and by generating
ischemic injuries. These secondary insults are mostly concomitant to the extracra-
nial injuries, such as lung trauma or obstructed airway, often observed in severe
multitrauma patients. Reduced oxygen delivery to the injured brain further alters the
homeostasis of the parenchymal environment, causing cerebral hypoxic and ischemic
insults and aggravating the traumatic tissue damage.
The cerebral endothelium is particularly vulnerable to the shearing-stretching
forces applied to the brain at the time of trauma. This impact causes the opening of
tight junctions that normally isolate the parenchyma from the systemic circulation,
