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Volume 41 Issue 3
Mar.  2025
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Article Navigation >  CHINESE JOURNAL OF BURNS AND WOUNDS  > 2025  >  41(3): 268-276
Hu ZX,Bian HN,Ma D,et al.Analysis of the clinical features and prognostic influencing factors of toxic epidermal necrolysis[J].Chin J Burns,2021,37(8):738-746.DOI: 10.3760/cma.j.cn501120-20200416-00230.
Citation: Xie WB,Hu XL,Wei S,et al.Effects and mechanism of metformin on the proliferation and expression of fibrotic proteins of human hypertrophic scar fibroblasts[J].Chin J Burns Wounds,2025,41(3):268-276.DOI: 10.3760/cma.j.cn501225-20231220-00259.
shu

Effects and mechanism of metformin on the proliferation and expression of fibrotic proteins of human hypertrophic scar fibroblasts

doi: 10.3760/cma.j.cn501225-20231220-00259
  • 1.

    Clinical Medicine Department of Jiangxi Medical College, Nanchang University, Nanchang 330006, China

  • 2.

    Department of Burns and Cutaneous Surgery, Burn Center of PLA, the First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China

Funds:

General Program of National Natural Science Foundation of China 82172209

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  • Corresponding author: Shi Jihong, Email: biojhshi@126.com
  • Received Date: 2023-12-20
    Abstract
  •   Objective  To investigate the effects and mechanism of metformin on the proliferation and expression of fibrotic proteins of human hypertrophic scar (HS) fibroblasts (Fbs).  Methods  The study was an experimental study. From June 2021 to June 2022, 5 patients with HS were admitted to the Department of Burns and Cutaneous Surgery of the First Affiliated Hospital of Air Force Medical University, including 3 males and 2 females, aged from 21 to 36 years. HS tissue was collected, Fbs were isolated and cultured, and Fbs of passage 5 to 7 were used for experiment. Fbs were taken and cultured in their respective media supplemented with phosphate buffered solution (PBS) or metformin at final molarities of 5, 10, 20, and 40 mmol/L for 48 hours. The cell proliferation activity was detected using the cell counting kit-8 (CCK-8), and the proliferation inhibition rate of cells was calculated. The content of hydroxyproline in the cell culture supernatant was measured using a hydroxyproline assay kit. The phosphorylation levels of protein kinase B (Akt) and mammalian target of rapamycin (mTOR) in the cells were detected by Western blotting, and the ratios of phosphorylated Akt (p-Akt) to Akt and phosphorylated mTOR (p-mTOR) to mTOR were calculated. After 24 hours of culture, the mRNA expressions of type Ⅰ collagen, type Ⅲ collagen, and α-smooth muscle actin (α-SMA) in the cells were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction. Another batch of Fbs were divided into control group (with conventional culture), LY294002 group, metformin group, and LY294002+metformin group. LY294002, metformin, and LY294002+metformin were added to the culture media of the last three groups, respectively, with the final molarities of LY294002 and metformin being 20 μmol/L and 10 mmol/L, respectively. CCK-8 was used to detect the cell proliferation activity at 0 (immediately), 24, and 48 hours of culture. After 48 hours of culture, Western blotting was used to detect the phosphorylation levels of Akt and mTOR in the cells, and the ratios of p-Akt to Akt and p-mTOR to mTOR were calculated. The sample size for the cell proliferation inhibition rate experiment was 4, and the sample size for the other experiments was 3.  Results  After 48 hours of culture, compared with the cells treated with PBS, the proliferation inhibition rates of the cells treated with 5, 10, 20, and 40 mmol/L metformin were significantly increased (with t values of 10.69, 14.20, 19.73, and 52.54, respectively, P<0.05), the content of hydroxyproline in the culture supernatants of the cells treated with 10, 20, and 40 mmol/L metformin was significantly decreased (with t values of 8.06, 7.86, and 10.25, respectively, P<0.05), and the ratios of p-Akt to Akt in the cells treated with 10, 20, and 40 mmol/L metformin and the ratios of p-mTOR to mTOR in the cells treated with 20 and 40 mmol/L metformin were significantly decreased (with t values of 2.82, 4.28, 9.88, 5.66, and 9.08, respectively, P<0.05). After 24 hours of culture, compared with those treated with PBS, the mRNA expressions of type Ⅰ collagen and α-SMA in the cells treated with 5, 10, 20, and 40 mmol/L metformin and the mRNA expressions of type Ⅲ collagen in the cells treated with 10, 20, and 40 mmol/L metformin were significantly decreased (with t values of 4.35, 8.53, 9.57, 14.77, 4.14, 5.58, 7.89, 9.37, 5.18, 6.85, and 9.15, respectively, P<0.05). At 24 and 48 hours of culture, the proliferation activities of the cells in LY294002 group (with t values of 6.30 and 13.60, respectively) and metformin group (with t values of 6.47 and 10.69, respectively) were significantly lower than those in control group (P<0.05). After 48 hours of culture, the ratios of p-Akt to Akt in the cells of LY294002 group and metformin group were 0.554±0.027 and 0.681±0.029, respectively, which were significantly lower than 1.053±0.193 in control group (with t values of 4.45 and 3.31, respectively, P<0.05). The ratio of p-Akt to Akt in the cells of LY294002+metformin group was 0.387±0.023, which was significantly lower than that in metformin group (t=5.95, P<0.05). After 48 hours of culture, the ratio of p-mTOR to mTOR in the cells of LY294002 group was significantly lower than that in control group (t=4.01, P<0.05), and the ratio of p-mTOR to mTOR in the cells of LY294002+metformin group was significantly lower than that in metformin group (t=6.05, P<0.05).  Conclusions  Metformin can inhibit the proliferation and expression of fibrotic proteins type Ⅰ collagen, type Ⅲ collagen, and α-SMA of human HS Fbs through phosphatidylinositol 3-kinase/Akt/mTOR signaling pathway.

