Inhibitory effects of lidocaine on cerebral vasospasm in a rabbit model of subarachnoid hemorrhage

Following subarachnoid hemorrhage, vasoconstrictor substances, cellular apoptosis, blood coagulation, and vascular cell proliferation affect the onset of cerebral vasospasm. Previous studies from our laboratory have revealed that injection of lidocaine （2 mg） into the cisterna magna reduces cerebral vasospasm and nerve functional impairment in an animal model of subarachnoid hemorrhage. The present study determined the optimal lidocaine dose for vasospasm and brain injury by injecting different doses of lidocaine into the cisterna magna in a rabbit model of subarachnoid hemorrhage. Results showed that endothelin, tumor necrosis factor-a, and interleukin-6 levels significantly increased in plasma, and calcitonin gene-related peptide levels significantly decreased in plasma （P 〈 0.05）. The number of neurons was decreased, the number of cells expressing c-Fos increased in the hippocampus, and cross-sections and diameters of basilar arteries were reduced （P 〈 0.05）. These changes significantly improved following injection of lidocaine （1,2, 4, and 6 mg） into the cisterna magna. A dose of 6 mg lidocaine into the cisterna magna resulted in optimal effects on cerebral vasospasm and brain injury following subarachnoid hemorrhage.

Hypertensive-Nimodipine Therapy for Middle Cerebral Artery Vasospasm after Resection of Glioblastoma Multiforme: A Case Report and Literature Review

Delayed cerebral ischemia (DCI) due to post-brain tumor resection vasospasm is an often unrecognized yet debilitating complication. We present a patient with DCI after the resection of glioblastoma multiforme (GBM). To our knowledge, this is the first report on DCI after GBM resection. A 52-year-old female patient with headache for one month underwent subtotal resection of a left temporal GBM encasing the proximal middle cerebral artery (MCA). She was well during the immediate postoperative period but developed right upper limb dense monoparesis on postoperative day four with computed tomographic angiography confirming left MCA vasospasm. Symptoms were significantly alleviated with weeklong hypertensive therapy and nimodipine administration;however they recurred soon after cessation of treatment. A high index of clinical suspicion is needed for the diagnosis of post-tumor resection DCI. Any new postoperative neurological deficit that cannot be explained by hemorrhage, seizures or infection should be expeditiously investigated by angiography or transcranial Doppler sonography. Prompt initiation of hypertensive and nimodipine therapy can possibly reverse neurological deficit. Treatment should be guided by Doppler, angiographic or perfusion imaging studies and not by clinical improvement alone.

Prospective Evaluation of Post-Traumatic Vasospasm and Post-Injury Functional Outcome Assessment: Is Cerebral Ischemia Going Unrecognized in Patients with Traumatic Brain Injury?

Background: Secondary injury processes such as posttraumatic vasospasm (PTV) play a critical role in the development of cerebral ischemia/infarction after traumatic brain injury (TBI). The objectives of this study were to evaluate the incidence of cerebral vasospasm in patients with moderate to severe TBI and to assess post-injury functional outcome. Study Design: A prospective observational study was conducted in patients with moderate and severe blunt TBI. Transcranial Doppler (TCD) ultrasound was performed within the first 72 hours and then daily for up to 7 days. Patient characteristics and outcome data including functional outcome as assessed by the Extended Glasgow Outcome Scale (GOS-E) were collected and compared between patients with and without PTV. Results: Twenty-three patients met our inclusion criteria. While there was a 47.8% incidence of vasospasm as detected by TCD, there was no significant difference in hospital LOS or mortality between patients with and without PTV. Of the two patients with PTV who died, both had a cerebral infarct or cerebral ischemia. In evaluating overall GOS-E among patients with a cerebral focal injury, patients with PTV had a significantly higher GOS-E score when compared to patients without PTV (8.0 vs. 6.8, p = 0.01). Conclusions: The high incidence of PTV and the role of clinically significant vasospasm after TBI remain unclear. While functional outcome was better in patients with a focal injury and vasospasm, patients who died had cerebral ischemia or infarction. We hypothesize that there is an interaction between impaired cerebral autoregulation, PTV and poor outcomes in patients with TBI.

