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 Haemorrhage10-15% all strokes (Caucasians)20-30% in Asian/AfricanPathology (80-90% of all ICH) Hypertensive angiopathy Amyloid angiopathySitesBasal Ganglia Putamen (40%), thalamus (15%), caudate (5-10%)Cerebellum (10%), pons (10%)Lobar (10-20%)Hae
2、matoma evolutionEarly haematoma expansionOnset-CT interval (h)ProspectiveRetrospectiveBrottFujiiKazuiTakizawa 0-338%18%36%17% 3-6N/A8%16%6% 6-24N/A2%10%0%Peri-haematomal oedema in ICH Precise aetiology unclear cytotoxic vs vasogenic Is there a peri-haematomal ischaemic penumbra? Rational acute BP lo
3、wering requires better understanding of peri-haematomal oedemaSurgical treatmentSTICH trial resultsMedical treatmentrFVII (NovoSeven)Mayer et al. NEJM 2005; 352: 777-85Reduction of haematoma expansionMayer et al. NEJM 2005; 352: 777-85北大医院临床诊治方案Role of blood pressureobservational studies - mortality
4、SBP (mm Hg)1 month mortality (%)FogelholmVemmosOnset of ICH3-6 6-12 hours12hrs to one week1-4 weeksmonthsBP loweringhaemorrhagerebleedingoedemastroke recurrence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
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, q4-6h 依那普利 0.625-1.2 mg q6h, 根据需要调节剂量Guidelines for Acute BP ManagementStart medicationTargetICHAHA (1999) 180/105 mm Hg 180/105 mm Hg ISH (2003) 180/105 mm Hg 180/105 mm HgNZ (2003)Mean BP 130 mm HgMean
6、BP 220/120 mm Hg180/100-105 mm Hg (HT) 160-180/90-105 mm Hg (non-HT)UK (2004)if complications are apparentNot describedINTERACT pilot phase(Lancet Neurology 2008; 7: 391-399.)PathophysiologyElevated Blood PressureOngoing bleedingRe-bleedingHaematoma sizePoor outcomeCerebral oedema Vanguard PhaseProt
7、ocol SchemaRandomisationAcute ICH - onset within 6 hoursSBP 150 and 220 mmHgRepeat CT scans 24 + 72 hrsVital signs and BP over 7 days28 day and 3 month follow-upIntensive BP loweringTarget SBP 140mmHgGuideline-based BP managementTarget SBP 180 mmHgSystolic blood pressure differencesMean systolic BP
8、over time including 95% CITimeMean BP130140150160170180190Systolic BP: ControlSystolic BP: TreatmentTime 0Time 115min30min45min1hr6hr12hr18hr24hrday2amday2pmday3amday3pmday4amday4pmday5amday5pmday6amday6pmday7amday7pmday28amday28pmCrude mean (SD) change in hematoma volume by groupVolume (ml)Guidelin
9、e groupIntensive groupBaseline24 hours12.715.414.215.2 Clinical outcomes at 90 daysStandard(n = 201)Intensive(n = 203)pDeath or dependency49480.81Death12100.51Dependency41360.98Modified Rankin Score, median 2 20.66NIHSS, median220.97Barthel Index score, median95950.77MMSE, median28270.97EuroQoL, EQ5
10、D, median, %78750.97Early intensive blood pressure lowering enhances hematoma resolution but does not affect perihematoma edema:Yining HuangPeking University First Hospital, Beijing, ChinaOn behalf of C Anderson, Q Li, E Heeley, B Peng, C Skulina, J Wang, for the INTERACT Investigators Secondary aim
11、sTo determine the effects of early intensive blood pressure lowering treatment on hematoma and perihematoma edema growth over 72 hoursSecondary analyses: patient flow404 Patients randomized201 Guideline-based BP lowering145 in hematoma analysis1 Patient not ICH151 in hematoma analysis131 in edema an
12、alysis139 in edema analysis14 Unable to estimate edema volume12 Unable to estimate edema volume56 Missing CT data at 24h and/or 72h51 Missing CT data at 24h and/or 72h203 Early intensive BP loweringMean BP after randomization2000 15 30 45 60 612 18 241501005023456728 90MinutesHoursDaysMean blood pre
13、ssure (mm Hg)GuidelineIntensiveSBP 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 (P 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
14、 hematoma volume over 72 hoursPerihematoma edema analysis Early intensive BP lowering had no clear effects on absolute or relative increase in perihematoma edema volume over 72 hoursYN 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 of stroke