     

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  • 中毒性表皮坏死松解症（toxic epidermal necrolysis，TEN）和史蒂文斯-约翰逊综合征（Stevens-Johnson syndrome，SJS）同属于SJS/TEN疾病谱，是以黏膜及皮肤损伤为主要表现的迟发型超敏反应。SJS和TEN为同一疾病谱的不同阶段，病损面积<10%TBSA为SJS，病损面积>30%TBSA为TEN，病损面积≥10%TBSA且≤30%TBSA为SJS/TEN重叠，其中TEN为最严重类型且85%与药物相关［1, 2］。TEN发病率为0.4/1 000 000~1.9/1 000 000，其病死率可达50%，主要死亡原因为脓毒症［3, 4］。目前，TEN仍缺乏循证证据支持的标准治疗方案［5］，故临床上需加强对该疾病的循证证据收集，为临床治疗方案的制订提供有效依据。本文拟通过分析46例TEN病例，归纳此类患者临床特征，探讨可能影响其预后的相关因素。

    1.   对象与方法

    本回顾性观察性研究经广东省人民医院伦理审查委员会批准，批号：KY-Q-2021-152-01。

    1.1   入选标准

    纳入标准：2008年1月—2019年3月入住广东省人民医院的非创伤性皮肤黏膜损伤患者，出院诊断含TEN。排除标准：（1）出院诊断中TEN为非主要诊断且本次入院未予治疗。（2）经外院治疗病情稳定后入院。

    1.2   临床资料与分组统计

    共46例TEN患者符合入选标准，纳入本研究。（1）统计所有患者性别、年龄、入院时诊断情况，并发脓毒症患者入住科室类别、有和无ICU/烧伤与创面修复外科治疗史脓毒症患者病死比例，患者死亡原因。（2）以2018版脓毒症诊断标准［6］为依据，根据是否并发脓毒症，将患者分为脓毒症组（32例）与非脓毒症组（14例）；根据是否死亡，将患者分为死亡组（9例）与存活组（37例）。①统计脓毒症组与非脓毒症组患者可疑致病原、合并基础疾病的具体情况，入院时血液中转氨酶/胆红素、肌酐与血小板计数异常情况，病程中病原微生物检测及耐药情况。②统计脓毒症组和非脓毒症组患者、死亡组和存活组患者入院时性别、年龄、病损面积、TEN严重程度评分（SCORTEN）系统评分、合并基础疾病情况以及病程中血微生物培养阳性情况、激素使用情况、丙种球蛋白使用情况等一般资料与相关因素。

