缺血性卒中的溶栓治疗资料.ppt

缺血性卒中的 溶栓治疗,上海市第五人民医院药剂科 季闽春 2016.6,溶栓治疗是目前国内外公认的积极挽救缺血缺氧脑组织行之有效的方法。,溶栓治疗的作用机制,脑组织中几乎无葡萄糖和氧的储备，因此对缺血缺氧非常敏感。为了维持脑组织的正常神经功能，必须有源源不断的血液供应。,张蓉(综述), 吴军(审核). 脑梗死溶栓与抗栓治疗进展.卒中与神经疾病 2014;21(6):399-402,当局部脑组织血流量,脑电功能障碍,神经细胞的电衰竭,神经细胞的膜衰竭,膜衰竭后68h出现血管源性的水肿及胶质细胞为主的细胞水肿，随即出现神经细胞的坏死，此时即使缺血部位的脑组织血供恢复正常，梗死的神经细胞不能恢复相应功能。,神经传导消失，但神经细胞仅丧失部分功能，形态学上改变轻微。,对于处在电衰竭和膜衰竭之间的脑组织，称之为缺血半暗带。,当血流量介于2035之间时溶栓治疗效果明显，可以恢复全部功能或部分功能。,Time is Brain！,张蓉(综述), 吴军(审核). 脑梗死溶栓与抗栓治疗进展.卒中与神经疾病 2014;21(6):399-402,Wechsler LR. Intravenous Thrombolytic Therapy for Acute Ischemic Stroke. N Engl J Med 2011;364:2138-46.,Wechsler LR. Intravenous Thrombolytic Therapy for Acute Ischemic Stroke. N Engl J Med 2011;364:2138-46.,When?,溶栓治疗的主要目的 挽救缺血半暗带的脑组织 因此涉及到溶栓治疗时间窗的问题。 按照美国国立神经疾病与卒中研究所的研究表明，溶栓治疗进行的时间是影响预后的关键。 就目前来说，大多数学者认同溶栓治疗时间窗为36h。,时间窗,张蓉(综述), 吴军(审核). 脑梗死溶栓与抗栓治疗进展.卒中与神经疾病 2014;21(6):399-402,国家卫生计生委脑卒中防治工程委员会 脑卒中防治系列指导规范编审委员会.中国急性缺血性脑卒中静脉溶栓指导规范.2016,对缺血性脑卒中发病 3 h 内 (I 级推荐，A 级证据）和 34. 5 h ( I 级推荐，B 级证据）的患者，应按照适应证和禁忌证（见表 2、3) 严格筛选患者，尽快静脉给予 rt-PA 溶栓治疗。,2016 年中国脑卒中大会发布 中国急性缺血性脑卒中静脉溶栓指导规范,Lancet 2014; 384: 192935,NINDS=National Institute of Neurological Disorders and Stroke; ECASS=European Cooperative Acute Stroke Study; ATLANTIS=Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke; EPITHET=Echoplanar Imaging Thrombolytic Evaluation Trial; IST=International Stroke Trial.,Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4.5h of stroke onset, with earlier treatment associated with bigger proportional benefits.,Interpretation,卒中急救移动单元 （Stroke Emergency Mobile Unit，STEMO） 配备神经科医师、技术员、护理人员、CT机即时实验室、远程医疗连接等开展溶栓治疗。,Golden hour,Figure 2. Mobile Stroke Unit. An ambulance (A) equipped with point-of care laboratory system and telemedicine devices (B) and CT (C) required for prehospital stroke treatment.,JAMA Neurol 2015 ;72(1):25-30,The use of STEMO increases the percentage of patients receiving thrombolysis within the golden hour. Golden hour thrombolysis entails no risk to the patients safety and is associated with better short-term outcomes.,CONCLUSIONS AND RELEVANCE,How?,是指静脉推注或滴注溶栓药物溶解血栓，让闭塞的血管再通，使缺血半暗带恢复灌注，挽救濒死的脑组织，改善临床结局。,静脉溶栓,张蓉(综述), 吴军(审核). 脑梗死溶栓与抗栓治疗进展.卒中与神经疾病 2014;21(6):399-402,常采用Seldinger技术穿刺股动脉或颈动脉，借助数字减影血管造影(digital subtraction angiography，DSA)图像示踪，了解脑梗死部位、范围、侧支循环建立程度及闭塞程度，将导管或微导管放至闭塞血管内(非接触性溶栓）或直接与栓子接触(接触性溶栓)，再注射溶栓药物，进行超选择性动脉内溶栓治疗。,动脉溶栓,张蓉(综述), 吴军(审核). 脑梗死溶栓与抗栓治疗进展.卒中与神经疾病 2014;21(6):399-402,N Engl J Med 2015;372:11-20.,a pragmatic, phase 3, multicenter clinical trial with randomized treatment-group assignments, open-label treatment, and blinded end-point evaluation.,MR CLEAN,Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN),In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe.,CONCLUSIONS,是指在静脉溶栓的基础上进行全脑血管造影，若发现残余血栓，则再进行动脉溶栓，如此既兼顾了静脉溶栓简单、迅速和动脉溶栓血管再通率高的优点，因而得到学者们高度重视。,动静脉联合溶栓,张蓉(综述), 吴军(审核). 脑梗死溶栓与抗栓治疗进展.卒中与神经疾病 2014;21(6):399-402,一、动脉溶栓及静脉-动脉序贯溶栓,(1)动脉溶栓越早，效果越好，应尽早实施治疗(I级推荐，B级证据)； (2)动脉溶栓有益于经严格选择的患者，适用于发病6 h内的大脑 中动脉供血区的急性缺血性脑卒中(I级推荐，B级证据)； (3)发病24 h内、后循环大血管闭塞的重症脑卒中患者，经过严格评估可行动脉溶栓(级推荐，C级证据)； (4)静脉动脉序贯溶栓治疗是一种可供选择的方法(级推荐，B级证据)； (5)动脉溶栓要求在有条件的医院进行(I级推荐，C级证据)。,推荐意见,Which?,Ellis K, Brener S. New fibrinolytic agents for MI:As effective as current agents but easier to administer. CCJM 2004;71(1):20-37,溶栓药物,Ellis K, Brener S. New fibrinolytic agents for MI:As effective as current agents but easier to administer. CCJM 2004;71(1):20-37,FDA于1996年首次批准用于缺血性卒中超急性期治疗，这也是目前唯一一个被批准的，在缺血性卒中急性期应用可改善预后的药物。,重组组织型纤溶酶原激活剂 （recombinant tissue plasminogen activator，rt-PA） 阿替普酶,溶栓治疗是目前最重要的恢复血流措施之一，重组组织型纤溶酶原激活剂 (rt-PA) 和尿激酶 (UK) 是我国目前使用的主要溶栓药。,国家卫生计生委脑卒中防治工程委员会 脑卒中防治系列指导规范编审委员会.中国急性缺血性脑卒中静脉溶栓指导规范. 