Experimental investigation on the prevention of delayed cerebral vasospasm with Tong Qiao Huo Xue Tang

Objective To investigate the prevention effects and the physicochemical mechanisms of action of Tong Qiao Huo Xue Tang on delayed cerebral vasospasm(DCD) after subarachnoid hemorrhage(SAH).Methods Macaca cynomolgus were divided into two groups and underwent craniectomy,a semipermeable microdialysis catheter was placed adjacent to right middle cerebral artery (MCA).Therapeutic group were exposed to Tong Qiao Huo Xue Tang and control group to placebo via oral .Results The diameter of proximal MCA in therapeutic group changed slightly on 7th day after operation(P >0.05),whereas it decreased prominently(P< 0.05) in control group with severe vasospasm.OxyHb concentration:There’s no significant difference between the two groups on 2nd ～5th day(P >0.05),the concentration of therapeutic group(was zero after 8 days) was lower than that of control group (became zero after 12 days) on 6th ～8th day(P< 0.05).The peak value of therapeutic group (on 5th day) was lower than that of control group (on 7th day)(P< 0.05).Conclusion Tong Qiao Huo Xue Tang can prevent DCV after SAH effectively and decreasing OxyHb concentration around vessels after SAH maybe the mechanism.

丁苯酞胶囊联合依达拉奉在自发性蛛网膜下腔出血术后CVS中的效果

目的探讨丁苯酞胶囊联合依达拉奉在自发性蛛网膜下腔出血术后脑血管痉挛(cerebral vasospasm,CVS)中的应用价值,分析其对脑脊液红细胞和神经功能的影响。方法回顾性分析2020年2月—2022年2月广东省中山大学附属汕头医院/汕头市中心医院收治的80例蛛网膜下腔出血术后CVS患者,按用药方式分为2组。在综合治疗基础上,对照组(n=40)用依达拉奉治疗,研究组(n=40)联合丁苯酞胶囊治疗。比较2组脑脊液红细胞数值、神经功能及不良反应。结果治疗后7、14 d,2组脑脊液红细胞计数均逐渐降低,其中研究组治疗后7、14 d脑脊液红细胞计数分别为(32.52±3.54)×10^(12)/L、(5.52±1.58)×10^(12)/L,低于对照组的(40.20±8.21)×10^(12)/L、(10.25±1.65)×10^(12)/L,差异有统计学意义(P<0.05);治疗后7、14 d,2组美国国立卫生研究院卒中量表(National Institute of Health stroke scale,NIHSS)评分均逐渐降低,且研究组更低;Barthel指数均逐渐升高,且研究组更高,差异有统计学意义(P<0.05)。2组不良反应总发生率比较,差异无统计学意义(P>0.05)。结论丁苯酞胶囊联合依达拉奉治疗自发性蛛网膜下腔出血术后CVS对微循环和脑组织灌注有改善作用,利于神经功能恢复,不增加不良反应。

Establishment of a new symptomatic cerebral vasospasm model following subarachnoid hemorrhage in rabbit

Objective To establish an experimental model of symptomatic cerebral vasospasm(CVS) after subarachnoid hemorrhage(SAH)in rabbits. Method 2 weeks after the ligation of bilateral common carotid arteries, We induced CVS by injecting arterial blood twice via a cranial hole 2 mm×2 mm and then neurological symptoms ,cerebral blood flow(rCBF) and food intake were evaluated. Results Food intake and rCBF decreased and neurological disorders were observed. Conclusion An experimental rabbit model of symptomatic CVS can be established by injecting blood via a cranial hole after bilateral common carotid arteries ligation.

Role of endothelin in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage

A model of cerebral vasospasm (CVS) associated with subarachnoid hemorrhage (SAH) was prepared on male Sprague-Dawley rats by a single intracisternal injection (i. c.) of 150 μl autologous fresh blood directly to Willis circle.The process of CVS was monit

Studies of the antagonistic effect of BQ-123 on cerebral vasospasm induced by intracisternal injection of endothelin-1 and subarachnoid hemorrhage

