江榮才腦損傷與糖皮質(zhì)激素

1、腦損傷與糖皮質(zhì)激素,張建寧 江榮才天津醫(yī)科大學(xué)總醫(yī)院神經(jīng)外科天津市神經(jīng)病學(xué)研究所,2015年8月22日濟南, 中國,引子,1960年代,腦外傷常規(guī)使用糖皮質(zhì)激素 1990年代，神經(jīng)外科醫(yī)生采用大劑量糖皮質(zhì)激素治療急性脊髓損傷，至今還被作為急性脊髓損傷的常規(guī)療法 ; 腦外傷、腦出血等也常使用大劑量糖皮質(zhì)激素2004年Crash使用后，糖皮質(zhì)激素被“不建議”應(yīng)用于腦外傷2013年《中國神經(jīng)外科重癥管理專家共識》推

2、薦糖皮質(zhì)激素應(yīng)用于：膠質(zhì)瘤、腦膜瘤和轉(zhuǎn)移癌等腫瘤周圍水腫，不建議大劑量沖擊療法治療腦外傷.,Loriaux L. Glucocorticoid therapy in the intensive care unit. N Engl J Med. 2004,350(16):1601-1602.中華醫(yī)學(xué)會神經(jīng)外科學(xué)分會.中國神經(jīng)外科重癥管理專家共識.中華醫(yī)學(xué)雜志2013,93:1765-1778,神經(jīng)外科領(lǐng)域應(yīng)用糖皮質(zhì)激素情況,引子,激素減

3、少腦水腫？修復(fù)血腦屏障？同樣是中樞神經(jīng)系統(tǒng)，為什么大劑量激素有益于脊髓損傷卻對腦外傷有害？糖皮質(zhì)激素可以減少腦損傷導(dǎo)致的HPA軸損傷？,為什么應(yīng)用激素？,糖皮質(zhì)激素抑制免疫系統(tǒng)、擴散細菌感染？糖皮質(zhì)激素擾亂血糖代謝，導(dǎo)致高血糖風(fēng)險？糖皮質(zhì)激素導(dǎo)致應(yīng)激性消化道潰瘍風(fēng)險？……,為什么反對應(yīng)用激素？,NASCIS IJAMA 1984; 251:45-52,,影響糖皮質(zhì)激素治療中樞神經(jīng)損傷的臨床多中心研究:（The Nationa

4、l Acute Spinal Cord Injury Study, NASCIS）,引子,劑量：100mg~1000mg團注，然后25~250mg q6h，10天 結(jié)論：與對照組相比，無效，反而影響傷口預(yù)后陰性原因：可能是用藥太遲，劑量不夠以及應(yīng)用時間過長,方案：487 例:傷后8小時啟用，24小時療程：第1h劑量 30mg/kg 靜脈用, 其余23小時劑量5.4mg/kg/h 對照組為納洛酮和安慰劑結(jié)論：6個月隨訪，MP

5、治療促進神經(jīng)功能恢復(fù)，完全和不完全 SCI均有效，而對照組無明顯療效,NASCIS IINEJM 1990; 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 后續(xù) 23 h167 例:第1h MP 30 mg/kg+ 5.4 mg/kg/h后續(xù) 47 hrs 166 例:Tirilazad（ 替拉扎特，

6、一種抗氧化藥）2.5 mg/kg q6h × 48 hrsConclusions：如果傷后3小時內(nèi)接受MP，其療程應(yīng)該延續(xù)到24 hrs.如果傷后3-8小時內(nèi)接受MP,其療程應(yīng)該延續(xù)到48 hrs. 小于8小時內(nèi)應(yīng)用者均有效減輕脊髓損傷,引子,甲強龍劑量：第一個4小時: 2g 靜脈輸注. 然后以 0.4g/h 持續(xù)48h，劑量 達到19.2g總劑量: 48小時內(nèi)21.2g,引子,Roberts I, Yates

7、 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

8、-1328.,CRASH試驗- 49個國家、239家醫(yī)院 ，歷時5年（1999- 2004). 計劃納入GCS<14TBI10008 例（傷后8hs). 隨機分為 MP 和安慰劑組（靜脈持續(xù)輸注48hs )MP組死亡率明顯高于對照組 原因不明,早期應(yīng)用高劑量MP可導(dǎo)致液壓打擊TBI模型死亡率增高,模擬CRASH動物實驗,Chen X, Zhang KL, Yang SY, Dong JF, Zhang JN. Glucoc