2016,Ramee SR, White CJ. Acute Stroke Intervention. Curr Probl Cardiol 2014;39:5976,使用方法：rtPA 0.9 mgkg(最大剂量为90 mg)静脉滴注，其中10在最初1 min内静脉推注，其余持续滴注1 h，用药期间及用药24 h内应严密监护患者(见表5)(I级推荐，A级证据)。,溶栓药物剂量,中华医学会神经病学分会，中华医学会神经病学分会脑血管病学组.中国急性缺血性脑卒中诊治指南2014.中华神经科杂志 2015；48（4）：246-257,小剂量 vs 标准剂量,入选患者来自中国急性缺血性卒中溶栓监测登记研究（Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China，TIMS-China）。 TIMS-China是一个前瞻性、多中心、急性缺血性卒中静脉溶栓监测登记研究，自2007年5月至2012年4月，本研究共登记了来自全国67家中心的1440例阿替普酶静脉溶栓患者。,选取发病4.5 h内且阿替普酶使用剂量约为0.6 mg/kg（0.50.7 mg/kg）及0.9 mg/kg（0.850.95 mg/kg）的静脉溶栓患者，对溶栓后症状性颅内出血（symptomatic intracranial hemorrhage，SICH）、死亡率及90 d随访结局等进行比较。,回顾性研究,本研究提示，在中国人群中，标准剂量（0.9 mg/kg）较低剂量（0.6 mg/kg）阿替普酶静脉溶栓具有更好的有效性，且不会显著增加SICH风险。,结论,N Engl J Med 2016;,ENhanced Control of Hypertension and Thrombolysis strokE stuDy (ENCHANTED),The study is being conducted in Australia and in other countries around the world. It has been designed, and is being conducted, by doctors and medical research scientists at The George Institute for Global Health, a medical research institute affiliated with the University of Sydney, in collaboration with similar people around the world.,Subsequent research studies have confirmed benefits of rtPA in patients of different ages and in different populations, when used up to four and a half hours after the onset of ischaemic stroke. However, research in the last 10 years suggests that a slightly lower dose of rtPA 0.6 mg per kilogram body weight is equally effective and possibly even safer in terms of the risk of brain haemorrhage.,As most of this research has been conducted in Japan, low-dose rtPA (0.6 mg/kg) is the standard approved treatment for acute ischaemic stroke in that country. One hypothesis is that Japanese people, and possibly other Asian people, are more sensitive to rtPA than Caucasian people, but another explanation is that the dose of rtPA depends on the size of the clot in the brain causing the stroke. Examination of blood vessels in the brain during administration of rtPA has shown that most clots dissolve quickly after the injection of rtPA, that is before the full dose is given over an hour.,Why Part A?,However, as there have been no carefully designed research studies to compare between patients who have received the 0.9 mg/kg and 0.6 mg/kg doses of rtPA, we do not know which of the two doses is the best and safest. Also, given that rtPA is an expensive drug, which costs between $1000 and $2000 in most countries around the world, there are significant financial gains for patients, doctors and governments responsible for health care in knowing whether the 0.6 mg/kg dose, which costs less, is equally good or better, or possibly worse, than the 0.9 mg/kg dose.,There is uncertainty about the best management strategy for elevated blood pressure after the onset of acute ischaemic stroke. Studies have suggested that very high blood pressure makes good recovery from stroke less likely, and possibly increases the risk of bleeding in the brain.,Why Part B?,In an international, multicenter, prospective, randomized, open-label trial with blinded outcome evaluation, two doses of intravenous alteplase were compared in patients with an acute ischemic stroke who were eligible for thrombolytic therapy; administration of the drug was commenced within 4.5 hours after the onset of the stroke.,1 Does low-dose (0.6 mg/kg) intravenous (i.v.) recombinant tissue plasminogen activator (rtPA) provide equivalent benefits compared to standard-dose (0.9 mg/kg) rtPA? 2 Does intensive blood pressure (BP) lowering (130-140 mmHg systolic target) improve outcomes compared to the current guideline recommended level of BP control (180 mmHg systolic target)? 3 Does low-dose