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Which of the following is NOT a mechanism of secondary brain insults?
What characterizes the mechanisms of primary injury in traumatic brain injury?
What does an increase in intracranial pressure (ICP) typically indicate in the context of traumatic brain injury?
Which mechanism of injury in traumatic brain injury involves concussive effects?
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What is thought to mediate changes in postsynaptic glutamate receptors?
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Which factor can contribute to ischemic/hypoxic mechanisms in secondary insults after a traumatic brain injury?
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What free radical is produced in response to high mitochondrial calcium levels?
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What cellular damage is associated with the formation of peroxynitrite?
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What is the role of NMDA receptors in the context provided?
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Which of the following substances is implicated in cellular damage as a result of nitration?
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What is a significant consequence of Calcium overload in neurons?
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What occurs in the initial 30 minutes post-injury regarding glucose utilization?
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What role does the neurotransmitter glutamate play in excitotoxicity?
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What is one consequence of impaired oxidative metabolism following trauma?
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What effect does mitochondrial dysfunction have in the context of calcium overload?
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What is a common final pathway resulting from calcium influx?
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What exacerbates cellular damage following traumatic injury?
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Which ion's release into the extracellular space is a critical event during excitotoxicity?
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What is one result of the failure of presynaptic membrane ion pumps?
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Which of the following statements accurately describes the state of neuronal function post-trauma?
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What is primarily affected during secondary injury in traumatic brain injury (TBI)?
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Which factor can lead to impaired cerebral blood flow (CBF) in the context of TBI?
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What relationship does the Monro-Kellie Doctrine describe?
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What is considered a pathological level of intracranial pressure (ICP)?
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How does loss of autoregulation affect cerebral blood flow (CBF)?
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Which of the following describes the focus of focal injury in TBI?
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What role does inflammation play in the context of secondary brain injury?
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What process can lead to neuronal death following TBI?
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What is the primary consequence of elevated intracranial pressure (ICP)?
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What occurs during the acidosis following a traumatic brain injury?
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Which of these is a common outcome of secondary injuries after TBI?
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Which mechanism is NOT considered part of the secondary brain injury process?
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What is one effect of excitotoxicity in the context of post-TBI complications?
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What condition can exacerbate ischemia in traumatic brain injury?
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Study Notes
Traumatic Brain Injury
- Traumatic brain injury (TBI) involves 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 between the initial injury and secondary insult suggests potential for intervention and modification of the outcome.
- The discussion focuses on the pathophysiology of traumatic brain injury at a cellular level.
Mechanisms of Primary Injury in TBI
- Impact causes:
- Extradural hematoma
- Subdural hematoma
- Contusion
- Intracerebral hemorrhage
- Skull fracture
- Inertial forces cause:
- Concussion syndromes
- Diffuse axonal injury
- Ischemic and hypoxic injury can also occur.
Mechanisms of Secondary Brain Insults
- Secondary brain insults can be systemic or intracranial:
- Systemic:
- Arterial hypotension
- Hypoxia
- Hyper-/hypocapnia
- Hyper-/hypoglycemia
- Hyperthermia
- Disturbances of water and electrolyte balance
- Intracranial:
- Mass lesion
- Brain edema, hyperemia
- Increased Intracranial Pressure (ICP)
- Decreased Cerebral Perfusion Pressure (CPP)
- Vasospasms
- Epileptic seizures
- Inflammation
- Systemic:
- These secondary insults can affect substrate transport within brain tissue, cerebral blood flow, and brain metabolism.
- Mass effect causes tissue ischemia.
Secondary Injury in TBI
- Secondary injury tends to follow ischemia precipitated by the initial insult.
- Global secondary injury:
- Hypoxia and ischemia of the brain
- Reduced cerebral blood flow can be due to raised intracranial pressure
- Focal or local secondary injury:
- Impaired cerebral blood flow or change in the extra-cellular environment due to altered or damaged tissue
- While passive damage is instantaneous, secondary brain insults occur from hours to several days after TBI and significantly alter the prognosis.
Time is Important
- There are dynamic changes following injury.
