Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial.

OBJECTIVE--To determine the efficacy of oral nimodipine in reducing cerebral infarction and poor outcomes (death and severe disability) after subarachnoid haemorrhage. DESIGN--Double blind, placebo controlled, randomised trial with three months of follow up and intention to treat analysis. To have an 80% chance with a significance level of 0.05 of detecting a 50% reduction in an incidence of cerebral infarction of 15% a minimum of 540 patients was required. SETTING--Four regional neurosurgical units in the United Kingdom. PATIENTS--In all 554 patients were recruited between June 1985 and September 1987 out of a population of 1115 patients admitted with subarachnoid haemorrhage proved by the results of lumbar puncture or computed tomography, or both. The main exclusion criterion was admission to the neurosurgical units more than 96 hours after subarachnoid haemorrhage. There were four breaks of code and no exclusions after entry. One patient was withdrawn and in 130 treatment was discontinued early. All patients were followed up for three months and were included in the analysis, except the patient who had been withdrawn. INTERVENTIONS--Placebo or nimodipine 60 mg was given orally every four hours for 21 days to 276 and 278 patients, respectively. Treatment was started within 96 hours after subarachnoid haemorrhage. END POINTS--Incidence of cerebral infarction and ischaemic neurological deficits and outcome three months after entry. MEASUREMENTS--Demographic and clinical data, including age, sex, history of hypertension and subarachnoid haemorrhage, severity of haemorrhage according to an adaptation of the Glasgow coma scale, number and site of aneurysms on angiography, and initial findings on computed tomography were measured at entry. Deterioration, defined as development of a focal sign or fall of more than one point on the Glasgow coma scale for more than six hours, was investigated by using clinical criteria and by computed tomography, by lumbar puncture, or at necropsy when appropriate. All episodes of deterioration and all patients with a three month outcome other than a good recovery were assessed by a review committee. MAIN RESULTS--Demographic and clinical data at entry were similar in the two groups. In patients given nimodipine the incidence of cerebral infarction was 22% (61/278) compared with 33% (92/276) in those given placebo, a significant reduction of 34% (95% confidence interval 13 to 50%). Poor outcomes were also significantly reduced by 40% (95% confidence interval 20 to 55%) with nimodipine (20% (55/278) in patients given nimodipine v 33% (91/278) in those given placebo). CONCLUSIONS--Oral nimodipine 60 mg four hourly is well tolerated and reduces cerebral infarction snd improves outcome after subarachnoid haemorrhage.     

Rationale of the SEAS study: Serial Echocardiography After Subarachnoid haemorrhage,a prospective national,multicentre, multidisciplinary,cohort study to evaluate cardiac abnormalities following intracranial haemorrhage

The SEAS study is a prospective national, multicentre, multidisciplinary, cohort study in which the cardiac abnormalities following aneurysmal subarachnoid haemorrhage are studied. Incidence, clinical implications and predictive variables of cardiac abnormalities following aneurysmal subarachnoid haemorrhage will be studied. Cardiac abnormalities are defined as ECG changes, echocardiographic function abnormalities, and biochemical changes. A total of 350 patients will be included over a period of three years including follow-up.     

尼莫地平联合丁基苯酞对外伤性蛛网膜下腔出血患者脑微循环的影响

目的:探究尼莫地平联合丁基苯酞对外伤性蛛网膜下腔出血患者脑微循环的影响。方法:选取我院外伤性蛛网膜下腔出血患者36例,随机分为实验组和对照组,每组18例。对照组给予尼莫地平治疗,实验组给予尼莫地平联合丁基苯酞治疗。观察并比较两组患者治疗前后脑微循环的变化情况。结果:实验组总有效率(88.9%)高于对照组(61.1%),差异有统计学意义(P0.05);与治疗前相比,两组脑血容量(CBV)、脑血流量(CBF)水平均增高,平均通过时间(MTT)水平降低(P0.05);与对照组相比,实验组CBV和CBF水平较高,MTT较低(P0.05);与对照组相比,实验组格拉斯哥昏迷评分(GOS)评分较高、临床并发症发生率较低、6个月病死率较低,差异有统计学意义(P0.05)。结论:尼莫地平联合丁基苯酞可有效改善外伤性蛛网膜下腔出血患者的脑微循环,提高患者的生存率。     

