Studies on concentration-time profiles of nimodipine enantiomers following intravenous and oral administration of nimodipine in patients with subarachnoid hemorrhage.

After i.v. and oral administration of nimodipine the concentration-time profiles of the drug and its enantiomers were studied in seven patients with subarachnoid hemorrhage. Concentrations of nimodipine, (+)-(R)-, and (-)-(S)-nimodipine were analyzed using a new stereoselective high-performance liquid chromatographic method. During the first 3 h after oral administration the concentrations of (+)-(R)- and (-)-(S)-nimodipine were significantly different, the (-)-(S)-enantiomer being found in much lesser concentrations compared to the (+)-(R)-enantiomer. The results indicate that if uptake from the gastrointestinal system is equal for the two enantiomers, then (-)-(S)-nimodipine is metabolized at a much faster rate compared to (+)-(R)-nimodipine after oral administration of the drug in patients with subarachnoid bleeding. After i.v. administration; no significant differences between the concentrations of the (-)-(S) and the (+)-(R) isomers were demonstrated.

Effect of nimodipine on cerebral blood flow and cerebrovascular reactivity after subarachnoid haemorrhage.

The aim of the present study was to investigate the effect of nimodipine on autoregulation of cerebral blood flow (CBF), CO2 reactivity and cerebral oxygen metabolism (CMRO2) in patients with subarachnoid haemorrhage (SAH). Eight patients with severe SAH were studied with repeated CBF and CMRO2 measurements on the first day of the bleeding and after at least 12 h of treatment of nimodipine. An initial resting study, an autoregulation study and a hyperventilation study was performed. CBF was measured using the 133-Xenon intravenous method. CMRO2 was calculated as AVDO2 x CBF. Nimodipine did not significantly change CBF and CMRO2 in the initial resting study. After induced arterial hypotension intact autoregulation was found before as well as after treatment with nimodipine. Beneficial effects of nimodipine were found on CO2 reactivity and CMRO2 during hypotension that may be explained as a positive effect on cerebral ischaemia.

Are cerebral aneurysms atherosclerotic?

BACKGROUND AND PURPOSE: The aim of our study was to investigate plasma and genetic risk factors for rupture of cerebral aneurysms. METHODS: In London, a case-control study was made of 56 consecutive patients admitted to a regional neurosurgical service for treatment of ruptured cerebral aneurysm and of 93 control subjects. A further 40 consecutive patients admitted in Arhus with ruptured cerebral aneurysm also were studied. RESULTS: The British case-control study showed that smoking was associated with an increased risk of ruptured cerebral aneurysm (odds ratio, 9.1; 95% confidence interval [CI], 3.4 to 23.8; P < .001 for a history of > 10 pack years). After age and sex adjustment, factors associated with ruptured cerebral aneurysm included a cholesterol concentration in the highest tertile (> or = 6.3 mmol/L; odds ratio, 10.2; 95% CI, 3.9 to 26.7; P < .001), an apolipoprotein B concentration in the highest tertile (> or = 0.84 g/L; odds ratio, 6.4; 95% CI, 2.5 to 16.3; P < .001), and concentrations of HDL cholesterol in the lowest tertile (< 1.1 mmol/L; odds ratio, 3.6; 95% CI, 1.4 to 8.2; P < .01). History of hypertension was of less importance (odds ratio, 4.0; 95% CI, 1.41 to 11.7; P < .01). Smoking history (P < .001) and increased concentrations of cholesterol (P < .0001) were the most important independent risk factors associated with ruptured cerebral aneurysm on multivariate analysis. The histories of hypertension and smoking, together with apolipoprotein B levels, in the Danish patients were similar to those in the British patients. In the entire patient group, the frequencies of two polymorphic variations in the type III collagen gene and polymorphisms at the apolipoprotein B, apolipoprotein C-III, and haptoglobin gene loci were not different from control subjects or the normal population; allele frequencies in British and Danish patients were similar. CONCLUSIONS: An atherosclerotic profile including increased total cholesterol concentration and a long smoking history may contribute to the rupture of cerebral aneurysms. This study provides no support for the hypothesis that inherited abnormalities of type III collagen are a common cause of cerebral aneurysms.

Pathophysiology of subarachnoid haemorrhage. Experimental and clinical data.

