1、缺血性卒中的 溶栓治療,上海市第五人民醫(yī)院藥劑科 季閩春 2016.6,溶栓治療是目前國內(nèi)外公認(rèn)的積極挽救缺血缺氧腦組織行之有效的方法。,溶栓治療的作用機(jī)制,腦組織中幾乎無葡萄糖和氧的儲(chǔ)備，因此對(duì)缺血缺氧非常敏感。為了維持腦組織的正常神經(jīng)功能，必須有源源不斷的血液供應(yīng)。,張蓉(綜述), 吳軍(審核). 腦梗死溶栓與抗栓治療進(jìn)展.卒中與神經(jīng)疾病 2014;21(6):399-402,當(dāng)局部腦組織血流量,腦電功能障礙,神經(jīng)細(xì)胞的電衰竭,神經(jīng)細(xì)胞的膜衰竭,膜衰竭后68h出現(xiàn)血管源性的水腫及膠質(zhì)細(xì)胞為主的細(xì)胞水腫，隨即出現(xiàn)神經(jīng)細(xì)胞的壞死，此時(shí)即使缺血部位的腦組織血供恢復(fù)正常，梗死的神經(jīng)細(xì)胞不能恢復(fù)相應(yīng)

2、功能。,神經(jīng)傳導(dǎo)消失，但神經(jīng)細(xì)胞僅喪失部分功能，形態(tài)學(xué)上改變輕微。,對(duì)于處在電衰竭和膜衰竭之間的腦組織，稱之為缺血半暗帶。,當(dāng)血流量介于2035之間時(shí)溶栓治療效果明顯，可以恢復(fù)全部功能或部分功能。,Time is Brain！,張蓉(綜述), 吳軍(審核). 腦梗死溶栓與抗栓治療進(jìn)展.卒中與神經(jīng)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 T

3、hrombolytic Therapy for Acute Ischemic Stroke. N Engl J Med 2011;364:2138-46.,When?,溶栓治療的主要目的 挽救缺血半暗帶的腦組織 因此涉及到溶栓治療時(shí)間窗的問題。 按照美國國立神經(jīng)疾病與卒中研究所的研究表明，溶栓治療進(jìn)行的時(shí)間是影響預(yù)后的關(guān)鍵。 就目前來說，大多數(shù)學(xué)者認(rèn)同溶栓治療時(shí)間窗為36h。,時(shí)間窗,張蓉(綜述), 吳軍(審核). 腦梗死溶栓與抗栓治療進(jìn)展.卒中與神經(jīng)疾病 2014;21(6):399-402,國家衛(wèi)生計(jì)生委腦卒中防治工程委員會(huì) 腦卒中防治系列指導(dǎo)規(guī)范編審委員會(huì).中國急性缺血性腦卒中靜脈溶栓指

4、導(dǎo)規(guī)范.2016,對(duì)缺血性腦卒中發(fā)病 3 h 內(nèi) (I 級(jí)推薦，A 級(jí)證據(jù)）和 34. 5 h ( I 級(jí)推薦，B 級(jí)證據(jù)）的患者，應(yīng)按照適應(yīng)證和禁忌證（見表 2、3) 嚴(yán)格篩選患者，盡快靜脈給予 rt-PA 溶栓治療。,2016 年中國腦卒中大會(huì)發(fā)布 中國急性缺血性腦卒中靜脈溶栓指導(dǎo)規(guī)范,Lancet 2014; 384: 192935,NINDS=National Institute of Neurological Disorders and Stroke; ECASS=European Cooperative Acute Stroke Study; ATLANTIS=Alteplase

5、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 treat

6、ment, 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,卒中急救移動(dòng)單元 （Stroke Emergency Mobile Unit，STEMO） 配備神經(jīng)科醫(yī)師、技術(shù)員、護(hù)理人員、CT機(jī)即時(shí)實(shí)驗(yàn)室、遠(yuǎn)程醫(yī)療連接等開展溶栓治療。,Gold

7、en 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 th

8、e golden hour. Golden hour thrombolysis entails no risk to the patients safety and is associated with better short-term outcomes.,CONCLUSIONS AND RELEVANCE,How?,是指靜脈推注或滴注溶栓藥物溶解血栓，讓閉塞的血管再通，使缺血半暗帶恢復(fù)灌注，挽救瀕死的腦組織，改善臨床結(jié)局。,靜脈溶栓,張蓉(綜述), 吳軍(審核). 腦梗死溶栓與抗栓治療進(jìn)展.卒中與神經(jīng)疾病 2014;21(6):399-402,常采用Seldinger技術(shù)穿刺股動(dòng)脈或頸動(dòng)脈

9、，借助數(shù)字減影血管造影(digital subtraction angiography，DSA)圖像示蹤，了解腦梗死部位、范圍、側(cè)支循環(huán)建立程度及閉塞程度，將導(dǎo)管或微導(dǎo)管放至閉塞血管內(nèi)(非接觸性溶栓）或直接與栓子接觸(接觸性溶栓)，再注射溶栓藥物，進(jìn)行超選擇性動(dòng)脈內(nèi)溶栓治療。,動(dòng)脈溶栓,張蓉(綜述), 吳軍(審核). 腦梗死溶栓與抗栓治療進(jìn)展.卒中與神經(jīng)疾病 2014;21(6):399-402,N Engl J Med 2015;372:11-20.,a pragmatic, phase 3, multicenter clinical trial with randomized treatm