- Primary injury occurs immediately, while secondary injury is delayed.
Secondary Injury Pathways
- Secondary injury can occur through various pathways:
- Glial injury and dysfunction
- Destruction of microvasculature
- Energy failure
- Inflammation
- Ionic disturbance/excitotoxicity
Loss of Autoregulation
- Loss of autoregulation proceeds reduction in Cerebral Blood Flow (CBF) and neuronal ischemia.
- This process can lead to:
- Decreased protein synthesis
- Selective gene expression
- Acidosis
- Water shifts
- Glutamate release
- Electrical failure
- Membrane failure
- Neuronal death
- Impaired function
- Cell death
Raised Intracranial Pressure (ICP)
- The Monro-Kellie Doctrine establishes a relationship between intracranial contents and pressure; the intracranial volume is constant so changes in one component leads to changes in another.
- After severe head injury, intracranial pressure is elevated in greater than 72% of patients.
- 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 been clearly established as a causative factor.
- After trauma, the parenchymal compartment may undergo an increase in volume due to:
- Edema (vaso and cytogenic)
- Secondary to physical, ischemic, or excitotoxic activity
- Traumatic mass lesions
- Obstruction of CSF flow
- Viscoelastic change (compliance of parenchyma)
Deranged Calcium Homeostasis
- Injury differs by tissue type but is precipitated by calcium influx.
- Deranged calcium homeostasis contributes to:
- White matter (axons):
- Disconnection or secondary axotomy
- Progressive and delayed degenerative process
- Axonal membranes become leaky
- Grey matter (neuronal cells):
- Excitotoxic cell death
- Initiation of programmed cell death
- Post-synaptic receptor modifications
- White matter (axons):
- Calcium overload leads to:
- 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
Destructive Cascade
- Calcium influx initiates a destructive cascade:
- Protease
- Nitric oxide synthase
- Phospholipase A2
- Endonucleases
- Protein kinases
- Protein phosphatases
- Nitric oxide
- Arachidonic acid
- Free radicals
- Cytoskeleton breakdown
- DNA fragmentation
- Lipid peroxidation
- Mitochondrial membrane damage
Alterations in Glucose Metabolism
- Post-traumatic glucose metabolism:
- Initial 30 minutes post-injury glucose utilisation increases, followed by a 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 up to 7x normal lactate concentration.
- However, there is evidence that high lactate levels exist even where blood flow limitations don’t exist; this suggests that trauma affects mitochondrial phosphorylation, causing a shift toward anaerobic metabolism.
- Neuronal dysfunction is thus partly a result of acidosis but also affected by concurrent membrane damage, ionic flux, disruption of the blood-brain barrier, and cerebral edema.
Excitotoxicity
- Excitotoxicity is precipitated by the neurotransmitter glutamate.
- Conventional theory states that trauma-induced changes to presynaptic membrane ion pumps lead to the initial depolarisation, followed by the dependant release of glutamate and calcium into the extracellular space (ECS).
- Recent opinion suggests that trauma-induced changes to post-synaptic glutamate receptors (pharmacology, kinetics and composition) contribute to excitotoxicity.
- 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-α.
- This leads to:
- Generation of neuronal nitric oxide (a free radical)
- Increased production of free radicals (due to high mitochondrial calcium)
- Mixes with NO to form peroxynitrite
- Lipid peroxidation
- DNA fragmentation
- Cellular damage
Conclusion
- Traumatic brain injury is a complex process involving a series of primary and secondary events that significantly impact neurological function.
- Calcium influx, altered glucose metabolism, and excitotoxicity are key mechanisms contributing to the pathology of TBI.
- Understanding these mechanisms is crucial for developing effective treatments and interventions in order to improve outcomes for patients with TBI.
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Description
This quiz delves into the complex mechanisms of traumatic brain injury (TBI), focusing on both primary and secondary insults. It explores the cellular pathophysiology, the types of injuries caused by impact and inertial forces, and the systemic effects that can influence outcomes. Test your knowledge on the latest understanding of TBI and its multifaceted nature.