To clarify whether the endothelin A (ETA)-receptor antagonist BQ-123 can prevent the development of cerebral vasospasm (CVS) induced by endothelin (ET-1) and subarachnoid hemorrhage (SAH), which has been controversia11y reported by various authors. We have performed investigations in anesthetized Sprague-Dawley rats- Intracisternal injection (i. c. ) of ET-l (10-11, 10-10, 10-9 mol/kg) could induce acute dose-dependent CVS, furthermore, the highest dose of ET-l (lO-’ mo1/kg) had a biphasic response in CVS of a 24-hour duration. However, the CVS by ET-1 (10-9 mol/kg) could be prevented effectively by previous i. c. of BQ-123 in a dose-dependent manner (10-9, 10-8, 10-7 mol/kg), of which the i. c- of BQ-123 (10-7mol/kg) could abolish the CVS completely. i. c. of BQ-123 (10-7 mol/kg) before SAH induced by a single i. c, of 150 pl autologous fresh blood directly to the Willis circle cou1d prevent the following CVS largely, which was a biphasic response and long-lasting (duration of 72 h). We conclude that subarachnoid application of ETA-receptor antagonist can effecti vely prevent CVS induced by ET-1 and SAH, and ET-1 may be the major mediator responsible for the CVS following SAH.

INFLUENCE OF GINKGO BILOBA EXTRACT ON NITRIC OXIDE AND ENDOTHELIN-1 DURING CEREBRAL VASOSPASM IN RATS

Objective.To investigate the effects of Ginkgo biloba extracton cer ebral vasospasmafter subarachnoid hemorrhageand its influence on n itric oxideand endothelin-l .Methods.Noncraniotomy models of SAH in Wistar rats were used and animals were divided into sham-operated group ,SAH group,saline-treated group and EGb-treated group.Diameter of basilar a rtery was measured.Regional cerebral blood flow,NO and ET-1levels in blood,and calcium content in brain tissue within24hours after SAH were dete cted.Pathological examination of hippocampus CA1sub-field was also performed .Results.Sham operation did not alter the above parameters.Induction of SAH l ed to a marked spasm of basilar artery.rCBF decreased obviously and consecutive ly within24hours after SAH.Meanwhile NO level in serum decreased,ET-1level in plasma and calcium content in brain tissue significantly in-creased.Pyra midal cells in hippocampus CA1subfield were severely damaged.EGb significantly antago-nized the pathological alterations of the above parameters.Conclusion .Alterations of NO,and ET-1play an important role in the development of CV S after SAH.EGb exerts its protective effects on CVS by inhibitng the above pat hological alterations.

Research on the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage

目的 :进一步研究脑血管痉挛的发生机理 ,为临床治疗服务。方法 :采用 1 4只成年家犬 ,实验组 9只 ,对照组 5只 ,通过 2次枕大池注血法建立蛛网膜下腔出血 (SAH)模型。观察痉挛血管的自由基变化、血管活性、血管造影像、超微结构变化。另外 2 0只犬用来观察血管扩张剂的作用。结果 :实验组较对照组自由基含量高 ,血管活性降低 ,血管狭窄 ,管壁损害重。结论 :尼莫地平对急性痉挛有效 ,对慢性痉挛无效 ;慢性血管痉挛是以管壁结构性狭窄为特点。

Experimental and clinical study on effect of endovascular dilation on symptomaticcerebral vasospasm

Objective To undertake animal experimentation and clinical study on the safety and efficacy of percutaneous transluminal angioplasty (PTA) and intraarterial papaverine (IAP) infusion for treatment of refractory symptomatic cerebral vasospasm (CVS). Methods In the experimental study, vasospasm was induced in rabbits by double injections of blood into the cisterna magna, IAP infusion was given on either the 4th day or the 7th day after occurrence of subarachnoid hemorrhage (SAH), and then neurological observation, angiography, light and electron microscopy were done. In the clinical study, since September 1996, 22 patients with refractory symptomatic CVS involving 50 vascular territories received dilation therapy by PTA and IAP within 24 hours of clinical neurological deterioration. Results In the experimental study, all the rabbits except two in the 'the 4th day' group showed angiographic dilation in all of the spastic basilar arteries, and neurological improvement; in the ' the 7th day' group angiographic dilation appeared in 4 (57. 1% ) out of 7 rabbits. After 24 hours, 1 rabbit in each group had recurrence of neurological deficits and angiographic constriction. In the clinical study after aneurysm clipping or endovascular coil embolization was done, within 72 hours of SAH all patients underwent endovascular treatment: PTA alone in 3 cases, IAP alone in 14 cases, PTA and IAP in the remaining 5 cases. All vessel segments were dilated satisfactorily after endovascular treatment. Clinical improvement was significant in 13 cases,moderate in 7, minimal or none in 2; 2 cases died on the 7th day after endovascular dilation treatment. Conclusion Endovascular dilating techniques, namely, PTA, IAP and a combination of PTA and IAP, are safe and effective for treatment of symptomatic CVS refractory to medical therapy.

