不同剂量尼莫地平动脉内灌注治疗蛛网膜下腔出血后脑血管痉挛的实验研究
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摘要
目的:蛛网膜下腔出血(SAH)后脑血管痉挛(CVS)是颅内动脉瘤病人高死亡率和致残率的主要原因,CVS的主要危害是导致脑缺血缺氧性损害,但目前对CVS机理及导致脑损害的相关基础尚未完全阐明,缺乏有效的防治手段。大量的临床和基础研究表明“钙超载”是诱发SAH后CVS的重要环节之一,而具有舒张血管功能及神经保护作用的Ca离子拮抗剂一一尼莫地平(nimodipine)是防治SAH后CVS疗效肯定的药物之一。为此,我们采用实验性兔SAH模型,评价动脉内灌注尼莫地平治疗SAH后CVS的疗效以及剂量的选择。
方法:采用“枕大池二次注血法”制备兔SAH后CVS模型,两次注血间隔48小时,每次注血1ml置换出等量脑脊液(CSF)。随机将80只纯种新西兰大白兔分成4大组,每组20只,均用枕大池二次注血法建立CVS模型,其中3组分别用低、中、高三种不同剂量的尼莫地平行选择性动脉灌注治疗,另一组的20只新西兰兔作为对照,仅用动脉灌注生理盐水治疗。通过行为学、HE染色和脑血管造影等方法。
结果:尼莫地平组兔神经功能状况明显好于对照组。尼莫地平中、高剂量组与尼莫地平低剂量组相比,治疗效果有显著性差异,其能更有效的治疗CVS (P<0.05),尼莫地平中、高剂量组之间在治疗有效率上未见明显差异。基底病理学检查进一步证实血管痉挛的发生通过动脉灌注治疗,可以显著减少CVS引起的脑神经细胞凋亡。
结论:尼莫地平选择性动脉灌注能够有效的缓解和治疗CVS的临床症状,并能够有效的缓解CSV引起的大脑病理损伤和凋亡。中剂量组已达到治疗效果,增加剂量无意义。
Objective: Cerebral vasospasm(CVS) following subarachnoid hemorrhage(SAH) is a major cause of high mortality and morbitidy for those experiencing the rupture of intracranial aneurysm, and it often induces ischemic neurological deficits. but its ture mechanism secondary impairment still remain unclear, and there is no effective method to prevent and treat CVS. Lots of clinical and experimental studies have showd that“calcium over loading”is one important cause of cerebral vasospasm following subarachnoid hemorrhage. Antagon of calcium一nimodipine, with the effect of vessels--dilation and neuroprotection is effective in preventing cerebral vasospasm following subarachnoid hemorrhage. In the present study we assessed the anti--CVS effect of intraarterial infusion nimodipine and choosed appropriate doses of nimodpine in a rabbit mode1 of subarachnoid hemorrhage.
Method: CVS model was established by using“double subrachnoid hemohrrage, Which injecting arterial blood twice through the citerna magna 48 hours apart,1 millilter each time. Eighty rabbits were equally randomized to four groups,there are twenty rabbits in each group. Three of all were treated by using intraarterial infusion different doses of nimodipine, the other is control group with infusing physiological saline . we observed the behavior changes, moprhological changes and the result of selective angiography of the vertebral artery.
Result: Nerve function of the rabbits of nimodipine group were better obviously than the rabbits of control group. The middle and high doses nimodipine groups have marked efficiency than the low doses nimodipine group in preventing CVS of SAH(P<0.05). Both of middle and high doses nimodipine groups have not apparently different in preventing CVS of SAH. The pathological study revealed that the selective arterial perfusion of nimodipine could reduce the apoptosis of cerebral nerve induced by CVS.
Conclusion: Selective vertebral arterial perfusion of nimodipine could greatly resolve the CVS both clinically and pathologically. The middle doses nimodipine is best.
