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Magnesium Sulfate for Cerebral Palsy Prevention
- 1. MAGNESIUM SULFATE FOR CEREBRAL PALSY PREVENTION A. Goodwin-Samson, MD B. Brocato, DO
- 6. Ischemic Brain Injury (IBI)
- 7. Hypoxia-Ischemia at Neuronal Level
- 13. Depolarization of Presynaptic Neuron Postsynaptic Neuron Presynaptic Neuron
- 20. Post Magnesium: NDMA Receptor Ca 2+
- 25. Postnatal Magnesium: Status at Discharge
- 35. ACTOMgSO4 - Inclusion criteria
- 49. Table 1 1
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- Initial after a asphyxial event there is an increase of systemic BP and a redistribution of cardiac output so that the brain recieves an increased proportion of the cardiac output. After sustained insult both this CBF autoregulation and BP starts to fail. The end results is a decrease in the blood flow to the brain and resulting ischemic brain injury. Brain hypoxia and ischemia due to systemic hypoxemia, reduced cerebral blood flow (CBF), or both are the primary physiological processes that lead to hypoxic-ischemic encephalopathy. The initial compensatory adjustment to an asphyxial event is an increase in the CBF due to hypoxia and hypercapnia. This is accompanied by a redistribution of cardiac output such that the brain receives an increased proportion of the cardiac output. A borderline increase in the systemic blood pressure (BP) further enhances the compensatory response. The BP increase is due to increased release of epinephrine; these are classic early cardiovascular compensatory responses to asphyxia. In the fetus and newborn suffering from acute asphyxia, after the early compensatory adjustments fail, the CBF can become pressure-passive, at which time brain perfusion is depends on systemic BP. As BP falls, CBF falls below critical levels, and the brain suffers from diminished blood supply and a lack of sufficient oxygen to meet its needs. This leads to intracellular energy failure.
- Most of the metabolic energy of neurons is expended on maintaining ion gradient across the cell membrane. The sodium potassium pump pumps out 3 sodium ions for each 2 potassium ions. This keep extracellular K+ low and extracellular sodium high. The unequal pumping of Na (3) and K (2) results in a more positive charge on the outside as compared to the inside making the neuron polarized. This pump is driven by energy stored in Adenosine triphosphate molecules (or ATP) >
- Another ATP-driven pump helps keep extracellular calcium ion 10,000X more concentrated than within the cytoplasm. Other pump such voltage gated and ion exchanges also regulate ion concentrations
- ATP molecule are made in the mitochondria. Once the ATP is used for energy a phosphate is removed and results in adenosine diphosphate or ADP and hydrogen ion (acid) Generally making ATP requires O2
- . But in the absence of O2 some energy can be generated outside the mitochondria by glycolyis. (on anareobic) In glycolysis a glucose molecule produces 2 ATP and lactate. Once the is a lack of blood flow to the brain ATP can be regenerated from ADP by phosphate for phosphocreatine (pCr) Glycolysis uses glucose to produce 2 ATP and lactate With the breakdown of ATP from it produces adenoside diphophate (ADP)and hydrogen ion (acid)
- Net breakdwon of glycolis Within two mins of ischemia extracellular pH can drop about 7.3 to 6.7 A reduction of ATP synethesis caused by hypoxia disrupts ionic equilirbirum across the membrane (or deplorization). K quickly exits the cell, while There is also rapid influx of sodium, chloride and water resulting in cell swelling and lysis.
- Deplorizing of the presynaptic membranes results in release of the neurotransmitter glutamate. Glutamte is one of the most important excitatory neurotransmitters in the brain. The postsynaptic membrane have many glutamate receptors notably N-Methyl-D-Aspartate NMDA and AMPA receptors.
- Loss of membrane potentional or depolarization leads to the opening of voltage gated calcium channels. In addition NMDA stimulated calcium channel results in an increase in cytosolic calcium NMDA is particulary adept at allowing large amounts of calcium ion to enter the cells. This is particularly important in the fetal brain because of the larger proportion of NMDA receptors in the neurons than in the adult brain. It is important to note that these NMDA dependent reaction are delayed and may occur 24 hours after the insult.
- High levels of Ca iis excitotxicic which initiate brain ischemia. The excessive increase in intracellular calcium interferes with many enzymatic reactions. Activation of Phospholiipase which leads to membrand phospholipid hydrolysis with the subquent disruption of cellular and organelle membranes. Alterations of the arachidonic acid cycle which effects prostaglandin syntehesis, gene expression, protein synthesis and increases free radical activate proteolytic ezyme (a=calpains breack down cell protein esp thosy in cytoskeleton of neuron. ) Cytochrome C initiator of apoptosis It is believed that the influx of calcium through the NMDA stimulated calcium concentration is a delayed mechanism that can occur 24 hours after initial insult
- Several lines of research in experimental animals have implicated a role for the excitatory amino acid glutamate in the production of hypoxia ischemic brain damage in the immature brain. These studies provide evidence that excessive glutamate leads to morphologic alterations characteristic of ischemic neuronal necrosis. Given the premise that excessive stimulation of neurons by glutamate promotes cellular death and antagonist to the nmda receptor should be neuroprotective
- Several molecules have been suggested as candidate scavengers and protectors fr clinical use in fetal and neonatal brain hypoxia/perfusion failure
- Magnesium is essential for a number of cellular function including
- Distributions of perinatal factors, neonatal baseline characteristics and severity of hyoxic-ischemic encephalopathy were similar in treated and control groups. No significant differences were observed in duration of clinical seizures, or need for assisted ventilation. Survival with normal results of cranial computed tomography, electroencephalography and establishment of oral feeding by 14 days of age, was significantly more frequent in the treated group than in the control group (12/17 vs 5/16, P = 0.04). No significant differences in blood pressure, heart rate or respiratory rate were observed between groups.