Mitigation effect of atorvastatin on cerebral vasospasm after subarachnoid hemorrhage in rats and its effect on expression of Mitofusin-2 and BDNF

Objective:To investigate the mitigation effect of atorvastatin on cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) in rats and its effect on mitochondrial fusion protein 2 (Mitofusin-2) and brain-derived neurotrophic factor (BDNF), which provides an experimental basis and a new method for the prevention and treatment of CVS after SAH.Methods:30 male SD rats were randomly divided into the sham operation group, the model group and the treatment group, with 10 rats in each group. In the model group and the treatment group, the subarachnoid hemorrhage model was made by the double injection of blood in the occipital cistern, and the sham operation group was injected with physiological saline in the same manner. The treatment group was given atorvastatin 20 mg/kg, which was dissolved in 2 mL of distilled water. The sham operation group and the model group were given 2 mL of distilled water. The body weight, mortality, neurological deficit, basilar artery inner diameter, wall thickness and smooth muscle cell apoptosis were observed in the rats 5 d after intervention. The expression levels of Mitofusin-2 and BDNF in each group were observed.Results:The body weight of the three groups was from low to high in the sham operation group, the treatment group and the model group, and the difference was statistically significant. One rat died in the sham operation group and the treatment group, respectively, 2 rats died in the model group and there was no significant difference in mortality between the three groups. The scores of the three groups of neurological function were from low to high among the model group, treatment group and sham operation group, and the difference was statistically significant. The diameter of the three groups of blood vessels was from small to large among the model group, treatment group and sham operation group, and the difference was statistically significant. The apoptotic rate of the three groups of vascular endothelial cells was from small to large among the model group, treatment group and sham operation group, and the difference was statistically significant. The expression levels of Mitofusin-2 were from low to high among the sham operation group, model group and treatment group, respectively.Conclusion:Atorvastatin can alleviate the occurrence of CVS after SAH and alleviate brain tissue damage, and its mechanism may be related to up-regulation of Mitofusin-2 expression.

Clinical Efficacy of Shenmai Injection in the Treatment of Cerebral Vasospasm after Ruptured Aneurysm Surgery

Objective: To investigate the therapeutic effect of Shenmai Injection on postoperative cerebral vasospasm in patients with ruptured aneurysms. Methods: Seventy patients undergoing craniotomy for ruptured aneurysms in our hospital were selected as study subjects and randomly divided into control (n = 33) and research (n = 37) groups, they were treated with nimodipine and nimodipine combined with Shenmai injection after operation. The blood flow velocity in the middle cerebral artery (MCA) before and at 1, 3, 7, 11 and 14 days after surgery and the incidence of cerebral vasospasm during these days were compared, and the GCS scores at 14 days postoperatively and GOS scores at 6 months postoperatively were compared between the two groups. Results: There were no statistically significant differences in the occurrence of cerebral vasospasm, GCS or GOS scores between the two groups (P > 0.05), but the period of postoperative cerebral vasospasm in the study group was significantly shorter than that in the control group. Conclusion: Shenmai injection has the effect of shortening the cycle of occurrence of cerebral vasospasm after the operation of ruptured aneurysms, promoting patients to recover as early as possible and reducing their physical and mental burden.

