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1、血压控制 与 脑出血治疗和预防,北京大学第一医院神经科 黄一宁教授 ,Primary Intracerebral Haemorrhage,10-15% all strokes (Caucasians) 20-30% in Asian/African Pathology (80-90% of all ICH) Hypertensive angiopathy Amyloid angiopathy Sites Basal Ganglia Putamen (40%), thalamus (15%), caudate (5-10%) Cerebellum (10%), pons (10%) Lobar
2、 (10-20%),Haematoma evolution,Early haematoma expansion,Peri-haematomal oedema in ICH,Precise aetiology unclear cytotoxic vs vasogenic Is there a peri-haematomal ischaemic penumbra? Rational acute BP lowering requires better understanding of peri-haematomal oedema,Surgical treatment STICH trial resu
3、lts,Medical treatment rFVII (NovoSeven),Mayer et al. NEJM 2005; 352: 777-85,Reduction of haematoma expansion,Mayer et al. NEJM 2005; 352: 777-85,北大医院临床诊治方案,平扫CT应该作为首选，对脑出血和蛛网膜下腔出血均很敏感。 核磁对可疑的脑出血诊断和处理上也很有帮助。脑出血包括硬膜外和硬膜下出血、蛛网膜下腔出血、脑室出血、梗塞后出血以及脑实质出血。 一定要考虑到：凝血疾病、外伤、血管损伤、静脉血栓形成，以及动脉瘤破裂。,下述步骤应该是同步进行,评估生命
4、体症：判断患者做影像学检查时是否能忍受，是否要插管。 若认为需要插管，可以使用超短作用的神经肌肉阻断剂或者镇静剂，避免长时间影响观察患者运动功能和神经功能。 对于血压严重升高的患者应该评估是否有心肌的损伤。,血液检查：PT、INR、PTT、血小板计数和全血计数、DDimer、纤维蛋白原、电解质、BUN、Cr、血糖、肝功能、血型。 需要与神经外科联系： 小脑出血时神经外科急症； 非优势半球的脑叶出血，临床神经功能进行性加重； 对于特殊患者，如年轻患者、优势半球不清楚，等情况下，考虑需要减压术者。,根据指南控制血压。,所有需要连续静脉降压的患者，都应该急诊放置动脉导管，监测血压和中心静脉压，同时使
5、用静脉降压药。 一旦决定药静脉降压治疗，必须指定专人床旁监测血压和治疗效果，直至血压得到控制。,Role of blood pressure observational studies - mortality,admission BP and mortality,SBP (mm Hg),1 month mortality (%),Fogelholm,Vemmos,Onset of ICH,3-6 6-12 hours,12hrs to one week,1-4 weeks,months,BP lowering,haemorrhage,rebleeding,oedema,stroke recur
6、rence,BP lowering Potential therapeutic mechanisms,脑出血患者血压控制方案,拉贝洛尔labetalol 5100mg/h， 间断注入，每次1040mg，或者 连续点滴 28mg/min 我国药典禁忌在脑出血使用拉贝咯尔 艾司洛尔esmolol 负荷量500mcg/kg；维持量 50200 mcg.kg-1min 硝普钠 nitroprusside 0.5-10 mcg.kg-1min-1 尼卡地平 nicardipine 5mg/h, 每15分钟增加 2.5mg/h, 最大量为15mg/h 肼苯哒嗪 hydralazine 10-20mg, q
7、4-6h 依那普利 0.625-1.2 mg q6h, 根据需要调节剂量,Guidelines for Acute BP Management,对于脑出血早期几个小时内可以根据下述步骤：,收缩压 230mmHg， 或者舒张压 140mmHg，间隔5分钟测量2次血压，开始使用硝普钠 收缩压 180230 mmHg， 舒张压 105140mmHg，或者平均动脉压 130 mmHg， 间隔20分钟测量2次，开始静脉使用拉贝洛尔、艾司洛尔、依那普利，避免口服或舌下含服硝苯地平。 收缩压70mmHg。 当怀疑由于降低血压引起临床症状恶化，应考虑调整血压。,问题,什么时候降血压 降到多少合适 降压速度,I
8、NTERACT pilot phase (Lancet Neurology 2008; 7: 391-399.),Pathophysiology,Elevated Blood Pressure,Ongoing bleeding Re-bleeding,Haematoma size,Poor outcome,Cerebral oedema,Vanguard Phase Protocol Schema,Randomisation,Acute ICH - onset within 6 hours,SBP 150 and 220 mmHg,Repeat CT scans 24 + 72 hrs Vit
9、al signs and BP over 7 days 28 day and 3 month follow-up,Intensive BP lowering,Target SBP 140mmHg,Guideline-based BP management,Target SBP 180 mmHg,Systolic blood pressure differences,Crude mean (SD) change in hematoma volume by group,Volume (ml),Guideline group,Intensive group,Baseline,24 hours,12.
