Pathophysiology - Traumatic Brain Injury

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Information about Pathophysiology - Traumatic Brain Injury
Science-Technology

Published on June 3, 2009

Author: docdave

Source: authorstream.com

Traumatic Brain Injury Pathophysiology Dr David Roytowski MBChB, MBA Department of Neurosurgery Groote Schuur Hospital: Traumatic Brain Injury Pathophysiology Dr David Roytowski MBChB, MBA Department of Neurosurgery Groote Schuur Hospital Introduction: 2 Introduction Traumatic brain injury following the initial insult sets in motion a sequence of pathological events that are delayed and progressive Initial injury is tear, shear and hemorrhage followed by a delay then onset of secondary insult - The delay suggests that there is room for intervention and modification of the outcome Focus of today’s discussion on the pathophysiology of Traumatic Brain Injury will primarily be at a “cellular” level Mechanisms of Primary Injury in TBI : 3 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 Brain Insults: 4 Mechanisms of Secondary Brain Insults Intracranial Mass lesion Brain oedema, hyperemia ICP ⇑ , CPP ⇓ Vasospasms Epileptic seizures Inflammation Systemic Arterial hypotension Hypoxia Hyper-/hypokapnia Hyper-/hypoglycemia Hyperthermia Disturbances of water and electrolyte balance *Mass effect causes tissue ischemia Substrate transport within brain tissue Cerebral blood flow Brain metabolism Secondary Injury in TBI tends to follow ischemia precipitated by the initial insult: 5 Secondary Injury in TBI tends to follow ischemia precipitated by the initial insult Global Hypoxia and ischemia of the brain Reduced cerebral blood flow can be due to raised intracranial pressure Focal / local Impaired cerebral blood flow or change in the extra-cellular environment due to altered/ damaged tissue While passive damage is instantaneous, secondary brain insults occur from hours to several days after TBI and significantly alters the prognosis Time is important - there are dynamic changes following injury: 6 Time is important - there are dynamic changes following injury Hours Days Weeks / Months Ca ++ , Na + , Free Radicals, Glut 8 hrs 7 Necrosis Apoptosis Repair Remodeling Plasticity Functional Recovery I N J U R Y 14 2 Inflammation Primary Injury Secondary Injury Reference: Barone &Feuerstein JCBF, 1999, Modified , An overview of the major pathways of secondary injury: 7 An overview of the major pathways of secondary injury Reference: Canadian Medical Association Journal, Traumatic Brain Injury: Can the consequences be stopped?, April 22, 2008, 1163-1170 Destruction of micro vasculature Glial Injury and dysfunction Inflammation Energy failure Ionic disturbance / Excitoxicity Loss of autoregulation proceeds reduction in CBF and neuronal ischemia : 8 0 20 40 60 80 100 Normal CBF Oligaemia Impaired Electrocortical Function Electrical Failure Ionic Pump Failure Cell Death Ischemic Penumbra Ischemic core ↓ Protein synthesis Selective gene expression Acidosis Water shifts Glutamate release Electrical failure Membrane failure Neuronal death Loss of autoregulation proceeds reduction in CBF and neuronal ischemia Cerebral Perfusion Pressure (mmHg) Cerebral blood flow (ml/100g/min) 100 50 50 100 150 50 100 150 Head Injury Cerebral blood flow (ml/100g/min) Raised intracranial pressure in TBI : 9 Raised intracranial pressure in TBI Intracranial Pressure After severe head injury, intracranial pressure is elevated in greater than 72%of patients 2 A complex relationship exists between CPP, CBF and ICP, ICP > 20mmHg is considered pathological, but must be considered in context Elevated ICP is a marker of poor outcome, but has not clearly been established as a causative factor After trauma, the parenchymal compartment may undergo an increase in volume due to: Oedema (vaso and cytogenic) Secondary to physical, ischemic or excitotoxic activity Traumatic mass lesions Obstruction of CSF flow Viscoelastic change (compliance of parenchyma) Monro-Kellie Doctrine 1 Establishes a relationship between intracerebral contents and pressure v.intracranial (constant) = v.brain + v.CSF + v.blood + v.mass lesion 1 Mokri B (June 2001). "The Monro-Kellie hypothesis: applications in CSF volume depletion". Neurology 56 (12): 1746-8 2 Youmans, Neurological Surgery, Fourth Edition Injury differs by tissue type, but is precipitated by Calcium influx: 10 Injury differs by tissue type, but is precipitated by Calcium influx Grey Matter (Neuronal Cells) Excitotoxic cell death Initiation of programmed cell death Post-synaptic receptor modifications White Matter (Axons) Disconnection or secondary axotomy Progressive and delayed degenerative process Axonal membranes become leaky Deranged Calcium Homeostasis Common final pathway as a result of Calcium overload Early mitochondrial swelling Membrane depolarisation Opening of membrane transition pores Release of initiating factors of programmed cell death Mitochondrial dysfunction and energy failure Calcium influx due to ATP pump failing Calcium influx initiates a destructive cascade: 11 Calcium influx initiates a destructive cascade CALCIUM Overload Protease NO synthase Phospolipase A2 Endonucleases Protein kinases phosphatases Cytoskeleton breakdown Mitochondrial damage Lipid peroxidation membrane damage DNA fragmentation “Secondary” genes Apoptosis Free radicals Notric oxide Arachidonic acid Alterations in glucose metabolism exacerbate cellular damage: 12 Alterations in glucose metabolism exacerbate cellular damage Post-traumatic glucose metabolism Initial 30 minutes post-injury glucose utilisation increases, followed by drop that remains persistently low for 5 - 10 days Early hyperglycolysis results from disrupted ionic gradients across neuronal cell membranes and activation of energy-dependent ionic pumps Evidence shows that there is impairment in oxidative metabolism following trauma, leading to a depletion of ATP with subsequent rise in anaerobic metabolism Rise in extracellular lactate is thought to be a result of decreased cerebral blood flow in the face of increased energy demand with upto 7x normal lactate concentration However there is evidence that high lactate levels exist even where blood flow limitations don’t exist - suggests that trauma affects mitochondrial phosphorylation, causing a shift toward anaerobic metabolism Neuronal dysfunction is thus partly a result of acidosis, but also effected by concurrent membrane damage, ionic flux, disruption of the blood brain barrier and cerebral oedema Excitoxicity, precipitated by the neurotransmitter glutamate: 13 Potassium release into ECS Excitoxicity, precipitated by the neurotransmitter glutamate Failure of presynaptic membrane ion pumps Initial depolarisation dependant release of GLUTAMATE Conventional Theory Recent Opinion 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 CALCIUM 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 Thank you: 14 Thank you

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