    转氨酶/胆红素异常判定标准为≥1种相关指标异常。SCORTEN系统评分标准［7］：年龄>40岁，并发恶性肿瘤，心率>120次/min，血糖>14 mmol/L，碳酸氢盐<20 mmol/L，表皮剥脱>10%TBSA，血尿素氮>10 mmol/L，以上7项存在1项计1分。

    1.3   入院后治疗

    入院后早期予糖皮质激素（剂量相当于泼尼松1~2 mg·kg-1·d-1）及丙种球蛋白（剂量为400 mg·kg-1·d-1）冲击治疗，丙种球蛋白持续应用5 d，激素于病情控制后逐步减量，当皮损再发或加重时再次应用丙种球蛋白［8］。早期行经验性抗感染，其后根据药物敏感试验结果予更换敏感抗生素，同时维持水、电解质平衡，保护脏器功能，积极处理原发病及并发症，加强皮肤黏膜管理及营养支持等治疗，必要时予血浆置换、血液透析、体外膜氧合等替代治疗。

    1.4   统计学处理

    采用SPSS 19.0统计软件处理数据。计量资料数据不符合正态分布，以M（min，max）表示；计数资料数据用频数（百分比）表示，组间比较行χ2检验或Fisher确切概率法检验（软件自动略去该统计量值）；等级资料数据以频数表示，组间比较行Mann-Whitney U检验。分别对脓毒症组和非脓毒症组患者、死亡组和存活组患者进行一般资料及相关因素比较的单因素分析，将差异有统计学意义的指标设为自变量，以发生脓毒症或死亡为因变量，进行二分类多因素logistic回归分析，筛选影响TEN患者并发脓毒症或死亡的独立危险因素。P<0.05为差异有统计学意义。

    2.   结果

    2.1   一般资料及预后

    46例TEN患者中男30例、女16例，男女比例为1.88∶1.00；年龄54.5岁（8个月，92.0岁）。入院诊断为大疱性表皮松解症11例（23.91%）、剥脱性皮炎9例（19.57%）、TEN 9例（19.57%）、大疱性表皮松解型药疹7例（15.22%）、SJS 6例（13.04%）、重症药疹4例（8.70%）。

    并发脓毒症患者入住科室有感染科、内分泌科、风湿免疫科、肾内科、口腔科、皮肤科、ICU、烧伤与创面修复外科、急诊科、心外科、保健科。13例并发脓毒症患者有ICU/烧伤与创面修复外科治疗史，其中死亡5例；19例并发脓毒症患者无ICU/烧伤与创面修复外科治疗史，其中死亡4例。有ICU/烧伤与创面修复外科治疗史脓毒症患者病死比例为5/13，与无此类科室治疗史患者的4/19相近（P=0.427）。

    死亡患者均并发了脓毒症，死亡原因为脓毒症6例、呼吸衰竭2例、急性肾衰竭1例。

    2.2   脓毒症组与非脓毒症组可疑致病原与合并基础疾病及器官功能损伤情况

    脓毒症组患者可疑致病原种类较多，以别嘌醇与非甾体类消炎药为主；非脓毒症组患者可疑致病原以别嘌醇与精神类药物为主。见表1。脓毒症组患者合并10种基础疾病，主要为恶性肿瘤与肾脏疾病；非脓毒症组患者合并4种基础疾病。见表2。

    表1  2组中毒性表皮坏死松解症患者可疑致病原分布（例）
    组别例数别嘌醇非甾体类消炎药头孢类抗生素中成药喹诺酮类抗生素精神类药物沙利度胺双氢克尿噻不明药物非药物
    脓毒症组328433211181
    非脓毒症组143211130003
    注：非药物指病毒感染、烧烤及护发素等
    下载: 导出CSV 
    | 显示表格
    表2  2组中毒性表皮坏死松解症患者合并基础疾病情况（例）
    组别例数恶性肿瘤系统性红斑狼疮类风湿合并干燥综合征强直性脊柱炎痛风单纯高血压单纯冠心病高血压合并冠心病高血压合并瓣膜病肾脏疾病
    脓毒症组325211141216
    非脓毒症组141100020001
    下载: 导出CSV 
    | 显示表格

