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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