尼莫地平对动脉瘤性蛛网膜下腔出血脑血管痉挛的临床疗效研究

目的:观察尼莫地平对动脉瘤性蛛网膜下腔出血脑血管痉挛的临床疗效及安全性,为临床治疗提供依据。方法:对我院2010年2月~2013年2月期间收治的92例动脉瘤性蛛网膜下腔出血患者进行随机分为观察组和对照组,每组46例。两组患者入院后均进行常规治疗,绝对卧床休息、镇静、给予氨甲环酸止血、脱水降颅压、防治感染及对症治疗。观察组在上述治疗基础上给予尼莫地平(德国拜尔公司)持续微泵静脉注射20 mg·d-1,连用14 d,后改为口服尼莫地平片40 mg,qid,至第21天,根据监测血压调整剂量。观察两组患者1个月内脑血管发病情况、CT评价情况,并进行对比分析。结果:两组患者治疗后,观察组有效率91.3%;对照组有效率73.91%。两组比较差异明显,观察组疗效明显优于对照组,具有统计学意义(P0.05)。两组患者在治疗期间,观察组发生脑血管痉挛4例,占8.7%;对照组发生脑血管痉挛26例,占56.52%,两组比较差异明显,具有统计学意义(P0.05)。结论:尼莫地平能够显著降低动脉瘤性蛛网膜下腔出血脑血管痉挛的发生率,对脑血管再出血具有积极防治作用,建议推广应用。     

Toxicity of myoglobin and haemoglobin: oxidative stress in patients with rhabdomyolysis and subarachnoid haemorrhage

Haemolytic events, such as those following rhabdomyolysis and subarachnoid haemorrhage, often result in pathological complications such as vasoconstriction. Haem-protein cross-linked myoglobin and haemoglobin are generated by ferric-ferryl redox cycling, and thus can be used as markers of oxidative stress. We have found haem-protein cross-linked myoglobin in the urine of patients suffering from rhabdomyolysis and haem-protein cross-linked haemoglobin in the cerebrospinal fluid of patients following subarachnoid haemorrhage. These findings provide strong evidence that these respiratory haem proteins can be involved in powerful oxidation processes in vivo. We have previously proposed that these oxidation processes in rhabdomyolysis include the formation of potent vasoconstrictor molecules, generated by the myoglobin-catalysed oxidation of membranes, inducing nephrotoxicity and renal failure. Haem-protein cross-linked haemoglobin in cerebrospinal fluid suggests that a similar mechanism of lipid oxidation is present and that this may provide a mechanistic basis for the delayed vasospasm that follows subarachnoid haemorrhage.     

Subarachnoid haemorrhage: older patients have low cerebral blood flow.

Daily estimations of hemispheral cerebral blood flow using the xenon-133 inhalation technique was made in 116 patients during the first three weeks after subarachnoid haemorrhage. The patients'' cerebral perfusion on average remained less than the normal perfusion expected for their age (based on a single estimation of cerebral blood flow in 67 volunteers). On each separate day after subarachnoid haemorrhage cerebral blood flow was inversely related to the patient''s age. Older patients seem especially at risk of developing cerebral ischaemia after subarachnoid haemorrhage. The clinical outcome was more often unfavourable in older patients--that is, in those who tended to have the lowest cerebral blood flow. Present results support the view that episodes of low cerebral blood flow lead to a poor outcome after subarachnoid haemorrhage. Because of the risk of inducing cerebral ischaemia great care should be exercised by physicians administering hypotensive drugs to older patients after subarachnoid haemorrhage.     

阿托伐他汀联合尼莫地平治疗蛛网膜下腔出血的临床疗效及对血清S-100B、Ang水平的影响

目的:探讨阿托伐他汀联合尼莫地平治疗蛛网膜下腔出血的临床疗效及对患者血清蛋白(S-100B)、血管生成素(Ang)水平的影响。方法:选择2015年1月至2016年1月我院收治的蛛网膜下腔出血患者90例,采用随机数表法分为观察组(n=45)和对照组(n=45)。观察组采用阿托伐他汀联合尼莫地平进行治疗,对照组采用尼莫地平治疗。比较两组患者的临床疗效及治疗前后脑动脉平均血流速度、美国国立卫生研究院卒中量表(NIHSS)、日常生活能力量表(BI)、血清S-100B、人血管生成素(ANG)水平的变化及不良反应的发生情况。结果:治疗后,观察组总有效率为93.33%,显著高于对照组(73.33%,P0.05)。治疗后,两组患者脑动脉平均血流速度、NIHSS及BI评分均较治疗前明显改善,且观察组患者脑动脉平均血流速度、BI评分均高于对照组;NIHSS评分明显低于对照组(P0.05);治疗后,两组血清S-100B、ANG水平较治疗前均显著降低(P0.05),且观察组血清S-100B、ANG水平均明显低于对照组(P0.05)。观察组并发症发生率为13.33%,明显低于对照组(46.67%,P0.05)。结论:阿托伐他汀联合尼莫地平治疗蛛网膜下腔出血患者的疗效及安全性均明显优于单用尼莫地平治疗治疗,可能与其有效降低血清S-100B、ANG水平有关。     

Recovery after subarachnoid haemorrhage.