When a saccular aneurysm suddenly ruptures the intracranial pressure (ICP) abruptly rises to reach a level at about the diastolic blood pressure in 1 to 2 minutes. Unless a haematoma is formed ICP will soon fall and reach a steady level in about 10 minutes. In the days following the initial SAH several pathophysiological events take place. Regional CBF and the cerebral metabolic rate of oxygen (CMRO2) are reduced resulting in so-called luxury perfusion due to an uncoupling between flow and metabolism. The arteriovenous difference of oxygen is always reduced. CMRO2 falls parallel to increasing severity of vasospasm. CBF below 20 ml/100 g/min in cases of severe diffuse spasm inevitably result in brain tissue infarction. The development of vasospasm, which reaches a maximum between the 5th and 9th day after SAH, is accompanied by CSF lactacidosis and intracranial hypertension. The reactivity of the cerebral arteries after SAH is often impaired. Cerebral autoregulation to arterial hypotension is disturbed even in mild cases, and globally fails in severe vasospasm. On the other hand the reactivity of the cerebral vasculature to changes in arterial PCO2 is always preserved although reduced. Only in the presence of severe tissue acidosis will both modes of reactivity be damaged--so-called total vasoparalysis.

Nonpulsatile cardiopulmonary bypass disrupts the flow-metabolism couple in the brain.

The effect of cardiopulmonary bypass on the relationship between brain glucose consumption and regional blood flow is unknown. We measured this relationship in pigs subjected to 3 hours of pulsatile or nonpulsatile cardiopulmonary bypass at normothermia and compared the results to the relationship established in a control group of pigs. A total of 10 regions were sampled in both hemispheres of the porcine brain. In control pigs, cerebral blood flow averaged 46 ml/100 gm and the glucose consumption, 21 mumol/100 gm/min. The ratio between blood flow and glucose consumption was close to 2 ml/mumol in all regions. In pulsatile cardiopulmonary bypass both the whole-brain average and the regional values declined, so that the ratio remained the same, about 2 ml/mumol. In nonpulsatile cardiopulmonary bypass regional blood flow remained normal; the average was 49 ml/100 gm/min, whereas the average glucose consumption declined to 16 mumol/100 gm. In regions with high blood flow rates, the ratio between blood flow and glucose consumption increased to about 3 ml/mumol, indicating perfusion in excess of metabolic demand. We conclude that nonpulsatile cardiopulmonary bypass at normothermia affects the metabolic flow regulation in the brain by interfering with the myogenic contractility of cerebral arterioles.

Cerebrovascular reactivity in patients with ruptured intracranial aneurysms.

The cerebral vasomotor reactivity to arterial hypotension and hypocapnia was studied in 34 patients between the 3rd and 13th day after rupture of an intracranial saccular aneurysm. Using the intra-arterial xenon-133 injection method, regional cerebral blood flow (rCBF) and cerebral metabolic rate of oxygen (CMRO2) were measured. The intraventricular pressure and cerebrospinal fluid (CSF) lactate and pH levels were determined. The degree of vasospasm was measured on angiograms taken immediately following the rCBF study. The patients were graded clinically according to the system of Hunt and Hess. Cerebral autoregulation was intact in patients in good clinical condition, but was impaired in patients in poor clinical condition. There was a close correlation between the degree of vasospasm and the degree of autoregulatory impairment, which varied from focal disturbances to global impairment. Intracranial hypertension and CSF lactic acidosis were commonly found in association with vasoparalysis. Cerebrovascular response to hyperventilation was generally preserved, although often reduced. During hyperventilation, the cerebral perfusion pressure became elevated, and increases in CMRO2 were often found, even in patients with severe diffuse spasm and cerebral ischemia. The clinical significance of the results in relation to the treatment of delayed cerebral ischemia and to the use of intraoperative induced hypotension is discussed.

Regional CBF, intraventricular pressure, and cerebral metabolism in patients with ruptured intracranial aneurysms.

Regional cerebral blood flow (rCBF), cerebral metabolic rate of oxygen (CMRO2), intraventricular pressure, and lactate/pH levels in the cerebrospinal fluid (CSF) were measured in 38 patients with ruptured intracranial aneurysms between the 3rd and 13th day after subarachnoid hemorrhage (SAH). Angiography was performed following the rCBF study and the degree of vasospasm was measured on the angiograms. The patients were graded clinically according to the system of Hunt and Hess. Cerebral vasospasm significantly influenced rCBF: global reductions and focal changes (ischemia, hyperemia, and tissue peaks) were commonly associated with vasospasm. Patients with severe diffuse spasm always had global ischemia (21 +/- 5 ml/100 gm/min), and cerebral infarctions were demonstrated subsequently, The CMRO2 was more reduced than rCBF, indicating an uncoupling between flow and metabolism. This relative luxury perfusion was associated with CSF lactic acidosis and intracranial hypertension. The arteriovenous difference of oxygen was equally reduced in all categories of patients, probably due to the primary insult of SAH. The CMRO2 decreased concomitantly with arterial caliber, indicating a secondary impairment of cerebral metabolism due to vasospasm.

