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蛛网膜下腔出血颅内血管痉挛及炎症的相关标记物探讨

作者 / Author:曲良卓

摘要 / Abstract:

目的 探讨蛛网膜下腔出血(SAH)患者脑脊液(CSF)中白细胞介素-6(IL-6)及其他生物标记对早期诊断脑血管痉挛及脑室炎的价值。方法 选取80例SAH患者为研究对象,自脑室外引流中获取CSF并分离相关的血清生物标记物,通过曲线下面积(AUC)、截止值、敏感度与特异性评估各标记物与脑血管痉挛、脑室炎及并发症的关系。结果 33例患者发生脑血管痉挛,21例发生脑室炎,26例为单纯SAH,3组IL-6水平分别为(7 621±4 438)pg/mL、(4 117±4 652)pg/mL、(244.9±24

关键词 / KeyWords:

蛛网膜下腔出血,脑室炎,脑血管痉挛,标记物,脑脊液,血清

蛛网膜下腔出血颅内血管痉挛及炎症的相关标记物探讨

曲良卓
开封市中心医院检验科,河南 开封 475000
作者简介:曲良卓,Email:lixin7607@163.com
【摘要】  目的  探讨蛛网膜下腔出血(SAH)患者脑脊液(CSF)中白细胞介素-6(IL-6)及其他生物标记对早期诊断脑血管痉挛及脑室炎的价值。方法  选取80例SAH患者为研究对象,自脑室外引流中获取CSF并分离相关的血清生物标记物,通过曲线下面积(AUC)、截止值、敏感度与特异性评估各标记物与脑血管痉挛、脑室炎及并发症的关系。结果  33例患者发生脑血管痉挛,21例发生脑室炎,26例为单纯SAH,3组IL-6水平分别为(7 621±4 438)pg/mL、(4 117±4 652)pg/mL、(244.9±240.5)pg/mL(P<0.001);CSF内IL-6水平能够很好地评估区分脑室炎及单纯SAH(AUC 1.00,截止值707 pg/mL,敏感度100%,特异性100%),而区分脑血管痉挛与脑室炎的潜力为中等。血管痉挛患者CSF中IL-6水平显著高于单纯SAH患者。结论  SAH患者发生脑血管痉挛或脑室炎时CSF的IL-6水平明显升高,可通过截止值确定具体的并发症类型,以辅助指导及早给予临床干预。
【关键词】  蛛网膜下腔出血;脑室炎;脑血管痉挛;标记物;脑脊液;血清
【中图分类号】  R743.35    【文献标识码】  A    【文章编号】  1673-5110(2018)19-2165-06  DOI:10.12083/SYSJ.2018.19.470
Discussion on related markers of intracranial vasospasm and inflammation in subarachnoid hemorrhage
QU Liangzhuo
Department of Clinical LaboratoryKaifeng Central HospitalKaifeng 475000,China
Abstract】  Objective  To investigate the value of interleukin-6 (IL-6) and other biomarkers in cerebrospinal fluid (CSF) in patients with subarachnoid hemorrhage (SAH) for early diagnosis of cerebral vasospasm and ventriculitis.Methods  Eighty patients with SAH were enrolled in the study.CSF was obtained from extraventricular drainage and related serum biomarkers were isolated.The markers and cerebral vasospasm were evaluated by area under the curve (AUC),cutoff,sensitivity and specificity.The relationship between ventriculitis and complications.Results  33 patients developed cerebral vasospasm,21 patients developed ventriculitis,26 patients were treated with SAH alone,and the average IL-6 levels in the 3 groups were (7 621±4 438) pg/mL,(4 117±4 652) pg/mL,(244.9 ±240.5) pg/mL (P<0.001);IL-6 levels in CSF can be well assessed to distinguish between ventriculitis and SAH alone (AUC 1.00,cut-off 707 pg/mL,sensitivity 100%,specificity 100%) And the potential to distinguish between cerebral vasospasm and ventriculitis is moderate.IL-6 levels in CSF were significantly higher in patients with vasospasm than in patients with SAH alone.Conclusion  The level of IL-6 in CSF is significantly increased in patients with SAH after cerebral vasospasm or ventriculitis.The specific type of complications can be determined by cut-off value to assist in early clinical intervention.
