题目：一例脑出血病人的循证治疗决策

1、题目：一例脑出血病人的循证治疗决策学号：0720110046姓名：王 岩评分一、病例资料：患者，男,46岁，有风湿性心病7-8年，一年前行二尖瓣置换术。一日前，骑车摔倒， 枕部着地当时有昏迷（具体时间不详），后由他人送到别院做简单治疗,之后到我院行 头颅ct:显示左脑顶枕叶深部脑门质出血并破入脑室系统。此次病程中呕吐一次，为胃 内容物患者一直服用华法林4.5 mgo查体:神清,精神软，双瞳孔等大，对光反应灵敬. 颈部稍抵抗无具他阳性体征凝血酶原时间（pt） 50.2 s、国际标准化比值（inr） 5. 9 o二、分析病例及提出问题：患者46岁，有风湿性心脏病病史，并做过二尖瓣膜置换手术。因外力

2、作用导致 脑损伤，ct显示左脑顶枕叶深部脑口质出血并破入脑室系统。对于安装有金属心脏 瓣膜的患者，需长期服用华法林抗凝，当这一类患者出现脑内出血的急症时，该如何 止血？是否停用抗凝药物？神经科医师往往处于两难境地。所面临的问题如下：1. 如果突然屮止抗凝药物治疗，能否导致反弹性高凝状态。抗凝和止血该如何平衡？ 2华发林的使用该作何调整？三、文献证据检索：根据所提出的问题,我们以“valve replacement （瓣膜置换术）/mechanical mitral valve prosthesis （机械人工瓣膜）"and ''intracranial hemorrh

3、age （颅内出血）/brain hemorrhage （脑出血）”为关键词,从medline ±,从1967-2007年，共得到29篇 相关文章。以"oral anticoagulation （ 口 服抗凝药物）"and "'intracranial hemorrhage/brain hemorrhage为关键词，从medline ±,从1967-2007年，共得到31篇相关文章。lu4tintracranial hemorrhage”为关键词，限定"practice guideline” 从 medline 上， 得到脑出

4、血治疗指南2篇；以“oral anticoagulation为关键词，限定“practice guideline,得到口服抗凝剂治疗指南2篇。四、检索结果:根据情况进行筛检，最后得到相关文献共14篇，论著7篇，脑出血治疗指南1 篇，系统综述1篇;oral anticoagulation指南3篇，系统综述1篇。（如下表）临床问题rctmeta-analyzeguidelinecase studiesreview需解决问题100141需解决问题200431五、评价证据的真实性、可靠性、适用性：问题（1）:如果突然中止抗凝药物治疗，能否导致反弹性高凝状态。抗凝和止血该phanc,等报道，52例安装有

5、机械主动脉瓣和（或）二尖瓣的患者，因发生ich人院, 采用新鲜冷冻血浆和维生素k治疗，停止抗凝治疗的小位时间为10天，发病后30天 内缺血发作的可能性为2.9% （c级）。另外，wijdicl?】等也证实，抗凝治疗发生颅内出血的病人，停用华法林2天3 个月（平均8天），无栓塞及出血发生（c级）。bertram m> beattie jn等的病例对照实验也均证明对于急性期患者，屮断口服抗 凝剂10-14，脑内发生栓塞的事件非常低的 （c级）。而有关逆转或突然终止抗凝治疗可能导致的反弹性高凝状态的顾虑，目前看来并 无证据支持；相反，研究显示，未能使凝血指标恢复正常与脑实质继续出血、血肿扩 大

6、和转归恶化密切相关（a级）。因此，尽管对这部分特殊的脑出血患者的治疗方案，尚无多屮心随机对照实验或 系统评价的证据支持，但从现有的证据来看，对于心脏机械瓣膜置换术后抗凝发生颅 内出血的病人，在治疗期间短暂逆转或停止抗凝1014 d看來是相对安全的。问题（2）:华发林的使用该作何调整?根据口服抗凝药物的指南建议，监控国际化标准值inr是十分必要的，研究证明, 口服抗凝药物时,inr控制在2.0-4.5 z间时，发生1ch的风险大约在0.33.7%（a级）, inr每增加0.5个单位，脑内出血的危险就增加1.47 （a级）。该病人tnr5.9,属于相对高危人群。我们根据指南建议，以inr作为抗凝监

