Traumatic Brain Injury - Pathophysiology PDF

Traumatic Brain Injury - Pathophysiology David Roytowski Photo by Stefan Els 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 hemor...

Traumatic Brain Injury - Pathophysiology David Roytowski Photo by Stefan Els 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 Impact Extradural, Subdural, Contusion, Intracerebral Hemorrhage, Skull Fracture Inertial Concussion syndromes, Diffuse Axonal Injury Ischemic / Hypoxic Mechanisms of Secondary Brain Insults Systemic Intracranial Arterial hypotension Mass lesion Hypoxia Brain oedema, hyperemia Hyper-/hypocapnia ICP ⇑ , CPP ⇓ Hyper-/hypoglycemia Vasospasms Hyperthermia Epileptic seizures Disturbances of water and Inflammation electrolyte balance 1. Substrate transport within brain tissue 2. Cerebral blood flow 3. Brain metabolism *Mass effect causes tissue ischemia 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 Primary Injury Secondary Injury Reference: Barone &Feuerstein JCBF, 1999, Modified  An overview of the major pathways of secondary injury Glial Injury and dysfunction Destruction of micro vasculature Energy failure Inflammation Ionic disturbance / Excitoxicity Reference: Canadian Medical Association Journal, Traumatic Brain Injury: Can the consequences be stopped?, April 22, 2008, 1163-1170 Loss of autoregulation proceeds reduction in CBF and neuronal ischemia ↓ Protein 100 synthesis Selective gene Acidosis 100 Head Injury 80 expression Water shifts Cerebral blood flow Cerebral blood flow Glutamate (ml/100g/min) (ml/100g/min) release 60 Electrical failure Membrane 40 failure Neuronal 50 death 20 0 Failure Failure Impaired Function Electrical Cell Death Normal CBF Oligaemia Ionic Pump Electrocortical 50 100 150 Ischemic Penumbra Ischemic core Cerebral Perfusion Pressure (mmHg) Raised intracranial pressure in TBI Monro-Kellie Doctrine1 Intracranial Pressure Establishes a relationship between intracerebral contents After severe head injury, intracranial pressure is elevated in and pressure greater than 72%of patients2 v.intracranial (constant) = v.brain + v.CSF + v.blood + v.mass lesion 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) 1Mokri B (June 2001). "The Monro-Kellie hypothesis: applications in CSF volume depletion". Neurology 56 (12): 1746-8 2Youmans, Neurological Surgery, Fourth Edition Injury differs by tissue type, but is precipitated by Calcium influx Deranged Calcium Homeostasis White Matter (Axons) Grey Matter (Neuronal Cells)  Disconnection or secondary axotomy  Excitotoxic cell death  Progressive and delayed degenerative  Initiation of programmed cell death process  Post-synaptic receptor modifications  Axonal membranes become leaky Common final pathway as a result of Calcium overload  Early mitochondrial swelling  Mitochondrial dysfunction and energy failure  Membrane depolarisation  Calcium influx due to ATP pump failing  Opening of membrane transition pores  Release of initiating factors of programmed cell death Calcium influx initiates a destructive cascade CALCIUM Overload Protease NO Phospholipase Endonucleases Protein synthase A2 kinases phosphatases Nitric Arachidonic oxide acid Free radicals “Secondary” genes Cytoskeleton Apoptosis DNA breakdown Lipid peroxidation fragmentation Mitochondrial membrane damage damage 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 Conventional Failure of Initial Potassium Theory presynaptic depolarisation Release of release into membrane ion dependant release CALCIUM ECS pumps of GLUTAMATE Increased current response to AMPA- receptor agonists Reduction in expression of receptors Release of Trauma-induces AMPA receptor CALCIUM containing the GluR2 subunit (I.e. more changes to Recent Opinion permeable to Ca) postsynaptic Thought to be mediated by TNF- α Glutamate receptor - pharmacology, Generation of neuronal nitric oxide (a Nitration kinetics and free radical) Lipid peroxidation composition NMDA Receptor Increased production of of free DNA fragmentation radicals (due to high mitochondrial Ca) mixes with NO to form Peroxynitrite CELLULAR DAMAGE AMPA - α-amino-3-hydroxy-5-methyl-4-isoxazleproprionic acid NMDA - N-methyl-D-aspartic acid Thank you Source: Internet, https://www.flickr.com/photos/42740619@N03/3940167228