Many of these factors relating to cerebral blood flow were studied many years ago by Heiss and by Siesjo and by others. The critical threshold of CBF below which functional impairment occur has been determined in several animal species, including macaque monkeys and gerbils. The critical level for infarction is approximately 23 mL/100 g/min (normal is 55 mL/100 g/min); if, after a short period of time, CBF is restored to normal levels, the impairment of function can be reversed. Reduction of CBF below 10 to 12 mL/ 100 g/min causes infarction, almost regardless of its duration. The critical level of hypoperfusion that abolishes function and leads to tissue damage is therefore a CBF between 12 and 23 mL/100 g/min but the likelihood of complete infarction is also dependent on the duration of ischemia. Modern techniques such as CT and MR perfusion imaging are able to give comparable values in clinical stroke work.
At these levels of blood flow the electroencephalogram (EEG) is slowed, and below this level it becomes isoelectric. In the region of marginal perfusion, the K level increases (as a result of efflux from injured depolarized cells) and adenosine triphosphate (ATP) and creatine phosphate are depleted. These biochemical abnormalities are reversible if the circulation is quickly restored to normal. Disturbance of calcium ion homeostasis and accumulation of free fatty acids interfere with full recovery of cells. A CBF of 6 to 8 mL/100 g/min causes marked ATP depletion, increase in extracellular K, increase in intracellular Ca, and cellular acidosis, invariably leading to histologic signs of necrosis. These changes do not become apparent for several hours. Free fatty acids (appearing as phospholipases) are activated and destroy the phospholipids of neuronal membranes. Prostaglandins, leukotrienes, and free radicals accumulate, and intracellular proteins and enzymes are denatured. Cells then swell, a process called cellular, or cytotoxic, edema (see “Brain Edema” in Chap. 30). Similar abnormalities affect mitochondria even before other cellular changes are evident.
Regarding anoxic damage of the brain, a historically interesting phenomenon was studied by Ames and Nesbett. They found that cells could withstand complete absence of O2 for 20 min and postulated that a long period of tolerance of retinal neurons to complete anoxia in vitro, in comparison to that in vivo, is related to what they called the no-reflow phenomenon (swelling of capillary endothelial cells, which prevents the restoration of circulation as originally described by Ames et al).
One area of interest has focused on the role of excitatory neurotransmitters in stroke, particularly glutamate and aspartate, which are formed from glycolytic intermediates of the Krebs cycle. These neurotransmitters, released by ischemic cells, excite neurons and produce an intracellular influx of Na and Ca. These changes are in part responsible for irreversible cell injury, but this must be an oversimplification. Some current attempts at therapy, for example, are directed at limiting the extent of infarction by blocking the glutamate receptor, particularly the NMDA (N-methyl-d-aspartate) channel—one of several calcium channels that open under conditions of ischemia and set in motion a cascade of cellular events eventuating in neuronal death (apoptosis). However, even complete blockade of the NMDA channels has not prevented cellular death, presumably because dysfunction of several other types of calcium channels continues and allows calcium entry to cells. Additional biochemical events must be induced by ischemia, including the production of free radicals, which leads to peroxidation and disruption of the outer cell and mitochondrial membranes. Clearly, the cascade of intracellular events that lead to neuronal death is likely to be more complex than is currently envisioned.