Pathophysiology Of Traumatic Brain Injury

Presenter - Dr.Rajan Kumar

Introduction
Traumatic brain injury (TBI)

leading cause of morbidity & mortality

< 45 years of age

Biomechanical & neuropathological classification

A. Focal brain damage - contact injury

B. Diffuse brain damage - acceleration/ deceleration injury

Primary Brain Injury

@SITE Focal Primary Diffuse Contrecoup DAI

Traumatic brain injury

Initial insult sets in motion a sequence of

pathological events
Delayed and progressive

 Initial injury - tear, shear and hemorrhage

Delay

onset of secondary insult The delay - there is room for intervention & modification of the outcome

Mechanisms of Primary Injury in TBI

Impact

Extradural, Subdural, Contusion, Intracerebral Hemorrhage, Skull Fracture

Inertial

Concussion syndromes, Diffuse Axonal Injury

Ischemic / Hypoxic

Mechanisms of secondary insults

Systemic Arterial hypotension Hypoxia Hyper-/hypocapnia Hyper-/hypoglycemia Hyperthermia Disturbances of water and electrolyte balance

Mechanisms of secondary insults

Intracranial
Mass lesion Brain oedema, hyperemia ICP , CPP Vasospasms

Epileptic seizures
Inflammation

Pathophysiology in TBI
cellular level Structural level

General pathophysiology
Direct tissue damage
impaired regulation of CBF and metabolism Ischemia like state Lactic acid accumulation

Increased membrane permeability

oedema

 Anaerobic metabolism inadequate to maintain cellular energy states

ATP-stores deplete
Failure of energy dependent membrane ion pumps

 Second stage o Terminal membrane depolarization o Excessive release of excitatory neurotransmitters

o Activation of NMDA, voltage dependent Calcium

and sodium channels

o Influx leads to catabolic intracellular processes

 Ca2+ activates o Lipid peroxidases

o Proteases
o Phospholipases o Increase the intracellular conc. of FFA & free radicals

 Activation of caspases, translocases & endonucleases initiates progressive structural changes of biological membranes & the

nucleosomal DNA
These events lead to membrane degradation of

vascular and cellular structures

Finally leads to necrosis or apoptosis

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Calcium influx initiates a destructive cascade

Calcium Overload

Proteas e

NO Phospolip Endonuclea Protein synthas ase A2 ses kinases e Nitric Arachido phosphata ses oxide nic acid Free radical s Lipid peroxidation membrane damage

Cytoskelet on breakdow n

Mitochon drial damage

DNA fragmentati on

Secondary genes Apoptosis

Specific pathophysiology
Cerebral blood flow Hypo perfusion & hyper perfusion Cerebral ischemia poor outcome Critical threshold of CBF 15 ml/100g/min In addition to metabolic stress and ionic perturbations, shear forces with structural injury of neuronal cell bodies, astrocytes, microglia, cerebral microvasculature & endothelial cell damage.

Mechanism
Morphological injury - mechanical displacement Hypotension in the presence of autoregulatory

failure
Inadequate nitric oxide availability or cholinergic neurotransmitters Potentiation of prostaglandin-induced vasoconstriction

 May also develop cerebral hyperperfusion CBF >55 ml/100g/min Hyperaemia immediate post traumatic

ischemia
Increase in CBF beyond metabolic demand leads

to vasoparalysis with consecutive increase in

cerebral blood volume leads to raised ICP

 Increase in CBF > metabolic demand

Vasoparalysis

CBF

Raised ICP

Cerebrovascular autoregulation
Imp mechanism to provide CBF at any time Basis for the m/mt of CPP & ICP Impairment reflect increased risk for secondary brain damage After TBI, CBF autoregulation impaired Inconsistent Autoregulatory vasoconstriction more resistant than vasodilation more sensitive to damage from low CPP

 As ICP and approaches MAP, cerebral

blood flow
Results in CPP Compensatory mechanisms attempt to MAP As CPP , cerebral vasodilation occurs to blood volume

This leads to further ICP, CPP and so

on

CO2-reactivity
Cerebrovascular constriction or dilation due to
hypo or hypercapnia In severe TBI & poor outcome impaired in early stages cf intact or even enhanced in most other patients (target for ICP m/mt in hyperaemic states)

 Hypercarbia causes cerebral vasodilation

Results in blood volume ICP CPP

Compensatory mechanisms attempt to MAP

As CPP , cerebral vasodilation occurs to blood volume And, the cycle continues

 Hypotension results in CPP cerebral

vasodilatation
Results in blood volume ICP CPP
And, the cycle continues

Cerebral vasospasm
Important secondary insult Determines ultimate outcome > 1/3rd & severe damage Onset day 2-15 Hypoperfusion - 50% of pts developing spasm

Mechanism of vasospasm
- chronic depolarization of vascular smooth muscle (reduced K+ channel activity) - release of ET -Reduced avail of NO, c-GMP depletion -Potentiation of PG induced vasoconstriction -Free radical formation