10、7,15.4,14.2,15.2,Clinical outcomes at 90 days,Early intensive blood pressure lowering enhances hematoma resolution but does not affect perihematoma edema:,Yining Huang Peking University First Hospital, Beijing, China,On behalf of C Anderson, Q Li, E Heeley, B Peng, C Skulina, J Wang, for the INTERAC
11、T Investigators,Secondary aims,To determine the effects of early intensive blood pressure lowering treatment on hematoma and perihematoma edema growth over 72 hours,Secondary analyses: patient flow,404 Patients randomized,201 Guideline-based BP lowering,145 in hematoma analysis,1 Patient not ICH,151
12、 in hematoma analysis,131 in edema analysis,139 in edema analysis,14 Unable to estimate edema volume,12 Unable to estimate edema volume,56 Missing CT data at 24h and/or 72h,51 Missing CT data at 24h and/or 72h,203 Early intensive BP lowering,Mean BP after randomization,200,0,15,30,45,60,6,12,18,24,1
13、50,100,50,2,3,4,5,6,7,28,90,Minutes,Hours,Days,Mean blood pressure (mm Hg),SBP 14 mm Hg at 1 hour (P0.0001) SBP 12 mm Hg from 1-24 hours (P0.0001) SBP 11 mm Hg from 1-3 days (P0.0001),Guideline,Baseline to 24h,Intensive,Guideline,Baseline to 72h,Intensive,15,10,5,0,Absolute increase in edema volume
14、(ml),Overall -2.4ml over 72 hours (P=0.1) using repeated measure,(Adjustments were made for location and baseline volume of hematoma, and time from onset to CT), -2.1ml (P=0.09),- 2.7ml (P=0.1),Adjusted mean (95% CI) values for absolute increase in edema volume (mL),Guideline,Baseline to 24h,Intensi
15、ve,Guideline,Baseline to 72h,Intensive,120,100,80,60,20,Relative increase in edema volume (%),40,Overall +2% over 72 hours (P=0.1) using repeated measure,(Adjustments were made for location and baseline volume of hematoma, and time from onset to CT),-3% (P=0.8),+6% (P=0.6),Adjusted mean (95% CI) val
16、ues for relative increase in edema volume (%),Summary of results,Hematoma analysis Early intensive BP lowering treatment lowered systolic BP by 10 mm Hg was associated with reduction in absolute (-2.8ml; P=0.002) and relative (-10%; P=0.04) increase in hematoma volume over 72 hours Perihematoma edem
17、a analysis Early intensive BP lowering had no clear effects on absolute or relative increase in perihematoma edema volume over 72 hours,Cilostazol v.s. Aspirin in Secondary Stroke Prevention,YN Huang, C Yan, W Jiang, et al Lancet Neurology 2008, May,阿司匹林已经成为公认的缺血性卒中二级预防首选药物,Guidelines for prevention
18、 of stroke in patients with ischemic stroke or TIAs, Stroke, 2006;37:577-617 AHA/ACC guidelines for secondary prevetion for patients with coronary and other atherosclerotic vascular disease: 2006 update, JACC 2006； 47( 10），2130,NATURE REVIEWS - DRUG DISCOVERY VOLUME 2; OCTOBER 2003; 1-15,Stronger In
19、hibition of Platelets: Combine different Pathways,+,积极抗血小板治疗对不稳定性心绞痛作用只有在最初的几个星期明显 (CURE),Aspirin + Clopidogrel,Aspririn + placebo,after 4 weeks and after 4.5 Month,Added Benefit of Clopidogrel to ASA treatment in Unstaible Angina Patients,RRR: 6.4% (95% CI: - 4.6% 到 16.3%) (p=0.244),ASA + 氯吡格雷 (15.