Serial measurement of regional cerebral blood flow in patients with SAH using 133Xe inhalation and emission computerized tomography.

A noninvasive three-dimensional method for measuring cerebral blood flow (CBF), xenon-133 inhalation and emission computerized tomography, was used to investigate the CBF changes accompanying delayed neurological deterioration following subarachnoid hemorrhage (SAH). A total of 67 measurements were performed on 20 patients in Hunt and Hess' clinical Grades I to III in the first 21 days post SAH. Five patients with normal CBF tomograms on admission developed delayed neurological deficits in the 2nd week after hemorrhage, at which time repeat CBF tomograms in four patients revealed large areas of well defined regional flow decrease in the vascular territories of the anterior or middle cerebral arteries. Severe vasospasm was noted in three of these patients in whom arteriography was performed in the 2nd week post SAH. Diffuse bihemispheric CBF decreases were noted later in the course of delayed neurological deficits; however, measurements obtained soon after the onset of focal symptoms suggest that the only CBF decreases directly produced by vasospasm in Grade III patients are regional changes.

Reversal of cerebral arterial spasm by intrathecal administration of a calcium antagonist (nimodipine).

Specific antagonists to the influx of calcium, necessary for the excitation-contraction coupling process in arterial smooth muscle, are potentially useful in the treatment of cerebral vasospasm but systemic hypotension might limit their clinical applicability. We studied the effect of the calcium antagonist nimodipine (BAY e 9736) on cerebral arterial spasm, intraventricular pressure and blood pressure (BP), when administered into the cerebral ventricles of the dog. Cerebral vasospasm was produced by the injection of autologous blood into the cisterna magna. In a group of 8 dogs, 100 micrograms of nimodipine was injected into the lateral ventricle. The effect of the drug on the basilar artery was monitored angiographically. Nimodipine always relieved spasm, and often the relaxation surpassed the resting vessel diameter. In a control group, the injection of placebo did not relax the spastic arteries. Determinations using gas chromatography of nimodipine in CSF and blood demonstrated that a concentration of 1 microgram/ml in cisternal CSF was sufficient to reduce spasm while concomitant plasma concentrations of 0.004 micrograms/ml did not result in significant BP reduction.

Intracranial arterial aneurysms in children and adolescents.

Throughout the period 1943 to 1980, 1368 patients with verified intracranial saccular aneurysms were treated in the University of Aarhus neurosurgical department. Forty-three (3.1%) patients (25 boys and 18 girls) were 19 years old or younger, and 33 (77%) had an onset of symptoms typical of subarachnoid bleeding. Using the classification system of Hunt and Hess as a basis for clinical assessment on admission, 58% of the patients could be placed in Grade I or II. Cerebral vasospasm was demonstrated in 53% of the patients undergoing angiography between the 4th and 16th day after hemorrhage. There was no increased morbidity or mortality in the group of patients with vasospasm, and no cerebral infarction was demonstrated at necropsy. Therefore, it is possible that vasospasm is of minor prognostic significance in children. In 15 patients (37%), aneurysm rupture was accompanied by intracerebral hematoma. The mortality rate in this group of 15 patients was 50%, whereas in the group without hematoma it was 26%. The overall mortality rate was 33%. The surviving 29 patients were followed for 3 months to 14 years. Twenty-three patients made a good recovery (80% of survivors and 54% of the total series), five were moderately disabled, and one was severely disabled.

Intracranial pressure changes following aneurysm rupture. Part 3: Recurrent hemorrhage.

Continuous monitoring of intraventricular pressure (IVP) was performed before and during 13 recurrent hemorrhages occurring in 10 patients between the 3rd and 14th day after the initial rupture of an intracranial saccular aneurysm. Before re-rupture, nine patients were of Hunt and Hess' clinical Grade III of IV. Severe angiographic vasospasm was demonstrated in six patients. In the period between ruptures, IVP and mean arterial blood pressure were significantly increased compared to pressures in patients who did not rebleed. Ventricular drainage of cerebrospinal fluid (CSF) to a level of 25 mm Hg did not increase the rate of rebleeding (17% of patients). On the other hand, the use of drainage while the repeat rupture was taking place seemed to exert a deleterious effect on the natural mechanisms that lead to arrest of hemorrhage. In five patients with CSF drainage during their rebleed, the steady-state IVP level after the repeat rupture was significantly increased, and four patients died from large intracerebral hemorrhages. These results suggest that drainage of CSF should be avoided during recurrent hemorrhage, and should not be resumed until a steady-state IVP level has been reached.