7、控指标，逐步调整华法林剂量, 直到inr控制在1.323之间z （a级）o六、结合病人情况和临床专业知识，治疗方案如下：1、暂时停止抗凝治疗，停用华法林。2、给予甘露醇脱水，新鲜冷冻血浆和维生索kl2-13o3、考虑到种族的差异问题，根据国外文献结合我国学者研究资料，将屮止抗凝时间 限制在2-7天内凶，同时进行侮口监测inr。4、第7天，停用维生素k1，加服华法林，每犬1.5 mg开始，每2h 1次监测inr至 脑出血病情稳定，根据inr逐步调整华法林剂量。七、效果评价：20天后再次复查ct:脑血肿吸收。继续监控inr并调整华法林剂量，25天后病 人岀院，华法林剂量调整至每天3.75 mg ,

8、tnr 2.3，随访至今。参考文献：1 phan tg koh m, wijdicks ef: safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk. arch neurol 2000;57: 171()-17132 wijdicks ef;heublein dm;burnett jc jr .increase and uncoupling of adrenomedullin from the natriuretic pe

9、ptide system in aneurysmal subarachnoid hemorrhage. j neurosurg.2001,9(2):252-2563 ananthasubramaniam k, beattie jn, rosman hs, j ay am v, borzak s: how safely and for how long can warfarin therapy be withheld in prosthetic heart valve patients hospitalized with a major hemorrhage? chest 2001; 119:

10、478-484.4 bertram m, bonsanto m, hacke w, schwab s: managing the therapeutic dilemma: patientswith spontaneous intracerebral hemorrhage and urgent need for anticoagulation.j neurol 2000; 247: 209-214.5 hart rg;boop bs;anderson dc. ond anticoagulants and intracranial hemorrhage facts and hypotheses.

11、stroke995.26:147114776 steiner t, diringer m, rosand j: intracerebral hemorrhage associated with oral anticoagulanttherapy: current practices and open questions stroke 2006; 37: 256-627 the stroke prevention in reversible ischemia trial (spirit) study group: a randomizedtrial of anticoagulants versu

12、s aspirin after cerebral ischemia of presumed arterial origin. ann neurol 1997; 42: 857-865.8 guidelines on oral anticoagulation: third edition. br j haematol 1998; 101: 374-387.9 hanley jp: warfarin reversal. j clin pathol 2004; 57: 1132-1139.10 ansell j, hirsh j, dalen j, bussey h, anderson d, pol

13、ler l，jacobson a, deykin d, matchar d: managing oral anticoagulant therapy. chest 2001; 119: 22s-38s.fl lbaker ri, coughlin pb, gallus as, harper pl, salem hh, wood em: warfarin reversal:consensus guidelines, on behalf of the australasian society of thrombosis and haemostasis. med j aust 2004; 181:4

14、92-497.12 nee r , doppenschmidt d , donovan dj 、et al. intravenous versus subcutaneousvitamine ki in reversing excessive oral anticoagulation. am j cardiol ,1999 ,83 (2) :28628x131 recommendations for the management of intracranial haemorrhage - part i: spontaneous intracerebral haemorrhage the euro

15、pean stroke initiative writing committee and the writing committee for the eusi executive committee. cerebrovasc dis. 2(x)6;22(4):294-316. epub 2006 jul 28.14董力,石应康,hi子朴，等.心脏机械瓣膜置换术后抗凝治疗中的颅内出血.中华胸心血管外科 杂志,2003, 19: 206.附：主要参考文献摘要:1 phan tg koh m, wijdicks ef: safety of discontinuation of anticoagula

16、tion in patients with intracranial hemorrhage at high thromboembolic risk. arch neurol 2000;57: 1710-1713background limited data are available to guide the management of anticoagulation in patients with intracranial hemorrhage (ich) at high thromboembolic risk.objective to review the management of a