    入院时，脓毒症组、非脓毒症组转氨酶/胆红素异常患者比例分别为12/32、3/14，组间比较，差异无统计学意义（χ2=0.530，P=0.467）；脓毒症组肌酐升高患者比例为21/32，明显高于非脓毒症组的1/14（χ2=13.349，P<0.001）；脓毒症组血小板计数减少患者比例为24/32，明显高于非脓毒症组的0（P<0.001）。

    2.3   病原微生物检测及耐药情况

    脓毒症组和非脓毒症组分别有21、8例患者病原微生物检测阳性，其中前一组患者阳性标本来源分布包括血液7例、呼吸道分泌物10例及皮肤分泌物11例，后一组患者阳性标本来源分布包括血液4例、呼吸道分泌物1例及皮肤分泌物4例。脓毒症组与非脓毒症组患者各标本检出病原微生物情况及耐药情况分别见表3、4。脓毒症组患者中耐药菌感染14例，其中5例合并多种耐药菌，检出菌株中耐甲氧西林（MRS）菌株有9株、产内酰胺酶耐药菌11株、产超广谱β-内酰胺酶（ESBL）耐药菌4株、多重耐药菌2株、全耐药菌4株。该组患者中血液标本培养出的病原菌共9株，8株为耐药菌、6株为革兰阳性菌。非脓毒症组患者中耐药菌感染6例，其中1例合并多种耐药菌，检出菌株中MRS菌株有3株、产内酰胺酶耐药菌5株、产ESBL耐药菌1株、多重耐药菌1株。

    表3  脓毒症组21例患者各标本病原微生物检出情况及耐药情况（株）
    标本来源与病原微生物名称检出菌株数耐药菌株数
    血液
    表皮葡萄球菌22
    鲍曼不动杆菌22
    金黄色葡萄球菌11
    粪肠球菌10
    松鼠葡萄球菌11
    肺炎克雷伯菌11
    溶血葡萄球菌11
    呼吸道分泌物
    溶血葡萄球菌32
    白色念珠菌30
    嗜麦芽寡养单胞菌20
    中间葡萄球菌10
    鲍曼不动杆菌10
    金黄色葡萄球菌11
    大肠埃希菌10
    解甘露醇罗尔斯顿菌10
    铜绿假单胞菌10
    麦芽单胞菌10
    嗜麦芽窄食单胞菌10
    皮肤分泌物
    鲍曼不动杆菌44
    金黄色葡萄球菌44
    肺炎克雷伯菌20
    屎肠球菌10
    大肠埃希菌11
    光滑球拟酵母菌10
    枯草芽孢杆菌10
    铜绿假单胞菌11
    白色念珠菌10
    光滑念珠菌10
    下载: 导出CSV 
    | 显示表格
    表4  非脓毒症组8例患者各标本病原微生物检出情况及耐药情况（株）
    标本来源与病原微生物名称检出菌株数耐药菌株数
    血液
    金黄色葡萄球菌11
    表皮葡萄球菌11
    人葡萄球菌11
    溶血葡萄球菌11
    呼吸道分泌物
    鲍曼不动杆菌11
    皮肤分泌物
    大肠埃希菌11
    阴沟肠杆菌10
    热带念珠菌10
    表皮葡萄球菌11
    粪肠球菌10
    下载: 导出CSV 
    | 显示表格

    2.4   影响TEN患者并发脓毒症及死亡的单因素分析

    脓毒症组与非脓毒症组患者中男性均多于女性，年龄分别为57.5（22.0，92.0）岁、38.0岁（8个月，72.0岁），SCORTEN系统评分分别为3.0（1.0，6.0）、1.5（1.0，3.0）分。脓毒症组与非脓毒症组患者性别、年龄、病损面积、血微生物培养阳性情况、激素使用情况、丙种球蛋白使用情况相近（P>0.05）；脓毒症组合并基础疾病患者比例、SCORTEN系统评分4~6分患者比例明显高于非脓毒症组（P<0.05或P<0.01），见表5。

    表5  脓毒症组与非脓毒症组TEN患者一般资料及相关因素比较（例）
    组别例数性别年龄病损面积SCORTEN系统评分
    男女<60岁≥60岁30%~49%TBSA50%~69%TBSA≥70%TBSA1~3分4~6分
    脓毒症组322111171587171715
    非脓毒症组1495104437140
    统计量值χ2<0.001χ2=1.346Z=-0.236—
    P值>0.9990.2460.8140.002
    注：TBSA为体表总面积，SCORTEN为中毒性表皮坏死松解症（TEN）严重程度评分；“—”表示无此统计量值
    下载: 导出CSV 
    | 显示表格

