第六章 討論
第二節 建議
經過此次研究結果顯示在人體顱內動脈瘤破裂產生蜘蛛膜下腔出血的 臨床病人中發維生素 C、維生素 E 和 TBARS，在早期(第一天)就可以有明顯
的改變，所以可以推論自由基在顱內動脈瘤破裂的早期就立刻產生並發生 作用；而此次所採用三十七位臨床病人中也有十位病患(27%)，經血管攝影 檢查已經可以發現有早期(兩天內)就有血管痙攣的現象。
根據以上的結論，臨床上在治療對於顱內動脈瘤破裂產生蜘蛛膜下腔 出血的病人，可以考慮在發病時立即採用對抗自由基的藥物，包括維生素 C 和維生素 E 等來降低脂質過氧化反應來治療，尤其有血管痙攣的病人更應 及早給予對抗自由基的藥物治療。
至於進一步的臨床研究未來可以將顱內動脈瘤破裂產生蜘蛛膜下腔出 血的病人分為兩組用前瞻性的研究方法，以維生素 C 和維生素 E 的分別投 與與否，比較其血管痙攣及預後程度。
參 考 文 獻
Allcock JM, Drake CG (1965) Reptured intracranial aneurysms-the role of arterial spasm. J Neurosurg 22: 21-29
Allen GS (1985) Cerebral arterial spasm. Clin Neurosurg. 32-70
Asano T, Sasaki T, Koide T, Takakura K, Sano K (1984) Experimental evaluation of the beneficial effect of an antioxidant on cerebral vasospasm. Neuro. Res. 6:49-53
Banks MA,(1997) Vitamin E and polyunsaturated fats：antioxidant and peroxidant relationship. Baskin SI, Salem H eds. Oxidants, antioxidants, and free radical. Taylor and Francis.95-112
Barrows LJ, Hunter FT, Banker BQ (1955) The nature and clinical significance of pigments in the cerebrospinal fluid. Brain 78:59-80
Boscoboinik D, Szewczyk A, Azzi A (1990) Alfa-tocopherol (vitamin E) regulates vascular smooth muscle cell proliferation and protein kinase C activity. Arch Biochem Biophys. 286:264.
Cafe C, Torri C, Bertorelli F, Tartara F, et al. (1995) Free Rad Biol Med. 19:853-857
Carr A, Frei B (1999) Dose vitamin C act an pro-oxidant under physiological conditions. FASEB J. 13:1007-1024.
Cook DA, Weir BKA, Okwuasaba FK, Krueger CA (1979) Effects of hemoglobin on smooth muscle. Proc West Pharmacol Soc. 22:429-434
Edlow JA, Caplan CR (2000) Avoiding pitfalls in the diagnosis of SAH.
N. England Journal of Medicine. 342:29-36.
Faruqi R. de. Motta, Dicorleto P (1994) Alpha-tocopherol inhibitors agonist-induced monocrtic cell adhesion to cultured human endothelial cells. J. Clin. Invest. 94:592-600.
Findlay JM, Macdonald RL, Weir BKA (1991) Current concepts of
pathophysiology and management of cerebral vasospasm following aneurismal Subarachnoid hemorrhage. Cerebrovasc. Brain Metab. Rev.
3:336-361
Frei B (1999) Molecular and biological mechanisms of antioxidant action. FASEB J. 13.
Frei B, England L, Ames BN (1989) Ascorbate is an outstanding antioxidant in human blood plasma. PNAS. 86:6377-6381.
Frei B, Stocker R, Ames BN (1988) Antioxidant defenses and lipid peroxidation in human blood plasma. Proc. Natl. Acad. Sci USA . 85:
9748-9752
Glascott PA, Tsyganskaya M, Gilfor E, Zern,M A , Farber JL (1996) The antioxidant function of the physiological cantent of vitamin C. Mol Pharmacol. 50:994-999.