17、nticoagulation in patients with ich at high thromboembolic risk.patients and methods we reviewed the management of anticoagulation in 141 patients who have a high risk of ischemic stroke and have ich while taking warfarin. the 30-day risk of ischemic stroke while not taking anticoagulation treatment

18、 was determined using kaplan-meier survival estimates.results the indications for anticoagulation were a prosthetic heart valve (52 patients group 1), atrial fibrillation and cardioembolic stroke (53 patients group 2), and a recurrent transient ischemic attack or an ischemic stroke (36 patients grou

19、p 3j). a prior ischemic stroke occurred in 14 (27%) of group 1 patients and in 23 (43%) of group 2 patients. death occurred in 43% of the 141 patients. the median time not taking warfarin in this cohort was 10 days. three patients had an ischemic stroke within 30 days of warfarin therapy discontinua

20、tion. using kaplan-meier survival estimates, the probability of having an ischemic stroke at 30 days following warfarin therapy cessation in groups 1, 2, and 3 was 2.9% (95% confidence interval, 0%-8.0%), 2.6% (95% confidence interval, 0%-7.6%), and 4.8% (95% confidence interval, 0%136%), respective

21、ly. in the 35 patients who had warfarin therapy restarted, none had recurrence of ich during the same hospitalization.conclusions discontinuation of warfarin therapy for 1 to 2 weeks has a comparatively low probability of embolic events in patients at high embolic risk. this should be taken into con

22、sideration when deciding whether to continue or discontinue anticoagulation in these patients at high embolic risk. early recurrence of ich is exceedingly uncommon.2 wijdicks ef;heublein dm;burnett jc jr jncrease and uncoupling of adrenomedullin from the natriuretic peptide system in aneurysmal suba

23、rachnoid hemorrhage. j neurosurg.2001,9(2):252-256object: natriuresis is a common systemic manifestation of aneurysmal subarachnoid hemorrhage (sah). natriuresis and its accompanying hypovolemia may be a major contributing factor in the pathophysiology of symptomatic cerebral vasospasm methods: the

24、authors studied 14 consecutive patients with aneurysmal sah and compared levels of adrenomedullin (adm), a novel endogenous natriuretic peptide that possesses additional profound vasodilatory properties, with the natriuretic peptide system twofold increase over control values, but no correlation was

25、 found with atrial natriuretic peptide (anp), brain natriuretic peptide (bnp), and c-natriuretic peptide (cnp) from the natriuretic peptide system at day 5 post-sah, adm levels were significantly elevated in patients with vasospasm documented angiographically or on transcranial doppler studies as co

26、mpared with those who suffered no vasospasm (mean 61.9 pg/ml compared with 15.3 pg/ml, p < 0.01).conclusions: the authors conclude that an elevation of adm in plasma may indicate a physiological regulatory attempt to induce cerebral vasodilation. the regulation of adm is uncoupled from anp, bnp,

27、and cnp. ananthasubramaniam k，beattie jn, rosman hs, jay am v, borzak s: how safely and for how long can warfarin therapy be withheld in prosthetic heart valve patients hospitalized with a major hemorrhage? chest 2001; 119: 478-484study objectives: to identify the risk of thromboembolism after withh

28、olding or reversing the effect of warfarin therapy following a major hemorrhage.design: retrospective medical record reviewsetting: tertiary-care hospital.patients: twenty-eight patients with prosthetic heart valves receiving warfarin were hospitalized for major hemorrhage from 1990 to 1997. the mea

29、n ± sd age was 61 ± 11 years (15 men and 13 women). twenty patients had st. jude valves, 4 patients had carpentier-edwards bioprosthetic valves, 2 patients had starr edwards valves, and 2 patients had bjork-shiley valves. valves were in the mitral position in 12 patients, the aortic positi