    死亡组、存活组患者SCORTEN系统评分分别为5（3，6）、2（1，6）分。存活组和死亡组患者性别、合并基础疾病情况、病损面积、血微生物培养阳性情况、激素使用情况、丙种球蛋白使用情况相近（P>0.05）；死亡组年龄≥60岁患者比例、SCORTEN系统评分4~6分患者比例明显高于存活组（P<0.05或P<0.01），见表6。

    表6  死亡组与存活组TEN患者一般资料及相关因素比较（例）
    组别例数性别年龄病损面积SCORTEN系统评分
    男女<60岁≥60岁30%~49%TBSA50%~69%TBSA≥70%TBSA1~3分4~6分
    死亡组9722712618
    存活组372314251211818298
    统计量值χ2=0.242χ2=4.412Z=-1.124χ2=11.627
    P值0.6230.0360.2610.001
    注：TBSA为体表总面积，SCORTEN为中毒性表皮坏死松解症（TEN）严重程度评分；“—”表示无此统计量值
    下载: 导出CSV 
    | 显示表格

    2.5   影响TEN患者并发脓毒症及死亡的二分类多因素logistic回归分析

    脓毒症组与非脓毒症组单因素分析中差异有统计学意义的因素为合并基础疾病情况、SCORTEN系统评分，对合并基础疾病情况进行赋值，无=0、有=1，SCORTEN系统评分以原始值代入进行二分类多因素logistic回归分析，结果显示SCORTEN系统评分为影响TEN患者并发脓毒症的独立危险因素（P<0.01），见表7。

    表7  影响46例TEN患者并发脓毒症的二分类多因素logistic回归分析结果
    影响因素β值Wald值比值比95%置信区间P值
    合并基础疾病情况0.9081.2592.4790.508~12.1010.262
    SCORTEN系统评分1.1077.2513.0251.352~6.7690.007
    注：SCORTEN为中毒性表皮坏死松解症（TEN）严重程度评分
    下载: 导出CSV 
    | 显示表格

    存活组与死亡组单因素分析中差异有统计学意义的因素为年龄和SCORTEN系统评分，对年龄进行赋值，<60岁=0、≥60岁=1，SCORTEN系统评分以原始值代入进行二分类多因素logistic回归分析，结果显示SCORTEN系统评分为影响TEN患者死亡的独立危险因素（P<0.05），见表8。

    表8  影响46例TEN患者死亡的二分类多因素logistic回归分析结果
    影响因素β值Wald值比值比95%置信区间P值
    年龄0.4790.1971.6150.195~13.3670.657
    SCORTEN系统评分1.0146.2332.7571.244~6.1100.013
    注：SCORTEN为中毒性表皮坏死松解症（TEN）严重程度评分
    下载: 导出CSV 
    | 显示表格

