Donald Boisvert

Cerebral Arterial Spasm – A Controlled Trial of Nimodipine in Patients with Subarachnoid Hemorrhage

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, Fishers 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.

Nimodipine and Chronic Vasospasm in Monkeys: Part 1 Clinical and Radiological Findings

The efficacy of the calcium channel blocker nimodipine in the prevention of chronic cerebral vasospasm (VSP) and delayed ischemia after subarachnoid hemorrhage (SAH) in monkeys was examined in a blind, randomized, placebo-controlled trial. The primate model developed in this laboratory reliably induces chronic cerebral vasospasm and can induce pathologically proven delayed ischemic neurological deficits (DINDs). With standard microsurgical procedures, an average 6.4-ml autologous hematoma was placed directly against the major anterior cerebral vessels in the right basal subarachnoid spaces of 24 monkeys. The monkeys were randomized to one of four groups and were treated orally q8h for 7 days with nimodipine (3, 6, or 12mg/kg)or placebo. An additional 2 monkeys underwent the surgical procedure without clot placement. Drug administration began between 14 and 20 hours after clot placement. Indices monitored before and after SAH included neurological status, angiographic cerebral vessel caliber, and cerebral blood flow. Significant VSP (25 to 100% reduction in vessel caliber) was present on Day 7 on the clot side in 83% of the animals (P less than or equal to 0.001). There was no significant difference (P greater than 0.05) in the incidence of VSP among the four groups. Similarly, there was no significant difference (P greater than 0.05) in the mean vessel caliber reduction after SAH among the four treatment groups. There was no VSP present on Day 7 in the sham-operated animals. One animal receiving high dose nimodipine (12 mg/kg p.o. q8h) developed a DIND on Day 5 after SAH. A second animal in the 12-mg/kg group developed a transient neurological deficit between Days 4 and 7.

Effects of Photoradiation Therapy on Normal Rat Brian

Laser photoradiation of the brain via an optical fiber positioned 5 mm above a burr hole was performed after the injection of hematoporphyrin derivative (HpD) in 33 normal rats and 6 rats with an intracerebral glioma. Normal rats received HpD, 5 or 10 mg/kg of body weight, followed by laser exposure at various doses or were exposed to a fixed laser dose after the administration of HpD, 2.5 to 20 mg/kg. One control group received neither HpD nor laser energy, and another was exposed to laser energy only. The 6 rats bearing an intracranial 9L glioma were treated with HpD, 5 mg/kg, followed by laser exposure at various high doses. The temperature in the cortex or tumor was measured with a probe during laser exposure. The rats were killed 72 hours after photoradiation, and the extent of necrosis of cerebral tissue was measured microscopically. In the normal rats, the extent of brain damage correlated with increases in the dose of both the laser and the HpD. In all 6 glioma-bearing rats, the high laser doses produced some focal necrosis in the tumors but also damaged adjacent normal brain tissue. We conclude that damage to normal brain tissue may be a significant complication of high dose photoradiation therapy for intracranial tumors.

Photoradiation therapy: Current status and applications in the treatment of brain tumors

Photoradiation therapy is achieved when a photosensitizing drug is activated by light to form products that are lethal to tumor cells. The most commonly used drug is hematoporphyrin derivative, which is preferentially taken up and retained by malignant tissue. Photoactivation is usually produced by using a dye laser tuned at 630 nm (red light). The primary mechanism of neoplastic cell damage in photoradiation therapy involves the production of free radicals formed during illumination of hematoporphyrin derivative by light of this wavelength. The treatment would seem to damage first the tumor cell membrane, then the cytoplasmic inclusions, and finally the nucleus. Photoradiation therapy has been quite effective in the treatment of superficial malignancies, especially in skin, breast, eye, bladder, bronchus, and stomach. Experience with brain tumors is still limited. Important unresolved problems in the application of photoradiation therapy to gliomas include relative uptake of hematoporphyrin derivative into the tumor, limited light penetration of the tissue, local heating, and damage induced in normal brain by photoradiation therapy.