方法:采用“枕大池二次注血法”制备兔SAH后CVS模型,两次注血间隔48小时,每次注血1ml置换出等量脑脊液(CSF)。随机将80只纯种新西兰大白兔分成4大组,每组20只,均用枕大池二次注血法建立CVS模型,其中3组分别用低、中、高三种不同剂量的尼莫地平行选择性动脉灌注治疗,另一组的20只新西兰兔作为对照,仅用动脉灌注生理盐水治疗。通过行为学、HE染色和脑血管造影等方法。
结果:尼莫地平组兔神经功能状况明显好于对照组。尼莫地平中、高剂量组与尼莫地平低剂量组相比,治疗效果有显著性差异,其能更有效的治疗CVS (P<0.05),尼莫地平中、高剂量组之间在治疗有效率上未见明显差异。基底病理学检查进一步证实血管痉挛的发生通过动脉灌注治疗,可以显著减少CVS引起的脑神经细胞凋亡。
结论:尼莫地平选择性动脉灌注能够有效的缓解和治疗CVS的临床症状,并能够有效的缓解CSV引起的大脑病理损伤和凋亡。中剂量组已达到治疗效果,增加剂量无意义。
Objective: Cerebral vasospasm(CVS) following subarachnoid hemorrhage(SAH) is a major cause of high mortality and morbitidy for those experiencing the rupture of intracranial aneurysm, and it often induces ischemic neurological deficits. but its ture mechanism secondary impairment still remain unclear, and there is no effective method to prevent and treat CVS. Lots of clinical and experimental studies have showd that“calcium over loading”is one important cause of cerebral vasospasm following subarachnoid hemorrhage. Antagon of calcium一nimodipine, with the effect of vessels--dilation and neuroprotection is effective in preventing cerebral vasospasm following subarachnoid hemorrhage. In the present study we assessed the anti--CVS effect of intraarterial infusion nimodipine and choosed appropriate doses of nimodpine in a rabbit mode1 of subarachnoid hemorrhage.
Method: CVS model was established by using“double subrachnoid hemohrrage, Which injecting arterial blood twice through the citerna magna 48 hours apart,1 millilter each time. Eighty rabbits were equally randomized to four groups,there are twenty rabbits in each group. Three of all were treated by using intraarterial infusion different doses of nimodipine, the other is control group with infusing physiological saline . we observed the behavior changes, moprhological changes and the result of selective angiography of the vertebral artery.
Result: Nerve function of the rabbits of nimodipine group were better obviously than the rabbits of control group. The middle and high doses nimodipine groups have marked efficiency than the low doses nimodipine group in preventing CVS of SAH(P<0.05). Both of middle and high doses nimodipine groups have not apparently different in preventing CVS of SAH. The pathological study revealed that the selective arterial perfusion of nimodipine could reduce the apoptosis of cerebral nerve induced by CVS.
Conclusion: Selective vertebral arterial perfusion of nimodipine could greatly resolve the CVS both clinically and pathologically. The middle doses nimodipine is best.
引文
[1] Janjua N.Mayer SA Cerebral vasospasm after subarachnoidhemorrhage. Cur Opin Crit Care.2003,9(2):I13一l l9.
[2] Biller J, Godersky JC, Adams HP Jr Management of aneurismal subarachnoid hemorrhage. Stroke,l988,l9(1O):1300—1305.
[3]Meyer FB.Calcium antagonists and vasospasm[J].Neurosurg Clin NAm,l990,1(2):367-376
[4]易声禹,费舟,徐如祥.尼莫地平救治重型颅腑损伤的理论基础与临床研究.中华神经外科杂志,1994,10(1):28-30.
[5]Gross PM, Wainman DS. Chew BH, et a1. Calcium-mediated metabolic stimulation of neuroendocrine structures by intraventricular endothelin—l in conscious rats. Brain Res,l 993,606(1):135-142.
[6]Gross PM, Beninger RJ, Shaver SW , et a1. M etabolic and neuroanatomical corelates of barel—rolling and oculoclonic convulsions induced by intraventricular endothelin-I: a novel peptidergic signaling mechanism in visuovestibular and oculomotor regulation.Exp Brain Res,1993,95(3):397—408.
[7]Gross PM, Zochodne DW , Wainman DS, et a1. Intraventricular endothelin一1 uncouples the blood flow: metabolism relationship in periventricular structures of the rat brain:involvement of L-type calcium channels.[J].Neuropeptides,l992,22(3):155-l65.