Ham AJL, Liebler DC (1997) Antioxidant reaction of vitamin E in the perfused rat liver: product distribution and effect of dietary vitamin E supplementation. Arch Biochem Biophys. 339:157-164.
Helen A, Vijayammal PL (1997) Vitamin C supplementation on hepatic oxidative stress induce by cigarette smoke. J Appl Toxicol. 17:
289-295.
Iuliano BA, Pluta RM, Jung C, et al. (2004) Endothelial dysfunction in a primate model of cerebral vasospasm. J Neurosurg. 100:287-294
Jacob RJ, Burri BJ (1996) Oxidative damage and defense. Am J Clin Nutr. 63:985-990.
Kamiyama K, Okada H, Suzuki J (1981) The relation between cerebral vasospasms and super oxide. Application of an experimental model of vasospasms induced by oxyhemoglobin in cats. Neurol. Med. Chir.
(Tokyo) 21:201-209
Kassell NF, Sasaki T, Colohan ART, Nazar G (1985): Cerebral vasospasm following aneurismal subarachnoid hemorrhage. Stroke.16:562-572.
Kassell NF, Torner JC（1983）: Aneurysmal rebleeding : A preliminary
report from the cooperative aneurysm study . Neurosurgery. 13:479
Kassell NF, Drake CG（1982）：Timing of aneurysm surgery . Neurosurgery.
10:514
Kavanagh RJ, Kam PCA (2001) Lazaroids : efficacy and mechanism of action of the 21-aminosteroids in neuroprotection. British J. of Anaesthesia. 86:110-119
Keaney JF, Simon DI, Freedman JE (1999) Vitamin E and vascular homeostasis: implications atherosclerosis. FASEB J . 13:965-976
Laureaux C , Therond P, Rousselot DB, Troupel SE, Legrand A, Delattre J (1997)
α
-tocopherol enrichment of high-density lipoproteins:stabilization of hydroperoxides produced during copper oxidation.
Free Rad Biol Mol. 22:185-194.
Ljunggren B, Saveland H, Brandt L, Zygmunt S (1985) Early operation and overall outcome in aneurysmal subarachnoid hemorrhage. J
Neurosurg. 62:547
Lopez-Barneo J, Weir EK (1998) Oxygen regulation of ion channels and gene expression.Futura published company. New York.
Macdonald RL, Weir BK（1994）Cerebral vasospasm and free radicals.Free radical biology & Medicine. 5：633-643
Macdonald RL, Weir BKA, Grace MGA, Chen MH, Martin TP, Young,JD (1992) Mechanism of cerebral vasospasm following subarachnoid hemorrhage in monkeys. Can J Neuro Sci. 19:419-427
Macdonald RL, Weir BKA （1991）A review of hemoglobin and the pathogenesis of cerebral vasospasm. Stroke. 22:971-982
Marzatico F, Gaetani P, Tartara F, Bertorelli L, Feletti F, Adinolfi D, Tancioni F, Baena RR (1998) Antioxidant status and α
1-antiproteinase activity in subarachnoid hemorrhage patients. Life Science. 63(10):821-826
May JM (1999) Is ascorbic acid an antioidant for the plasma membrane.
FASEB J.13:995-1006.
May JM, Qu ZC, Morrow JD (1996) Interaction of ascorbate and
α
-tocopherol in resealed human erythrocyte ghosts. J Biol Chem. 271:10577-10582.
May JM, Qu ZC, Whitesell RR, Cobb CE (1996) Ascorbate recycling in human erythrocytes: Role of glutathione in reducing dehydroascorbate.
Free Rad Biol Med. 20(4):543-551.
Mayberg MR, Okada T, Bark DH (1990) The significance of morphological changes in cerebral arteries after subarachnoid hemorrhage. J Neurosurg. 72:626-633
Mc Cormick WF, Acosta-Rua GJ (1970) The size of intracranial saccular aneurysms: an autopsy study. J Neurosurg.33:422-427
Mehlhorn RJ (1991) Ascorbate and dehydroascorbic acid-medicated reduction of free radicals in the human erythrocyte J. Biol Chem.
