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PRESENTER: DR SONIA NEUROANAESTHESIA
PGIMER
an impact, penetration or rapid movement
of the brain within the skull that results in
altered mental state.
DEFINITION
CLASSIFICATION
•PRIMARY INJURY
•SECONDARY INJURY
•MILD(13-15)
•MODERATE(9-12)
•SEVERE(<9)
Primary injury: consequence of direct
impact.( coup/ countercoup)
Secondary injury: due to subesquent
events.
Why??????Common than any other neurological disease or event
Poor prognosis
High morbidity and mortality
TBI
NEUROCHEM-ICAL
FACTORS
BBB AND CBF
DISRUPTI-ON
GLUCOSEMETABOLISM
INFLAMM-ATION
AND FREERADICALS
CEREBRAL BLOOD FLOW
Significant alteration in CBF
In experimental animal models -mild to moderate TBI, showed a significant drop off in blood flow (70-80% of normal) , and with more severe injury the drop off neared ischemic levels.
Some association with stroke.
Morphological injury
hypotension in the presence of
autoregulatory failure
inadequate availability of nitric oxide or
cholinergic neurotransmitters,
potentiation of prostaglandin-induced
vasoconstriction.
Cerebral hyperemia –can present in the
initial stage leading to cerebral edema and
raised ICP.
Cerebrovascular autoregulation and CO2-reactivity
Hyperemia in a setting of impaired
autoregulation is generally associated
with intractable increases in intracranial
pressure and ultimately, poorer cerebral
perfusion and worse
outcome.(breakthrough phenomenon)
CO2 reactivity –may be preserved.
CEREBRAL VASOSPASM
Seen in one third patients
Post traumatic day 2-5
Endothelial dysfunction, decreased NO.
BBB DYSFUNCTION
Due to mechanical damage
Becomes permeable to blood borne factors
Activation of coagulation cascade-thrombus- ischemic injury
Pro-inflammatory mediators, activation of cell adhesion molecules
Vasogenic and cytotoxic edema
IONIC FLUX AND GLUTAMATERedistribution of ions and
neurotransmitters, altering the membrane
potential
GLUTAMATE
K+,Ca2+
18
Potassium release into
ECS
Excitoxicity, precipitated by the
neurotransmitter glutamate
Failure of
presynaptic
membrane ion
pumps
Initial
depolarisation
dependant
release of
GLUTAMATE
Con
ve
ntio
nal
Th
eo
ryR
ece
nt O
pin
ion
Release of CALCIUM
Trauma-induces
changes to
postsynaptic
Glutamate
receptor -
pharmacology,
kinetics and
composition
AMPA receptor
NMDA Receptor
AMPA - -amino-3-hydroxy-5-methyl-4-isoxazleproprionic acid
NMDA - N-methyl-D-aspartic acid
• Increased current response to
AMPA-receptor agonists
• Reduction in expression of
receptors containing the GluR2
subunit (I.e. more permeable to Ca)
• Thought to be mediated by TNF-
Release of CALCIU
M
• Generation of neuronal nitric oxide
(a free radical)
• Increased production of of free
radicals (due to high mitochondrial
Ca) mixes with NO to form
Peroxynitrite
• Nitration• Lipid peroxidation• DNA fragmentation
CELLULAR DAMAGE
19
Protease NO synthas
e
Phospolipase A2
Endonucleases
Protein kinases
phosphatases
Cytoskeleton
breakdown
Mitochondrial damage
Lipid peroxidation membrane
damage
DNA fragmentatio
n
“Secondary” genes
Apoptosis
Free radicals
Notric oxide
Arachidonic acid
CA2+ INFLUX LEADING TO
DESTRUCTIVE CASCADE
Cerebral glucose metabolism in
TBI
Initial phase of hyperglycolysis followed
by decraesed glucose metabolism
This initial increase in CMRglc is due to
an increased requirement of cellular
energy to restore the ionic balance and
neuronal membrane potential.
Hyperglycolysis has been observed
within the first 8 days after severe human
head injury.
Increase in glucose metabolism may or
may not be accompanied by increase in
the CBF, leading to uncoupling of the
CMRO2/CBF ratio
Activation of anaerobic pathways
followed by accumulation of lactate.
Increase in the lactate levels in CSF,
altered lactate/ pyruvate ratio and
negative A-V difference in the lactate
levels.
Decreased glucose uptake-
decreased CBF(uncoupling)
defects in glucose transporter function
decreased metabolic demand for glucose.
Adult rat studies have shown decreased
neuronal glucose transporter (GLUT1)
immunoreactivity 2-4 hours after FP
injury
18F-DG kinetic changes following
moderate to severe TBI in humans have
determined that hexokinase activity was
globally decreased, with glucose transport
impairments occurring specifically within
the contusion sites.
Inhibition of the glycolytic pathway:
Increased activity of pentose phosphate
pathway
Decreased NAD+ levels
Decreased activity of PDH
POST TBI ENERGY CRISIS
Reactive molecules with unpaired electrons.
ROS and RNS.
˙OH , ONOOˉ, O2˙ˉ, H2O2, NO˙
Scavengers- superoxide dismutase(SOD),
glutathione peroxidase, vit E, C, catalase.
FREE RADICALS IN TBI
Lipid peroxidation of polyunsaturated fatty acids
Oxidation or nitration of proteins
Activation of DNA repair enzymes (PARP)
ROLE OF MITOCHONDRIATwo mechanisms
Ca2+ influx
Free radical damage
Apootosis vs necrosis
NEUROINFLAMMATION
More with contusions and hemorrhages
Surge for pro-inflammatory mediators
Followed by increased synthesis of
chemokines and cell adhesion molecules
(ICAM -1, V-CAM 1) leading to influx of
inflammatory cells, though the direct
invasion of WBC,s is not there.
Target – by monoclonal antibodies.
Upregulation of IL-1, TNF-ß within hours
after the injury
Affects the normal tissue, leading to scar
formation.
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