快速解除急性脑受压致二次脑损伤机理的实验研究
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摘要
背景：业已证明，巨大硬膜外血肿(血肿量＞100ml)致死致残的病机不仅仅是导致脑组织移位，更重要的它必然压迫周围脑组织，使其缺血缺氧，进而触发一系列生化瀑布反应(Ca2+超载、酸中毒、自由基增多等)。因此，多年来人们倡导的“及时清出血肿，降低颅内压”是救治本病符合逻辑的原则。但奇怪的是，Shalamo等人在犬的急性硬膜外血肿的模型中却发现，当颅内压(intracerebral pressure，ICP)＞75mmHg持续60分钟解压后脑水肿反而进一步加重，ICP二次进行性增高而最终死亡。此外，近10年来，我们与国内多家神经外科中心在开展巨大硬膜外血肿清除术的临床实践中均发现，硬膜外血肿病人仅在血肿清除术后3～12小时，曾一度显著减轻的病情就已再度恶化。CT复查发现，所有病例的脑水肿显著加剧。这些病例死后尸检见血肿周围和远离血肿对侧的脑组织均有高度水肿、血管内皮细胞及血脑屏障严重受损、神经元大量坏死。术后部分患者即使生命得以保存，但也长期处于昏迷状态，最终多死于并发症，使其死亡率仍然高达30％。然而，目前国内外对这些致命性的病理生
快速解除急性脑受压致二次脑损伤机理的实验研究中文摘要
理过程尚缺乏深入的基础研究，其是否与二次脑损伤有关及详尽机制
如何，均无相关报道，更无从有疗效显著的对策问世。根据缺血再灌
注损伤理论，我们推测:因血肿压迫而处于高颅压低灌注的广泛已损
伤的脑组织在过快解压后快速回缩，并由此遭受急剧而广泛的再灌注
损伤，从而使脑组织遭受第二次打击(the second hit)，进一步加
重原发脑损害。
实验目的:为了验证再灌注损伤假说，本课题创建新西兰大白兔
巨大硬膜外血肿模型，利用激光共聚焦显微镜等多项先进方法研究巨
大硬膜外血肿骤然解压对脑血流量(rCBF)、脑结构和神经细胞内
[CaZ十」i的影响，以试图阐明快速解除急性脑受压后脑损伤的机制，
为重症脑外伤和脑出血的救治提供实验性理论依据。
实验材料及方法:健康成年新西兰大白兔50只，雌雄不限，体
重2.5士0.3kg。随机分为正常对照组(5只)、实验组(4O只)、模
型证实组(5只)。实验组再随机分为脑血流测定组(5只)和7个
时相点，脑庙时(P)、解压后10min(DIOmin)、解压后lh(Dlh)、
解压后6h(D6h)、解压后24h(D24h)、解压后48h(D48h)和解
压后72h(D72h)，每时相点5只动物。监测硬膜外血肿新西兰大白
兔减压前后局部脑皮质血流量、游离[C a2+]i与脑含水量的动态变化并
分析其相关性。
实验结果:
一、压迫后损伤区可见神经元深染、核皱缩，细胞周围出现空隙，
间有变性坏死;解压后10分钟(momin)可见血管损伤与出血，血管
快速解除急性脑受压致二次脑损伤机理的实验研究中文摘要
周围水肿，以及神经元变性坏死;解压后24小时(D24h)以血管闭
塞及周围水肿，神经元变性坏死为特征。
二、正常条件下，新西兰大白兔顶叶皮质的CBF为65 .98士
H.79ml.1009一’.min一，，脑疵时明显降低。解除压迫后，CBF迅速升高，
D10min后达到高峰，而后逐渐下降，D24h达到低谷，继之缓慢恢复，
D72h基本正常。
三、脑庙时，与正常对照值相比，[CaZ+」i明显增高;解除压迫
后，与压迫组相比，仅lh，[CaZ+〕i即已显著升高(P<0.01)，D24h
达到高峰，D72h接近正常。
四、压迫后，脑组织含水量显著增加(P<0.05);解压后6小时再
次大幅度升高，于D24h达高峰，D72h接近正常。经直线回归分析，解压
后细胞内游离〔CaZ十」i与脑组织含水量呈显著正相关
(v=38，r=0.469，P<0.01)。
结论
本实验结果证明，快速解除急性脑受压后，使正处于高颅压低灌
注的广泛己损伤脑组织因过快解压后快速回缩，并由此遭受急剧而广
泛的再灌注损伤，从而使脑组织遭受第二次打击，进一步加重原发脑
损害。这可能是快速解除急性脑受压后二次脑损伤的重要机制之一，
值得深入研究。
Background: There is proved that the lethal and disable pathogenesis of huge epidural hematoma is not only the removal of brain content around, but also the ischemia and hypoxia of the tissue caused by compression provoking series of biochemical waterfalls (such as calcium overload, acidosis, free radicals increasing, etc).Therefore, the key to treat patients with epidural hematoma is rapid evacuation of hematoma and reduction of intracerebral pressure has no doubt. However, Shalamo found that in the dogs with epidural hematoma brain edema aggravated further on the contrary , intracerebral pressure (ICP) kept increasing once again after the hematoma decompression and all the animals died in the long run , which was much surprising. In addition, our 10 years' clinical practices and other neurosurgical centers showed that the patient's
condition once remarkably alleviating became deteriorating only 3~12 hours after operation, this is very obscure to us. The brain edema notably aggravating is obvious in the reexamined CT pictures. Many finding lacking reluctant basic research, such as more serious brain edema in the tissue around and aloof the hematoma; serious damages to endothelium and blood-brain barrier; lots of necrosis of Neuron are obvious in the dead body examination. In spite of surviving after the operation, Partial patients were either in long-term coma and died of the complications ,which led the mortality was up to 30%.According to the theory of ischemia/reperfusion injury, We infer: the widely-damaged brain tissue which has low perfusion because of the hematoma compression rapidly contract with quick decompression, and then the brain experiences ischemia/reperfusion injury.