Cerebral metabolic dysfunction

Metabolism cerebral O2 & glucose consumption Cerebral energy state tissue concentration of phosphocreatine & ATP Or indirectly by lactate:pyruvate ratio Both are reduced after TBI Degree of metabolic failure relates to severity of primary insult Outcome worse lower metabolic rates

 Reduction in post-traumatic cerebral metabolism due to primary insult - mitochondrial dysfunction -Reduced respiratory rates & ATP production -Reduced avail of nicotinic co-enzyme pool -Intramitochondrial Ca2+ overload

 Hypermetabolism of glucose due to massive transmembrane ionic fluxes neuroexcitation which is not met by increase in CBF secondary ischemic insults

Cerebral oxygenation
Imbalance between cerebral oxygen delivery & cerebral oxygen consumption Critical threshold 15-10 mmHg ptO2 infarction of neuronal tissue occur Oxygen deprivation of the brain with consecutive secondary brain damage may occur even in the presence of normal CPP or ICP.

Excitotoxicity & oxidative stress

Massive release of excitatory neurotransmitters (glutamate) Overstimulation of ionotropic & metabotropic glutamate receptors with consecutive ca2+, Na+ & K+ fluxes

Trigger catabolic processes including blood

brain barrier disruption

 Generation of

o oxygen free radicals

o Superoxides

o Hydrogen peroxides
o Nitric oxide o Peroxinitrite

 Induces

-peroxidation of cellular & vascular structures

-Protein oxidation

-Cleavage of DNA
-Inhibition of mitochondrial electron transport

chain
Can lead to cell death

Excitoxicity, precipitated by the neurotransmitter glutamate

Failure of presynaptic membrane ion pumps Initial depolarisation dependant release of GLUTAMATE Conventional Theory Potassium release into ECS Release of CALCIUM

Trauma-induces changes to postsynaptic Glutamate receptor pharmacology, kinetics and composition

AMPA receptor

Recent Opinion

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- 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

Release of CALCIU M

NMDA Receptor

Nitration Lipid peroxidation DNA fragmentation CELLULAR DAMAGE

AMPA - -amino-3-hydroxy-5-methyl-4-isoxazleproprionic acid NMDA - N-methyl-D-aspartic acid

Oedema
Cytotoxic brain oedema

- intracellular water accumulation of neurons,

astrocytes & microglia irrespective of integrity of the vascular endothelial wall.

 Cause

-increased cell membrane permeability for ions

-ionic pump failure due to energy depletion -cellular reabsorption of osmotically active solute

 Vasogenic brain oedema - Cause -mechanical or autodigestive disruption or

functional breakdown of the endothelial cell

layer of vessels

Allows for uncontrolled ion and protein ion &

protein transfer to extracellular compartments

Inflammation
Release of cellular mediators proinflammatory cytokines Prostaglandins Free radicals Complement Induce chemokines & adhesion molecules Mobilize immune & glial cells

 Tissue infilteration of leucocytes facilitated via

Upregulation of cellular adhesion molecules (Pselectin, ICAM-I, VCAM-I) Response injured & tissue eliminated and astrocytes produce microfilaments to synthesise scar tissue

Necrosis vs apoptosis
Necrosis In response to severe mechanical or ischemic/hypoxic tissue damage with excessive release of neurotransmitters & metabolic failure Autolysis of biological membranes

Cell detritus antigen, removed by

inflammatory processes

 Apoptosis o Morphologically intact in immediate period o Later on evident o Delayed onset of cellular deterioration opportunity for therapeutic (anti-apoptotic) interventions

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Time is important
Hours Days 7 2
Ca++ , Na+, Free Radicals, Glut Necrosis

Weeks / Months 14

8 hrs

I N J U R Y

Apoptosis
Inflammation
Repair Remodeling

Plasticity Functional Recovery

Primary Injury
Reference:

Secondary Injury , Barone &Feuerstein JCBF, 1999, Modified

Structural Pathophysiology
Pressure exerted downward on Brain cerebral cortex or RAS
altered level of consciousness

 Brain stem
o BP and bradycardia - vagal stimulation
o irregular respirations or tachypnea o unequal/unreactive pupils - oculomotor nerve paralysis o posturing

seizures dependent on location of injury

Herniation

 Levels of Increasing ICP

Cerebral cortex and upper brain stem
BP rising and pulse rate slowing
Pupils reactive Cheyne-Stokes respirations Initially try to localize and remove painful stimuli

 Middle brain stem

Wide pulse pressure and bradycardia

Pupils nonreactive or sluggish

Central neurogenic hyperventilation Extension

 Levels of Increasing ICP

Lower Brain Stem / Medulla
Pupil blown (side of injury) Ataxic or absent respirations Flaccid Irregular or changing pulse rate

Decreased BP
Usually not survivable

 Herniation
transtentorial herniation uncal herniation

Conclusion
TBI combines mechanical stress to brain tissue with an imbalance between CBF & metabolism, excitotoxicity, oedema formation, and inflammatory and apoptotic processes. Understanding pathophysiology help in better m/mt of ICP, CPP.

Thank You