[8] Zhang Q, Jiang X, Jiang W, et a1. Preparation of nimodipine-loaded microemulsion for intranasal delivery and evaluation on the targeting eficiency to the brain.1nt J Pharm,2004,275(1-2):85-96.
[9]Endo S, Branson PJ, A lksne JF. Experimental model of symptomatic vasospasm in rabbits. J.Stroke, 1988, 19 (11):1420-1425.
[10]Liszczak TM, Varsos VG, Black PM, et al. Cerebral arterial constriction after experimental subarachnoid hemorrhage is associated with blood components within the arterial wall.J Neurosurg, 1983, 58(1):18-26.
[11]Touho H, Karasawa J, Ohnishi H, et al. Selective angiography of the vertebral artery in the rabbit:technical note. J SurgNeurol,1996, 46(1) : 84-86.
[12]Echlin. Spasm of basilar and vertebral arteries caused by experimengtal subarachnoid hemorrhage[J].JNeurosury,1965;23:1.
[13] Ozkan U, Aydin MD, Kemaloglu MS, et a1. Efect of nimodipine on histo1ogical alterations in basilar artery following the bilateral colnrfloll carotid artery ligation (preliminary study). Aeta edica(Hradec Kralove), 2004, 47(1): 7-12.
[14] Han DH, Lee S. Effect of nimodipine treatment on outcome in surgical cases of aneurysmal SAH. J Neurosurg, l993, 78: 346.
[15] Jacobson MD. Reactive oxygen species and programmed cell death. Trends Biochem Sci. 1996, 21(3): 83-86.
[16]秦怀洲,高国栋,赵振伟,等.实验性蛛网膜下腔出血后脑血管痉挛兔海马组织中Bel-2和Bax mRNA的表达.第四军医大学学报, 2003; 24(9): 776—778.
[17]白万胜,高国栋,赵振伟,等.兔脑血管痉挛后海马CA1区c-FOS表达及尼莫地平的神经保护作用.第四军医大学学报, 2003; 24(23): 2171—2174.
[18] Firat MM, Gelebek V, Orer HS, et al. Selective intraarterial nimodipine treatment in an experimental subarachnoid hemorrhage model. AJNR Am J Neuroradiol. 2005, 26(6): 1357-1362.
[19] Grotenhuis JA, Bettag W, Fiebach BJ, et al. Intracarotid slow bolus injection of nimodipine during angiography for treatment of cerebral vasospasm after SAH. A preliminary report. J Neurosurg, 1984, 61(2):231-240.
[20] B?ker DK, Solymosi L, Wassmann H. Immediate postangiographic intraarterial treatment of cerebral vasospasm after subarachnoid hemorrhage with nimodipine. Report on 3 cases. Neurochirurgia (Stuttg). 1985, 28 (Suppl 1):118-120.
[21] Oran I, Cinar C. ontinuous intra-arterial infusion of nimodipine during embolization of cerebral aneurysms associated with vasospasm. AJNR Am J Neuroradiol. 2008, (2):291-295.
[22] Hui C, Lau KP. Efficacy of intra-arterial nimodipine in the treatment of cerebral vasospasm complicating subarachnoid haemorrhage. Clin Radiol. 2005,60(9):1030-1036.
[23] H?nggi D, Turowski B, Beseoglu K, et al. Intra-Arterial Nimodipine for Severe Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage: Influence on Clinical Course and Cerebral Perfusion. AJNR Am J Neuroradiol. 2008, 27, [Epubahead of print]
[24] Auer LM, lto Z, Suzuki A, et al. Prevention of symptomatic vasospasm by topically applied nimodipine.Acta Neurochirurgica, l982, 63(1-4): 297-302.
[1] Levati A,Solaini C,Boselli L. Prevention and treatment of vasospasm, J Neurosurg Sci, 1998, 42(1 supply): 27-31.
[2] Biller J, Godersky JC, Adams HP. Management of aneurismal subarachnoid hemorrhage. Stroke, l988, l9(1O): 1300-1305.
[3] Meyer FB.Calcium antagonists and vasospasm.Neurosurg Clin Nam, l990, 1(2): 367-376.