Objective: In order to test the hypothesis of ischemia/reperfusion injury , this project paid focus on the effects of rapid decompression on the regional cerebral blood flow(CBF), brain structure and [Ca2+]i.
Methods: 50 New Zealand rabbits were at random divided into a control group(nl=5) , model testifying group (n2=5), and experimental groups (n3=40), which are once more divided into the CBF testing group and 7 group of brain hernitate , D10min, Ih, 6h, 24h, 48h, 72h. The changes
of blood flow , [Ca2+]i and brain tissue water content were measured and their correlations were analyzed.
Results
1 The cell deeply dying, karyon shrinking , broadened space around the cell , some denaturalization and necrosis were observed after compression, the lesion and haemorrhage of Vascellum, edema with broadened space were observed 10min after evacuation. While the brain damage of 24hr post operation were characterized by the blood vessel closing up and necrosis of Neuron.
2 The CBF of parital cortex was 65.98 ?1.79ml.loog-1.min-1 in normal condition, and it decreased notably as brain herniationo it had a short-timed fugacious hyper-reperfusion following depression and decreased gradually ,reached peak in 24 hours. Then it resume slowly and reach normal level in 72h.
3 [Ca2+]i increased remarkably after being pressed ; it had a short-timed decreasing following depression and increased gradually ,reached peak in 24 hours.
4 , The correlation between [Ca2+]i and brain water has magnificant value (v=38,r=0.493,P<0.01).
Conclusions
These findings indicate that the widely-damaged brain tissue which has low perfusion because of the hematoma compression
rapidly contract with quick decompression , which is the major mechanism of secondary brain insults with quick brain decompression and is worthy of being further studied
快速解除急性脑受压致二次脑损伤机理的实验研究中文摘要
理过程尚缺乏深入的基础研究，其是否与二次脑损伤有关及详尽机制
如何，均无相关报道，更无从有疗效显著的对策问世。根据缺血再灌
注损伤理论，我们推测:因血肿压迫而处于高颅压低灌注的广泛已损
伤的脑组织在过快解压后快速回缩，并由此遭受急剧而广泛的再灌注
损伤，从而使脑组织遭受第二次打击(the second hit)，进一步加
重原发脑损害。
实验目的:为了验证再灌注损伤假说，本课题创建新西兰大白兔
巨大硬膜外血肿模型，利用激光共聚焦显微镜等多项先进方法研究巨
大硬膜外血肿骤然解压对脑血流量(rCBF)、脑结构和神经细胞内
[CaZ十」i的影响，以试图阐明快速解除急性脑受压后脑损伤的机制，
为重症脑外伤和脑出血的救治提供实验性理论依据。
实验材料及方法:健康成年新西兰大白兔50只，雌雄不限，体
重2.5士0.3kg。随机分为正常对照组(5只)、实验组(4O只)、模
型证实组(5只)。实验组再随机分为脑血流测定组(5只)和7个
时相点，脑庙时(P)、解压后10min(DIOmin)、解压后lh(Dlh)、
解压后6h(D6h)、解压后24h(D24h)、解压后48h(D48h)和解
压后72h(D72h)，每时相点5只动物。监测硬膜外血肿新西兰大白
兔减压前后局部脑皮质血流量、游离[C a2+]i与脑含水量的动态变化并
分析其相关性。
实验结果:
一、压迫后损伤区可见神经元深染、核皱缩，细胞周围出现空隙，
间有变性坏死;解压后10分钟(momin)可见血管损伤与出血，血管
快速解除急性脑受压致二次脑损伤机理的实验研究中文摘要
周围水肿，以及神经元变性坏死;解压后24小时(D24h)以血管闭
塞及周围水肿，神经元变性坏死为特征。
二、正常条件下，新西兰大白兔顶叶皮质的CBF为65 .98士
H.79ml.1009一’.min一，，脑疵时明显降低。解除压迫后，CBF迅速升高，