10、ent-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 an

11、terior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe.,CONCLUSIONS,是指在靜脈溶栓的基礎(chǔ)上進(jìn)行全腦血管造影，若發(fā)現(xiàn)殘余血栓，則再進(jìn)行動(dòng)脈溶栓，如此既兼顧了靜脈溶栓簡單、迅速和動(dòng)脈溶栓血管再通率高的優(yōu)點(diǎn)，因而得到學(xué)者們高度重視。,動(dòng)靜脈聯(lián)合溶栓,張蓉(綜述), 吳軍(審核). 腦梗死溶栓與抗栓治療進(jìn)展.卒中與神經(jīng)疾病 2014;21(6):399-402,一、動(dòng)脈溶栓及靜脈-動(dòng)脈序貫溶栓,(1)動(dòng)脈溶栓越早，效果

12、越好，應(yīng)盡早實(shí)施治療(I級(jí)推薦，B級(jí)證據(jù))； (2)動(dòng)脈溶栓有益于經(jīng)嚴(yán)格選擇的患者，適用于發(fā)病6 h內(nèi)的大腦 中動(dòng)脈供血區(qū)的急性缺血性腦卒中(I級(jí)推薦，B級(jí)證據(jù))； (3)發(fā)病24 h內(nèi)、后循環(huán)大血管閉塞的重癥腦卒中患者，經(jīng)過嚴(yán)格評(píng)估可行動(dòng)脈溶栓(級(jí)推薦，C級(jí)證據(jù))； (4)靜脈動(dòng)脈序貫溶栓治療是一種可供選擇的方法(級(jí)推薦，B級(jí)證據(jù))； (5)動(dòng)脈溶栓要求在有條件的醫(yī)院進(jìn)行(I級(jí)推薦，C級(jí)證據(jù))。,推薦意見,Which?,Ellis K, Brener S. New fibrinolytic agents for MI:As effective as current agents but ea

13、sier to administer. CCJM 2004;71(1):20-37,溶栓藥物,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年首次批準(zhǔn)用于缺血性卒中超急性期治療，這也是目前唯一一個(gè)被批準(zhǔn)的，在缺血性卒中急性期應(yīng)用可改善預(yù)后的藥物。,重組組織型纖溶酶原激活劑 （recombinant tissue plasminogen activator，rt-PA）

14、阿替普酶,溶栓治療是目前最重要的恢復(fù)血流措施之一，重組組織型纖溶酶原激活劑 (rt-PA) 和尿激酶 (UK) 是我國目前使用的主要溶栓藥。,國家衛(wèi)生計(jì)生委腦卒中防治工程委員會(huì) 腦卒中防治系列指導(dǎo)規(guī)范編審委員會(huì).中國急性缺血性腦卒中靜脈溶栓指導(dǎo)規(guī)范. 2016,Ramee SR, White CJ. Acute Stroke Intervention. Curr Probl Cardiol 2014;39:5976,使用方法：rtPA 0.9 mgkg(最大劑量為90 mg)靜脈滴注，其中10在最初1 min內(nèi)靜脈推注，其余持續(xù)滴注1 h，用藥期間及用藥24 h內(nèi)應(yīng)嚴(yán)密監(jiān)護(hù)患者(見表5)(I級(jí)

15、推薦，A級(jí)證據(jù))。,溶栓藥物劑量,中華醫(yī)學(xué)會(huì)神經(jīng)病學(xué)分會(huì)，中華醫(yī)學(xué)會(huì)神經(jīng)病學(xué)分會(huì)腦血管病學(xué)組.中國急性缺血性腦卒中診治指南2014.中華神經(jīng)科雜志 2015；48（4）：246-257,小劑量 vs 標(biāo)準(zhǔn)劑量,入選患者來自中國急性缺血性卒中溶栓監(jiān)測(cè)登記研究（Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China，TIMS-China）。 TIMS-China是一個(gè)前瞻性、多中心、急性缺血性卒中靜脈溶栓監(jiān)測(cè)登記研究，自2007年5月至2012年4月，本研究共登記了來自全國67家中心的1440例阿替普酶靜脈

16、溶栓患者。,選取發(fā)病4.5 h內(nèi)且阿替普酶使用劑量約為0.6 mg/kg（0.50.7 mg/kg）及0.9 mg/kg（0.850.95 mg/kg）的靜脈溶栓患者，對(duì)溶栓后癥狀性顱內(nèi)出血（symptomatic intracranial hemorrhage，SICH）、死亡率及90 d隨訪結(jié)局等進(jìn)行比較。,回顧性研究,本研究提示，在中國人群中，標(biāo)準(zhǔn)劑量（0.9 mg/kg）較低劑量（0.6 mg/kg）阿替普酶靜脈溶栓具有更好的有效性，且不會(huì)顯著增加SICH風(fēng)險(xiǎn)。,結(jié)論,N Engl J Med 2016;,ENhanced Control of Hypertension and Thr

17、ombolysis 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 U

18、niversity 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

19、 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 i

20、schaemic 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 i

21、n 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 m

22、g/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

23、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 v

24、ery 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

25、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) lowerin