266(5):2724-31
Mezzetti A, Lamenico D, Pierdomenico AD, Calafiore AM, Costantini F, Riario-Sforza GR, Imbastaro T, Neri M.,Cuccurullo F (1995) Vitamin E, C and lipid peroxidation in plasma and arterial tissue of smokers and non-smoker. Atherosclerosis. 112:91-99
Mottram P , Shige H, Nestel P (1999) Vitamin E improves arterial compliance in middle- age men and woman. Atherosclerosis. 145:
399-404
Polidore MC, Frei B, Rordorf G, Ogilvy CS, Koroshetz WJ, Beal MF (1997) Increased levels of plasma cholesteryl ester hydroperoxides in patients with Subarachnoid hemorrhage. Free Radical Biology &
Medicine. 5:762-767
Romner B, Ljunggren B, Brandt L (1989) Transcranial Doppler sonography within 12 hours after Subarachnoid hemorrhage. J Neurosurg. 70:732-726
Sakaki S,Kuwabara H,Ohta S (1986) Biological defence mechanism in the pathogenesis of prolonged cerebral vasospasm in the patients with
ruptured intracranial aneurysms. Stroke 17:196-202
Sano K (1988) cerebral vasospasm as a deficiency syndrome. In:Wikins, R.H., ed. Cerebral vasospasm . New York : Raven Press; 285-295
Sasaki S, Ohta S, Nakamura H, Takeda S (1988) Free radical reaction and biological defense mechanism in the pathogenesis of prolonged vasospasm in experimental subarachnoid hemorrhage. Journal of Cerebral Blood Flow and Metabolism.8:1-8
Sasaki T, Tanishima T, Asano T, Mayanagi Y, Sano K (1979) Significance of lipid peroxidation in the genesis of chronic vasospasm following rupture of an intracranial aaneurysm. Acta Neurochir. (supple.) (wein) 28:536-540
Simon E , Paul JL, Atger V. Simon A, Moatti N (1998) Erythrocyte antioxidant status in asyotomatic hypercholesterolemic men.
Atherosclerosis. 138:375-381
Siesjo BK, Agardh CD, Bengtsson F (1989) Free radicals and brain damage; Cerebrolvasc Brain metab Rev. 1:165-211
Stehbens WE （1972）: Pathology of the Cerebral Blood Vessels.St Louis, Mosby. 252-283
Tanishima T (1980) Cerebral vasospasm: contractile activity of hemoglobin in isolated canine basilar arteries. J Neurosurg. 53:
787-793
Tokoro K(1984) Cerebral vasospasm and lipoperoxide
damage-morphological localization and measurement of lipoperoxide in prolonged cerebral vasospasm. No shinkei Geka 12:1049-1058
Travis,MA, Hall ED (1987) The effects of chronic two-fold dietary vitamin E supplementation on Subarachnoid hemorrhage-induced brain hypoperfusion. Brain research. 418:366-370.
Weir, B.; Grace, M.; Hansen, J.; Rothberg, C. (1978) Time course of vasospasm in man. J Neurosurg. 48:173-178
Wilkins RH (1976) Aneurysm rupture during angiography. Does acute vasospasm occur? Surg Neurol. 5:299-303
Winkler BS, Orselli SM, Rex TS (1994) The redox couple between glutathione and ascorbic acid: A chemical and physiological perspective. Free Rad Biol Mol. 17:333-349.
