We enrolled 125 neurologically normal patients with intracranial aneurysms in a multi-institution, prospective, double-blind, randomized, placebo-controlled trial within 96 hours of their subarachnoid hemorrhage, to determine whether treatment with the calcium blocker nimodipine would prevent or reduce the severity of ischemic neurologic deficits from arterial spasm. A deficit from cerebral arterial spasm that persisted and was severe or caused death by the end of the 21-day treatment period occurred in 8 of 60 patients given placebo and in 1 of 56 given nimodipine (P = 0.03, Fisher's exact test). Analysis of the amount of basal subarachnoid blood on pre-entry CAT scans in patients with deficits from spasm showed that an increase in subarachnoid blood was not associated with a worse neurologic outcome among patients who received nimodipine, unlike the situation in patients given a placebo. There were no side effects from nimodipine. We conclude that nimodipine should be given to patients who are neurologically normal after subarachnoid hemorrhage in order to reduce the occurrence of severe neurologic deficits due to cerebral arterial spasm.
The authors have developed a method to induce chronic cerebral vasospasm after subarachnoid hemorrhage (SAH) in monkeys. With microsurgical techniques, 33 monkeys had a frontotemporal craniectomy and unilateral opening of the subarachnoid cisterns. Cerebrospinal fluid was drained and a fresh hematoma, obtained from an average of 7 ml of autologous blood, was carefully placed against the major arteries of the anterior circulation on one side. The 30 monkeys studied for 7 to 14 days after the SAH were allocated randomly to two treatment groups of 15: one group received placebo and the other nimodipine, 1 mg/kg every 8 hours. Indices monitored before and after SAH included neurological status, cerebral blood flow, computerized tomography, and angiographic vessel caliber. In the placebo group, delayed ischemic neurological deficit developed in one monkey 4 days after clot placement and was present at sacrifice on Day 14. No such deficit occurred in the nimodipine group. The effect of nimodipine on vessel caliber at this dosage was equivocal. Significant vasospasm (31% to 100% reduction in vessel caliber) developed in 87% (26 of 30) of the animals. Overall, vasospasm was slightly more common in the placebo group: in this group, on Days 7 and 14, the incidence of vasospasm was significantly higher (p less than 0.05) than in the nimodipine group. However, the average percentage reduction in vessel caliber of the maximally constricted vessel in each monkey was not significantly different between the two groups.
The aim of this study was to establish normative data as gestation advances for pulsed Doppler evaluation of both the ophthalmic artery and the central retinal artery. After measuring intraocular pressure and blood pressure, pulsed Doppler ultrasonographic examination was performed on the ophthalmic and central retinal arteries in both eyes of 125 normal pregnant women. Nomograms, with 95% prediction intervals, have been generated for the Doppler indices, reflecting blood flow in both the ophthalmic and the central retinal arteries. The use of this technique in the management of pregnancy induced hypertension can now be better evaluated.
Striatal microdialysis was performed in rats subjected to 20 min of transient forebrain ischemia produced by occlusion of the carotid arteries during hemorrhagic hypotension. Extracellular changes of dopamine, serotonin, and their metabolites were monitored before, during, and after the ischemic insult at 10-min intervals by on-line HPLC analysis. During ischemia, extracellular dopamine increased dramatically (156 times baseline), as did 3-methoxytyramine (3-MT), whereas 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) decreased (15-25% of baseline). Upon reperfusion, dopamine was cleared from the extracellular fluid within 40 min and reached a stable level (70% of baseline). DOPAC and HVA increased (250-330%) transiently and reached their maximum 1 h following reperfusion, whereas 3-MT decreased to undetectable levels within 20 min. Although baseline levels of serotonin were not detectable, serotonin and 5-hydroxyindoleacetic acid showed a qualitatively similar temporal pattern to dopamine and its acid metabolites. Killing rats by cervical dislocation produced changes in extracellular dopamine, serotonin, and their metabolites that were almost identical to those seen during ischemia. Pargyline pretreatment 2 h before ischemia had marginal effects on the postischemic clearing of dopamine. The pargyline pretreatment, however, did increase the survival rate of rats subjected to ischemia, and this protective effect might be due to the pargyline-induced blockade of the post-ischemic monoamine oxidase-mediated increase in dopamine metabolism and the concurrent production of the potentially neurotoxic molecule, hydrogen peroxide.
Chronic cerebral vasospasm was induced in monkeys by placement of an autologous blood clot after the basal cisterns had been opened over the arteries of the circle of Willis on one side. The experimental protocol was detailed in Part 1 of this paper. Twenty of the 30 monkeys studied from both groups (one receiving placebo and the other nimodipine) underwent cerebral fixation (Day 14) at controlled pressure by intra-arterial perfusion. The arteries at the base of the brain were studied by light microscopy and scanning (SEM) and transmission electron microscopy (TEM). Cerebral angiography on Day 7 showed that vasospasm was significantly more common (p less than 0.0001) and more severe (p less than 0.01) on the clot side compared to the control or non-clot side. Vasospasm was less severe on Day 14, just before sacrifice. On SEM, 80% of the 20 middle cerebral artery (MCA) specimens that had been in spasm (Day 7) showed marked corrugation , and in some the endothelium had a fish-scale appearance. All of the 10 MCA's on the clot side examined by TEM that had been in spasm (Day 7) showed marked changes such as endothelial swelling, subendothelial proliferation, corrugation of the elastic lamina, and myonecrosis. With few exceptions, none of the basilar arteries or MCA's on the non-clot (control) side showed any abnormalities. The pathological findings of vessels in spasm were considered to be slightly less severe in the nimodipine group; however, the trial drug (1 mg/kg/8 hrs) did not prevent such abnormalities from occurring. The ultrastructural changes in the arterial walls of specimens from both placebo and nimodipine groups in vasospasm are described. Since dramatic changes are present in the vessel walls even after radiologically visible vasospasm has almost completely abated, we believe that vasospasm is due to long-lasting smooth-muscle constriction and not to vessel wall thickening caused by a cellular or subcellular infiltrate.
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