Penetration of hematoporphyrin derivative into rat brain and intracerebral 9L glioma tissue.

SummaryBrain and glioma tissue levels of tritiated hematoporphyrin derivative (3H-HPD) were measured in normal and 9L intracerebral glioma-bearing rats at 24 hours following administration of3H-HPD 2–20 mg/kg and at 24–120 hours after3H-HPD 10 mg/kg. Levels of3H-HPD in blood, liver, spleen and muscle were also measured.Tissue levels of3H-HPD increased progressively as the dose was increased. In animals given 10 mg/kg, gradual decreases in tissue levels occurred between 24 and 72 hours but thereafter remained stable. The3H-HPD level in gliomas was consistently 2–3 × greater than in brain tissue, despite changes in dosage and time interval. High levels of activity were measured in normal brain tissue at all dosage levels, and subsequent clearance of the3H-HPD from brain, glioma, and other tissues was slow; at 120 hours after administration of 10 mg/kg, approximately 50% of the 24 hour level was still present.These results indicate that although a dose- and time-independent preferential uptake of hematoporphyrin derivative occurs in intracerebral gliomas, persistent high levels may be present in the surrounding brain. The disadvantages of using hematoporphyrin derivative rather than its individual components in studies of HPD uptake and photosensitization in the brain are discussed.

Photoradiation therapy of 9L-gliosarcoma in rats: hematoporphyrin derivative (types I and II) followed by laser energy

SummarySuspensions of 9L-gliosarcoma cells were inoculated into the brain or flank of rats and photoradiation therapy (PRT) was applied to the resulting tumors. The PRT consisted of hematoporphyrin derivative (HpD), type I or II, followed by single-fiber laser energy 24, 48, or 72 h later. Necrotic foci in brain tumors were most numerous following laser exposure 24 h after HpD; they were more than twice as common, and with less damage to healthy tissue, after HpD II than after HpD I with the same laser dose. Neither lifespan nor the final weight of brain tumor was affected by the type of HpD or whether PRT was applied once or twice. In rats with flank tumor, multiple PRT (up to × 4) did not delay tumor growth; also, 11 of 12 PRT-treated flank tumors grew after implantation at various sites in healthy rats. We conclude that HpD II is a more effective photosensitizer than HpD I. However, the value of PRT will be limited until a lethal dose of laser energy can be delivered throughout a tumor without destroying vital healthy tissue.

Brain tolerance to middle cerebral artery occlusion during hypotension in primates

The aim of this study was to determine the duration of middle cerebral artery occlusion required to produce significant ischemic damage when the occlusion occurs during controlled systemic hypotension. In 21 anesthetized cynomolgus monkeys, an IV infusion of sodium nitroprusside was used to lower the mean arterial blood pressure to 45-50 mmHg for 90 minutes. Middle cerebral artery occlusion for 15, 30, 45, or 60 minutes was performed during the hypotensive period. Neurological function was then evaluated every 8 hours for a total of 72 hours. At the end of the observation period, the monkeys were again anesthetized, magnetic resonance imaging was performed, and the brain was perfused with 10% buffered formalin. Neurological deficits were observed after 30 minutes, but not after 15 minutes, of middle cerebral artery occlusion, and rapidly increased in incidence and severity when the duration of occlusion was increased. After 60 minutes of occlusion, all the monkeys exhibited severe deficits. Four monkeys died during the observation period--two in each of the 45- and 60-minute occlusion groups. Histopathological examination revealed that little or no ischemic damage resulted from a 15-minute occlusion during hypotension. However, severe ischemic damage began to occur after only 30 minutes of occlusion, and all monkeys subjected to middle cerebral artery occlusion for 60 minutes developed extensive regions of infarction. The size and incidence of these infarctions correlated well with the lesions observed in the magnetic resonance images. These results demonstrate that the duration of middle cerebral artery occlusion that produces cerebral infarction in primates is drastically reduced when the occlusion occurs at hypotensive levels commonly employed during neurovascular surgical procedures.

Inhibition of ischemia-induced brain catecholamine alterations by clonidine.