New Developments in Drug Therapy and Research of Cerebral Vasospasm

In this manuscript a comprehensive coverage of recent developments in the drug therapy of vasospasm while providing the background information that neuroscientists need to understand its rationale. The range of new agents available for treatment of cerebral vasospasm is expanding rapidly along with rapid advances in pharmacology and physiology that are uncovering the mechanisms of this disease. Although there are many publications for treatment of cerebral vaso-spasm, most are focusing on different aspects of vasospasm treatment and many have limited value due to insufficient quality. Moreover, the complexity of this, in many cases deleterious condition, is enormous and the information needed to understand drug effects is accordingly often not readily available in a single source. A number of pharmacological and medical therapies are currently in use or being investigated in an attempt to reverse cerebral vasospasm, but only a few have proven to be useful. Current research efforts promise the eventual production of new medical therapies. At last, recommendations for the use of different treatment stages based on currently available clinical data are provided.

显微手术治疗颅内动脉瘤术后CVS发生的相关因素及对预后的影响

目的探讨显微手术治疗颅内动脉瘤的临床效果,并分析影响术后脑血管痉挛(CVS)发生的相关因素及对预后的影响。方法回顾性分析2009年5月-2013年5月于郑州人民医院收治的128例颅内动脉瘤患者的临床资料。评价总体治疗效果,并分别应用单因素及Logistic多因素分析影响患者术后CVS发生的相关因素及对预后的影响。结果 128例患者总体治疗效果良好,术后发生CVS 32例(25.00%),与非CVS组比较,CVS组术后治愈率显著下降,而死亡率显著上升,差异有统计学意义(P<0.05)。经单因素分析可知,影响患者显微手术术后CVS发生的相关因素包括年龄、Hunt-Hees分级、Fisher’s分级、动脉瘤位置、手术时机、感染、基础疾病、终板造瘘、腰穿次数、血糖及白细胞水平。经Logsitic多因素进一步分析可知,Hunt-Hees分级、Fisher’s分级、动脉瘤位置、终板造瘘、腰穿次数是影响显微手术治疗颅内动脉瘤术后CVS发生的独立危险因子,并影响预后。结论显微手术治疗颅内动脉瘤临床效果良好,但须防范Hunt-Hees分级、Fisher’s分级、动脉瘤位置、终板造瘘、腰穿次数等影响术后CVS发生的独立危险因素,改善颅内动脉瘤患者预后。

实验性SAH后CVS与ET、NO的关系

目的 研究兔症状性蛛网膜下腔出血（SAH）后脑血管痉挛（CVS）与内皮素（ET）和一氧化氮（NO）的关系。方法 采用双侧颈动脉结扎和枕大池二次注血法制成兔SAH模型，观察SAH前后动物进食量和神经功能改变，用放射免疫方法和硝酸还原酶法分别测定血液和脑脊液中ET和NOx-含量，以氢清除法测定局部脑血流量(rCBF)。结果 SAH后大部分动物进食量有不同程度的下降,所有动物均有不同程度的神经功能障碍和rCBF下降。SAH后血液和脑脊液中ET含量增加，NOx-含量下降（P<0.01）。上述变化随出血时间延长和出血量的增加而增大。结论 兔双侧颈动脉结扎后枕大池二次注血法可制成可靠的症状性SAH后CVS模型。SAH后ET和NO含量的改变与CVS 的发生密切相关，并进而导致临床症状的恶化。rCBF、动物进食量和神经功能改变可作为评价SAH后CVS的客观指标。

显微手术治疗颅内破裂动脉瘤后脑血管痉挛(CVS)发生的影响因素

目的研究分析显微手术治疗颅内破裂动脉瘤后脑血管痉挛（CVS）发生的影响因素。方法回顾性分析本院2014年11月-2016年1月收治并采取显微手术治疗的颅内破裂动脉瘤患者51例临床资料。结果通过统计分析发现,A组高龄患者比例、Fisher分级Ⅱ级以上者,以及SAH 3周内行手术且术前SAH次数2次以上患者血管痉挛发生率高于B组,差异有统计学意义（P〈0.05）。结论显微手术治疗颅内动脉瘤后脑血管痉挛的因素复杂,需结合患者病情实际状态,选择恰当合理的治疗时机,通过良好的显微手术技巧降低脑血管痉挛发生率。

