Lecture 25: Pathogenesis Of Perinatal Brain Injury Flashcards
What results from perinatal brain injury
Death
Motor dysfunction
Impaired cognition
When do babies get brain injury
Before, during or after birth
Causes of perinatal brain injury
HIAT
Hypoxia - ischaemia (reduced oxygen & blood flow to brain)
Infection (common in preterm babies) [maternal, fetal/postnatal, cytokine production]
Accident/trauma
Teratogens (drug use, smoking alcohol) -> directly affect brain(poison, injury) & 2° actions on oxygenation, nutrient provision & blood flow to brain
Causes of fetal hypoxia - ischemia
Placental abruption
Prolonged labour
Preterm lung development
Severe tight umbilical cord knot (baby moving in placenta)
Twisted umbilical cord and moderate meconium staining
Cardiovascular instability / congenital heart disease (cerebral hypoperfusion)
Cardio respiratory arrest
Define asphyxia
- adults & fetus
What does severe asphyxia result in
Impaired respiratory gasses exchange: O2 lack, CO2 excess
Adults: breathing interruption/ inadequate oxygen supply
Fetus: insufficient oxygen supply & CO2 removal (placental/umbilical cord compromise)
Severe -> Hypoxia-ischemia
What is hypoxia
What causes high altitude hypoxia (altitude sickness)
What is hypoxemia
Low oxygen (insufficient to tissue to maintain bodily function)
Altitude sickness : Partial pressure O2 decreases due to high altitude (low atmospheric pressure)
Oxygen reduction in arterial blood
Define ischemia
What is partial pressure
What is the driving force for oxygenation in the body?
What is PO2 in the body?
Blood supply reduction
Pressure enforced by a gas in a mixture of other gases
Partial pressure of oxygen in the body.
Measure of O2 dissolved in body
What contributes to blood oxygenation
PO2 dissolved in blood, O2 bound to haemoglobin, haemoglobin concentration
What is hypercapnia?
What does it lead to
High CO2 dissolved in blood
Metabolic and respiratory acidosis
What is respiratory acidosis?
What is metabolic acidosis?
Too much carbon dioxide - Water + CO2 -> H2CO3 (carbonic acid)
Anaerobic metabolism (hypoxia) produce lactate -> Lactic acid accumulation in blood from too much lactic acid
What is the importance of the umbilical cord/ placenta?
Remove waste products
Mother provide nutrients and oxygen
draw mindmap
Describe how fetal asphyxia & impaired blood supply leads to brain injury
- Fetal asphyxia/ impaired blood circulation -> fetal hypoxia(O2 less) -> anaerobic metabolism & lactate production -> metabolic acidosis
- Fetal asphyxia/impaired blood circulation -> impaired waste removal (CO2 more) -> CO2 accumulate -> respiratory acidosis
Hypoxia & (R & M) acidosis -> impaired cardiovascular system -> reduced brain blood flow & oxygen -> brain injury
Brain injury - term infant
- Basal ganglia/ thalamic pattern
- Watershed pattern
- Neuronal loss
- Associated with : severe disability & acute sentinel events (very severe umbilical cord occlusion)
- Neuronal loss
- Vascular watershed zones affected (further away from blood supply, injured first)
- white matter & overlying cortex - injured
- deficits : cognitive, less sever motor
- associate : events like prolonged labour
- Vascular watershed zones affected (further away from blood supply, injured first)
Oligodendrocyte loss
Brain injury - preterm infant
- Grey matter & cerebral cortex
- White matter
Brain of preterm babies are..
- Widely spread
- Most vulnerable, focal cystic necrosis (white matter holes), non cystic oligodendrocyte cell death, diffuse myelination failure, cystic & diffuse white matter lesions, ventriculomegaly (ventricles -> too large) , white matter tract atrophy
Smaller
Cerebral palsy
- challenges
Results from asphyxia / preterm birth
- learning disabilities
- limb contractures
- abnormal walking
- arm & leg weakness
- swallowing/feeding problems
- spine curvature
How does asphyxia affect fetal brain perfusion
Low BP -> increase cell death, low brain blood flow, low blood perfusion to brain -> low O2 & glucose delivery -> cell death pathway activate
How can umbilical cord occlusion cause brain injury
Reduced fetal O2 & glucose delivery -> impaired cardiovascular function -> reduced blood pressure & flow to brain -> brain injury
What are some fetal response to maintain brain perfusion during asphyxia?
Why can they be dangerous
- Low heart rate -> protective mechanism to preserve energy
- Early BP increase, peripheral blood flow reduction (vasoconstriction) to non essential organs
- reduced energy supply -> reduce brain activity (try)
When hypotension occurs, brain damage occurs.
Ischaemia & reduced blood oxygenation -> energy failure -> brain cell death
What happens to brain metabolic activity during asphyxia
Reduced to match reduced energy supply.
Adenosine mediated (in part)
Normal cellular homeostatic functions that would be affected by hypoxia - ischaemia
homeostatic
- Intra/extracellular ion gradient (membrane potential) maintenance by ion pumps -> ATP dependent.
- no ATP -> cell damage (membrane potentials loss) - Aerobic/anaerobic respiration -> ATP Production
- Oxygen/energy delivery to brain cells (blood perfusion to brain)
- Matching cellular metabolic activity to energy supply
Cellular homeostasis
Explain oxidative phosphorylation in aerobic metabolism and when anaerobic metabolism is employed.
What happens when there is insufficient ATP?
Oxidative phosphorylation (aerobic metabolism):
- mitochondria
- produce 38 ATP (lots)
Anaerobic metabolism (glycolysis):
- brain -> very high ATP demand but limited stores
- relied on during hypoxia -> limiting factor: oxygen
- produced 2 ATP (less)
- less effective & acidosis
Insufficient ATP: ATP-dependent membrane pump failure, Na+, Ca2+, Cl- build up in cells and K+ out of cells, electrochemical gradient & extrude Ca2+ & Na+ ability loss, anoxic depolarisation
How does
- anoxic depolarisation
- cell swelling
- excitotoxicity
caused by lack of ATP lead to brain cell death?
Hypoxia -> neurons depolarise-> glutamate release in synaptic cleft -> neighboring neurons trigger to depolarise -> cells hyperpolarise -> cells: transient electrically silent - no activate -> spreading depression waves (cannot fire)
Ions into cell -> water move in too by osmosis -> reversible or necrosis
Excessive glutamate -> toxic -> glutamate receptors overactivation -> increase [Ca2+] -> trigger injury & cell death pathways
How does brain cells die by
- necrosis
- apoptosis
- Cell swells and lyses due to excessive osmosis and hyperhydration -> cell death product release into extracellular space -> inflammatory response
- Selective cell death upregulated with injury. No inflammatory response and energy dependent signaling pathway. Tightly regulated physiological process