Valkonen MM, Kuusi T (2000) Vitamin C prevents the acute atherogenic effects of passive smoking. Free Rad Biol Mol. 28:428-436
Verlooy J, Van Reempts J, Haseldonckx M, Borgers M, Selosse P (1991) Singlet oxygen induced cerebral vasospasm: An experimental study in rats. Acta Neurol Belg. 91:151-157
YamamotoY, Feri B, Ames BN (1990) Assay of lipid hydroperoxides using high-performance liquid chromatography with isoluminal
chemiluminescence detection. Methods in Enzymology. 186:371-380
附 錄
試 劑 來 源
99 % Alcohol Scharlau Acetyl chloride Fisher Scientific Acetate (CH3COOH) Merck 1-Butanol Merck Benzene Fisher Scientific 1-Chloro-2,4-ditrobenzene ( CDNB) Sigma 2, 4-Dinitrofluorobenzene（FDNB） Sigma 5,5
′
-Dithio-bis (2-Nitrobenoic acid) ( DTNB) Sigma Drabkins′
s reagent Sigma Dithiothreitol (DTT) Sigma EDTA SigmaN-Ethylmaleimide (NEM) Sigma 30 %H2O2 Merck
HCl Fisher Scientific Hexane Merck
Heptane Sigma
試 劑 來 源
H2SO4 Merck Indoacetic acid（IAA） Sigma Lauryl sulfate (SDS) Sigma Magnesium chloride hexahydrate (MgCl .6H2O) Sigma Methanol Tedia NADPH 日本和光公司 NaCl Merck Olive oil Sigma Oxized glutathione (GSSG) Sigma
Potassium cyanide ( Na2WO4 . 2H2O) Fluka Potassium phosphate (KH2PO4 . 7H2O) Sigma
Phosphoric acid Tedia Phosphotungstic acid Sigma Perchloric acid (PCA) GFS Potassium bicarbonate (KHCO3) Sigma Potassium carbonate (K2CO3) Sigma
Retinyl acetate Sigma
試 劑 來 源
Sodium phosphate (Na2HPO4) Sigma Sodium phosphate (NaH2PO4) Sigma Sodium acetate (CH3COONa) 日本和光公司 α-Tocopheryl acetate Sigma Thiobarbituric acid ( TBA) Sigma 1,1,3,3-Tetramethoxypropane (TMP) Sigma Trichloro acetic acid （TCA） Sigma Vanillin Sigma
附表：
表一、顱內動脈瘤破裂患者之基本資料(N＝37) Age Sex
（M:F）
Angio.time
（hrs）
GCS HHGS CT-Fisher grade
Mortality Vasospasm
62±16 20:17 13.4±5.4 12±4 3±1 3±1 38% 27%
Angio.time：住院至血管攝影時間 GCS：昏迷指數
HHGS：Hunt and Hess grade scale
CT Fisher grade：Fisher 氏電腦斷層 SAH 級數 Mortality：死亡率
Vasospasm：早期血管痙攣(< 48 小時)
表二、正常人與顱內動脈瘤破裂患者第一天之血漿脂質過氧化反應及維生 素 C、維生素 E 之變化
Normal（N=274；mean age:48）Aneurysms（N=37；mean age:62）
Mean Mean（住院第一天）
維生素 C（mg/dl） 1.26±0.71 0.83±0.48*
維生素 E（ug/ml） 8.95±3.91 6.99±2.96*
TBARS（um） 2.51±1.53 4.08±2.02*
Normal ：對照組
Aneurysms：動脈瘤破裂患者
*P< 0.001 by the analysis of Mann-Whitney U test
表三、死亡（14/37）與存活（23/37）兩組動脈瘤破裂患者全部平均血漿 抗氧化物和脂質過氧化物的濃度相關性統計
存活(M±SD)人數 23 死亡(M±SD)人數 14 維生素 C （mg/dl） 0.73±0.36 0.73±0.45 維生素 E （ug/ml） 6.56±2.85 7.48±3.65 TBARS（um） 3.69±2.17 4.09±2.16
表四、維生素 C、維生素 E 及 TBARS 與動脈瘤破裂後無早期血管痙攣患者的 昏迷指數等相關性
GCS HHGS CT-Fisher
CC P CC P CC P
維生素 C (mg/dl)
0.17 0.22 0.10 0.32 -0.20 0.19 維生素 E
(ug/ml)
-0.17 0.22 0.25 0.12 0.04 0.42 TBARS (um) 0.18 0.20 -0.25 0.13 0.23 0.15 CC：Correlation of Coefficient
P：P value of correlation analysis
表五、有早期血管痙攣的患者血漿抗氧化物及過氧化物濃度變化的關聯性 統計
GCS HHGS CT-Fisher
CC P CC P CC P
維生素 C (mg/dl) 0.09 0.42 -0.66 ＊0.04 -0.55 0.08 維生素 E (ug/ml)
0.58 0.07 -0.66 ＊0.04 -0.33 0.21 TBARS (um) 0.45 0.13 -0.53 0.09 -0.33 0.21
*.Correlation is significant at the .05 level (1-tailed).
