Value of cerebral hypoxic-ischemic injury markers in the early diagnosis of sepsis associated encephalopathy in burn patients with sepsis
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摘要:
目的 探讨脑缺血缺氧性损伤标志物在烧伤脓毒症患者脓毒症相关性脑病（SAE）早期诊断中的价值。 方法 采用回顾性病例系列研究方法。2018年10月—2021年5月，郑州市第一人民医院收治41例符合入选标准的烧伤脓毒症患者，其中男23例、女18例，年龄18~65（35±3）岁。按住院期间是否发生SAE，将患者分为SAE组（21例）及非SAE组（20例）。比较2组患者性别、年龄、深Ⅱ度烧伤面积、Ⅲ度烧伤面积、急性生理学和慢性健康状况评价Ⅱ（APACHE Ⅱ）评分。统计2组患者脓毒症确诊后（以下简称确诊后）12、24、48 h的血清中枢神经特异蛋白S100β、神经元特异性烯醇化酶（NSE）水平，确诊后12、24、48、72、120、168 h血清白细胞介素6（IL-6）、IL-10、肿瘤坏死因子α（TNF-α）、Tau蛋白、促肾上腺皮质激素（ACTH）、皮质醇水平，确诊后1、3、7 d大脑中动脉平均血液流速（VmMCA）、搏动指数、脑血流指数（CBFi）。对数据行 χ 2检验、重复测量方差分析、独立样本 t检验及Bonferroni校正，行多因素logistic回归分析筛选预测SAE发生的自变量，绘制预测烧伤脓毒症患者发生SAE的受试者操作特征（ROC）曲线，计算曲线下面积（AUC）和最佳阈值及最佳阈值下的敏感度、特异度。 结果 2组患者性别、年龄、深Ⅱ度烧伤面积、Ⅲ度烧伤面积、APACHE Ⅱ评分均相近（ χ 2=0.02， t值分别为0.71、1.59、0.91、1.07， P>0.05）。确诊后12、24、48 h，SAE组患者血清S100β、NSE水平均明显高于非SAE组（ t值分别为37.74、77.84、44.16，22.51、38.76、29.31， P<0.01）。确诊后12、24、48、72、120、168 h，SAE组患者血清IL-10、Tau蛋白、ACTH水平均明显高于非SAE组（ t值分别为10.68、13.50、10.59、8.09、7.17、4.71，5.51、3.20、3.61、3.58、3.28、4.21，5.91、5.66、4.98、4.69、4.78、2.97， P<0.01）；确诊后12、24、48、72、120 h，SAE组患者血清IL-6、TNF-α水平均明显高于非SAE组（ t值分别为8.56、7.32、2.08、2.53、3.37，4.44、5.36、5.35、6.85、5.15， P<0.05或 P<0.01）；确诊后12、24、48 h，SAE组患者血清皮质醇水平均明显高于非SAE组（ t值分别为5.44、5.46、3.55， P<0.01）。确诊后1 d，SAE组患者VmMCA、CBFi均明显低于非SAE组（ t值分别为2.94、2.67， P<0.05）；确诊后1、3、7 d，SAE组患者搏动指数均明显高于非SAE组（ t值分别为2.56、3.20、3.12， P<0.05或 P<0.01）。确诊后12 h的血清IL-6、确诊后24 h的血清Tau蛋白、确诊后24 h的血清ACTH、确诊后24 h的血清皮质醇为烧伤脓毒症患者发生SAE的独立危险因素（比值比分别为2.42、1.38、4.29、4.19，95%置信区间分别为1.76~3.82、1.06~2.45、1.37~6.68、3.32~8.79， P<0.01）。对41例烧伤脓毒症患者，确诊后12 h的血清IL-6预测SAE发生的ROC的AUC=0.92（95%置信区间为0.84~1.00），最佳阈值为157 pg/mL，敏感度为81%，特异度为89%；确诊后24 h的血清Tau蛋白预测SAE发生的ROC的AUC=0.92（95%置信区间为0.82~1.00），最佳阈值为6.4 pg/mL，敏感度为97%，特异度为99%；确诊后24 h的血清ACTH预测SAE发生的ROC的AUC=0.96（95%置信区间为0.89~1.00），最佳阈值为14.7 pg/mL，敏感度为90%，特异度为94%；确诊后24 h的血清皮质醇预测SAE发生的ROC的AUC=0.93（95%置信区间为0.86~1.00），最佳阈值为89 nmol/L，敏感度为94%，特异度为97%。 结论 血清Tau蛋白和ACTH、皮质醇对烧伤脓毒症患者并发SAE具有较高临床诊断价值。 Abstract:Objective To explore the value of cerebral hypoxic-ischemic injury markers in the early diagnosis of sepsis associated encephalopathy (SAE) in burn patients with sepsis. Methods A retrospective case series study was conducted. From October 2018 to May 2021, 41 burn patients with sepsis who were admitted to Zhengzhou First People's Hospital met the inclusion criteria, including 23 males and 18 females, aged 18-65 (35±3) years. According to whether SAE occurred during hospitalization, the patients were divided into SAE group (21 cases) and non-SAE group (20 cases). The gender, age, deep partial-thickness burn area, full-thickness burn area, and acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) scores of patients