D10min后达到高峰，而后逐渐下降，D24h达到低谷，继之缓慢恢复，
D72h基本正常。
三、脑庙时，与正常对照值相比，[CaZ+」i明显增高;解除压迫
后，与压迫组相比，仅lh，[CaZ+〕i即已显著升高(P<0.01)，D24h
达到高峰，D72h接近正常。
四、压迫后，脑组织含水量显著增加(P<0.05);解压后6小时再
次大幅度升高，于D24h达高峰，D72h接近正常。经直线回归分析，解压
后细胞内游离〔CaZ十」i与脑组织含水量呈显著正相关
(v=38，r=0.469，P<0.01)。
结论
本实验结果证明，快速解除急性脑受压后，使正处于高颅压低灌
注的广泛己损伤脑组织因过快解压后快速回缩，并由此遭受急剧而广
泛的再灌注损伤，从而使脑组织遭受第二次打击，进一步加重原发脑
损害。这可能是快速解除急性脑受压后二次脑损伤的重要机制之一，
值得深入研究。
Background: There is proved that the lethal and disable pathogenesis of huge epidural hematoma is not only the removal of brain content around, but also the ischemia and hypoxia of the tissue caused by compression provoking series of biochemical waterfalls (such as calcium overload, acidosis, free radicals increasing, etc).Therefore, the key to treat patients with epidural hematoma is rapid evacuation of hematoma and reduction of intracerebral pressure has no doubt. However, Shalamo found that in the dogs with epidural hematoma brain edema aggravated further on the contrary , intracerebral pressure (ICP) kept increasing once again after the hematoma decompression and all the animals died in the long run , which was much surprising. In addition, our 10 years' clinical practices and other neurosurgical centers showed that the patient's
condition once remarkably alleviating became deteriorating only 3~12 hours after operation, this is very obscure to us. The brain edema notably aggravating is obvious in the reexamined CT pictures. Many finding lacking reluctant basic research, such as more serious brain edema in the tissue around and aloof the hematoma; serious damages to endothelium and blood-brain barrier; lots of necrosis of Neuron are obvious in the dead body examination. In spite of surviving after the operation, Partial patients were either in long-term coma and died of the complications ,which led the mortality was up to 30%.According to the theory of ischemia/reperfusion injury, We infer: the widely-damaged brain tissue which has low perfusion because of the hematoma compression rapidly contract with quick decompression, and then the brain experiences ischemia/reperfusion injury.
Objective: In order to test the hypothesis of ischemia/reperfusion injury , this project paid focus on the effects of rapid decompression on the regional cerebral blood flow(CBF), brain structure and [Ca2+]i.
Methods: 50 New Zealand rabbits were at random divided into a control group(nl=5) , model testifying group (n2=5), and experimental groups (n3=40), which are once more divided into the CBF testing group and 7 group of brain hernitate , D10min, Ih, 6h, 24h, 48h, 72h. The changes
of blood flow , [Ca2+]i and brain tissue water content were measured and their correlations were analyzed.
Results
1 The cell deeply dying, karyon shrinking , broadened space around the cell , some denaturalization and necrosis were observed after compression, the lesion and haemorrhage of Vascellum, edema with broadened space were observed 10min after evacuation. While the brain damage of 24hr post operation were characterized by the blood vessel closing up and necrosis of Neuron.