[4] Mayberg MR, Batjer CHH, Dacey R, et al. Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage, A statement for healthcare professionals from a special writing group of the stroke council American Heart Association. Circulation,1994, 90: 2592-2605.
[5]易声禹,费舟,徐如祥.尼莫地平救治重型颅脑损伤的理论基础与临床研究.中华神经外科杂志,1994,10(1):28-30.
[6]于莹,赵从海,田宇.尼莫地平不同给药途径治疗蛛网膜下腔出血后脑血管痉挛.中华神经医学杂志,2005,4(3):314-316.
[7] Feigin VL, Rinkel GJ. Calcium antagonists in patients with aneurysmal subarachnoid hemorrhage: a systematic review. Neurology, 1998,50(4):876-883.
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[9] Treggiari-Venzi MM, Suter PM, Romand JA. Review of medical prevention of vasospasm after aneurysmal subarachnoid hemorrhage: a problem ofneurointensive care.Neurosurgery,200l,48(2): 249-26l.
[10] Auer LM, lto Z, Suzuki A, et al. Prevention of symptomatic vasospasm by topically applied nimodipine.Acta Neurochirurgica, l982, 63(1-4): 297-302.
[11] Dorhout Mees SM, Rinkel GJ, Feigin VL, et al. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2007, 18(3): 269-277.
[12]林敬明,吴忠,杨卫红.蛛网膜下腔出血后继发脑血管痉挛的血液流变学变化.广东药学院学报, 2001, 17(3):2l1-213.
[13]朱晓波,李虹彦,于金录,等.尼莫地平对兔蛛网膜下腔出血后症状性脑血管痉挛的影响.中国老年医学杂志2006, 9(26):1235-1237.
[14] Ozkan U, Aydin MD, Kemaloglu MS, et a1. Efect of nimodipine on histo-1ogical alterations in basilar artery following the bilateral colnrfloll carotid artery ligation (preliminary study). Aeta Medica(Hradec Kralove), 2004, 47(1): 7-12.
[15] Jacobson MD. Reactive oxygen species and programmed cell death. Trends Biochem Sci. 1996, 21(3): 83-86.
[16]秦怀洲,高国栋,赵振伟,等.实验性蛛网膜下腔出血后脑血管痉挛兔海马组织中Bel-2和Bax mRNA的表达.第四军医大学学报, 2003; 24(9): 776—778.
[17]白万胜,高国栋,赵振伟,等.兔脑血管痉挛后海马CA1区c-FOS表达及尼莫地平的神经保护作用.第四军医大学学报, 2003; 24(23): 2171—2174.
[18] Pickard JD, Muray GD, Illingworth R, et a1. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorhage:British aneurysm nimodipine trial.Br Med J Clin Res, l989, 298(6674): 636-642.
[19] Han DH, Lee S. Effect of nimodipine treatment on outcome in surgical cases ofaneurysmal SAH. J Neurosurg, l993, 78: 346.
[20] Neil-Dwyer G, Mee E, Dorance D, et al. Early intervention with nimodipine in subarachnoid haemorhage. Eur Heart J, l987, 8 (Suppl 1); 4l-47.
[21] Petruk KC, West M, Mohr G, et al. Nimodipine treatment in poor grade aneurysm patients. J Neurosurg, 1988, 68(4); 505-5l7.
[22] Allen GS, Ahn HS, Preziosi TJ, et al. Cerebral arterial spasm: a controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med, l983, 308(11); 6l9-624.
[23] Porchet F, Chiolero R, de Tribolet N. Hypotensive effect of nimodipine during treatment for aneurysmal subarachnoid hemorrhage. Acta Neurochirurgica,l995, 137(1-2): 62-69.
[24]徐如祥,陈长才,杨俊,等.钙拮抗剂尼莫地平救治重型颅脑损伤的临床研究.解放军医学杂志,l997,22(2):102-104.
[25] Auer LM. Acute surgery of cerebral aneurysms and prevention of symptomatic vasospasm. Acta Neurochirurgica, 1983, 69(3-4):273-281.
[26] Auer LM, Brandt L, Ebeling U, et a1. Nimodipine and early aneurysm operation in good condition SAH patients. Acta Neurochirurgica, l986, 82(1-2):7-13.