OBJECTIVE--To determine the implications of subarachnoid haemorrhage for quality of life and aftercare. DESIGN--Prospective follow up study of patients surviving subarachnoid haemorrhage over one year (at discharge, three months, and one year) by examination of cognitive functions (a test battery) and changes in everyday life (semistructured interview). SETTING--Regional neurosurgical unit at a tertiary referral centre. PATIENTS--100 Patients with subarachnoid haemorrhage; 17 were lost during the study because of ineligibility (further surgery, previous head injury, relevant psychiatric history, and cultural differences), loss of contact, and non-compliance; a further 13 patients who developed a neurological deficit were considered separately. MAIN OUTCOME MEASURE--Performance on cognitive test battery and reported changes in quality of life. RESULTS--At discharge patients with and without neurological deficit scored below established norms with most tests, but by three months the difference had resolved in patients without deficit. Reduced quality of life attributable to subarachnoid haemorrhage at one year mainly included less energy (seven patients), adverse emotional changes (five), early retirement, affected social life, and domestic tension (three each). None reported reduced capacity for work. CONCLUSIONS--Patients surviving subarachnoid haemorrhage without neurological symptoms have a good prognosis and should be encouraged to return to a normal lifestyle within about three months.     

Digoxin-like immunoreactive substance in patients with aneurysmal subarachnoid haemorrhage.

Digoxin was measured by radioimmunoassay in the plasma of 25 patients with aneurysmal subarachnoid haemorrhage who had not received digoxin treatment. After heating the plasma an endogenous substance cross reacting with antibodies to digoxin was identified in 18 cases. The presence of this substance was significantly related to the total amount of blood and to the presence of blood in the frontal interhemispheric fissure and could not be explained by hypertension or intake of water and sodium. A negative sodium balance and volume depletion occurred more often in patients who were positive for digoxin, but this relation did not reach statistical significance. It is concluded that a digoxin-like natriuretic factor is released in response to a subarachnoid haemorrhage, probably as a result of hypothalamic damage.     

Endothelin-1 induces contraction of human and Australian possum gallbladder in vitro

This study examined the role of the renin-angiotensin and vasopressin systems on systolic blood pressure (SBP) variability following subarachnoid haemorrhage (SAH) in conscious rats. Animals received no treatment, the angiotensin II AT1 receptor antagonist, losartan, or the vascular vasopressin receptor antagonist, AVPX. SAH resulted in a transient sympathetic activation as estimated from the increase in the mid-frequency oscillations of SBP (3.2 +/- 0.8 mm Hg2, 3 hours after the injury vs. 1.3 +/- 0.3 mm Hg2 in control conditions, p < 0.01). On the second and fourth day following SAH, a marked elevation in the low-frequency component of SBP was observed (7.1 +/- 1.0 mm Hg2 on day 2 vs. 2.6 +/- 0.3 mm Hg2 in control conditions, p < 0.001 and 6.3 +/- 1.1 mm Hg2 on day 4 vs. 2.6 +/- 0.3 mm Hg2 in control conditions, p < 0.01). Pre-treatment with losartan prevented the acute rise in the mid-frequency oscillations in SBP and partially reduced the low-frequency component observed at 2 and 4 days. Administration of AVPX on the second and fourth day following SAH normalised the elevated low-frequency oscillations in SBP. This study indicates that the modifications in SBP variability observed in the early and delayed stage after subarachnoid haemorrhage involve angiotensin II. Vasopressin seems to be implicated in the delayed development of low-frequency fluctuations of SBP.     

大鼠脑血管痉挛时NO和ET—1变化及尼莫地平的影响

目的探讨蛛网膜下腔出血(SAH)后脑血管痉挛(CVS)时脑组织一氧化氮(NO)和内皮素-1(ET-1)含量变化及尼莫地平(ND)对其影响。方法将135只Wistar大鼠随机均分为SAH组、ND处理组和假手术组,观察手术前后基底动脉管径,及24h内局部脑血流量(rCBF)、脑组织NO和ET-1含量动态改变,并行海马病理检查。结果SAH后rCBF明显而持续降低,基底动脉管径显著缩小;海马CAl区锥体细胞严重受损;脑组织NO和ET-1含量均在SAH后1～24h显著增加(P＜0．05～0．01)。ND处理后使上述异常变化均减轻。结论SAH后脑组织NO、ET-1增多可能参与了CVS所致脑损害过程,ND通过减轻CVS和拮抗脑组织NO及ET-1的病理性改变而发挥脑保护作用。     

Lumbar puncture in spontaneous subarachnoid haemorrhage.