9、orticoids aggravate retrograde memory deficiency associated with traumatic brain injury in rats. J Neurotrauma. 2009 Feb 11;26:253-60.,糖皮質(zhì)激素應(yīng)用與TBI后腦水腫,Patent No. of Small animal stereo fixture：CN200610129584.8,Chen X, Zh

10、ang 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.,生理劑量甲強龍可以減少TBI后腦水腫，減少BBB破壞和促進緊密連接蛋白高表達（Claudin

11、5),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

12、:69-80.,糖皮質(zhì)激素應(yīng)用與TBI后腦水腫,生理劑量MP不誘導(dǎo)神經(jīng)損傷,Physiological 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 Neurotr

13、auma 2009,26:253; Zhang B, et al. Brain Res 2011,1382: 165-72,高劑量MP導(dǎo)致下丘腦凋亡神經(jīng)元增多,Injury ControlHE Staining,Injury ControlTUNEL Staining,High-dose GCsHE Staining,High-dose GCsTUNEL Staining,,,To investigate the underly

14、ing 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 insufficiency a

15、ssociated with traumatic brain injury in rats. Brain Res. 2011 Mar 25;1382:298-307.,高劑量MP導(dǎo)致垂體前葉凋亡神經(jīng)細胞增多,To investigate the underlying cause of increased mortality induced by high-dose GCs application,Chen X, Zhang B, Cha

16、i Y, Dong B, Lei P, Jiang R, Zhang J. Methylprednisolone exacerbates 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

17、糖皮質(zhì)激素代謝變化,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.: Stress function of survival and dead rats 7 days after FPI: The peak

18、 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大鼠的激素應(yīng)激不足,Fig. The Stress Insufficiency of Dead and Survival Rats after day 7：The CII

19、of dead rats (1.352) significantly lowered as compared to survival rats (5.5) and these rats (5.496) before FPI.,TBI大鼠的激素應(yīng)激不足,Fig. The incidence of Stress Insufficiency (SI) 7 days after TBI：The incidence of SI (58.3%) i

20、n High-dose MP group was significantly higher than that of SI in Low-dose MP group (6.7%) and that of SI in Injury Control group (13.3%).,不同劑量MP對7天期TBI大鼠的激素分泌影響,Fig. The incidence of Stress Insufficiency (SI) 14 days aft

21、er 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.,不同劑量MP對晚期TBI大鼠的激素分泌影響,＜,＞,TBI患者繼發(fā)HPA軸損傷,急性腦外傷可導(dǎo)致原發(fā)與繼發(fā)性

22、HPA軸損傷。不同性質(zhì)的損傷和不同嚴重程度的腦外傷有不同的特征性的激素變化，而這些變化又與患者的臨床表現(xiàn)、并發(fā)癥和預(yù)后等密切相關(guān),,TBI患者的激素抑制實驗,48 Cases.接受地塞米松抑制實驗（dexamethasone suppression test, DST)。在傷后 1,3, 4, 5天取血測Cortisol水平。而1.5mg地塞米松應(yīng)于損傷后3天的24:00pm口服。血清Cortisol水平降低超過服藥前的50%者被診斷為

23、DST陽性反應(yīng)，而少于50%者認為是DST陰性反應(yīng)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

24、The suppression rate of DST increased with the GCS score reduced.,A,B,Mild,Moderate,Severe,GCS score,Inhibition rate,DXM suppression rate,TBI傷情越重發(fā)生DST陰性反應(yīng)者比例越高；而DST陽性者則預(yù)后更好.,Mild,Moderate,Severe,Type of TBI,Case numbers,

25、Positive,Negative,TBI患者的激素抑制實驗,The critical illness related corticosteroid insufficiency (CIRCI),HPA軸是最重要的內(nèi)分泌軸，HPA軸損傷，可以導(dǎo)致應(yīng)激糖皮質(zhì)激素分泌不良(CIRCI,) CIRCI則嚴重影響多系統(tǒng)疾病。,Lim SY, et al. Prognostic significance of different subgroup

26、classifications of critical illness-related corticosteroid insufficiency in patients with septic shock. Shock. 2011 Oct;36(4):345-9.,TBI患者激素補充原則,TBI后, GCs治療目標(biāo)應(yīng)該不是腦水腫而是HPA軸相關(guān)損傷.中型和重型TBI約60%發(fā)生HPA功能異常 （CIRCI)我們觀察的48例患者中，