    2.6   典型病例

    患者女，53岁，因左小腿皮肤溃疡自行口服氧氟沙星和克林霉素后出现口唇、面部皮肤红肿，并逐步延展至躯干、四肢，伴有水疱形成、表皮剥脱，立即至当地医院治疗（具体不详），诊断为SJS、脓毒症、血小板减少症。治疗期间患者症状逐步加重，皮肤剥脱范围逐渐增大，并伴有黑便，遂于发病第4天转入广东省人民医院烧伤与创面修复外科治疗。既往身体健康。入院时体格检查：头面颈部、躯干、四肢多处见大片红斑及水疱形成，面积约60%TBSA，头面颈部、躯干、上肢见皮肤剥脱，创基红润、潮湿、痛觉敏感，口唇黏膜、眼结膜溃烂、渗出，双手、双下肢水疱尼氏征（+），左胫前见直径约2.5 cm类圆形溃疡创面，基底见老化肉芽覆盖，无明显脓性分泌物（图1）。入院时查血：ALT 55 U/L、AST 61 U/L、总胆红素9.5 μmol/L、肌酐43.12 μmol/L、血小板计数80×109/L。入院诊断：TEN、皮肤慢性溃疡（左小腿）。入院SCORTEN系统评分3分，予重症监护，停用所有发病前使用过的药物，创面清创包扎，卧悬浮床，予每8小时1次亚胺培南/西司他丁500 mg抗感染，每天1次甲泼尼龙80 mg、丙种球蛋白20 g（持续用药5 d）免疫治疗，同时予抑酸、生长抑素改善消化道出血，护肝、维持水电解质平衡，鼻饲肠内营养，利多卡因、地塞米松、庆大霉素混合稀释液漱口，妥布霉素地塞米松眼膏涂眼。治疗3 d患者症状无明显加重，下肢少许新增红斑，将甲泼尼龙用药改为每天1次地塞米松15 mg，持续用药5 d，患者红斑、水疱无增加，红斑颜色逐渐变深，创面疼痛减轻，遂将地塞米松用药改为每天1次甲泼尼龙80 mg并逐步减量至20 mg每天1次（每5天减量20 mg）。创面定期清创换药包扎。病程中微生物培养阴性。经治疗2周，患者创面基本被覆新生上皮，红斑已褪色，口唇、眼黏膜愈合，无黑便，肝功能指标降至正常，予带药出院（图2）。出院诊断：同入院诊断。出院时追问患者用药史，患者因左小腿溃疡疼痛有口服卡马西平（精神类药物）病史，入院后已停用，告知患者以后避免使用。随访2个月，患者病情无复发。

    1  中毒性表皮坏死松解症患者入院时全身多处表皮剥脱、黏膜溃烂。1A.正面；1B.背面
    下载: 全尺寸图片 幻灯片
    2  中毒性表皮坏死松解症患者出院时创面均为新生上皮覆盖。2A.正面；2B.背面
    下载: 全尺寸图片 幻灯片

    3.   讨论

    TEN的诊断需结合临床及病理表现，目前沿用的是Bastuji-Garin等提出的分类标准［9］。TEN早期表现类似感冒症状，多有发热，随后皮肤水疱形成（尼氏征阳性），黏膜溃烂、表皮剥脱，且皮肤剥脱达30%TBSA以上，伴或不伴脏器功能损伤［10, 11］；TEN病理表现为表皮全层坏死、剥脱，KC凋亡，极少炎症细胞浸润［12］。国外多数研究显示TEN患者中女性多于男性［13, 14］，而本研究显示男性多于女性，与国内Yang等［3］调查结果一致，其可能原因为随着我国生活水平的提高，因高尿酸服用降尿酸药物诱发TEN比例增加，而男性为高尿酸高发人群。TEN临床罕见，非专科医师缺乏对该疾病的认识，易导致误诊或诊断不规范，本研究中的病例入院诊断为TEN的不到1/5（19.57%）。

    有研究显示，影响TEN患者病死率的因素有年龄、SCORTEN系统评分>3分、起病至转烧伤中心>5 d、合并基础疾病及恶性肿瘤等［15, 16］。早期诊断、尽早停用致敏药物及尽快转至ICU或烧伤中心被认为能有效改善TEN患者预后［17］。本研究中有ICU/烧伤与创面修复外科治疗史脓毒症患者病死比例较无此类科室治疗史患者高，但差异无统计学意义（P>0.05），该结果与目前主流观点相反，原因可能为有ICU/烧伤与创面修复外科治疗史患者均未早期转至该科治疗，而转科时病情已危重。因此，早期多学科合作明确诊断，尽早启动积极规范的治疗对患者的愈后意义重大［18, 19, 20］。TEN患者的主要死亡原因为脓毒症导致的MODS［3］，本研究死亡病例中死亡原因为脓毒症者达2/3。

    国内一项荟萃分析显示，TEN主要致病药物为抗生素（25.4%）、抗惊厥药（22.0%）和解热镇痛药（18.3%）［21］；而另一项国际多中心研究表明，诱发TEN最多见药物为别嘌醇［16］，与本研究结果一致。导致该差异的因素可能为生活、饮食习惯或地域差异。对于使用可疑药物后出现剥脱性皮炎、水疱型皮损并进行性加重患者，应尽早明确诊断，停用相关药物。

