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complexes I, II, and IV, of the respiratory chain. It has been demonstrated that ischemia damages complex I selectively. If in the elderly there is less complex I, then the cell has less chance of survival. There are cellular proteins that are neuro-protectant. The anti-cell death protein bcl-2, may be such a protein that can be genetically manipulated to be over-expressed and, therefore, prevent cellular injury. The adenovirus team transfer of GDNF improves traumatic brain injury outcomes, as does IGF-1 and BFGF.
Our armamentarium at this point addresses large systems using medication, CSF drainage and possibly manipulation of temperature. Hypothermia inhibits sodium potassium ATPase nitric oxide production and glutamate release. Therefore, glutamate is not taken up into the post-synaptic astrocytes, there is no excitatory amino acid activation, no energy stores are consumed causing glycolysis and lactic acidosis. Hypothermia inhibits acidosis and lactic acidosis when lactic acidosis is expected, but may actually cause swelling in normal cells. Hypothermia also decreased inflammation by decreasing cytokinin and interleukon-8. We have also used barbiturates to suppress neuronal action potential amplitude, increased GABA and inhibitory amino acids, reduce neuro-transmitter vesicle release, suppress excitatory post-synaptic potentials leading to reduced neuronal metabolic demands, decreasing the need for anaerobic metabolism and, therefore, less lactate, less membrane collapse and less subsequent release of excitatory amino acids and less depletion of energy reserves. Induction of barbiturate coma reduces lactate 37%, glutamate 59% and aspartate 66%, as measured by microdialysis in humans.
Two other medications that worked to reduce edema are Diamox and indomethacin. Diamox relaxes vascular smooth muscle, decreases CSF production and increases cerebral blood flow. The effect lasts approximately 45 minutes. Vasodilation can also be produced by nitric oxide and prostacyclins, however, we have heard about the deleterious effects of both of these. Indomethacin also acts by reducing water content. It inhibits prostacyclin and causes vasoconstriction, which is less desirable. Its use in ischemia, therefore, is not warranted.
The blood brain barrier is not a brick wall like once thought. It is an organization that needs to be better understood. It continues to be protective at times when it is leaking. Under reversible conditions the leakage of substances through the blood brain barrier help thwart off deleterious consequences. However, when that leakage cannot be controlled and those substances, which at fewer concentrations are beneficial become toxic at higher concentrations, this is when we must intervene. It is the timing to intervene, the mechanism to intervene and still what to intervene that needs to be learned, and only at that time will we make significant changes in the treatment of traumatic brain injury.
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