自由基清除剂对减少大鼠SAH后CVS的研究

目的通过建立大鼠蛛网膜下腔出血模型并应用自由基清除剂对其进行治疗,观察大鼠脑基底动脉的病理变化及其管壁上细胞间粘附因子1(ICAM-1)、白介素6(IL-6)在治疗前、后的动态变化,为进一步明确脑血管痉挛(cerebral vasospasm,CVS)的发病机制及治疗脑血管痉挛提供理论依据。方法取Sprague Dawley(SD)大鼠98只,观察正常大鼠及治疗大鼠SAH前后基底动脉管径的变化;行免疫组化染色对大鼠脑基底动脉进行免疫学检测,观察ICAM-1、IL-6在血管壁上表达的动态变化;行原位杂交检测观察大鼠脑基底动脉管壁上ICAM-1、IL-6在分子水平表达的动态变化。结论1自由基清除剂能够抑制SAH后CVS的免疫炎症反应;2应用自由基清除剂对防治CVS有一定效果,能够有效缓解CVS。

蛛网膜下腔出血后血清MMP-9和TIMP-1对CVS的预测作用研究

目的探讨基质金属蛋白酶-9(MMP-9)和基质金属蛋白酶抑制因子-1(TIMP-1)的表达水平及其在蛛网膜下腔出血(SAH)中预测脑血管痉挛(CVS)发生的意义。方法采用酶联免疫法检测32例蛛网膜下腔出血(SAH)患者作为实验组,分别于SAH后术前,术后第1、3、7天及出院当天采血,检测血清中MMP-9和TIMP-1的水平,并与20例体检正常者(对照组)进行比较。结果除SAH的CVS患者在第7天TIMP-1蛋白表达趋于正常外,CVS和非CVS患者在术后各时间点观察组血清MMP-9和TIMP-1水平均明显高于对照组,差异有统计学意义(P<0.05),且与患者血浆MMP-9和TIMP-1呈显著正相关(P<0.05);对照组MMP-9和TIMP-1无显著相关性(P>0.05),且SAH的CVS患者较非CVS患者MMP-9在术后第3、7天,增高更明显,SAH术后第3天TIMP-1的表达在CVS和非CVS均明显增高,而在CVS患者在第7天蛋白表达趋于正常。结论 SAH的CVS和非CVS患者血清MMP-9和TIMP-1的蛋白均有显著增高,且CVS患者的TIMP-1蛋白表达时间与非CVS患者有差异,同时检测患者血清MMP-9和TIMP-1的蛋白表达量对预测SAH后CVS的发生具有指导意义。

ET在SAH后继发CVS病理机制中的作用

采用单次注射１５０μｌ自体新鲜血液至大鼠蛛网膜下腔Ｗｉｌｌｉｓ环处，建立蛛网膜下腔出血（ＳＡＨ）后继发脑血管痉挛（ＣＶＳ）的动物模型。用激光多普勒血流仪滥测ＣＶＳ的过程，平行地对脑脊液（ＣＳＦ）和血浆作内皮素（ＥＴ）含量的放射免疫测定。在ＳＡＨ发生的同时静脉注射ＥＴ抗体（１∶１０００，５００μｌ），在ＳＡＨ前５ｍｉｎ及ＳＡＨ后不同时间脑池内注射ＥＴ抗体（１∶１０００，２０μｌ）。结果显示：（１）ＣＳＦ中ＥＴ升高在ＳＡＨ后１５ｍｉｎ和３０ｍｉｎ时有显著性意义；血浆中ＥＴ升高在ＳＡＨ后３０ｍｉｎ时有显著性意义。（２）ＳＡＨ前５ｍｉｎ向脑池内注射ＥＴ抗体能有效地预防ＣＶＳ，在ＳＡＨ后１５ｍｉｎ时同样的注射能大部分消除ＣＶＳ，但在ＳＡＨ后３０ｍｉｎ时只能部分消除ＣＶＳ，而在ＳＡＨ后２４ｈ同样的注射对ＣＶＳ无作用。（３）在ＳＡＨ发生的同时静脉注射ＥＴ抗体对ＣＶＳ无预防作用。上述结果提示：（１）ＣＳＦ中高水平的ＥＴ是ＳＡＨ后引起ＣＶＳ的重要因素；（２）在ＣＶＳ的发展过程中可分为早期ＥＴ依赖阶段和晚期非ＥＴ依赖阶段；（３）在ＳＡＨ后早期从蛛网膜下腔阻断ＥＴ是预防和逆转ＣＶＳ的重要途径和方法。