PATHOPHYSIOLOGY OF CHRONIC CEREBRAL VASOSPASMS

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About 10 new cases of ruptured aneurysm per 100,000 population may be anticipated each year. The average age of such patients is just over 50 years. While 15 or 20 % of sufferers die instantly the majority now survive to be hospitalized. If these patients do not die of the initial disruptive effects of their hemorrhage they then have to face a variety of life threatening delayed hazards including most importantly delayed ischemia from chronic vasospasm as well as rebleeding. It has been estimated that an effective therapy for vasospasm could save 5,000 lives in North America per year. In the past decade there has been progress in the medical management of the low blood flow resulting from the spasm of the larger basal conducting arteries consequent to the surrounding clot. Firstly, regional flow is increased by ensuring optimal circulating blood volume, hematocrit, pressure, viscosity and cardiac output. Secondly, neurological outcome has been improved by the use of calcium antagonists which operate by a mechanism other than the prevention of vasospasm in the large conducting arteries-they may dilate smaller vessels or provide an element of direct neuronal protection. These developments have not however directly attacked the basic problem of cerebral vasospasm. The pathophysiological chain of events and its biochemical correlates are largely unknown so that rational, direct therapy or prophylaxis is difficult. While complete removal of the inciting blood clot wihin 48 hours prevents vasospasm from developing in the primate model, total removal is not possible in patients and vigorous attempts at this carries additional surgical risks. A pharmacological intervention to halt the chemical reactions which ultimately lead to a spastic arterial segment would be preferable to the surgical prophylaxis if it were without significant side effects such as systemic hypotension. It is proposed to characterize the chemical, pharmacological and physiological changes associated with the development of chronic vasospasm in a primate model using direct clot application to the surgically exposed basal vessels sand sequential sampling of arteries and brain tissue. Treatment strategies will be applied as the mechanism is elucidated and as new and promising drugs and delivery techniques are introduced.