附圖：
圖一、動脈瘤破裂患者血漿維生素 C 的變化
1.26 0.83 0.72 0.79 0.78 0.85
0 0.5 1 1.5 2 2.5
1 2 5 10 15
住院日
維生素C(mg/dl)◎ 對照組
★ P < 0.05
ê
ê ê
ê ê
◎
圖二、動脈瘤破裂患者血漿維生素 E 的變化
8.95 6.99 5.97 7.05 8.33 8.06
0 4 8 12 16
1 2 5 10 15
住院日
維生素E(µg/ml)◎ 對照組
★ P < 0.05
◎
★
★
★
★
★
圖三、動脈瘤破裂患者血漿維生素 TBARS 的變化
4.08 4.35 3.31 2.65 2.17
0.47
圖四、動脈瘤破裂患者的死亡率及體內抗氧化物和脂質過氧化物濃度的相
2.36 2.122.40
圖五、顱內動脈瘤破裂患者有無早期血管痙攣(兩天內)死亡率的比較
圖六、顱內動脈瘤破裂患者第一天 HHGS 昏迷指數與血漿維生素 C 的相關分
圖七、顱內動脈瘤破裂患者第一天 HHGS 昏迷指數與血漿維生素 E 的相關分 析
＊P<0.05
14.27 9.95 6.1 5.09
0
14.27 9.95 6.1 5.09
0
圖八、有無早期血管痙攣患者血漿維生素 C、維生素 E 和 TBARS 的分析比較
Vaso spasm
1 2 5 10 15
Vaso spasm
1 2 5 10 15
圖九、比較有無早期血管痙攣患者血漿維生素 C、維生素 E 和 TBARS 與死亡
自述
我於民國 74 年畢業於國防醫學院醫學系後，於台北市三軍總醫院外科 服務並兼任國防醫學院助教，因對神經科學有濃厚興趣而專攻神經外科，
於民國 82 年取得神經外科專科醫師並任神經外科主治醫師，於民國 84 年 轉換人生跑道而離開。
先至美國 UCLA 醫學院進修神經外科三個月主攻腦內視鏡及腦顱底手 術，回國後於 84 年至 86 年服務於大里仁愛醫院，至民國 86 年底因緣轉至 彰基服務，於 87 年接任神經外科主任至今，其中於 88 年赴美國鳳凰城 Barrow 神經醫學中心專攻腦瘤及血管瘤手術二個月，於臨床工作百忙之 餘，有感於所學不足及對學術研究有興趣，於民國 91 年投考中國醫藥大學 臨床醫學研究所，在劉青山博士及蔡輔仁院長指導下從事顱內動脈瘤破裂 後蜘蛛膜下腔出血患者血漿中維生素 C、維生素 E 及脂質過氧化反應等相關 研究。
至今年(93 年)6 月提出初步成果寫成碩士論文(顱內動脈瘤破裂患者血 漿維生素 C 維生素 E 及脂質過氧化反應之相關性)，希望未來能持續在臨床 與學術研究上，對顱內動脈瘤破裂患者的治療能提供更好的方針。
彰化基督教醫院 神經外科 周啟文