缺血性卒中的溶栓治療

1、缺血性卒中的缺血性卒中的溶栓治療溶栓治療 上海市第五人民醫(yī)院藥劑科上海市第五人民醫(yī)院藥劑科季閩春季閩春2016.6 溶栓治療是目前國(guó)內(nèi)外公認(rèn)的積極挽救溶栓治療是目前國(guó)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。缺血缺氧腦組織行之有效的方法。溶栓治療的作用機(jī)制溶栓治療的作用機(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，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)。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)

2、:399-402當(dāng)局部腦組織血流量當(dāng)局部腦組織血流量腦電功能障礙腦電功能障礙神經(jīng)細(xì)胞的電衰竭神經(jīng)細(xì)胞的電衰竭神經(jīng)細(xì)胞的膜衰竭神經(jīng)細(xì)胞的膜衰竭膜衰竭后膜衰竭后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，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)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)功能。正常，梗死的神經(jīng)細(xì)胞不能恢復(fù)相應(yīng)功能。 神經(jīng)傳導(dǎo)消失，但神經(jīng)神經(jīng)傳導(dǎo)消失，但神經(jīng)細(xì)胞僅喪失部分功能，細(xì)胞僅喪失部分功能，形態(tài)學(xué)上改變輕微。形態(tài)學(xué)上改變輕微。對(duì)于處在電衰竭和膜衰竭對(duì)于處在電衰竭和膜衰竭

3、之間的腦組織，稱之為之間的腦組織，稱之為缺血半暗帶缺血半暗帶。當(dāng)血流量介于當(dāng)血流量介于2035之間時(shí)溶栓治療效果明之間時(shí)溶栓治療效果明顯，可以恢復(fù)全部功能或部分功能。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):399-402Wechsler LR. Intravenous Thrombolytic Therapy for Acute Ischemic Stroke. N Engl J Med 2011;364:2138-46.Wechsler LR. Intravenous Thr

4、ombolytic Therapy for Acute Ischemic Stroke. N Engl J Med 2011;364:2138-46.When?溶栓治療的主要目的溶栓治療的主要目的 挽救缺血半暗帶的腦組織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。因此涉及到溶栓治療時(shí)間窗的問題。 按照美國(guó)國(guó)立神經(jīng)疾病與卒中研究所的研究表明，按照美國(guó)國(guó)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。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)間窗時(shí)間窗張蓉(綜述), 吳軍(審

5、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(guó)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(guó)急性缺血性腦卒中靜脈溶栓指導(dǎo)規(guī)范.2016對(duì)缺血性腦卒中發(fā)病對(duì)缺血性腦卒中發(fā)病 3 h 內(nèi)內(nèi) (I 級(jí)推薦，級(jí)推薦，A 級(jí)級(jí)證據(jù)）和證據(jù)）和 34. 5 h ( I 級(jí)推薦，級(jí)推薦，B 級(jí)證據(jù)）級(jí)證據(jù)）的患者，應(yīng)按照適應(yīng)證和禁忌證（見表的患者，應(yīng)按照適應(yīng)證和禁忌證（見表 2、3) 嚴(yán)格篩選患者，盡快靜脈給予嚴(yán)格篩選患者，盡快靜脈給予 rt-PA 溶栓治溶栓治療。療。2016 年中國(guó)腦卒中大會(huì)發(fā)布年中國(guó)腦卒中大會(huì)發(fā)布中國(guó)急性缺血性腦卒中靜

6、脈溶栓指導(dǎo)規(guī)范中國(guó)急性缺血性腦卒中靜脈溶栓指導(dǎo)規(guī)范Lancet 2014; 384: 192935NINDS=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 Tri

7、al; 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 4.54.5h of stroke ons

8、et, with earlier treatment associated with bigger proportional benefits.Interpretation卒中急救移動(dòng)單元卒中急救移動(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、配備神經(jīng)科醫(yī)師、技術(shù)員、護(hù)理人員、CT機(jī)即機(jī)即時(shí)實(shí)驗(yàn)室、遠(yuǎn)程醫(yī)療連接等開展溶栓治療。時(shí)實(shí)驗(yàn)室、遠(yuǎn)程醫(yī)療連接等開展溶栓治療。Golden hourFigure 2. Mobile Stroke Unit. An ambulance (A) equipped with point-of car

