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(Continued from page 52)
will flow through only 80 to 85% of the capillaries while plasma flows through all of the capillaries. Hyperglycemia during ischemia decreases cerebral blood flow and decreases cerebral plasma volume and causes cytotoxic edema. How can oxygen delivery be increased during ischemic conditions? It is generally thought that once the oxygen molecule becomes saturated no additional oxygen can be delivered to the tissue. Only recently have studies been performed to determine the amount of human brain tissue PO2 that is needed. It has been found that brain tissue PO2 can predict outcome. Brain tissue PO2 greater than 40 mmHg at all times usually is associated with a good outcome, 30 to 40 mmHg is associated with moderate to severe disability, 20 to 30 mmHg is associated with a vegetative state, and less than 20 mmHg is usually associated with death. It has also been shown that by increasing PAO2 above supernormal thresholds from 129 to 137 mmHg increases human brain tissue PO2 from 25 to 81 mmHg.
Oxygen itself is not without detrimental effects. During reperfusion oxygen free radicals may be formed from nitric oxide synthetase, cytochrome P450 reductase, transferrin, monamine oxidase, xanthine oxidase, cyclo-oxygenase, mitochondrial NADH. If these free radicals are not scavenged by natural anti-oxidants, such as glutathione peroxide, superoxide dismutase and catalase (superoxide dismutase and catalase cannot get into the cell secondary to their large molecular weight), then these free radicals will cause direct cellular injury during reperfusion. Both the cyclo-oxygenase and xanthine oxidase generated free radicals can be blocked by indomethacin. Superoxide dismutase did not show a beneficial result when used in the phase III trials, however, there are new trials occurring with lecithinized superoxide dismutase, which has been shown to have more promising results. Brain glycerol is a marker for the membrane phospholipid breakdown and generation of free radicals. The glycerol increase can be seen immediately and is elevated for approximately four hours. It is not known if glycerol is a producer, byproduct or just an association with free radicals.
Much has been said about cellular and chemicals constituents, which under normal conditions do not necessarily cause problems, but under conditions of traumatic brain injury can be responsible for cell death. The genome is also involved in cellular injury. We have seen how there have been measurements of different messenger RNAs that lead to certain protein and are responsible for cellular death. There may be constituents in the edematous fluid itself, which causes programmed cell death 72 hours after injury. We know that the DNA is intact for three to four hours after traumatic brain injury, but programmed cell death may have already been initiated. This also indicates that there may be a window of opportunity for preservation. The immediate expression of early gene COX-2 may be a marker (or possibly a cause) of programmed cell death. There are age-related impairments of cerebral function that may be due to a functional decline in mitochondrial DNA (Continued on page 54)
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