30、on in 12 patients, and both mitral and aortic positions in 4 patients. the average interval from valve surgery to index bleeding was 7 years. twenty-five patients had gi or retroperitoneal hemorrhage, 2 patients had an intracranial hemorrhage, and 1 patient had a subdural hematoma.interventions: vit

31、amin k was administered to five patients and fresh frozen plasma was given to seven patients to reverse anticoagulation. the mean duration of anticoagulation withholding was 15 ± 4 days.measurements and results: none of the patients had thromboembolic complications. there were four in-hospital

32、deaths. twenty-two of the 24 hospital survivors resumed warfarin therapy at hospital discharge. at 6-month follow-up, 10 of 19 patients remaining on warfarin therapy had recurrent gi bleeding.conclusions: thromboembolic risk is low in prosthetic heart valve patients hospitalized with major hemorrhag

33、e when their warfarin therapy is reversed or withheld recurrent bleeding within 6 months of the resumption of anticoagulation is common, and aggressive treatment of the bleeding source and the risk-benefit ratio of continued anticoagulation need to be considered4 bertram m, bonsanto m, hacke w, schw

34、ab s: managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulationj neurol 2000; 247: 209-214physicians face a therapeutic dilemma in patients with acute hemorrhagic stroke requiring long-term, high-intensity anticoagulants because this tre

35、atment increases the risk of intracranial hemorrhage (ich) to 11-fold. we retrospectively studied 15 patients withich which occurred under anticoagulation with phenprocoumon, with an international normalized ratio (inr) of 2.5-6.5 on admission. hemispheric, thalamic, cerebellar, intraventricular, or

36、 subarachnoid hemorrhage without aneurysm occurred. absolute indications for anticoagulation were double, mitral, or aortic valve replacement, combined mitral valve failure with atrial fibrillation and atrial enlargement, internal carotid artery jugular vein graft, frequently recurring deep vein thr

37、ombosis with risk of pulmonary embolism, and severe nontreatable ischemic heart disease. as soon as the diagnosis of ich was established, inr normalization was attempted in all patients by administration of prothrombin complex, fresh frozen plasma, or vitamin k after giving phenprocoumon antagonists

38、 (and neurosurgical therapy in four patients) heparin administration was started. nine patients received fulldose intravenous and six low-dose subcutaneous heparin. the following observations were made: (a) all patients with effective, full-dose heparin treatment with a 1.5- to 2-fold elevation in p

39、artial thromboplastin time after normalization of the inr were discharged without complication, (b) three of four of the patients with only incomplete correction of the inr (> 135) experienced relevant rebleeding within 3 days (all patients with an inr higher than 1.5), two of whom were on full-d

40、ose heparin, (c) three of seven of the patients with normalized inr and without significant ptt elevation developed severe cerebral embolism. although our data are based on a retrospective analysis, they support treatment with intravenous heparin (partial thromboplastin time 1.5-2 times baseline val

41、ue) after normalization of the inr in patients with an ich and an urgent need for anticoagulation.5 hart rg;boop bs;anderson dc. oral anticoagulants and intracranial hemorrhage. facts and hypotheses.stroke.1995.26:14711477.background: intracranial hemorrhage is the most feared and lethal complicatio

42、n of oral anticoagulation. we review the frequency, predictors, and prognosis of this most common neurological complication of oral anticoagulation. summary of review: anticoagulation to conventional intensities increases the risk of intracranial hemorrhage 7- to 10-fold, to an absolute rate of near

43、ly 1 %/y for many stroke-prone patients. most (70%) anticoagulant-related intracranial hemorrhages are intracerebral hematomas (approximately 60% are fatal); the bulk of the remainder are subdural hematomas- predictors of anticoagulant-related intracerebral hematoma are advanced patient age, prior i

44、schemic stroke, hypertension, and intensity of anticoagulation. in approximately half of anticoagulated patients with intracerebral hematoma the bleeding evolves slowly over 12 to 24 hours, and emergency reversal of anticoagulation is crucial. conclusion: both patient factors and anticoagulation int