2 The CBF of parital cortex was 65.98 ?1.79ml.loog-1.min-1 in normal condition, and it decreased notably as brain herniationo it had a short-timed fugacious hyper-reperfusion following depression and decreased gradually ,reached peak in 24 hours. Then it resume slowly and reach normal level in 72h.
3 [Ca2+]i increased remarkably after being pressed ; it had a short-timed decreasing following depression and increased gradually ,reached peak in 24 hours.
4 , The correlation between [Ca2+]i and brain water has magnificant value (v=38,r=0.493,P<0.01).
Conclusions
These findings indicate that the widely-damaged brain tissue which has low perfusion because of the hematoma compression
rapidly contract with quick decompression , which is the major mechanism of secondary brain insults with quick brain decompression and is worthy of being further studied
引文
1．杨应明，许益明，郑少钦，等．注水法在巨大硬膜外血肿开颅术中的价值．河北医药，2000，22(7)：487～488．
2．王忠诚主编．神经外科学．武汉：湖北科学技术出版社，1998，287-288．
3. Wagnet KR, Xi G, Hua Y, et al. Early metabolic alterations in edematous perihematomal brain regions following experimental intracerebral hematoma.J Neurosurg,1998,88(6): 1058-1065.
4. Mendelow AD. Mechanisms of ischemic brain damage with intracerebral hemorrhage. Stroke,1993,24(1): 115-120.
5. Graham SH, Chert J. Programmed cell death in cerebral ischema.J Cere Blood Flow Metab,2001,21:99-109.
6. Shalamo P, Peter S, Ank R, et al.The effect of resuscitative moderate hypothermia following epidural brain compression on cerebral damage in a canine outcome model. J Neursurg, 1993,79: 241-253.
7. Matsuo Y, Izumiyamaa M,Onodera H,et al.Correlation between myeloperoxidase-quatified neutrophil accumulation and ischemic brain injury in the rat .Stroke,1994,25:1469-1475.
8. Hollingworth S,Soeller C,Baylor SM,et al.Sarcomeric Ca2+ gradients during activation of frog skeletal muscle fibres imaged with confocal and two-photon microscopy.J Physiol,2000, 526:3551-3560.
9. Pasztor B,Svmon L,Dorsch NW, et al.The hydrogen clearance method in assessment of blood flow in cortex, white matter and deep nuclei of baboons. Stroke,1973, 4(4): 556-567.
10. Penny BD, Russel WR.Experimental cerebral nussion.Brain,1941,64:93-104.
11. Lighthall JW, Dixon CE, Anderson TE. Experimental models of brain injury. J Neurotrauma,1989,6(2):83-97.
12. Shanlin RT, Sole MJ, Rahinfar M, et al. More lesions about essential hypertension for
epidural rat model.J Am Coll Cardiol,1988,2930:737-738.
13．杨静，蔡宏伟，谭秀娟．大鼠闭合性硬膜外球囊扩张脑损伤模型的建立．湖南医科大学学报，1999,24(6)：516-520．
14. Tanno H,Nockels RP, Pitts LH,et al.Breakdown of the blood-brain barrier after fluid percussive brain injury in the rat.J Neurotrauma, 1992,9:21-25.
15．陈伟强，杨应明，何明利，等．硬膜外血肿术后顽固性脑水肿的机制研究．脑与神经疾病杂志，2002，10(5)：297-299．
16．Marmarou．intracellular acidosis in human and experimental brain injury．J Neurotrauma,1992,9：551-557．
17. Tanno H,Nockels RP, Pitts LH,et al. Breakdown of the blood-brain barrier after fluid percussive brain injury in the rat. J Neurotrauma, 1992,9:21-25.
18. Garcia JH, Liu KF, Ho KL .Neuronal necrosis after middle cerebral artery occlusion in wistar rats progresses at different time intervals in the caudoputaman and the cortex. Stroke, 1995,20(4):636-643.
19. Jose Castillo, Antoni Davalos, Javier Naveior, et al. Neuroexcitatory Amino Acids and their relations to infarct size and neurological defici in ischemic stroke. Stroke, 1996,27(6):1060-1065.
20. Hara H,Sukamoto T, Kogure K. Mechanism and pathogenesis of ischemia-induced neuronal damage. Prog Neurobiol, 1993, 40(6):645-670.