Key words】  Subarachnoid hemorrhage;Ventricular inflammation;Cerebral vasospasm;Marker;Cerebrospinal fluid;Serum
      动脉瘤性蛛网膜下腔出血是神经外科的常见急症之一,脑血管痉挛及颅内感染可显著增加发病率及病死率[1-3]。研究显示,红细胞进入蛛网膜下腔及其后产生的裂解能够激活机体的免疫反应,增加CSF内的促炎症细胞因子水平,其可使患者临床预后恶化[4-5]。因此,本研究探讨IL-6及其他生物因子对脑室炎的诊断价值,并与单纯SAH患者的分子水平进行对比研究。
1  资料与方法
11  研究对象  选取2014-01—2016-12治疗的80例SAH患者为研究对象,依据Fisher分级及世界神经外科医师联盟(WFNS)分级系统对SAH的严重程度进行评估[6-7];通过CT、MRI及数字减影全脑血管造影(DSA)等检查手段确认出血点并进行相应血管夹闭等干预治疗。
12  血清及CSF生物标记物  脑室外引流的适应证为脑室内出血及脑积水和(或)不可评估的神经功能状态,放置引流管前静脉给予头孢呋辛抗生素预防。通过三通旋塞在严格无菌操作下抽取CSF样本,按照SAH常规诊疗,每日监测CSF内的IL-6、C反应蛋白及白细胞计数,每周2次监测血清降钙素原水平,或伴细菌感染或败血症则增加检测的频率。
13  脑血管痉挛及脑室炎的定义  脑室炎定义为CSF培养显示存在阳性微生物,临床存在感染的征象;葡萄糖水平<40 mg/dL或<50%血清葡萄糖水平;CSF蛋白水平升高(>50 mg/dL);CSF细胞数异常增多(100个/mm3);CSF革兰染色阳性。脑血管痉挛符合以下3个标准中的至少1项:(1)新出现的神经损害;(2)经颅多普勒超声检查示大脑中动脉或前动脉血流速度>120 cm/s,Lindegaard指数阳性,大脑中动脉与颈内动脉血流比值>3;(3)影像学检查存在脑血管痉挛。
14  统计学方法  采用SPSS 20.0软件,受试者工作特征曲线及曲线下面积用于评价每个生物标记物的诊断潜能;Youden J统计用于获得最大灵敏度与特异性的截止值;主要结果参数为阳性似然比(+LR)、阴性似然比(-LR)、敏感度及特异性;P<0.05为差异有统计学意义。
2  结果
21  患者基本信息  本组患者年龄(56.5±13.8)岁,男女比例为23∶17;79例患者出血原因为动脉瘤,其中10例存在动静脉的畸形;33例出现脑血管痉挛[出血后(5.8±4.4)d];WFNS分级≥IV与脑血管痉挛的发生显著相关(P<0.01);21例出现脑室炎[出血后(7.6±3.0)d];26例内未发现脑室炎与脑血管痉挛,为单纯SAH患者。
22  脑室炎与脑血管痉挛的生物标记物  首次诊断时脑室炎与脑血管痉挛前患者的CSF内IL-6含量分别(7 621±4 438)pg/mL、(4 117±4 652) pg/mL(P=0.66),显著高于单纯SAH患者的(244.9±240.5)pg/mL(P<0.01);脑室炎的AUC为0.847,截止值为3 200 pg/mL(敏感度86.4%,特异性83.6%,+LR 4.7,-LR 0.20)。
      脑室内的IL-6对鉴别脑室炎与单纯SAH具有非常优秀的诊断潜能(AUC 1.00,截止值712 pg/mL,敏感度100%,特异性100%,+LR ∞,-LR 0);脑血管痉挛患者CSF中IL-6水平显著高于单纯SAH出血患者(AUC 0.868,截止值540 pg/mL,敏感度88.0%,特异性92.1%,+LR 11.2,-LR 0.17);区分脑室炎与脑血管痉挛的诊断潜能为中度(AUC 0.766,截止值3 200 pg/mL,敏感度85.2%,特异性68.4%,+LR 2.7,-LR 0.16)(图1);血清IL-6分子表达对鉴别脑室炎与血管痉挛(P=0.66)或与单纯SAH无显著差异(P=0.98);CSF与血清IL-6含量比值在引流相关感染病例内显著高于单纯SAH者(P=0.003),而与脑室炎患者无显著性差异(P=0.12,表1)。
      脑室炎患者CSF内多形核细胞百分比与单纯出血患者相比亦显著升高(P=0.04),显著高于脑血管痉挛患者(P=0.03);血清C反应蛋白无显著性差异,其他参数与病情进展未见显著性关联(表1)。
表1  血清与CSF标记物对脑室炎的诊断潜能评价
Table 1  Evaluation of the diagnostic potential of serum and CSF markers for ventriculitis 
项目 CSF多形细胞百分比/% CSF与血清IL-6比值 血清IL-(pg/mL) 血清CRP (mg/dL)
AUC(95% CI) 0.772(0.6450.948) 0.796(0.6380.945) 0.585(0.4080.775) 0.667(0.5320.887)
截止值 65 55.8 11.2 5.9
敏感度(95% CI) 83.7(56.294.2) 87.5(60.397.2) 100(87.6100) 59.4(37.680.4)
特异性(95% CI) 75.2(48.383.5) 66.5(48.083.3) 23.2(10.038.7) 76.5(60.388.7)
阳性似然比(95% CI) 2.6(1.254.78) 2.7(1.444.99) 1.33(1.141.76) 2.44(1.185.03)
阴性似然比(95% CI) 0.21(0.090.79) 0.18(0.070.82) 0 0.50(0.341.05)