were compared between the two groups. The serum levels of central nervous system specific protein S100β and neuron specific enolase (NSE) at 12, 24, and 48 h after sepsis diagnosis (hereinafter referred to as after diagnosis), the serum levels of interleukin-6 (IL-6), IL-10, tumor necrosis factor α (TNF-α), Tau protein, adrenocorticotropic hormone (ACTH), and cortisol at 12, 24, 48, 72, 120, and 168 h after diagnosis, and the mean blood flow velocity of middle cerebral artery (VmMCA), pulsatility index, and cerebral blood flow index (CBFi) on 1, 3, and 7 d after diagnosis of patients in the two groups were counted. Data were statistically analyzed with chi-square test, analysis of variance for repeated measurement, independent sample t test, and Bonferroni correction. The independent variables to predict the occurrence of SAE was screened by multi-factor logistic regression analysis. The receiver operating characteristic (ROC) curve was drawn for predicting the occurrence of SAE in burn patients with sepsis, and the area under the curve (AUC), the best threshold, and the sensitivity and specificity under the best threshold were calculated. Results The gender, age, deep partial-thickness burn area, full-thickness burn area, and APACHE Ⅱ score of patients in the two groups were all similar ( χ 2=0.02, with t values of 0.71, 1.59, 0.91, and 1.07, respectively, P>0.05). At 12, 24, and 48 h after diagnosis, the serum levels of S100β and NSE of patients in SAE group were all significantly higher than those in non-SAE group (with t values of 37.74, 77.84, 44.16, 22.51, 38.76, and 29.31, respectively, P<0.01). At 12, 24, 48, 72, 120, and 168 h after diagnosis, the serum levels of IL-10, Tau protein, and ACTH of patients in SAE group were all significantly higher than those in non-SAE group (with t values of 10.68, 13.50, 10.59, 8.09, 7.17, 4.71, 5.51, 3.20, 3.61, 3.58, 3.28, 4.21, 5.91, 5.66, 4.98, 4.69, 4.78, and 2.97, respectively, P<0.01). At 12, 24, 48, 72, and 120 h after diagnosis, the serum levels of IL-6 and TNF-α of patients in SAE group were all significantly higher than those in non-SAE group (with t values of 8.56, 7.32, 2.08, 2.53, 3.37, 4.44, 5.36, 5.35, 6.85, and 5.15, respectively, P<0.05 or P<0.01). At 12, 24, and 48 h after diagnosis, the serum level of cortisol of patients in SAE group was significantly higher than that in non-SAE group (with t values of 5.44, 5.46, and 3.55, respectively, P<0.01). On 1 d after diagnosis, the VmMCA and CBFi of patients in SAE group were significantly lower than those in non-SAE group (with t values of 2.94 and 2.67, respectively, P<0.05). On 1, 3, and 7 d after diagnosis, the pulsatile index of patients in SAE group was significantly