21. Cruz J.Cerebral oxygenenration. Acta Neurochir, 1993,suppl 59:86-97.
22. Rosmff HL, Kochanek PK, Clark R, et al.Resuscitation from severe brain trauma. Crit Care MED, 1996,24(suppl 2):s48.
23. Groiselle C, Rocchisani JM, Moretti JL, et al. Improving the measurement of the 99Tc(m)-ECD brain perfusion index by temporal analysis. Nucl-Med-Commun,2000,21(9): 811-816.
24. Zhou F, Xiang Z, Feng WX, et al. Neuronal free Ca(2+) and BBB permeability and
ultrastructure in head injury with secondary insult. J Clin Neurosci,2001, 8(6): 561-563.
25. Obrist WO. Time couse of cerebral blood flow and metabolism in comatose patients with acute head injury. J Cerebral Blood Flow Metab,1993,13(Suppl 1): s157.
26. Sharp FR, Lu A, Tang Y,et al. Multiple molecular penumbras after focal cerebral ischemia. J Cerebral Blood Flow Metab, 2000,20:1011 - 1032.
27. Lipton P. Ischemic cell death in brain neurons. Physiol Rev, 1999,79:1431-1568..
28. Schanne FA, Kane AB,Young EE, et al.Calcium dependence of toxic cell death:a final common pathway, Scoence,1997,2.6:700-710.
29. Plesnila N, Ringel F, Chang RC,et al. Relevance of calcium homeostasis in glial cell swelling from acidosis. Acta-Neurochir-Suppl-(Wien), 1998,7:1203-1205.
30. Chen M, Simard JM.Cell swelling and a nonselective cation channel regulated by internal Ca2+ and ATP in native reactive astrocytes from adult rat brain. J-Neurosci, 2001, 21(17): 6512-6521.
31. Kristian T, Siejo BK.Calcium in ischemia cell death.Stroke,1998,29(3):705-731.
32. Elf K, Nilsson P, Enblad PO. Outcome after traumatic brain injury improved by an organized secondary insult program and standardized neurointensive care. Crit Care Med,2002,30(9): 2129-2134.
33. The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Hypotension. J Neurotrauma,2000,17(6-7): 591-595.
34．白红民，费舟，章翔，等．大鼠二次脑损伤模型的建立．中华创伤杂志，2002，18(4)：214-217．
35. Fei Z, Zhang X, Yi SY.Brain。TXA2 and PGI21evels related to diffuse axoanl injury with secondary.J Clin Neurosci,1999;6(4):306-308.
36. Zhou F, Xiang Z, Feng WX, et al. Neuronal free Ca(2+)and BBB permeability and ultrastructure in head injury with secondary insult. J Clin Neurosci,2001, 8(6): 561-563.
2．王忠诚主编．神经外科学．武汉：湖北科学技术出版社，1998，287-288．
3. Wagnet KR, Xi G, Hua Y, et al. Early metabolic alterations in edematous perihematomal brain regions following experimental intracerebral hematoma.J Neurosurg,1998,88(6): 1058-1065.
4. Mendelow AD. Mechanisms of ischemic brain damage with intracerebral hemorrhage. Stroke,1993,24(1): 115-120.
5. Graham SH, Chert J. Programmed cell death in cerebral ischema.J Cere Blood Flow Metab,2001,21:99-109.
6. Shalamo P, Peter S, Ank R, et al.The effect of resuscitative moderate hypothermia following epidural brain compression on cerebral damage in a canine outcome model. J Neursurg, 1993,79: 241-253.
7. Matsuo Y, Izumiyamaa M,Onodera H,et al.Correlation between myeloperoxidase-quatified neutrophil accumulation and ischemic brain injury in the rat .Stroke,1994,25:1469-1475.
8. Hollingworth S,Soeller C,Baylor SM,et al.Sarcomeric Ca2+ gradients during activation of frog skeletal muscle fibres imaged with confocal and two-photon microscopy.J Physiol,2000, 526:3551-3560.
9. Pasztor B,Svmon L,Dorsch NW, et al.The hydrogen clearance method in assessment of blood flow in cortex, white matter and deep nuclei of baboons. Stroke,1973, 4(4): 556-567.
10. Penny BD, Russel WR.Experimental cerebral nussion.Brain,1941,64:93-104.
11. Lighthall JW, Dixon CE, Anderson TE. Experimental models of brain injury. J Neurotrauma,1989,6(2):83-97.
12. Shanlin RT, Sole MJ, Rahinfar M, et al. More lesions about essential hypertension for
epidural rat model.J Am Coll Cardiol,1988,2930:737-738.