45、ensity importantly influence the rate of anticoagulation-related intracranial hemorrhage patient-related risk factors for this complication overlap with those for ischemic stroke. the risk/benefit equation of anticoagulation for elderly, stroke-prone patients is complex and differs from that for you

46、nger patients. the absolute rate reduction (not the relative risk reduction) of ischemic stroke by anticoagulation is the critical issue and must offset accentuation of often lethal brain hemorrhage.6 steiner t, diringer m, rosand j: intracerebral hemorrhage associated with oral anticoagulanttherapy

47、: current practices and open questions. stroke 2006; 37: 256-62.background and purpose: life-threatening intracranial hemorrhage, predominantly intracerebral hemoithage (ich), is the most serious complication of oral anticoagulant therapy (oat), with mortality in excess of 50%. early intervention fo

48、cuses on rapid correction of coagulopathy in order to prevent continued bleeding. summary of review: this article reviews the epidemiology of oat-associated ich (oat-ich), and current treatment options, with the aim of providing a framework for future studies of unresolved questions a number of acut

49、e treatments are available, but all have a significant risk of inducing thrombosis and other side effects, and vary in their rapidity of effect: vitamin k (very slow response time), fresh frozen plasma (slow response time, large volume of fluid required, transfusion-related acute lung injury), proth

50、rombin complex concentrates, and recombinant activated factor vii. cuitent practice is to adininister a combination of vitamin k and either fresh frozen plasma or prothrombin complex concentrates; the occasional use of recombinant activated factor vii has been reported. no prospective study has addr

51、essed the efficacy of, or outcomes from, the use of these practices. conclusions: current management of oat-ich is varied and not based on evidence from randomized controlled trials. well-designed clinical trials are essential if we are to identify the effective acute treatments for oat-ich that are

52、 urgently needed7 the stroke prevention in reversible ischemia trial (spirit) study group: a randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. ann neurol 1997; 42: 857-8砧.aspirin is only modestly effective in the secondary prevention after cerebra

53、l ischemia. studies in other vascular disorders suggest that anticoagulant drugs in patients with cerebral ischemia of presumed arterial (noncardiac) origin might be more effective. the aim of the stroke prevention in reversible ischemia trial (spirit) therefore was to compare the efficacy and safet

54、y of 30 mg aspirin daily and oral anticoagulation (international normalized ratio inr 3.0-4.5). patients referred to a neurologist in one of 58 collaborating centers because of a transient ischemic attack or minor ischemic stroke (rankin grade $3) were eligible. randomization was concealed, treatmen

55、t assignment was open, and assessment of outcome events was masked. the primary measure of outcome was the composite event " death from all vascular causes, nonfatal stroke, nonfatal myocardial infarction, or nonfatal major bleeding complication." the trial was stopped at the first interim

56、 analysis. a total of 1,316 patients participated; their mean follow-up was 14 months. there was an excess of the primary outcome event in the anticoagulated group (81 of 651) versus 36 of 665 in the aspirin group (hazard ratio, 2.3; 95% confidence interval |cij, 1.6-3.5). this excess could be attri

57、buted to 53 major bleeding complications (27 intracranial; 17 fatal) during anticoagulant therapy versus 6 on aspirin (3 intracranial; 1 fatal). the bleeding incidence increased by a factor of 1.43 (95% ci, 0.96-2.13) for each 0.5 unit increase of the achieved inr anticoagulant therapy with an inr r

58、ange of 3.0 to 4.5 in patients after cerebral ischemia of presumed arterial origin is not safe the efficacy of a lower intensity anticoagulation regimen remains to be determined baglin tp;keeling dm;watson hg guidelines on oral anticoagulation (warfarin): third edition-2005 update.2006,132(3),277-28

59、59 hanley jp: warfarin reversal. j clin pathol 2004; 57: 1132-1139.warfarin is the most commonly used oral anticoagulant in the uk it is associated with few side effects apart from haemorrhage the most appropriate way to reverse the anticoagulant effect of warfarin depends on the clinical circumstances. in serious bleeding, rapid reversal is required, whereas in minor bleedin