higher than that in non-SAE group (with t values of 2.56, 3.20, and 3.12, respectively, P<0.05 or P<0.01). Serum IL-6 at 12 h after diagnosis, serum Tau protein at 24 h after diagnosis, serum ACTH at 24 h after diagnosis, and serum cortisol at 24 h after diagnosis were the independent risk factors for SAE complicated in burn patients with sepsis (with odds ratios of 2.42, 1.38, 4.29, and 4.19, 95% confidence interval of 1.76-3.82, 1.06-2.45, 1.37-6.68, and 3.32-8.79, respectively, P<0.01). For 41 burn patients with sepsis, the AUC of ROC of serum IL-6 at 12 h after diagnosis for predicting SAE was 0.92 (95% confidence interval was 0.84-1.00), the best threshold was 157 pg/mL, the sensitivity was 81%, and the specificity was 89%. The AUC of ROC of serum Tau protein at 24 h after diagnosis for predicting SAE was 0.92 (95% confidence interval was 0.82-1.00), the best threshold was 6.4 pg/mL, the sensitivity was 97%, and the specificity was 99%. The AUC of ROC of serum ACTH at 24 h after diagnosis for predicting SAE was 0.96 (95% confidence interval was 0.89-1.00), the best threshold was 14.7 pg/mL, the sensitivity was 90%, and the specificity was 94%. The AUC of ROC of serum cortisol at 24 h after diagnosis for predicting SAE was 0.93 (95% confidence interval was 0.86-1.00), the best threshold was 89 nmol/L, the sensitivity was 94%, and the specificity was 97%. Conclusions Serum Tau protein, ACTH, and cortisol have high clinical diagnostic value for SAE complicated in burn patients with sepsis. -
Key words:
- Burns /
- Sepsis /
- Hypoxia-ischemia, brain /
- Brain diseases /
- Serum markers
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参考文献
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表1 2组烧伤脓毒症患者一般情况比较
组别 例数 性别（例） 年龄 （岁， 深Ⅱ度烧伤面积（%TBSA， Ⅲ度烧伤面积 （%TBSA， 急性生理学和慢性健康状况评价Ⅱ评分（分， 男 女 非SAE组 20 21 12 8 38±4 45±7 29±3 22±3 SAE组 13 8 37±5 48±5 28±4 23±3 统计量值 χ 2=0.02 t=0.71 t=1.59 t=0.91 t=1.07 P值 0.901 0.485 0.124 0.369 0.293 注：SAE为脓毒症相关性脑病，TBSA为体表总面积 
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表2 2组烧伤脓毒症患者血清S100β和NSE水平在脓毒症确诊后各时间点的比较（μg/L，
组别与指标 例数 12 h 24 h 48 h SAE组 21 S100β 2.38±0.21 3.52±0.16 2.45±0.18 NSE 18.4±2.2 26.3±1.8 21.8±2.0 非SAE组 20 S100β 0.35±0.12 0.42±0.08 0.38±0.11 NSE 6.3±1.1 8.4±1.0 6.8±1.1 t 1值 37.74 77.84 44.16 P 1值 <0.001 <0.001 <0.001 t 2值 22.51 38.76 29.31 P 2值 <0.001 <0.001 <0.001 注：NSE为神经元特异性烯醇化酶，SAE为脓毒症相关性脑病；S100β、NSE处理因素主效应， F值分别为18.36、7.12， P值均<0.001；时间因素主效应， F值分别为7.11、4.38， P值均<0.001；两者交互作用， F值分别为2.34、0.78， P值均<0.001； t 1值、 P 1值， t 2值、 P 2值分别为组间S100β、NSE于脓毒症确诊后各时间点比较所得
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表3 2组烧伤脓毒症患者SAE血清标志物在脓毒症确诊后各时间点的比较（