    SCORTEN系统评分是评估SJS/TEN严重程度及预测病死率（0~1分预测病死率为3.2%，2分预测病死率为12.1%，3分预测病死率为32.3%，4分预测病死率为58.3%，5分以上预测病死率为90%）的较好指标［22］。本研究单因素分析显示，合并基础疾病、SCORTEN系统评分>3分可能为TEN患者发生脓毒症的影响因素，二分类多因素logistic回归分析显示SCORTEN系统评分为影响TEN患者并发脓毒症的独立危险因素，故应在早期对TEN患者进行SCORTEN系统评分，对于合并基础疾病、SCORTEN系统评分>3分的患者，要尽早干预，重点防范脓毒症，以改善预后。

    TEN的治疗包括支持治疗及药物治疗。支持治疗是TEN治疗的关键［23］，包括保护脏器功能、防治感染、基础疾病治疗等，必要时需予血浆置换［24］、血液透析、体外膜氧合等替代治疗。本研究显示，并发脓毒症的TEN患者肾脏（肌酐升高）及血液系统并发症（血小板计数减少）发生比例较非脓毒症患者高（P<0.01），故对合并脓毒症的TEN患者应更加注意保护肾脏及造血功能。TEN的皮损类似于浅Ⅱ度烧伤创面，通常无须手术治疗，定期清创换药保持创面清洁，一般能自行愈合［25］，其他抗菌敷料或生物敷料亦可适当应用［26, 27］。体表病损面积进行性增加往往提示患者病情进展。在本研究中，创面的面积与预后未见有明确相关性，与McCullough等［25］的研究结果一致，但在全身治疗中应考虑体液丢失而需积极纠正水电解质平衡，并防止创面感染。本研究的脓毒症组患者血源性感染8/9为耐药菌，且2/3为革兰阳性菌，故经验性抗感染治疗时应选用抗耐药革兰阳性菌的药物。ICU可为患者提供有效的生命支持及脏器保护策略，而烧伤中心除了可以提供积极的创面治疗，也可为脓毒症的综合防治提供重要保障，此可能为国外学者及指南建议TEN患者尽早转ICU或烧伤科专科治疗的重要原因之一。关于TEN的药物治疗国内外学者无统一观点，因该病为迟发型超敏反应，而糖皮质激素有强抗过敏作用，且丙种球蛋白能阻断死亡受体路径，防止KC凋亡［28, 29］，故国内多数学者推荐激素联合丙种球蛋白治疗［30, 31, 32, 33］；由于TEN发病率低且病情重，无法进行大样本的前瞻性随机对照研究，目前暂无循证证据表明单独使用激素能改善预后［34, 35］，故国外学者多不推荐使用激素治疗［1，25］。本研究显示，TEN患者是否使用丙种球蛋白或激素与预后未见明显相关性（P>0.05），与国外多数研究结果［16］一致，但本研究并非随机对照研究且样本量少，故不能认为使用激素或丙种球蛋白对患者无益。

    本研究单因素分析显示年龄≥60岁、SCORTEN系统评分>3分可能为影响TEN患者死亡的因素，二分类多因素logistic回归分析显示SCORTEN系统评分为影响TEN患者死亡的独立危险因素，故对年龄≥60岁、SCORTEN系统评分高的患者应更加尽早进行综合性治疗以降低病死率。而死亡组与存活组患者性别、病损面积、合并基础疾病情况、血微生物培养阳性情况、丙种球蛋白及激素使用情况差异无统计学意义（P>0.05），可能原因为本研究病例数较少且为单中心研究，存在抽样偏差。该研究存在其他局限性，如自动出院患者有5例，其中可能有死亡病例而未纳入死亡组；病损面积均为估算；病例时间跨度较长，混杂因素较多。这些因素均可能对结果造成一定影响。

    综上，TEN发病率低但病死率高，早期易误诊，应引起临床医师重视；对于高频致病药物，临床应谨慎使用，必须应用时可检测有无相关易感基因以降低发病风险；TEN患者的主要死亡原因为脓毒症，为提高患者生存率，应重点防治脓毒症；及时转至有条件治疗科室如ICU和烧伤中心，能同时处理创面和治疗原发病及其相关并发症；TEN的药物治疗目前暂无一致观点，仍需更多样本进行随机对照研究，为临床治疗提供可靠的“标准”方案。

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