[27] Gross PM, Wainman DS, Chew BH, et a1. Calcium-mediated metabolic stimulation of neuroendocrine structures by intraventricular endothelin-l in conscious rats. Brain Res, l993, 606(1): 135-142.
[28] Gross PM, Beninger RJ, Shaver SW, et a1. M etabolic and neuroanatomical corelates of barel—rolling and oculoclonic convulsions in duced by intraventricular endothelin-I; a novel peptidergic signaling mechanism in visuovestibular and oculomotor regulation. Exp Brain Res,1993,95(3):397-408.
[29] Gioia AE, White RP, Bakhtian B, et a1. Evaluation of the efficacy of intrathecal nimodipine in canine models of chronic cerebral vasospasm. J Neurosurg, 1985, 62(5):72l-728.
[30] Marbacher S, Neuschmelting V, Graupner T, et al. Prevention of delayed cerebral vasospasm by continuous intrathecal infusion of glyceroltrinitrate and nimodipine in the rabbit model in vivo. Intensive Care Med. 2008,24.
[31] Firat MM, Gelebek V, Orer HS, et al. Selective intraarterial nimodipine treatment in an experimental subarachnoid hemorrhage model.AJNR Am J Neuroradiol. 2005, 26(6):1357-1362.
[32] Grotenhuis JA, Bettag W, Fiebach BJ, et al. Intracarotid slow bolus injection of nimodipine during angiography for treatment of cerebral vasospasm after SAH. A preliminary report. J Neurosurg, 1984, 61(2):231-240.
[33] B?ker DK, Solymosi L, Wassmann H. Immediate postangiographic intraarterial treatment of cerebral vasospasm after subarachnoid hemorrhage with nimodipine. Report on 3 cases. Neurochirurgia (Stuttg). 1985, 28 (Suppl 1):118-120.
[34] Oran I, Cinar C. ontinuous intra-arterial infusion of nimodipine during embolization of cerebral aneurysms associated with vasospasm. AJNR Am J Neuroradiol. 2008, (2):291-295.
[35] Hui C, Lau KP. Efficacy of intra-arterial nimodipine in the treatment of cerebral vasospasm complicating subarachnoid haemorrhage. Clin Radiol. 2005,60(9):1030-1036.
[36] H?nggi D, Turowski B, Beseoglu K, et al. Intra-Arterial Nimodipine for Severe Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage: Influence onClinical Course and Cerebral Perfusion. AJNR Am J Neuroradiol. 2008, 27, [Epub ahead of print]
[37] Zhang Q,Jiang X,Jiang W, et a1. Preparation of nimodipine-loaded microemulsion for intranasal delivery and evaluation on the targeting efficiency to the brain.Int J Pharm,2004.275(1-2):85-96.
[2] Biller J, Godersky JC, Adams HP Jr Management of aneurismal subarachnoid hemorrhage. Stroke,l988,l9(1O):1300—1305.
[3]Meyer FB.Calcium antagonists and vasospasm[J].Neurosurg Clin NAm,l990,1(2):367-376
[4]易声禹,费舟,徐如祥.尼莫地平救治重型颅腑损伤的理论基础与临床研究.中华神经外科杂志,1994,10(1):28-30.
[5]Gross PM, Wainman DS. Chew BH, et a1. Calcium-mediated metabolic stimulation of neuroendocrine structures by intraventricular endothelin—l in conscious rats. Brain Res,l 993,606(1):135-142.
[6]Gross PM, Beninger RJ, Shaver SW , et a1. M etabolic and neuroanatomical corelates of barel—rolling and oculoclonic convulsions induced by intraventricular endothelin-I: a novel peptidergic signaling mechanism in visuovestibular and oculomotor regulation.Exp Brain Res,1993,95(3):397—408.
[7]Gross PM, Zochodne DW , Wainman DS, et a1. Intraventricular endothelin一1 uncouples the blood flow: metabolism relationship in periventricular structures of the rat brain:involvement of L-type calcium channels.[J].Neuropeptides,l992,22(3):155-l65.
[8] Zhang Q, Jiang X, Jiang W, et a1. Preparation of nimodipine-loaded microemulsion for intranasal delivery and evaluation on the targeting eficiency to the brain.1nt J Pharm,2004,275(1-2):85-96.