Seventy-four patients with proved spontaneous subarachnoid haemorrhage were studied. Sixty-four underwent computed tomography and 55 underwent lumbar puncture. Seven cases deteriorated dramatically after lumbar puncture, six of these showing evidence of cerebral dislocation on further investigation. Four of the seven had not undergone computed tomography and three underwent computed tomography after lumbar puncture. Computed tomography of the brain could determine patients at risk of coning. It is suggested that computed tomography is the investigation of choice after spontaneous subarachnoid haemorrhage and that lumbar puncture, if still then necessary, should be avoided until computed tomography has been undertaken.     

Dopamine beta-hydroxylase activity after subarachnoid hemorrhage

Dopamine beta-hydroxylase activity was determined in the patients who underwent subarachnoid haemorrhage prior to had following surgery. Dopamine beta-hydroxylase activity was treated as an index of catecholaminergic system activity depending on the incidence and type of vasoconstriction. Dopamine beta-hydroxylase activity in 41 patients treated surgically was compared with the results obtained in 50 control individuals. Changes in the dopamine beta-hydroxylase activity were noted prior to and after surgery depending upon the incidence and type of vasoconstriction. However, the observed differences were statistically insignificant.     

Confocal microscopic evidence of decreased alpha-actin expression within rabbit cerebral artery smooth muscle cells after subarachnoid haemorrhage

Our objective was to determine whether subarachnoid haemorrhage modifies cerebral artery smooth muscle cell phenotype and the contractile protein -actin measured 7 days after haemorrhage. We used a rabbit subarachnoid haemorrhage model and immunofluorescence labelling of -smooth muscle actin, vimentin and desmin. The paired comparison between the haemorrhage and sham rabbits was performed using confocal laser-scanning microscopy. We found in the haemorrhage group significantly less intense -actin immunostaining (p = 0.036) and more intense vimentin immunostaining (p = 0.043) but no significant change in the intensity of desmin staining. Our results indicate an absolute decrease after subarachnoid haemorrhage in the amount of functional -actin and in the light of the literature may suggest a certain degree of dedifferentiation of smooth muscle cells in the cerebral artery wall.     

Diurnal variation in incidence of stroke: Oxfordshire community stroke project.

OBJECTIVE--To determine whether diurnal variation occurs in the onset of stroke. DESIGN--Community based study over four years. SETTING--Oxfordshire, United Kingdom. SUBJECTS--105,000 people, of whom 675 had a first ever stroke. 545 had a cerebral infarction, 66 had primary intracerebral haemorrhage, 33 had subarachnoid haemorrhage, and in 31 the type of stroke was not known. MAIN OUTCOME MEASURES--Time of stroke and degree of activity at onset. RESULTS--In the 578 patients for whom it was known whether onset occurred while asleep or awake, the proportion with onset during sleep was 25% (135/545) for cerebral infarction, 17% (11/66) for primary intracerebral haemorrhage, and 0% (0/33) for subarachnoid haemorrhage. This difference persisted if patients in whom it was not known whether they were asleep or awake at onset were classed as asleep. For all stroke types together there was a significant (chi 2 = 218.7, p less than 0.001) diurnal variation with a morning peak between 0800 and 1000, which persisted even after allowing for strokes first noted on waking by redistributing the hour of onset through the preceding eight hours (chi 2 = 47, p less than 0.001). A significant diurnal variation was also found in the onset of cerebral infarction (peak 0800-1000, chi 2 = 208.4, p less than 0.001). Fewer patients had other forms of stroke and the diurnal variations for primary intracerebral haemorrhage (peak 1000-1200) and subarachnoid haemorrhage (peaks 0800-1000 and 1800-2000) were not significant. There seemed to be a second smaller peak for all types of stroke. CONCLUSIONS--All types of stroke are most likely to occur after waking in the morning. The cause of the circadian variation requires further study.     