曲良卓10.jpg

图1  CSF IL-6鉴别脑室炎与单纯SAH、脑血管痉挛与单纯SAH、脑室炎与脑血管痉挛的临床诊断潜能比较
Figure 1  Comparison of clinical diagnosis potential of CSF IL-6ventricular inflamma-tion and simple SAHcerebral vasospasm and simple SAHventriculitis and cerebral vasospasm
3  讨论
      严重SAH患者通常处于插管及昏迷状态,临床表现及神经损害评估对预测具体的病理进展程度的作用十分有限[8-14]。由于脑室外引流相关的感染概率可增加约27%,抗生素的预防使用往往使革兰染色与细菌培养的阳性率降低[15-20]。文献报道SAH伴脑血管痉挛发生概率可达47%左右,然而可能受不同诊断标准影响,不同研究间的可比性有限[5-6,21-30]。本研究中脑血管痉挛的发生率为42.9%,且其与Fisher分级、患者临床预后较差相关。
      本研究主要目的在于评价血清和CSF内可溶性炎症生物标记物与脑室炎、脑血管痉挛早期诊断的相关性,其中重点评价了IL-6分子的表达,原因为目前大量的文献均报道其与颅内出血、脑外伤、脑膜炎等多种病变相关[31-40]。研究发现,IL-6的表达水平在SAH患者中显著升高,根据其相关的截止值还可有效对患者的脑血管痉挛与脑室炎进行区分,这与文献中的观点一致[41-43]。除此还发现,CSF与血清IL-6水平的比值与单独的CSF内IL-6水平相比并不能提高诊断的准确性,血清IL-6与CRP分子水平无法进一步评价患者病情的进展,分析原因可能为脑室炎为局部区域的炎症反应,对机体整个系统的影响性较小[44-49]
      除IL-6分子外,CSF内的多形核细胞百分比在脑室炎患者内显著升高,诊断的可靠性为中等,主要由于脑出血后红细胞在CSF内降解[50-51]。研究报道[52-57],多形细胞百分比对评价神经外科手术后脑膜炎的敏感性为94%,特异性为28%;研究显示,多形细胞百分比能够有效鉴别细菌性与坏死性脑膜炎[58-60]。因此,此参数可较好地辅助临床相关诊断,其中包括脑室外引流相关的脑室炎。
      本研究初步证实,SAH患者发生脑血管痉挛或脑室炎时CSF内IL-6水平明显升高,可通过截止值确定具体的并发症类型,以辅助指导及早给予临床干预。
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(收稿2017-10-15  修回2018-08-28)
本文责编:夏保军
本文引用信息:曲良卓.蛛网膜下腔出血颅内血管痉挛及炎症的相关标记物探讨[J].中国实用神经疾病杂志,2018,21(19):2165-2170.DOI:10.12083/SYSJ.2018.19.470
Reference information:QU Liangzhuo.Discussion on related markers of intracranial vasospasm and inflammation in subarachnoid hemorrhage[J].Chinese Journal of Practical Nervous Diseases,2018,21(19):2165-2170.DOI:10.12083/SYSJ.2018.19.470

 

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