9、e laboratory system and telemedicine devices (B) and CT (C) requiredfor prehospital stroke treatment.JAMA Neurol 2015 ;72(1):25-30The 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 i

10、s associated with better short-term outcomes.CONCLUSIONS AND RELEVANCEHow?是指靜脈推注或滴注溶栓藥物溶解血栓，讓閉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。瀕死的腦組織，改善臨床結(jié)局。靜脈溶栓靜脈溶栓張蓉(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常采用常采用Seldinger技術(shù)穿刺股動(dòng)脈或頸動(dòng)脈，借助數(shù)技術(shù)穿刺股動(dòng)脈或頸動(dòng)脈，借助數(shù)字減影血管造影字減影

11、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)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)管內(nèi)(非接觸性溶栓非接觸性溶栓）或直接與栓子接觸或直接與栓子接觸(接觸性溶接觸性溶栓栓)，再注射溶栓藥物，進(jìn)行超選擇性動(dòng)脈內(nèi)溶栓治，再注射溶栓藥物，進(jìn)行超選擇性動(dòng)脈內(nèi)溶栓治療。療。動(dòng)脈溶栓動(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靜脈溶栓靜脈溶栓要求的技術(shù)設(shè)備簡(jiǎn)單要求的

12、技術(shù)設(shè)備簡(jiǎn)單給藥時(shí)間快給藥時(shí)間快方便快捷方便快捷操作技術(shù)容易掌握操作技術(shù)容易掌握創(chuàng)傷相對(duì)較小創(chuàng)傷相對(duì)較小費(fèi)用較低費(fèi)用較低患者易于接受患者易于接受溶栓方法溶栓方法比較比較動(dòng)脈溶栓動(dòng)脈溶栓溶栓藥物劑量減少溶栓藥物劑量減少局部藥物濃度高局部藥物濃度高再通時(shí)間段、溶栓再通時(shí)間段、溶栓效果確切效果確切對(duì)纖溶系統(tǒng)影響小對(duì)纖溶系統(tǒng)影響小擴(kuò)大了溶栓時(shí)間窗擴(kuò)大了溶栓時(shí)間窗N Engl J Med 2015;372:11-20.a pragmatic, phase 3, multicenter clinical trial with randomized treatment-group assignments,

13、open-label treatment, and blinded end-point evaluation.MR CLEANMulticenter 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, intraar

14、terial 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，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(jiǎn)單、迅速和動(dòng)脈如此既兼顧了靜脈溶栓簡(jiǎn)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。們高度重視。動(dòng)靜脈聯(lián)合溶栓動(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.

15、卒中與神經(jīng)疾病 2014;21(6):399-402一、動(dòng)脈溶栓及靜脈一、動(dòng)脈溶栓及靜脈-動(dòng)脈序貫溶栓動(dòng)脈序貫溶栓(1)動(dòng)脈溶栓越早，效果越好，應(yīng)盡早實(shí)施治療動(dòng)脈溶栓越早，效果越好，應(yīng)盡早實(shí)施治療(I級(jí)推薦，級(jí)推薦，B級(jí)證據(jù)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)的大腦內(nèi)的大腦中動(dòng)脈供血區(qū)的急性缺血性腦卒中中動(dòng)脈供血區(qū)的急性缺血性腦卒中(I級(jí)推薦，級(jí)推薦，B級(jí)證據(jù)級(jí)證據(jù))；(3)發(fā)病發(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)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)脈溶栓估可行動(dòng)脈溶栓(級(jí)推薦，

16、級(jí)推薦，C級(jí)證據(jù)級(jí)證據(jù))；(4)靜脈靜脈動(dòng)脈序貫溶栓治療是一種可供選擇的方法動(dòng)脈序貫溶栓治療是一種可供選擇的方法(級(jí)推薦，級(jí)推薦，B級(jí)證據(jù)級(jí)證據(jù))；(5)動(dòng)脈溶栓要求在有條件的醫(yī)院進(jìn)行動(dòng)脈溶栓要求在有條件的醫(yī)院進(jìn)行(I級(jí)推薦，級(jí)推薦，C級(jí)證據(jù)級(jí)證據(jù))。推薦意見推薦意見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溶栓藥物溶栓藥物Ellis K, Brener S. New f

