Neurological Surgery 脳神経外科45巻3号

2017年03月発行

脳神経外科診療に役立つ薬物療法の知識

脳血管攣縮に対する薬物療法

著者： 菱川朋人¹ 伊達勲¹

所属機関： ¹岡山大学大学院医歯薬学総合研究科脳神経外科

ページ範囲：P.265 - P.270

Ⅰ．はじめに
　脳血管攣縮は，くも膜下腔に広がった血液によって，くも膜下出血発症から4〜14日後に惹起される脳主幹動脈の可逆的かつ数日ないし数週間にわたる持続的血管狭窄を意味する．症候性脳血管攣縮は，くも膜下出血発症から4〜14日後に，頭蓋内疾患や全身状態の悪化をはじめとする，他に原因を求めることができない脳の巣症状，麻痺，意識障害などが出現した状態で，かつ脳血管攣縮が確認された場合と定義される²⁵⁾．脳血管攣縮は脳血管撮影上約30〜70%に認められ，症候性脳血管攣縮は約20〜30%に認められる．くも膜下出血の死亡率は低下傾向にあるものの，死亡原因としての脳血管攣縮の占める割合は5〜6%であり，経年的に変化を認めていないのが現状である²⁹⁾．
　脳血管攣縮の病因に関する研究は，種々の観点から盛んに行われ50年以上の歴史を有するが，いまだその全貌が解明されるに至っていない¹⁴⁾（Table1）．病因が多様であるため，脳血管攣縮に対する根本的な治療法は存在せず，くも膜下出血発症後2週間は薬物療法，髄液管理，全身管理，血管内治療を組み合わせた対症療法を行い，脳血管攣縮を克服するしかないのが現状である．なかでも薬物療法は脳血管攣縮の治療の柱の1つであり，十分精通する必要がある．本稿では脳血管攣縮に対する薬物療法について言及している文献をレビューし，最新のトピックスを含めて解説する．

参考文献

1) Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J：Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev：CD000277, 2007

2) Dorhout Mees SM, van den Bergh WM, Algra A, Rinkel GJ：Antiplatelet therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev：CD006184, 2007

3) Dorhout Mees SM, Algra A, Vandertop WP, van Kooten F, Kuijsten HA, Boiten J, van Oostenbrugge RJ, Al-Shahi Salman R, Lavados PM, Rinkel GJ, van den Bergh WM；MASH-2 study group：Magnesium for aneurysmal subarachnoid haemorrhage（MASH-2）:a randomised placebo-controlled trial. Lancet 380：44-49, 2012

4) Haley EC Jr, Kassell NF, Torner JC：A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg 78：537-547, 1993

5) Hishikawa T, Takasugi Y, Shimizu T, Haruma J, Hiramatsu M, Tokunaga K, Sugiu K, Date I：Cerebral vasospasm in patients over 80 years treated by coil embolization for ruptured cerebral aneurysms. Biomed Res Int 2014：253867, 2014

6) Hishikawa T, Date I, Tokunaga K, Tominari S, Nozaki K, Shiokawa Y, Houkin K, Murayama Y, Ishibashi T, Takao H, Kimura T, Nakayama T, Morita A；For UCAS Japan and UCAS Ⅱ Investigators：Risk of rupture of unruptured cerebral aneurysms in elderly patients. Neurology 85：1879-1885, 2015

7) Jang YG, Ilodigwe D, Macdonald RL：Metaanalysis of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care 10：141-147, 2009

8) Kasuya H, Onda H, Sasahara A, Takeshita M, Hori T：Application of nicardipine prolonged-release implants：analysis of 97 consecutive patients with acute subarachnoid hemorrhage. Neurosurgery 56：895-902, 2005

9) Kramer AH, Fletcher JJ：Statins in the management of patients with aneurysmal subarachnoid hemorrhage：a systematic review and meta-analysis. Neurocrit Care 12：285-296, 2010

10) Lannes M, Teitelbaum J, del Pilar Cortés M, Cardoso M, Angle M：Milrinone and homeostasis to treat cerebral vasospasm associated with subarachnoid hemorrhage：the Montreal Neurosurgical Hospital protocol. Neurocrit Care 16：354-362, 2012

11) Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, Frey A, Roux S, Pasqualin A；CONSCIOUS-1 Investigators：Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage（CONSCIOUS-1). Randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke 39：3015-3021, 2008

12) Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Bach D, Frey A, Marr A, Roux S, Kassell N：Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping：a randomised, double-blind, placebo-controlled phase 3 trial（CONSCIOUS-2). Lancet Neurol 10：618-625, 2011

13) Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, Vajkoczy P, Wanke I, Bach D, Frey A, Nowbakht P, Roux S, Kassell N：Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke 43：1463-1469, 2012

14) 森　健太郎：混迷する脳血管攣縮の研究と治療．脳卒中の外科44：102-112, 2016

15) Mukherjee KK, Singh SK, Khosla VK, Mohindra S, Salunke P：Safety and efficacy of sildenafil citrate in reversal of cerebral vasospasm：a feasibility study. Surg Neurol Int 3：3, 2012

16) Munakata A, Ohkuma H, Nakano T, Shimamura N, Asano K, Naraoka M：Effect of a free radical scavenger, edaravone, in the treatment of patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 64：423-429, 2009

17) 日本脳卒中学会脳卒中ガイドライン委員会（編）：脳卒中治療ガイドライン2015，協和企画，東京，2015，pp205-208

18) Niu PP, Yang G, Xing YQ, Guo ZN, Yang Y：Effect of cilostazol in patients with aneurysmal subarachnoid hemorrhage：a systematic review and meta-analysis. J Neurol Sci 336：146-151, 2014

19) Numaguchi Y, Zoarski GH, Clouston JE, Zagardo MT, Simard JM, Aldrich EF, Sloan MA, Maurer PK, Okawara SH：Repeat intra-arterial papaverine for recurrent cerebral vasospasm after subarachnoid haemorrhage. Neuroradiology 39：751-759, 1997

20) 小野成紀，伊達　勲，大本堯史：脳血管攣縮における情報伝達の遺伝子発現．No Shinkei Geka 29：589-602, 2001

21) Origitano TC, Wascher TM, Reichman OH, Anderson DE：Sustained increased cerebral blood flow with prophylactic hypertensive hypervolemic hemodilution（“triple-H” therapy）after subarachnoid hemorrhage. Neurosurgery 27：729-740, 1990

22) Sadamasa N, Yoshida K, Narumi O, Chin M, Yamagata S：Milrinone via lumbar subarachnoid catheter for vasospasm after aneurysmal subarachnoid hemorrhage. Neurocrit Care 21：470-475, 2014

23) Shankar JJ, dos Santos MP, Deus-Silva L, Lum C：Angiographic evaluation of the effect of intra-arterial milrinone therapy in patients with vasospasm from aneurysmal subarachnoid hemorrhage. Neuroradiology 53：123-128, 2011

24) Shibuya M, Suzuki Y, Sugita K, Saito I, Sasaki T, Takakura K, Nagata I, Kikuchi H, Takemae T, Hidaka H, Nakashima M：Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Results of a prospective placebo-controlled double-blind trial. J Neurosurg 76：571-577, 1992

25) Shirao S, Yoneda H, Ishihara H, Kajiwara K, Suzuki M；Survey Study Members of Japan Neurosurgical Society：A proposed definition of symptomatic vasospasm based on treatment of cerebral vasospasm after subarachnoid hemorrhage in Japan：Consensus 2009, a project of the 25 Spasm Symposium. Surg Neurol Int 2：74, 2011

26) Tachibana E, Harada T, Shibuya M, Saito K, Takayasu M, Suzuki Y, Yoshida J：Intra-arterial infusion of fasudil hydrochloride for treating vasospasm following subarachnoid haemorrhage. Acta Neurochir（Wien）141：13-19, 1999

27) Tokiyoshi K, Ohnishi T, Nii Y：Efficacy and toxicity of thromboxane synthetase inhibitor for cerebral vasospasm after subarachnoid hemorrhage. Surg Neurol 36：112-118, 1991

28) Treggiari MM, Walder B, Suter PM, Romand JA：Systematic review of the prevention of delayed ischemic neurological deficits with hypertension, hypervolemia, and hemodilution therapy following subarachnoid hemorrhage. J Neurosurg 98：978-984, 2003

29) Vergouwen MD, Jong-Tjien-Fa AV, Algra A, Rinkel GJ：Time trends in causes of death after aneurysmal subarachnoid hemorrhage：a hospital-based study. Neurology 86：59-63, 2016

30) Yamamoto T, Mori K, Esaki T, Nakao Y, Tokugawa J, Watanabe M：Preventive effect of continuous cisternal irrigation with magnesium sulfate solution on angiographic cerebral vasospasms associated with aneurysmal subarachnoid hemorrhages：a randomized controlled trial. J Neurosurg 124：18-26, 2016

31) Yoneda H, Shirao S, Nakagawara J, Ogasawara K, Tominaga T, Suzuki M：A prospective, multicenter, randomized study of the efficacy of eicosapentaenoic acid for cerebral vasospasm：The EVAS study. World Neurosurg 81：309-315, 2014