Thomas R. Overton

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.

Quantitative Measurement of Bone Density Using Gamma-Ray Computed Tomography

A special purpose gamma-ray computed tomography scanner has been developed for precise measurements of bone density in the human appendicular skeleton. Details of the scanners hardware and of the software organization for system control and data analysis are given, together with an outline of the theoretical basis for conversion of measured linear attenuation coefficients to physical bone densities. Performance of the system was evaluated on bone-like phantoms. Clinically, a precision of ± 0.5% is obtained for bone density determinations. This device is being used in experimental studies and clinical investigations.

Clinical Grade, Regional Cerebral Blood Flow and Angiographical Spasm in the Monkey After Subarachnoid and Subdural Hemorrhage

Subarachnoid and subdural hemorrhage has been induced in the anesthetized monkey by injection of fresh autogenous blood via a needle inserted through a subfrontal twist drill hole. Serial angiographical studies and regional cerebral blood flow (rCBF) determinations were carried out concurrently for three hours following hemorrhage. The changes observed were subsequently correlated with the clinical state of the animals upon reversal of anesthesia. In general, angiographical vasospasm and a reduction in CBF occurred simultaneously. Occasionally, however, cerebral perfusion remained unaltered after SAH even though marked vasoconstriction of the intradural vessels was present. An excellent correlation between the severity of reduced perfusion and the degree of neurological deficit was found.

Regional Cerebral Blood Flow in Patients with Aneurysms: Estimation by Xenon 133 Inhalation

Seventy six regional cerebral blood flow (rCBF) studies were conducted on 32 patients who had a total of 39 aneurysms. Twenty three of these patients were studied pre- and post-operatively. Normal values were obtained from a control group of 33 subjects, each of whom underwent one rCBF study. Flow was reduced following subarachnoid hemorrhage (SAH); it increased significantly post-operatively. Lower flows were associated with poorer clinical grades. There was a greater variation in regional distribution of flow immediately following SAH than in normals or in patients who had recovered from the acute phase. rCBF studies correlated with CT scans demonstrated that a progressive increase in ventricular size was accompanied by a progressive reduction in flow. In addition, intraventricular hemorrhage (IVH) was associated with a significant reduction in cerebral blood flow (CBF). No significant correlation between CBF and spasm was demonstrable.

The Effect of Graded Hypocapnia and Hypercapnia on Regional Cerebral Blood Flow and Cerebral Vessel Caliber in the Rhesus Monkey: Study of Cerebral Hemodynamics Following Subarachnoid Hemorrhage and Traumatic Internal Carotid Spasm

Correlative cerebral blood flow (CBF) and vessel diameter studies were performed during graded Paco, change in control monkeys and in monkeys subjected to subarachnoid hemorrhage and internal carotid artery spasm. In the control series CBF increased linearly between PaCO2 values of 30 mm Hg and 60 mm Hg. An increase in PaCO2 from 40 mm Hg to 62 mm Hg produced a mean CBF increase of 74% while a reduction of PaCO2 to 25 mm Hg resulted in a decrease of 40%. Cerebral gray matter was more responsive to PaCO2 change than white matter. Caliber of the larger capacitance vessels did not provide an adequate index of the status of cerebral circulation. In the experimental series both SAH and traumatic internal carotid artery spasm caused a decreased hemodynamic responsiveness to PaCO2. However, when PaCO2 was raised to 60 to 65 mm Hg, marked increases in cerebral perfusion occurred (breakthrough phenomenon). In general, a poor correlation between CBF and vessel diameter studies was found in the postinsult period. The studies indicated: (1) SAH caused an increase in cerebrovascular resistance and a decrease in CBF, (2) hemodynamic responses to PaCO2 change, although diminished, were not abolished in the acute period after SAH, (3) hypercapnia (PaCO2 > 60 mm Hg) significantly increased cerebral perfusion whether or not vasospasm was alleviated, and (4) the small distal cerebral vessels were more reactive to PaCO2 change and were more intimately associated with regulation of cerebral perfusion.