13．杨静，蔡宏伟，谭秀娟．大鼠闭合性硬膜外球囊扩张脑损伤模型的建立．湖南医科大学学报，1999,24(6)：516-520．
14. Tanno H,Nockels RP, Pitts LH,et al.Breakdown of the blood-brain barrier after fluid percussive brain injury in the rat.J Neurotrauma, 1992,9:21-25.
15．陈伟强，杨应明，何明利，等．硬膜外血肿术后顽固性脑水肿的机制研究．脑与神经疾病杂志，2002，10(5)：297-299．
16．Marmarou．intracellular acidosis in human and experimental brain injury．J Neurotrauma,1992,9：551-557．
17. Tanno H,Nockels RP, Pitts LH,et al. Breakdown of the blood-brain barrier after fluid percussive brain injury in the rat. J Neurotrauma, 1992,9:21-25.
18. Garcia JH, Liu KF, Ho KL .Neuronal necrosis after middle cerebral artery occlusion in wistar rats progresses at different time intervals in the caudoputaman and the cortex. Stroke, 1995,20(4):636-643.
19. Jose Castillo, Antoni Davalos, Javier Naveior, et al. Neuroexcitatory Amino Acids and their relations to infarct size and neurological defici in ischemic stroke. Stroke, 1996,27(6):1060-1065.
20. Hara H,Sukamoto T, Kogure K. Mechanism and pathogenesis of ischemia-induced neuronal damage. Prog Neurobiol, 1993, 40(6):645-670.
21. Cruz J.Cerebral oxygenenration. Acta Neurochir, 1993,suppl 59:86-97.
22. Rosmff HL, Kochanek PK, Clark R, et al.Resuscitation from severe brain trauma. Crit Care MED, 1996,24(suppl 2):s48.
23. Groiselle C, Rocchisani JM, Moretti JL, et al. Improving the measurement of the 99Tc(m)-ECD brain perfusion index by temporal analysis. Nucl-Med-Commun,2000,21(9): 811-816.
24. Zhou F, Xiang Z, Feng WX, et al. Neuronal free Ca(2+) and BBB permeability and
ultrastructure in head injury with secondary insult. J Clin Neurosci,2001, 8(6): 561-563.
25. Obrist WO. Time couse of cerebral blood flow and metabolism in comatose patients with acute head injury. J Cerebral Blood Flow Metab,1993,13(Suppl 1): s157.
26. Sharp FR, Lu A, Tang Y,et al. Multiple molecular penumbras after focal cerebral ischemia. J Cerebral Blood Flow Metab, 2000,20:1011 - 1032.
27. Lipton P. Ischemic cell death in brain neurons. Physiol Rev, 1999,79:1431-1568..
28. Schanne FA, Kane AB,Young EE, et al.Calcium dependence of toxic cell death:a final common pathway, Scoence,1997,2.6:700-710.
29. Plesnila N, Ringel F, Chang RC,et al. Relevance of calcium homeostasis in glial cell swelling from acidosis. Acta-Neurochir-Suppl-(Wien), 1998,7:1203-1205.
30. Chen M, Simard JM.Cell swelling and a nonselective cation channel regulated by internal Ca2+ and ATP in native reactive astrocytes from adult rat brain. J-Neurosci, 2001, 21(17): 6512-6521.
31. Kristian T, Siejo BK.Calcium in ischemia cell death.Stroke,1998,29(3):705-731.
32. Elf K, Nilsson P, Enblad PO. Outcome after traumatic brain injury improved by an organized secondary insult program and standardized neurointensive care. Crit Care Med,2002,30(9): 2129-2134.
33. The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Hypotension. J Neurotrauma,2000,17(6-7): 591-595.
34．白红民，费舟，章翔，等．大鼠二次脑损伤模型的建立．中华创伤杂志，2002，18(4)：214-217．
35. Fei Z, Zhang X, Yi SY.Brain。TXA2 and PGI21evels related to diffuse axoanl injury with secondary.J Clin Neurosci,1999;6(4):306-308.
36. Zhou F, Xiang Z, Feng WX, et al. Neuronal free Ca(2+)and BBB permeability and ultrastructure in head injury with secondary insult. J Clin Neurosci,2001, 8(6): 561-563.