Local Delivery of Nimodipine by Prolonged-Release Microparticles—Feasibility,Effectiveness and Dose-Finding in Experimental Subarachnoid Hemorrhage

Background and Purpose

To investigate the effect of locally applied nimodipine prolonged-release microparticles on angiographic vasospasm and secondary brain injury after experimental subarachnoid hemorrhage (SAH).

Methods

70 male Wistar rats were categorized into three groups: 1) sham operated animals (control), 2) animals with SAH only (control) and the 3) treatment group. SAH was induced using the double hemorrhage model. The treatment group received different concentrations (20%, 30% or 40%) of nimodipine microparticles. Angiographic vasospasm was assessed 5 days later using digital subtraction angiography (DSA). Histological analysis of frozen sections was performed using H&E-staining as well as Iba1 and MAP2 immunohistochemistry.

Results

DSA images were sufficient for assessment in 42 animals. Severe angiographic vasospasm was present in group 2 (SAH only), as compared to the sham operated group (p<0.001). Only animals within group 3 and the highest nimodipine microparticles concentration (40%) as well as group 1 (sham) demonstrated the largest intracranial artery diameters. Variation in vessel calibers, however, did not result in differences in Iba-1 or MAP2 expression, i.e. in histological findings for secondary brain injury.

Conclusions

Local delivery of high-dose nimodipine prolonged-release microparticles at high concentration resulted in significant reduction in angiographic vasospasm after experimental SAH and with no histological signs for matrix toxicity.     

The expression of Cav3.1 on T-type calcium channels of rats with subarachnoid hemorrhage

To study delayed cerebral vasospasm (DCVS) induced by subarachnoid hemorrhage (SAH), 60 healthy Sprague Dawley (SD) rats were randomly divided into 5 groups (12 rats in each group), namely sham operation group, blood injection model group, nimodipine group, flunarizine hydrochloride group, and normal group. Then, the physiological parameters were detected, and after the rats were killed under anesthesia, the degree of nerve injury, vasospasm as well as the therapeutic effect of drugs were evaluated by Western Blot (WB). Neurological impairment (NI), endothelial contraction and spasm were obvious in rats following blood injection. The expression of Cav3.1 on T-type calcium channels was significantly higher in the blood injection model group than in the sham operation group along with the normal group. Moreover, Cav3.1 mRNA was expressed in all groups. The Cav3.1 expression in blood injection model group and two drug groups were significantly higher than that in sham operation group and lower than that in blood injection model group. Vasospasm was improved in two drug groups, which indicated that calcium channel antagonists nimodipine and flunarizine hydrochloride had a certain therapeutic effect on DCVS in rats. The decrease in body weight and food intake of the two groups of rats treated with drugs decreased, and the delayed vasospasm was improved, but the expression of Cav3.1 was not changed significantly, indicating nimodipine and flunarizine hydrochloride had a therapeutic effect on delayed vasospasm in rats, but Cav3.1 expression on calcium channels was not affected.     

Rationale and design of a double-blind, placebo-controlled, randomized trial to evaluate the safety and efficacy of nimodipine in preventing cognitive impairment in ischemic cerebrovascular events (NICE)

ABSTRACT: BACKGROUND: Stroke is the second most common cause of mortality and the leading cause of neurological disability, cognitive impairment and dementia worldwide. Nimodipine is a dihydropyridinic calcium antagonist with a role in neuroprotection, making it a promising therapy for vascular cognitive impairment and dementia. METHODS: The NICE study is a multicenter, randomized, double-blind, placebo-controlled study being carried out in 23 centers in China. The study population includes patients aged 30--80 who have suffered an ischemic stroke (<=7 days). Participants are randomly allocated to nimodipine (90 mg/d) or placebo (90 mg/d). The primary efficacy is to evaluate the level of mild cognitive impairment following treatment of an ischemic stroke with nimodipine or placebo for 6 months. Safety is being assessed by observing side effects of nimodipine. Assuming a relative risk reduction of 22 %, at least 656 patients are required in this study to obtain statistical power of 90 %. The first patient was recruited in November 2010. DISCUSSION: Previous studies suggested that nimodipine could improve cognitive function in vascular dementia and Alzheimer's disease dementia. It is unclear that at which time-point intervention with nimodipine should occur. Therefore, the NICE study is designed to evaluate the benefits and safety of nimodipine, which was adminstered within seven days, in preventing/treating mild cognitive impairment following ischemic stroke.     

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.     

Subdural Haematoma Simulating Primary Subarachnoid Haemorrhage

In three cases of subdural haematoma which resembled primary subarachnoid haemorrhage the diagnosis was made only by cerebral angiography. Angiography should be done whenever the diagnosis is in doubt.