组别与指标 例数 12 h 24 h 48 h 72 h 120 h 168 h SAE组 21 IL-6（pg/mL） 237±16 208±19 160±14 135±17 121±20 98±17 IL-10（pg/mL） 30.3±1.8 28.8±1.1 24.4±1.3 19.1±1.1 17.0±1.5 8.1±1.6 TNF-α（pg/mL） 17.1±1.6 15.8±1.5 13.3±1.4 10.8±1.3 8.7±1.0 6.5±1.1 Tau蛋白（pg/mL） 7.0±0.8 11.1±1.1 8.6±1.1 7.1±0.9 6.2±1.1 4.4±1.0 ACTH（pg/mL） 60.8±32.6 78.3±30.2 49.1±28.5 34.8±18.7 25.0±11.2 12.6±4.9 皮质醇（nmol/L） 895±178 1 225±132 602±180 456±84 391±80 329±70 非SAE组 20 IL-6（pg/mL） 191±18 167±16 150±18 122±17 100±20 88±19 IL-10（pg/mL） 25.2±1.2 24.1±1.1 20.4±1.1 16.3±1.1 14.0±1.2 6.1±1.0 TNF-α（pg/mL） 15.1±1.1 13.4±1.2 10.8±1.6 8.5±0.8 7.1±1.0 6.0±0.9 Tau蛋白（pg/mL） 5.4±1.0 9.0±1.1 7.4±1.0 6.1±0.9 5.1±1.0 3.2±0.9 ACTH（pg/mL） 16.3±4.2 18.1±1.3 16.8±5.8 14.8±3.9 12.4±3.4 8.6±3.6 皮质醇（nmol/L） 381±91 431±78 365±102 343±97 302±60 278±49 t 1值 8.56 7.32 2.08 2.53 3.37 1.79 P 1值 <0.001 <0.001 0.045 <0.001 <0.001 0.480 t 2值 10.68 13.50 10.59 8.09 7.17 4.71 P 2值 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 t 3值 4.44 5.36 5.35 6.85 5.15 1.85 P 3值 <0.001 <0.001 <0.001 <0.001 <0.001 0.216 t 4值 5.51 3.20 3.61 3.58 3.28 4.21 P 4值 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 t 5值 5.91 5.66 4.98 4.69 4.78 2.97 P 5值 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 t 6值 5.44 5.46 3.55 2.19 2.10 2.69 P 6值 <0.001 <0.001 <0.001 0.242 0.252 0.066 注：SAE为脓毒症相关性脑病，IL为白细胞介素，TNF-α为肿瘤坏死因子α，ACTH为促肾上腺皮质激素；IL-6、IL-10、TNF-α、Tau蛋白、ACTH、皮质醇处理因素主效应， F值分别为9.42、1.23、20.10、2.43、6.82、1.12， P值均<0.001；时间因素主效应， F值分别为13.41、3.91、23.43、1.92、11.32、2.91， P值均<0.001；两者交互作用， F值分别为0.79、12.12、15.60、0.48、4.91、0.31， P值均<0.001； t 1值、 P 1值， t 2值、 P 2值， t 3值、 P 3值， t 4值、 P 4值， t 5值、 P 5值， t 6值、 P 6值分别为组间IL-6、IL-10、TNF-α、Tau蛋白、ACTH、皮质醇于脓毒症确诊后各时间点比较所得
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表4 2组烧伤脓毒症患者脑血流参数在脓毒症确诊后各时间点的比较（
组别与指标 例数 1 d 3 d 7 d SAE组 21 VmMCA（cm/s） 36±21 42±20 46±21 搏动指数 1.7±0.5 1.5±0.3 1.4±0.3 CBFi 405±105 441±98 460±96 非SAE组 20 VmMCA（cm/s） 54±18 56±20 59±19 搏动指数 1.3±0.5 1.2±0.3 1.0±0.5 CBFi 490±102 513±99 524±104 t 1值 2.94 2.24 2.08 P 1值 0.015 0.093 0.135 t 2值 2.56 3.20 3.12 P 2值 0.042 0.009 0.009 t 3值 2.67 2.34 2.05 P 3值 0.036 0.075 0.141 注：SAE为脓毒症相关性脑病，VmMCA为大脑中动脉平均血液流速，CBFi为脑血流指数；VmMCA、搏动指数、CBFi处理因素主效应， F值分别为2.49、11.45、4.72， P值均<0.001；时间因素主效应， F值分别为4.61、13.51、5.17， P值均<0.001；两者交互作用， F值分别为1.12、7.89、3.78， P值分别为<0.001、0.183、<0.001； t 1值、 P 1值， t 2值、 P 2值， t 3值、 P 3值分别为组间VmMCA、搏动指数、CBFi于脓毒症确诊后各时间点比较所得
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表5 41例烧伤脓毒症患者发生脓毒症相关性脑病的多因素logistic回归模型的分析结果
因素 回归系数 标准误 比值比 95%置信区间 P值 确诊后12 h的血清IL-6（pg/mL） 0.45 0.08 2.42 1.76~3.82 <0.001 确诊后24 h的血清Tau蛋白（pg/mL） 0.62 0.09 1.38 1.06~2.45 0.002 确诊后24 h的血清ACTH（pg/mL） 0.45 0.34 4.29 1.37~6.68 0.007 确诊后24 h的血清皮质醇（nmol/L） 0.65 0.26 4.19 3.32~8.79 <0.001 注：确诊后为脓毒症确诊后；IL-6为白细胞介素6，ACTH为促肾上腺皮质激素
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