Ventricular Size and Cerebral Blood Flow Following Subarachnoid Hemorrhage

The relationship among ventricular size on computed tomography (CT), the clinical status of the patient, and cerebral blood flow alterations in subarachnoid hemorrhage is examined. Fifty patients with subarachnoid hemorrhage underwent a total of 71 cerebral blood flow measurements and 115 CT scans. Flow was measured noninvasively using 133Xe inhalation. It is demonstrated that increasing ventricular size is accompanied by clinical deterioration and also by a reduced flow. The effects of the various lesions (as demonstrated by CT) on cerebral perfusion are examined. Of the 23 patients scanned 5 days or less after hemorrhage, 12 had subarachnoid blood visible on the scan. These 12 had flows that averaged 20% lower than the other 11 when examined 6 to 17 days after the hemorrhage. Ventricular enlargement is more prevalent in the first week after the hemorrhage than in the second. Also, blood flow is maximally reduced at the end of the first week following hemorrhage.

Experimental subarachnoid hemorrhage in the cynomolgus monkey: evaluation of treatment with hypertension, volume expansion, and ventilation

We evaluated the treatment regime of dopamine-induced hypertension in association with volume expansion and ventilatory support in an experimental subarachnoid hemorrhage (SAH) model using the cynomolgus monkey. Regional cerebral blood flow, vessel caliber, intracranial pressure, and other pertinent physiological parameters were monitored throughout each study. We report the results for nine animals receiving treatment after an induced SAH and compare them with results obtained in a group of five animals not treated after SAH. Improvements in cerebral blood flow, vessel caliber, and morbidity and mortality rates were seen with this treatment. Seven of nine animals were alive at 20 hours after SAH in the treatment group, whereas all five animals in the untreated group died before this time. The mechanisms of action of this treatment are discussed. (Neurosurgery, 6: 57--62, 1980)

Skeletal challenge: An experimental study of pharmacologically induced changes in bone density in the distal radius, using gamma-ray computed tomography

SummaryBone density (BD) at the distal end of the radius was measured serially with gamma-ray computed tomography (γ-CT) in five groups of healthy postmenopausal women. One group comprised untreated controls; women in the other groups were subjected to pharmacologic challenge with putative activators and/or depressors of bone remodeling. The challenge agents, taken orally, were ergocalciferol (vitamin D2) alone and followed by calcium; calcitriol (1,25 OH)2D3), and prednisone. All of the subjects showed changes in BD following challenge; these changes were significant (P<0.05) for the groups receiving vitamin D2 and vitamin D2 plus calcium. Responses to ergocalciferol, calcitriol, and prednisone were similar within groups, whereas the group receiving ergocalciferol then calcium comprised two distinct subgroups: bone density transiently increased in one and decreased in the other. For all five groups, the direction of change in bone density in response to the challenge, and its duration and magnitude, were consistent with reported histomorphometric data. We conclude that γ-CT assessment of change in bone density after pharmacologic challenge provides a useful noninvasive approach to skeletal investigation.

Treatment of subarachnoid hemorrhage with sodium nitroprusside and phenylephrine: an experimental study.

The effectiveness of simultaneous intravenous sodium nitroprusside and phenylephrine in improving the cerebrovascular disturbances and survival rate after induced subarachnoid hemorrhage (SAH) was studied in the cynomolgus monkey. We measured regional cerebral blood flow (rCBF) using the intra-arterial xenon-133 clearance technique. In our experimental animal model, SAH was associated with a persistent reduction in rCBF, elevation of cerebrovascular resistance (CVR), cerebral vasospasm for the duration of the study (150 minutes), and poor survival. For animals receiving the treatment regime (administered approximately 25 minutes after the induced SAH), rCBF remained low, CVR was high, and cerebral vasospasm was persistent. Survival in this group was the same as that observed for the untreated animals. Simultaneous administration of sodium nitroprusside and phenylephrine was ineffective in improving rCBF, CVR, cerebral vasospasm, or survival after SAH. In the control group (receiving only the treatment and not an intracranial insult), rCBF was below resting levels both during and after therapy, indicating impaired cerebral autoregulation. (Neurosurgery, 5: 688--595, 1979).

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.