The effect of clonidine, an alpha 2-agonist, on ischemia-induced alterations in brain catecholamine and metabolite levels was studied in Mongolian gerbils subjected to 180 min of unilateral cerebral ischemia. The gerbils were randomly assigned to four treatment groups: sham-operated or unilateral carotid lesion; each pretreated with clonidine 0.4 mg/kg IP, or untreated. All animals were neurologically assessed and categorized as asymptomatic, neurological deficit or seizure activity at the time of sacrifice. Hemispheric levels of noradrenaline (NA), dopamine (DA), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured using high pressure liquid chromatography with electrochemical detection. No changes from control were found in animals that remained asymptomatic regardless of treatment. In untreated gerbils that exhibited neurological deficits, marked reductions in both NA and DA and increases in HVA occurred in the ischemic hemisphere. These alterations were greater in gerbils that developed seizures during the observation period. Ischemic animals pretreated with clonidine did not show any significant alterations in catecholamine or metabolite levels from clonidine-treated, sham-operated controls in spite of the presence of neurological deficits. Although significant reductions in NA and DA still occurred in pretreated animals that developed seizures, the changes were markedly less than in untreated gerbils. These results indicate that alpha 2-adrenoceptor stimulation is an effective approach for inhibition of ischemia-induced brain catecholamine alterations, and thus may provide a useful method for assessing the role of catecholamine release in the production of acute ischemic neuronal damage.

A feline model for experimental studies of peritumor brain edema

SummaryAn in vivo model for correlative imaging studies of intracerebral glial tumors and peritumor brain edema has been developed. Adult male and female cats implanted with 1 × 106 or 5 × 105 9L glioma cells had parietal tumors of 4 mm or greater in diameter and showed signs of increased intracranial pressure 13.7±1.9 days or 19.2±1.3 days after implantation. No immunosuppression was required and the success rate for tumor growth after implantation was 88%. Histologically, the tumor resembles a malignant astrocytoma.The tumor contained the highest water content (85.94%); peritumor white matter was more edematous (73.01%) than white matter in the contralateral hemisphere (69.04%), sham-operated (69.41%) and control brain (68.76%). There was no correlation between the size of the tumor and water content in tumor or white matter. Increased tissue albumin in peritumor white matter indicated blood-brain barrier dysfunction within the tumor and confirmed the vasogenic origin of the edema.Proton magnetic resonance imaging provided good spatial and contrast resolution with increased signal intensity in edematous white matter, decreasing with distance from the tumor. The large brain of this animal model allows the use of serial imaging and regional correlative biochemical measurements in a single animal. Other advantages of this model are its predictability and the short time required to produce tumors with marked peritumor edema.

Effect of reserpine-kanamycin treatment on chronic vasospasm after platelet-enriched subarachnoid hemorrhage in primates

A model of chronic cerebral vasospasm (VSP) analogous to the clinical situation was established by inducing subarachnoid hemorrhage (SAH) in monkeys. Platelets harvested from 4 ml of blood were added to autologous blood in an attempt to accentuate any effect that vasoactive substances such as serotonin, contained in platelets, might have on producing cerebral VSP. Antiserotonin medications were administered in an attempt to reduce the frequency or severity of angiographically proven VSP. Animals were divided into small (1 ml/kg) and large (1.2 to 1.5 ml/kg) hemorrhage groups and later were randomized equally to receive either saline placebo or reserpine (0.013 mg/kg i.m.) and kanamycin (50 mg/kg p.o.) administered 3 hours after SAH and daily thereafter to Day 7. In both the small and the large hemorrhage groups of treated animals, there was a significant reduction in serotonin levels (P less than 0.01 and P less than 0.05, respectively) compared to base line levels. In the groups of nontreated monkeys with small and large hemorrhages, serotonin levels were not statistically different from control values. Despite reduction of serotonin levels to 19 and 26% of the control values in the small and large hemorrhage, treated groups, there was no apparent difference in the frequency or severity of angiographically proven VSP. This study found no evidence that reserpine and kanamycin have a beneficial effect on preventing VSP when treatment is begun after SAH.