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1、脑损伤与糖皮质激素,张建宁 江荣才天津医科大学总医院神经外科天津市神经病学研究所,2015年8月22日济南, 中国,引子,1960年代,脑外伤常规使用糖皮质激素 1990年代，神经外科医生采用大剂量糖皮质激素治疗急性脊髓损伤，至今还被作为急性脊髓损伤的常规疗法 ; 脑外伤、脑出血等也常使用大剂量糖皮质激素2004年Crash使用后，糖皮质激素被“不建议”应用于脑外伤2013年中国神经外科重症管理专家共识推荐糖皮质激素应用于：胶质瘤、脑膜瘤和转移癌等肿瘤周围水肿，不建议大剂量冲击疗法治疗脑外伤.,Loriaux L. Glucocorticoid therapy in the intensive
2、 care unit. N Engl J Med. 2004,350(16):1601-1602.神经外科学分会.中国神经外科重症管理专家共识.中华医学杂志2013,93:1765-1778,神经外科领域应用糖皮质激素情况,引子,激素减少脑水肿？修复血脑屏障？同样是中枢神经系统，为什么大剂量激素有益于脊髓损伤却对脑外伤有害？糖皮质激素可以减少脑损伤导致的HPA轴损伤？,为什么应用激素？,糖皮质激素抑制免疫系统、扩散细菌感染？糖皮质激素扰乱血糖代谢，导致高血糖风险？糖皮质激素导致应激性消化道溃疡风险？,为什么反对应用激素？,NASCIS IJAMA 1984; 251:45-52,影响糖皮质激素
3、治疗中枢神经损伤的临床多中心研究:（The National Acute Spinal Cord Injury Study, NASCIS）,引子,剂量：100mg1000mg团注，然后25250mg q6h，10天 结论：与对照组相比，无效，反而影响伤口预后阴性原因：可能是用药太迟，剂量不够以及应用时间过长,方案：487 例:伤后8小时启用，24小时疗程：第1h剂量 30mg/kg 静脉用, 其余23小时剂量5.4mg/kg/h 对照组为纳洛酮和安慰剂结论：6个月随访，MP治疗促进神经功能恢复，完全和不完全 SCI均有效，而对照组无明显疗效,NASCIS IINEJM 1990; 332:1
4、405-11,NASCIS III JAMA 1997; 277:1597-1603,方案：166 例 :第1h MP 30 mg/kg +5.4 mg/kg/h 后续 23 h167 例:第1h MP 30 mg/kg+ 5.4 mg/kg/h后续 47 hrs 166 例:Tirilazad（ 替拉扎特，一种抗氧化药）2.5 mg/kg q6h 48 hrsConclusions：如果伤后3小时内接受MP，其疗程应该延续到24 hrs.如果伤后3-8小时内接受MP,其疗程应该延续到48 hrs. 小于8小时内应用者均有效减轻脊髓损伤,引子,甲强龙剂量：第一个4小时: 2g 静脉输注. 然后
5、以 0.4g/h 持续48h，剂量 达到19.2g总剂量: 48小时内21.2g,引子,Roberts I, Yates D, Sandercock P, et al. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet. 2004,364:1321-1328.,CRASH试验- 49个国
6、家、239家医院 ，历时5年（1999- 2004). 计划纳入GCS14TBI10008 例（伤后8hs). 随机分为 MP 和安慰剂组（静脉持续输注48hs )MP组死亡率明显高于对照组 原因不明,早期应用高剂量MP可导致液压打击TBI模型死亡率增高,模拟CRASH动物实验,Chen X, Zhang KL, Yang SY, Dong JF, Zhang JN. Glucocorticoids aggravate retrograde memory deficiency associated with traumatic brain injury in rats. J Neurotrau
7、ma. 2009 Feb 11;26:253-60.,糖皮质激素应用与TBI后脑水肿,Patent No. of Small animal stereo fixture：CN200610129584.8,Chen X, Zhang KL, Yang SY, Dong JF, Zhang JN. Glucocorticoids aggravate retrograde memory deficiency associated with traumatic brain injury in rats. J Neurotrauma. 2009， 11;26:253-60.,生理剂量甲强龙可以减少TBI
8、后脑水肿，减少BBB破坏和促进紧密连接蛋白高表达（Claudin5),Zhu H, Zhao ZL, Zhou Y, Chen X, Li Y, Liu X, Lu HJ, Zhang YJ, Zhang JN. High-dose glucocorticoid aggravates TBI-associated corticosteroid insufficiency by inducing hypothalamic neuronal apoptosis. Brain Res. 2013，1541:69-80.,糖皮质激素应用与TBI后脑水肿,生理剂量MP不诱导神经损伤,Physiologi
9、cal dose could not induce neural injury, but high-dose might aggravate the apoptosis in the injury area and lead to neurophysiological disturbance.,Chen X, et al. J Neurotrauma 2009,26:253; Zhang B, et al. Brain Res 2011,1382: 165-72,高剂量MP导致下丘脑凋亡神经元增多,Injury ControlHE Staining,Injury ControlTUNEL St