17、ibrinolytic agents for MI:As effective as current agents but easier to administer. CCJM 2004;71(1):20-37FDA于于1996年首次批準(zhǔn)用于缺血性卒中超急性期治療，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。應(yīng)用可改善預(yù)后的藥物。重組組織型纖溶酶原激活劑重組組織型纖溶酶原激活劑（recombinant tissue plasminogen activator，rt-PA） 阿替普酶阿替普酶

18、溶栓治療是目前最重要的恢復(fù)血流措施之一，重組組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織型纖溶酶原激活劑 (rt-PA) 和尿激酶和尿激酶 (UK) 是我國(guó)目是我國(guó)目前使用的主要溶栓藥。前使用的主要溶栓藥。國(guó)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(guó)急性缺血性腦卒中靜脈溶栓指導(dǎo)規(guī)范. 2016Ramee SR, White CJ. Acute Stroke Intervention. Curr Probl Cardiol 2014;39:5976 使用方法：使用方法：rtPA 0.9 mgkg(最大劑量為最大劑量為90 mg)靜脈滴注，其中

19、靜脈滴注，其中10在最初在最初1 min內(nèi)靜脈推內(nèi)靜脈推注，其余持續(xù)滴注注，其余持續(xù)滴注1 h，用藥期間及用藥，用藥期間及用藥24 h內(nèi)內(nèi)應(yīng)嚴(yán)密監(jiān)護(hù)患者應(yīng)嚴(yán)密監(jiān)護(hù)患者(見表見表5)(I級(jí)推薦，級(jí)推薦，A級(jí)證據(jù)級(jí)證據(jù))。溶栓藥物劑量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(guó)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小劑量小劑量 vs 標(biāo)準(zhǔn)劑量標(biāo)準(zhǔn)劑量 入選患者來自中國(guó)急性缺血性卒中溶栓監(jiān)測(cè)登記研入選患者來自中國(guó)急性缺血性卒中溶栓監(jiān)測(cè)登記研究（究（Thrombolysis Implementation and Monit

20、or of AcuteIschemic Stroke in China，TIMS-China）。）。 TIMS-China是一個(gè)前瞻性、多中心、急性缺血性卒是一個(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，自中靜脈溶栓監(jiān)測(cè)登記研究，自2007年年5月至月至2012年年4月，本月，本研究共登記了來自全國(guó)研究共登記了來自全國(guó)67家中心的家中心的1440例阿替普酶靜脈溶例阿替普酶靜脈溶栓患者。栓患者。選取發(fā)病選取發(fā)病4.5 h內(nèi)且阿替普酶使用劑量約為內(nèi)且阿替普酶使用劑量約為0.6 mg/kg（0.50.7 mg/kg）及）及0.9 mg/kg（0.850.95 mg/kg）的靜脈溶栓患者，對(duì)

21、溶栓后癥狀性）的靜脈溶栓患者，對(duì)溶栓后癥狀性顱內(nèi)出血（顱內(nèi)出血（symptomatic intracranial hemorrhage，SICH）、死亡率及）、死亡率及90 d隨訪結(jié)局等進(jìn)行比較。隨訪結(jié)局等進(jìn)行比較。回顧性研究回顧性研究本研究提示，在中國(guó)人群中，標(biāo)準(zhǔn)劑量（本研究提示，在中國(guó)人群中，標(biāo)準(zhǔn)劑量（0.9 mg/kg）較低劑量（較低劑量（0.6 mg/kg）阿替普酶靜脈溶栓具有更好）阿替普酶靜脈溶栓具有更好的有效性，且不會(huì)顯著增加的有效性，且不會(huì)顯著增加SICH風(fēng)險(xiǎn)。風(fēng)險(xiǎn)。結(jié)論結(jié)論N Engl J Med 2016;ENhanced Control of Hypertension an

22、d 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 t

23、he 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

24、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 acu

25、te 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 vesse

26、ls 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.

27、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 responsib

28、le 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

29、 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 outcomeevaluation, two doses of intravenous alteplase werecompared in p

30、atients with an acute ischemicstroke who were eligible for thrombolytic therapy;administration of the drug was commenced within4.5 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