15、in patients with ischemic stroke or TIAs, Stroke, 2006;37:577-617AHA/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; 1-15Stronger Inhibition of P
16、latelets: Stronger Inhibition of Platelets: Combine different PathwaysCombine different Pathways+Aspirin + ClopidogrelAspririn + placebo 0 3 6 9 12P0.0010.140.120.100.080.060.040.020.00Months of Follow-upCumulative Hazard Rate Vascular Death + MI+ Strokeafter 4 weeks and after 4.5 MonthAdded Benefit
17、 of Clopidogrel to ASA treatment in Unstaible Angina Patients RRR: 6.4% (95% CI: - 4.6% 到到 16.3%)(p=0.244) ASA + 氯吡格雷氯吡格雷 (15.7%) 安慰剂安慰剂 + 氯吡格雷氯吡格雷 (16.7%)IS、MI、VD、因急性缺血事件再住院、因急性缺血事件再住院累积事件率0.000.040.080.120.160.20随访月数 0 3 6 9121518ARR: 1.0% Lancet 2004; 364: 331-37N=7599 1-1.5年 Defined as recent IS
18、 or TIA with previous ischemic event or diabetesN Engl J Med 2006,354:10 6 12 18 24 301086420月Accumulation of events（）aspirinclopidogrel plus aspirinP=0.22N Engl J Med 2006,354:1Endpoints: MI, Stroke, Vascular deathSignificantly increased of bleeding events in the combination treatment of clopidogre
19、l plus aspirinPrimary Safety RR（95CI） p valueSevere bleeding 1.25(0.97-1.61) 0.09Moderate bleeding 1.62(1.27-2.10) 0.00125%62%NATURE REVIEWS - DRUG DISCOVERY VOLUME 2; OCTOBER 2003; 1-15Inhibition of Platelets: By different PathwaysInhibition of Platelets: By different Pathways多中心，双盲，随机，双模拟，阿司匹林对照多中
20、心，双盲，随机，双模拟，阿司匹林对照设计设计:spsCCilostazol StrokePrevention Study 年龄：年龄：18-75 卒中发病卒中发病1-6个月个月 影像学影像学 (CT/MRI)确认脑梗死确认脑梗死 Modified Rankin Scale 4 没有严重的系统疾病没有严重的系统疾病 填写知情同意书填写知情同意书spsCCilostazol StrokePrevention Study研究设计研究设计spsCCilostazol StrokePrevention Study主要终结指标主要终结指标次要终结指标次要终结指标 安全性安全性:卒中复发（梗死，出血，蛛网膜
21、下腔出血卒中复发（梗死，出血，蛛网膜下腔出血MRI 显示新的梗死显示新的梗死血管死亡血管死亡MITIAs血管事件血管事件: PAD, PE, DVT, etc其他事件死亡其他事件死亡不良事件不良事件; 实验室化验异常实验室化验异常; ECG 异常异常spsCCilostazol StrokePreventionStudyR = Randomization1218months double-blind,double-dummy,treatmentcilostazol 100mg bid(n=360)ASA 100mg qd6th month12th month18th monthFollow-u
22、p finish3th month1st month16month after cerebral infarctionRTreatment start(n=360)0 dayScreening by PE/MRI/LAB.etcMRI主要终结指标累计主要终结指标累计 Kaplan-Meier Curve 主要终点指标Aspirin 5.27%Cilostazol 3.26%RR 38.1% 脑出血脑出血/脑梗死脑梗死Aspirin 33.3%Cilostazol 9.1% 123456 Period of No. Code Sex Age Drug Treatment Outcome 1365
23、40559437692538MMMMMM695755534266aspirinaspirincilostazolaspirinaspirinaspirinPVSRecoveringRecoveringRecoveringRecoveringDeathspsCCilostazol StrokePrevention Study871111117months症状性脑出血加无症状性核磁显症状性脑出血加无症状性核磁显示血肿示血肿 ASA 7 cases ( 5 symptomatic hemorrhage, 2 hemotoma in MRI) Cilostazol 1 cases p=0.0349No
24、. 13623 Mar 200510 Oct 2004阿司匹林治疗阿司匹林治疗7月月Microbleeding found in 39%微出血发生的危险因素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二、一年后脑微出血的动态变化及影响因素93% 完成了完成了12个月个月以上的随诊以上的随诊, 复查了复查了MRI新增微出血新增微出血50例例 ITT PPITT PP 项目项目 ASAASA CilostrazolCilostrazol ASA ASA CilostrazolCilostrazol New Infarct (Flair)New Infarct (Flair) no n
25、o 305( 98.39%) 284( 97.26%) 305( 98.39%) 283( 97.25%)305( 98.39%) 284( 97.26%) 305( 98.39%) 283( 97.25%) yesyes 5( 1.61%) 8( 2.74%) 5( 1.61%) 8( 2.75%)5( 1.61%) 8( 2.74%) 5( 1.61%) 8( 2.75%) total total 310 292 310 291310 292 310 291 New New Lacunar(FlairLacunar(Flair) ) no no 282( 90.97%) 267( 91.4
26、4%) 282( 90.97%) 266( 91.41%)282( 90.97%) 267( 91.44%) 282( 90.97%) 266( 91.41%) yesyes 28( 9.03%) 25( 8.56%) 28( 9.03%) 25( 8.59%)28( 9.03%) 25( 8.56%) 28( 9.03%) 25( 8.59%) total total 310 292 310 291310 292 310 291 New Hemotoma(T2 New Hemotoma(T2* *) ) no no 306( 98.71%) 291( 99.66%) 306( 98.71%)
27、 290( 99.66%)306( 98.71%) 291( 99.66%) 306( 98.71%) 290( 99.66%) yesyes 4( 1.29%) 1( 0.34%) 4( 1.29%) 1( 0.34%)4( 1.29%) 1( 0.34%) 4( 1.29%) 1( 0.34%) total total 310 292 310 291310 292 310 291 New MB(T2 New MB(T2* *) ) no no 293( 94.52%) 275( 94.18%) 293( 94.52%) 274( 94.16%)293( 94.52%) 275( 94.18%) 293( 94.52%) 274( 94.16%) yesyes 17( 5.48%) 17( 5.82%) 17( 5.48%) 17( 5.84%)17( 5.48%) 17( 5.82%) 17( 5.48%) 17( 5.84%) Total Total 310 292 310 291310 292 310 291 结论结论 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！谢谢！