[9]Endo S, Branson PJ, A lksne JF. Experimental model of symptomatic vasospasm in rabbits. J.Stroke, 1988, 19 (11):1420-1425.
[10]Liszczak TM, Varsos VG, Black PM, et al. Cerebral arterial constriction after experimental subarachnoid hemorrhage is associated with blood components within the arterial wall.J Neurosurg, 1983, 58(1):18-26.
[11]Touho H, Karasawa J, Ohnishi H, et al. Selective angiography of the vertebral artery in the rabbit:technical note. J SurgNeurol,1996, 46(1) : 84-86.
[12]Echlin. Spasm of basilar and vertebral arteries caused by experimengtal subarachnoid hemorrhage[J].JNeurosury,1965;23:1.
[13] Ozkan U, Aydin MD, Kemaloglu MS, et a1. Efect of nimodipine on histo1ogical alterations in basilar artery following the bilateral colnrfloll carotid artery ligation (preliminary study). Aeta edica(Hradec Kralove), 2004, 47(1): 7-12.
[14] Han DH, Lee S. Effect of nimodipine treatment on outcome in surgical cases of aneurysmal SAH. J Neurosurg, l993, 78: 346.
[15] Jacobson MD. Reactive oxygen species and programmed cell death. Trends Biochem Sci. 1996, 21(3): 83-86.
[16]秦怀洲,高国栋,赵振伟,等.实验性蛛网膜下腔出血后脑血管痉挛兔海马组织中Bel-2和Bax mRNA的表达.第四军医大学学报, 2003; 24(9): 776—778.
[17]白万胜,高国栋,赵振伟,等.兔脑血管痉挛后海马CA1区c-FOS表达及尼莫地平的神经保护作用.第四军医大学学报, 2003; 24(23): 2171—2174.
[18] Firat MM, Gelebek V, Orer HS, et al. Selective intraarterial nimodipine treatment in an experimental subarachnoid hemorrhage model. AJNR Am J Neuroradiol. 2005, 26(6): 1357-1362.
[19] Grotenhuis JA, Bettag W, Fiebach BJ, et al. Intracarotid slow bolus injection of nimodipine during angiography for treatment of cerebral vasospasm after SAH. A preliminary report. J Neurosurg, 1984, 61(2):231-240.
[20] B?ker DK, Solymosi L, Wassmann H. Immediate postangiographic intraarterial treatment of cerebral vasospasm after subarachnoid hemorrhage with nimodipine. Report on 3 cases. Neurochirurgia (Stuttg). 1985, 28 (Suppl 1):118-120.
[21] Oran I, Cinar C. ontinuous intra-arterial infusion of nimodipine during embolization of cerebral aneurysms associated with vasospasm. AJNR Am J Neuroradiol. 2008, (2):291-295.
[22] Hui C, Lau KP. Efficacy of intra-arterial nimodipine in the treatment of cerebral vasospasm complicating subarachnoid haemorrhage. Clin Radiol. 2005,60(9):1030-1036.
[23] H?nggi D, Turowski B, Beseoglu K, et al. Intra-Arterial Nimodipine for Severe Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage: Influence on Clinical Course and Cerebral Perfusion. AJNR Am J Neuroradiol. 2008, 27, [Epubahead of print]
[24] Auer LM, lto Z, Suzuki A, et al. Prevention of symptomatic vasospasm by topically applied nimodipine.Acta Neurochirurgica, l982, 63(1-4): 297-302.
[1] Levati A,Solaini C,Boselli L. Prevention and treatment of vasospasm, J Neurosurg Sci, 1998, 42(1 supply): 27-31.
[2] Biller J, Godersky JC, Adams HP. Management of aneurismal subarachnoid hemorrhage. Stroke, l988, l9(1O): 1300-1305.
[3] Meyer FB.Calcium antagonists and vasospasm.Neurosurg Clin Nam, l990, 1(2): 367-376.
[4] Mayberg MR, Batjer CHH, Dacey R, et al. Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage, A statement for healthcare professionals from a special writing group of the stroke council American Heart Association. Circulation,1994, 90: 2592-2605.
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