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.中华医学会神经外科学分会.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
3、糖皮质激素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;
4、332:1405-11,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
5、注. 然后以 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-
6、 49个国家、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 Neur
7、otrauma. 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
8、减少TBI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,Physi
9、ological 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 ControlTUN
10、EL Staining,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 insu
11、fficiency 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
12、acute 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
13、.: Stress 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 r
14、ats (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%)
15、 and 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
16、量MP对晚期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 Th
17、e 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.,A,B,Mild,Moderate,Severe,GCS score,Inhibition rate
18、,DXM suppression rate,TBI伤情越重发生DST阴性反应者比例越高；而DST阳性者则预后更好.,Mild,Moderate,Severe,Type of TBI,Case numbers,Positive,Negative,TBI患者的激素抑制实验,The critical illness related corticosteroid insufficiency (CIRCI),HPA轴是最重要的内分泌轴，HPA轴损伤，可以导致应激糖皮质激素分泌不良(CIRCI,) CIRCI则严重影响多系统疾病。,Lim SY, et al. Prognostic significanc
19、e of different subgroup classifications of critical illness-related corticosteroid insufficiency in patients with septic shock. Shock. 2011 Oct;36(4):345-9.,TBI患者激素补充原则,TBI后, GCs治疗目标应该不是脑水肿而是HPA轴相关损伤.中型和重型TBI约60%发生HPA功能异常 （CIRCI)我们观察的48例患者中， 轻中重三种类型TBI的DST阴性率分别是 10.53%, 60% and 63.15%.发生HPA轴损伤的TBI患者
20、，在亚急性期接受应激剂量GCs可以降低其并发症与死亡率,TBI 3天内，避免大剂量GCs 通过检测血清GCs可以部分了解患者是否发生了CIRCI，必要时持续补充GCs对于确定发生HPA轴损伤者，必需补充应激剂量GCs TBI中晚期，也应该评价其HPA轴损伤情况，视情况补充GCs,TBI患者激素补充原则,A. High-dose,B. Continuous,C. Optimum,D. Replacement,A,B,C,D,Multicenter, randomized, double-blind, placebo-controlled HYPOLYTE (Hydrocortisone Poly
21、traumatise) study. 纳入了149 例重型外伤患者，复苏后患者被随机分配来接受氢化考的松治疗 (200 mg/d 连续 5 days,第6天100mg，第7天50mg)或安慰剂治疗.结果显示：糖皮质激素不足（corticosteroid insufficiency , CI)与系统性炎症密切相关，接受应激剂量氢化考的松者发生院内感染性肺炎比例最低.,Main Outcome MeasurePrimary：院内获得性肺感染 Secondary：呼吸机使用时间，是否低钠及死亡.,Roquilly A, et al. JAMA. 2011 Mar 23;305(12):1201-9,
22、Backgrounds：,Roquilly：TBI患者补充激素，可以改善预后,HYPOLYTE clinical trial,Roquilly A, et al. JAMA. 2011 Mar 23;305(12):1201-9,Roquilly：TBI补充激素，可以降低HAP发病率,Roquilly A, et al. JAMA. 2011 Mar 23;305(12):1201-9,Roquilly：TBI补充激素，可以减少呼吸机使用机会,P=0.03*,P=0.002*,All patients,Patients with Corticosteroids insufficiency,Ch
23、ange of Days ,6 d,8 d,Roquilly A, et al. JAMA. 2011 Mar 23;305(12):1201-9,*Comparison of hydrocortisone group vs placebo using a stratified Cox model. secondary outcome on day 28.,Roquilly：TBI补充激素，可以降低减少ICU住院时间,All patients,Patients with corticosteroid insufficiency,3%,5%,P=0.44,P=0.23,Mortality rat
24、es*,*secondary outcome on day 28.,Roquilly A, et al. JAMA. 2011 Mar 23;305(12):1201-9,Roquilly：TBI糖皮质激素不足，增加死亡率,A double-edged sword,Two-way effects of GCs after Neurotrauma,GCs,MortalityApoptosisCognitive deficits,TBI后的GCs补充要点,TBI早期，避免高剂量GCs部分TBI患者长期血清低GCs，需早作评价和尽早补充.检查HPA轴功能很重要，如果确定HPA轴损伤，需要给予适量GC
25、s补充. TBI晚期，需要评价HPA轴功能，如果需要，还需及时补充GCs.,TBI后的其他激素的异常,25%80%发生中枢性性腺功能低下2%15甲状腺功能低下 50%高泌乳素18%生长激素低下13%低皮质醇,mTBI和sTBI,TBI后的其他激素的异常,45例sTBI,早晨14天 08-10am cortisol,GH, PRL, IGF-1, TSH, fT3, fT4, FSH, LH,T and SHBG(men).下午14天 17-19pm cortisol, GH,Olivecrona Z1, Dahlqvist P, Koskinen LO.Acute neuro-endocrin
26、e profile and prediction of outcome after severe brain injury.Scand J Trauma Resusc Emerg Med. 2013 ,21:33.,TBI后的其他激素的异常,结论：sTBI14天垂体轴相关激素明显代谢异常。大部分患者Cortisol低于临界低限值，提示肾上腺分泌不足，但却与患者预后差无相关关系。早期垂体-性腺轴的强抑制与患者预后较好相关。长时间抑制甲状腺功能则导致高死亡率和预后功能不良。该研究结果还待进一步评估,TBI后的内分泌异常需要加强研究,TBI后GCs分泌异常，它与垂体下丘脑其他激素如T3、T4、FSH及其他激素变化规律及功能研究TBI患者继发性CIRCI的诊断标准如何更实用？简便？糖皮质激素补充哪种效果最佳且 糖皮质激素影响TBI的机制？,Thank You!,