20、7%),安慰剂 + 氯吡格雷 (16.7%),IS、MI、VD、因急性缺血事件再住院,累积事件率,0.00,0.04,0.08,0.12,0.16,0.20,随访月数,0,3,6,9,12,15,18,氯吡格雷在近期短暂脑缺血发作或缺血性卒中的高危患者中对动脉粥样硬化血栓形成的处理（MATCH）：,ARR: 1.0%,Lancet 2004; 364: 331-37,N=7599 1-1.5年,增加ASA，并为给高危的脑血管病患者病人带来额外的临床益处,MATCH研究显示，对高危的缺血性脑血管病患者，在氯吡格雷标准治疗的基础上增加阿司匹林，阿司匹林没有带来更多的临床益处(疗效/风险比) 增加A
21、SA导致更多的威胁生命的出血事件，主要是胃肠道出血和颅内出血。, Defined as recent IS or TIA with previous ischemic event or diabetes,Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) 氯吡格雷用于动脉粥样硬化血栓形成高危及稳定、处理和避免缺血,N Engl J Med 2006,354:1,CHARISMA,N Engl J Med 2006,354:1,Endp
22、oints: MI, Stroke, Vascular death,CHARISMA,Significantly increased of bleeding events in the combination treatment of clopidogrel plus aspirin,Primary Safety RR（95CI） p value,Severe bleeding 1.25(0.97-1.61) 0.09 Moderate bleeding 1.62(1.27-2.10) 0.001,25%,62%,Profess,NATURE REVIEWS - DRUG DISCOVERY
23、VOLUME 2; OCTOBER 2003; 1-15,Inhibition of Platelets: By different Pathways,多中心，双盲，随机，双模拟，阿司匹林对照,设计:,CSPS Trial,入组标准,年龄：18-75 卒中发病1-6个月 影像学 (CT/MRI)确认脑梗死 Modified Rankin Scale 4 没有严重的系统疾病 填写知情同意书,研究设计,主要终结指标 次要终结指标 安全性:,卒中复发（梗死，出血，蛛网膜下腔出血,MRI 显示新的梗死 血管死亡 MI TIAs 血管事件: PAD, PE, DVT, etc 其他事件死亡,不良事件;
24、实验室化验异常; ECG 异常,设计流程,R = Randomization,1218months double-blind, double-dummy,treatment,cilostazol 100mg bid,(n=360),ASA 100mg qd,6th month,12th month,18th month Follow-up finish,3th month,1st month,16month after cerebral infarction,R,Treatment start,(n=360),0 day,Screening by PE/MRI/LAB.etc,MRI,主要终结
25、指标累计 Kaplan-Meier Curve,终结分析,主要终点指标 Aspirin 5.27% Cilostazol 3.26% RR 38.1%,脑出血/脑梗死 Aspirin 33.3% Cilostazol 9.1%,脑出血患者,1 2 3 4 5 6,Period of No. Code Sex Age Drug Treatment Outcome,136 540 559 437 692 538,M M M M M M,69 57 55 53 42 66,aspirin aspirin cilostazol aspirin aspirin aspirin,PVS Recoverin
26、g Recovering Recovering Recovering Death,8 7 11 11 11 7,months,症状性脑出血加无症状性核磁显示血肿,ASA 7 cases ( 5 symptomatic hemorrhage, 2 hemotoma in MRI) Cilostazol 1 cases p=0.0349,No. 136,23 Mar 2005,10 Oct 2004,阿司匹林治疗7月,Microbleeding found in 39%,微出血发生的危险因素,二、一年后脑微出血的动态变化及影响因素,93% 完成了12个月以上的随诊, 复查了MRI,新增微出血50例
27、,New lesions found in Second MRI, ITT PP 项目 ASA Cilostrazol ASA Cilostrazol New Infarct (Flair) no 305( 98.39%) 284( 97.26%) 305( 98.39%) 283( 97.25%) yes 5( 1.61%) 8( 2.74%) 5( 1.61%) 8( 2.75%) total 310 292 310 291 New Lacunar(Flair) no 282( 90.97%) 267( 91.44%) 282( 90.97%) 266( 91.41%) yes 28( 9
28、.03%) 25( 8.56%) 28( 9.03%) 25( 8.59%) total 310 292 310 291 New Hemotoma(T2*) no 306( 98.71%) 291( 99.66%) 306( 98.71%) 290( 99.66%) yes 4( 1.29%) 1( 0.34%) 4( 1.29%) 1( 0.34%) total 310 292 310 291 New MB(T2*) no 293( 94.52%) 275( 94.18%) 293( 94.52%) 274( 94.16%) yes 17( 5.48%) 17( 5.82%) 17( 5.48%) 17( 5.84%) Total 310 292 310 291 ,结论,控制微出血发生的危险因素，降低症状性脑出血的发生。 指导脑梗死二级预防抗栓治疗，减少阿司匹林相关性脑出血的发生。 血压控制不好+使用阿司匹林可能是脑出血增加的重要因素。,谢谢！,