10、aining,High-dose GCsHE Staining,High-dose GCsTUNEL Staining,To investigate the underlying cause of increased mortality induced by high-dose GCs application,Chen X, Zhang B, Chai Y, Dong B, Lei P, Jiang R, Zhang J. Methylprednisolone exacerbates acute critical illness-related corticosteroid insuffici
11、ency associated with traumatic brain injury in rats. Brain Res. 2011 Mar 25;1382:298-307.,高剂量MP导致垂体前叶凋亡神经细胞增多,To investigate the underlying cause of increased mortality induced by high-dose GCs application,Chen X, Zhang B, Chai Y, Dong B, Lei P, Jiang R, Zhang J. Methylprednisolone exacerbates acute
12、 critical illness-related corticosteroid insufficiency associated with traumatic brain injury in rats. Brain Res. 2011 Mar 25;1382:298-307.,TBI大鼠的糖皮质激素代谢变化,Fig.: Serum Corticosterone in rats peaks 3hrs after FPI, reach its lowest point 2 days after FPI，and return to normal 7 days after FPI.,Fig.: St
13、ress function of survival and dead rats 7 days after FPI: The peak value of serum CORT of dead rats (471.403 ng/ml) was significantly lower than that of serum CORT of survival rats (885.50 ng/ml).,TBI大鼠的激素应激不足,Fig. The Stress Insufficiency of Dead and Survival Rats after day 7：The CII of dead rats (
14、1.352) significantly lowered as compared to survival rats (5.5) and these rats (5.496) before FPI.,TBI大鼠的激素应激不足,Fig. The incidence of Stress Insufficiency (SI) 7 days after TBI：The incidence of SI (58.3%) in High-dose MP group was significantly higher than that of SI in Low-dose MP group (6.7%) and
15、that of SI in Injury Control group (13.3%).,不同剂量MP对7天期TBI大鼠的激素分泌影响,Fig. The incidence of Stress Insufficiency (SI) 14 days after TBI：The incidence of SI in High-dose MP group (28.6%) was significantly higher than that of SI in Low-dose MP group (7.7%) and that of SI in Injury Control group.,不同剂量MP对晚
16、期TBI大鼠的激素分泌影响,TBI患者继发HPA轴损伤,急性脑外伤可导致原发与继发性HPA轴损伤。不同性质的损伤和不同严重程度的脑外伤有不同的特征性的激素变化，而这些变化又与患者的临床表现、并发症和预后等密切相关,TBI患者的激素抑制实验,48 Cases.接受地塞米松抑制实验（dexamethasone suppression test, DST)。在伤后 1,3, 4, 5天取血测Cortisol水平。而1.5mg地塞米松应于损伤后3天的24:00pm口服。血清Cortisol水平降低超过服药前的50%者被诊断为DST阳性反应，而少于50%者认为是DST阴性反应Fig. A The average cortisol concentration after oral dexamethasone. After administrating DXM (1.5mg), serum cortisol levels were significantly suppressed in the mild and moderate group. Fig. B The suppression rate of DST increased with the GCS score reduced.,
