Cerebral perfusion pressure(CPP) is the driving force for substrate(O2,glucose) delivery to the brain is defined as mean arterial pressure(MAP) minus intracranial pressure (ICP) and MAP is diastolic pressure plus 1/3(systolic pressure minus diastolic pressure).
The main substance use for energy production in the brain is glucose and O2.
Cerebral blood flow(CBF) can be used to calculate 0xygen delivery to the brain.
A standard formula is used DO2 =CaO2 xCBF which :
DO2 is delivered oxygen, CaO2 is arterial oxygen content.
CaO2 is dependent on Hb content and PaO2,normal CaO2 is 16-20ml O2/100ml arterial blood and normal CBF is 50ml/100 gmin.
Normal DO2 is (16 to 20 mlO2/100ml)x50ml/100g/min)=8 to 10 mlO2/100g/min.
Since normal O2 consumption (VO2) is 3,5 t0 5ml/100g/min therefore a safety factor of 1,5 to 2 DO2 to VO2.
Local area of the brain may have a different ratio DO2 to VO2 secondary to a pathologic CBF or on altered metabolic rate.
Brain ischemia symptoms are seen when CBF falls to about 20ml/100g/min or DO2=4ml O2/100G/minutes.
When DO2=3 ml/100g/min or CBF of 15ml/100g/min or CPP 30-40 mmHg EEG silence occurs and when CBF of 8 to 12 mmHg or DO2=2ml/100g/min, cellular ion leakage and eventual cell death.
Although the normal brain in normal activities,can tolerate large temporary increases in ICP,PaCo2,severe hypotensiion of MAP(30-60 mmHg)but even mild hypotension can cause permanent brain damage when it occurs in a state of
asphyxiation or brain injured patient.
Therefore systolic blood pressure should not be allowed to decrease below 90 mmHg and CPP should be maintained at minimum of 70 mmHg.
Strategies intended to protect the brain from ischemic hypoxic insults attempt to interrupt or attenuate these pathophysiologic process.
Avoidance of inadequate cerebral perfusion pressure,prevention of hypoxaemia and the surgical decompression if intracranial mass lesion are by far the most important and effective neuroprotective interventions.
BRAIN METABOLISM : (3,5)
The metabolic fuel required by CNS is provided almost exclusively by glycogenolysis of glycogen stored mainly in the liver and muscle.
Glucose oxydation occurs in three successive stages;glycolysis,the citric acid cycle,and the the electron transport chain.
If oxygen levels are adequate glycolysis convert glucose molecule(six carbon) into two three carbon pyruvate with a net gain of two molecules of ATP(adenosine triphosphate)for each molecule of glucose metabolized.
Pyruvate then enters the citric acid cycle which regard to energy production primary generates NADH from NAD(nicotine adenine dinuceotide).
The mitochondria use oxygen to couple the conversion of NADH back to NAD with the production of ATP from ADP(adenosine diphosphate) and inorganic phosphate.This process called oxydative phosphorylation forms three ATP molecules for each NADH converted and yields 38 ATP molecules for each glucose molecule metabolized. In reality however one molecule of glucose yields no more than 30-35 molecules of ATP.Because some of the glucose(1%-3%)is diverted into pentose phosphate pathway,some is used to sustain the small store of glycogen in the brain,and 5% to 8% is metabolized to lactate.
The pathway need oxygen if oxygen not present the mitochondria can neither make ATP nor regenerate NAD from NADH.
The metabolism of glucose need NAD as a cofactor and is blocked in its absence.Thus in the absence of oxygen,glycolysis proceeds by a modified pathway termed anaerobic glycolysis which generates only two molecules of ATP per molecule of glucose cannot satisfy even the most basic energy requirements of the brain.
CELLULAR PROCESS THAT REQUIRE ENERGY:(3)
The largest energy requirement in the brain is pumping ion across the cell membrane. Consentration of sodium,potasium,and calcium of a neuron are maintained against large electrochemicals gradient with respect to the outside of the cell.
When a neuron is not excited there is a slow leak of potassium out of the cells and of sodium and calcium into the cells.
Neuronal activity markedly increases the flow potassium,sodium and calcium for maintaining normal cellular ion consentration. Since ion pumping uses ATP
as an energy source, the ATP requirement of active neurons is greater than that for unexcited neurons.
If the energy production does not meet the demand of energy use in the brain the neuron first become unexcitable and then irreversible damage.
Neuron require energy to maintain their structure and internal function.
The cell's membranes,internal organelle and cytoplasma are made of carbohydrates,lipids and proteins that require energy for their synthesis.
Ion channels,enzymes and cell structural components are important protein molecules that are continuosly synthesized and degraded in normally function
ing neurons.Their metabolism also require energy.
Most cellular synthesis take place in the cell body and energy is needed for transport of components down the axon to nerve terminal.
Thus energy is needed to maintain the intergrity of the neuron even in absence of electrophysiologic activity.
BRAIN ISCHEMIA :(1,2,5)
All of the body organ the brain is the most sensitive to ischemia.
When the blood supply to the brain is decreased below a critical level,ischemic damaged occurs.
Ischemic injury is characterized by decrease in O2 delivery and supply of glucose and other metabolites.
The mechanism leading to neuronal damage are likely calcium is central in the pathophysiology, because the primary defect in cells mortality injured by a transient period of ischemia is an inability to regulate calcium ion since calcium ion play an important role in normal membrane excitation and cellular process.
Normally exracellular concentrations are maintained at a higher cocentration than free cytosolic concentrations by an ionic ATP dependent pump hence failure of ATP energy metabolism will have a deterious effect on this homeostasis.
One of the earliest manifestation of cerebral ischemia is an abrupt reduction in the concentration of energy metabolites and eventually ATP.
When tissue ATP is depleted the NaK ATP ase ion pumps fail, leading to Na+ inlux and K+ efflux and membrane depolarization accompanied by excessive release of excitatory neurotransmitter (glutamate,aspartate) and activation of NMDA(N methyl D aspartate),AMPA(@ amino-3-hydroxy-5-methyl-4-isoxazol proprionate) and voltage dependent calcium and sodium channels with results uncontrol influx Ca2+,which leads to disruption of mitochondrial and cell membranes and the release of free fatty acid(FFA) including arachidonic acids.
Since ATP is necessary to clear the calcium from cytosol then increased cytosolic calcium levels occurs.
Calcium activates many intracellular enzymes(lipid peroxidases,proteases and phospholipases) result enzymatic breakdown of membranes with subsequent release FFA and oxygen free radicals.
In addition activation of caspases (interleukin converting enzyme like protein) translocase and endonucleases initiate progressive structural changes of biological membranes and nucleosomal DNA(DNA fragmentation,inhibition of DNA repair).
Together these events lead to membrane degeneration of vascular and cellular structures and consecutive necrotic or apoptosis(programed cell death).
to be continued
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