27、輕中重三種類型TBI的DST陰性率分別是 10.53%, 60% and 63.15%.發(fā)生HPA軸損傷的TBI患者，在亞急性期接受應(yīng)激劑量GCs可以降低其并發(fā)癥與死亡率,TBI 3天內(nèi)，避免大劑量GCs 通過檢測血清GCs可以部分了解患者是否發(fā)生了CIRCI，必要時持續(xù)補充GCs對于確定發(fā)生HPA軸損傷者，必需補充應(yīng)激劑量GCs TBI中晚期，也應(yīng)該評價其HPA軸損傷情況，視情況補充GCs,TBI患者激素補充原則,A. Hi

28、gh-dose,B. Continuous,C. Optimum,D. Replacement,A,B,C,D,Multicenter, randomized, double-blind, placebo-controlled HYPOLYTE (Hydrocortisone Polytraumatise) study. 納入了149 例重型外傷患者，復(fù)蘇后患者被隨機分配來接受氫化考的松治療 (200 mg/d 連續(xù) 5 days,第6

29、天100mg，第7天50mg)或安慰劑治療.結(jié)果顯示：糖皮質(zhì)激素不足（corticosteroid insufficiency , CI)與系統(tǒng)性炎癥密切相關(guān)，接受應(yīng)激劑量氫化考的松者發(fā)生院內(nèi)感染性肺炎比例最低.,Main Outcome MeasurePrimary：院內(nèi)獲得性肺感染 Secondary：呼吸機使用時間，是否低鈉及死亡.,Roquilly A, et al. JAMA. 2011 Mar 23;305(12):1

30、201-9,Backgrounds：,Roquilly：TBI患者補充激素，可以改善預(yù)后,HYPOLYTE clinical trial,Roquilly A, et al. JAMA. 2011 Mar 23;305(12):1201-9,Roquilly：TBI補充激素，可以降低HAP發(fā)病率,Roquilly A, et al. JAMA. 2011 Mar 23;305(12):1201-9,Roquilly：TBI補充激素，可以

31、減少呼吸機使用機會,,,P=0.03*,P=0.002*,All patients,Patients with Corticosteroids insufficiency,Change 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 st

32、ratified Cox model. ?secondary outcome on day 28.,Roquilly：TBI補充激素，可以降低減少ICU住院時間,All patients,Patients with corticosteroid insufficiency,,,3%,5%,P=0.44,P=0.23,Mortality rates*,*secondary outcome on day 28.,Roquilly A, et

33、 al. JAMA. 2011 Mar 23;305(12):1201-9,Roquilly：TBI糖皮質(zhì)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補充要點,TBI早期，避免高劑量GCs部分TBI患者長期血清低GCs，需早作評價

34、和盡早補充.檢查HPA軸功能很重要，如果確定HPA軸損傷，需要給予適量GCs補充. TBI晚期，需要評價HPA軸功能，如果需要，還需及時補充GCs.,TBI后的其他激素的異常,25%–80%發(fā)生中樞性性腺功能低下2%–15甲狀腺功能低下 50%高泌乳素18%生長激素低下13%低皮質(zhì)醇,mTBI和sTBI,TBI后的其他激素的異常,45例sTBI,早晨1~4天 08-10am cortisol,GH, PRL, IGF-1,

35、TSH, fT3, fT4, FSH, LH,T and SHBG(men).下午1~4天 17-19pm cortisol, GH,Olivecrona Z1, Dahlqvist P, Koskinen LO.Acute neuro-endocrine profile and prediction of outcome after severe brain injury.Scand J Trauma Resusc Emerg Med

36、. 2013 ,21:33.,TBI后的其他激素的異常,結(jié)論：sTBI1~4天垂體軸相關(guān)激素明顯代謝異常。大部分患者Cortisol低于臨界低限值，提示腎上腺分泌不足，但卻與患者預(yù)后差無相關(guān)關(guān)系。早期垂體-性腺軸的強抑制與患者預(yù)后較好相關(guān)。長時間抑制甲狀腺功能則導(dǎo)致高死亡率和預(yù)后功能不良。該研究結(jié)果還待進一步評估,TBI后的內(nèi)分泌異常需要加強研究,TBI后GCs分泌異常，它與垂體下丘腦其他激素如T3、T4、FSH及其他激素變化規(guī)律及功能