咪达唑仑对中重型颅脑损伤患者炎性介质的影响

Effect of midazolam on inflammatory mediators in patients with moderate and severe brain injury

目的通过观察咪达唑仑对中重型颅脑损伤患者炎症反应的影响，探讨咪达唑仑的脑保护作用及机制。方法采用前瞻性研究方法，选择2013年4月至2016年7月江苏省苏北人民医院重症加强治疗病房（ICU）收治的120例中重型颅脑损伤患者，按随机数字表法分为常规治疗组（58例）和咪达唑仑组（62例）。两组均给予常规西医治疗，有手术指征者予以手术；咪达唑仑组在常规治疗基础上先静脉注射咪达唑仑2～3mg，再以0．05。0．10mg·kg^-1·h^-1持续静脉泵入，手术治疗患者于术后3h开始使用。于治疗前和治疗后24、48、72h测定平均动脉压（MAP）、心率（HR）、Riker镇静躁动评分（SAS）、脑电双频谱指数（BIS）；采用双抗体夹心酶联免疫吸附试验（ELISA）测定脑脊液及血浆白细胞介素-6（IL-6）、可溶性神经趋化蛋白（sFkn）水平；记录患者癫痫发生率及28d病死率。结果两组患者治疗前后MAP、HR稳定，差异均元统计学意义（均P〉0．05）。与治疗前比较，两组治疗后SAS和BIS均逐渐降低，72h达到最低[SAS评分（分）：常规治疗组为3．8±1．0比5．7±2．0，咪达唑仑组为3．6±0．9比5．8±1．7；BIS：常规治疗组为69±12比82±12，咪达唑仑组为72±15比82±12，均P〈O．05]，但两组间比较差异均无统计学意义（均P〉0．05），提示两组均达到了预期的镇静目标。ELISA结果显示：与治疗前比较，常规治疗组治疗24h后脑脊液IL-6、sFkn和血浆sFkn水平均呈短暂升高随后逐渐下降的趋势，血浆IL-6则持续降低；而咪达唑仑组各指标则从治疗24h起即表现出下降的趋势，并持续至72h。治疗后咪达唑仑组各时间点脑脊液及血浆IL-6、sFkn水平均明显低于常规治疗组，以72h达最低水平[脑脊液：IL-6（ng／L）为251．6±145．7比347．3±146．4，sFkn（ng/L）为289．7±79.3比423．6±132．8；血浆：IL-6为54．4±27．3比85．6±41．8，sFkn为919．9±426．3比1199．4±414．8，均P〈0．05]。咪达唑仑组癫痫发生率明显低于常规治疗组[1．61％（1／62）比10．34％（6／58），P〈0．05]，但两组28d病死率比较差异无统计学意义[11．29％（7／62）比10．34％（6／58），P〉0．05]。结论咪达唑仑可减少中重型颅脑损伤患者癫痫的发生，其脑保护作用可能与降低脑脊液及血浆IL-6、sFkn水平有关。

Objective To investigate the effect of midazolam on inflammatory response in patients with moderate and severe craniocerebral injury and its protective effect on the brain and mechanism. Methods A prospective study was conducted. One hundred and twenty patienis with moderate and severe craniocerebral injury admitted to the Intensive Care Unit （ICU） of Jiangsu Subei Peoples＇ Hospital from April 2013 to July 2016 were enrolled, and they were divided into a conventional treatment group （58 cases） and a midazolam group （62 cases） according to the random number table method. Both groups were given conventional western medicine treatment, and in cases with surgical indications, operations were performed; in midazolam group, additionally intravenous injection of midazolam 2 - 3 mg was given firstly, and then continuous intravenous infusion of the drug 0.05 - 0.10 mg· kg^-1· h^-1 was applied by a pump, and in operative patients, the above management was given 3 hours after operation. The mean arterial pressure （MAP）, heart rate （HR）, Riker sedation agitation score （SAS） and electroencephalogram bispectral index （BIS） were measured before and after treatment for 24, 48 and 72 hours, respectively. The levels of interleukin-6 （IL-6） and soluble nerve chemotactic protein （sFkn） in plasm and cerebrospinal fluid （CSF） were measured by double antibody sandwich enzyme linked immunosorbent assay （ELISA） at each time point; the incidence of epilepsy and 28-day mortality were recorded. Results Before and after treatment, the MAP and HR in the two groups of patients were stable, the difference being not statistically significant （both P 〉 0.05）. Compared with those before treatment, after treatment the SAS score and BIS in two groups of patients were gradually decreased, and at 72 hours reached the lowest levels （SAS score： conventional treatment group was 3.8 ± 1.0 vs. 5.7± 2.0, midazolam group was 3.6 ± 0.9 vs. 5.8 ± 1.7; BIS： conventional treatment group was 69± 12 vs. 82± 12, midazolam group was 72± 15 vs. 82± 12, all P 〈 0.05）, but there were no significant differences between the two groups （all P 〉 0.05）, suggesting that the two groups had achieved the desired goal of sedation. ELISA results showed： compared with those before treatment, after treatment for 24 hours, the CSF IL-6, sFkn and plasm sFkn levels were temporarily increased in short term, and then showed a tendency of gradually decreasing, and the plasm IL-6 presented persistently descending in the conventional treatment group, while in the midazolam group, since 24 hours after treatment, each index showed a trend of decrease and continued to 72 hours. After treatment at each time point, the CSF and plasm levels of IL-6 and sFkn were significantly lower in midazolam group than those of the conventional treatment group, and reached to the minimal levels at 72 hours [CSF： IL-6 （ng/L） was 251.6± 145.7 vs. 347.3± 146.4, sFkn （ng/L）： 289.7 ± 79.3 vs. 423.6± 132.8; plasm： IL-6 （ng/L） was 54.4 ± 27.3 vs. 85.6±41.8, SFkn （ng/L）： 919.9±426.3 vs. 1 199.4±414.8, all P 〈 0.05]. The incidence of epilepsy in the midazolam group was obviously lower than that in the conventional treatment group [1.61% （1/62） vs. 10.34% （6/58）, P 〈 0.05], but there was no significant difference between midazolam group and the conventional treatment group in the 28-day mortality [11.29% （7/62） vs. 10.34% （6/58）, P 〉 0.05]. Conclusion Midazolam can reduce the incidence of epilepsy in patients with moderate and severe traumatic brain injury, and its brain protective effect may be related to the decrease of CSF and plasm IL-6 and sFkn levels.