Dou XJ,Wang HY,Chen W,et al.Prospective study on the influence of dobutamine on blood perfusion in free flap repair of diabetic foot wounds[J].Chin J Burns Wounds,2023,39(8):746-752.DOI: 10.3760/cma.j.cn501225-20221220-00543.
Citation: Zhang SY,Ruan JJ,Jin DM,et al.Pan-cancer analysis of ubiquitin-specific protease 7 and its expression changes in the carcinogenesis of scar ulcer[J].Chin J Burns Wounds,2023,39(6):518-526.DOI: 10.3760/cma.j.cn501225-20230421-00137.

Pan-cancer analysis of ubiquitin-specific protease 7 and its expression changes in the carcinogenesis of scar ulcer

doi: 10.3760/cma.j.cn501225-20230421-00137
Funds:

Natural Science Foundation of Hubei Province 2021CFB532

Scientific Research Project of Hubei Provincial Health Commission WJ2021M260

Project of Shanghai Wang Zhengguo Trauma Medicine Development Foundation SZYZ-TR-10

More Information
  • Corresponding author: Ruan Qiongfang, Email: qf_ruan@126.com
  • Received Date: 2023-04-21
  •   Objective   To explore the biological role and clinical significance of ubiquitin-specific protease 7 (USP7) in the carcinogenesis of scar ulcer.   Methods   A retrospective observational study combined with bioinformatics analysis was used. The RNA expression profile data of USP7 in tumor and/or its corresponding paracancular normal tissue were obtained from The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus database, and the RNA sequencing data were transformed by log 2. The variations of USP7 gene were analyzed by cBioPortal database. The USP7 mRNA expression in tumor and adjacent normal tissue in TCGA database were obtained by using the "Gene_DE" module in TIMER 2.0 database. The survival rates of patients with high and low USP7 expression in cutaneous melanoma (SKCM), cervical squamous cell carcinoma (CESC), lung squamous cell carcinoma (LUSC), and head and neck squamous cell carcinoma (HNSC) were analyzed using the Gene Expression Profile Interactive Analysis 2 (GEPIA2) database, and the Kaplan-Meier survival curves were drawn. Sangerbox database was used to analyze the correlation of USP7 expression in pan-cancer with microsatellite instability (MSI) or tumor mutation burden (TMB) pan-cancer. Through the "correlation analysis" module in the GEPIA2 database, the correlation of USP7 expression in pan-cancer with the expression levels of five DNA mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, and EPCAM) and three essential DNA methyltransferases (DNMT)--DNMT1, DNMT3A, and DNMT3B were evaluated. The USP7 expression in CESC, HNSC, LUSC, and SKCM and its correlation with infiltration of immune cells (B cells, CD4 + T cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells) were analyzed by the "Immune-Gene" module in TIMER 2.0 database. The "Similar Genes Detection" module of GEPIA2 database was used to obtain the top 100 protein sets with similar expression patterns to USP7. Intersection analysis was performed between the aforementioned protein sets and the top 50 protein sets that were directly physically bound to USP7 obtained by using the STRING database. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis were performed for the two protein sets mentioned above using the DAVID database. The samples of normal skin, hypertrophic scar, scar ulcer, and scar carcinoma with corresponding clinicopathologic features were collected from the Department of Pathology of Tongren Hospital of Wuhan University & Wuhan Third Hospital from October 2018 to October 2022, and the USP7 expression in tissue was detected by immunohistochemical method, with the number of samples of 6. Data were statistically analyzed with Log-rank test, one-way analysis of variance, and Bonferroni test.   Results   In pan-cancer, the main gene variations of USP7 were mutation and amplification, and the top 3 tumors with the highest variation frequency (>6%) were bladder urothelial carcinoma, SKCM, and endometrial carcinoma. The main mutation of USP7 gene in pan-cancer was missense mutation. In SKCM with the highest mutation frequency, the main type of mutation was missense mutation in USP7_ICP0_bdg domain. USP7 mRNA expression in breast invasive carcinoma, bile duct carcinoma, colon carcinoma, esophageal carcinoma, HNSC, renal chromophobe cell carcinoma, hepatocellular carcinoma, lung adenocarcinoma, LUSC, prostate carcinoma, and gastric carcinoma was significantly higher than that in corresponding paracancer normal tissue ( P<0.05). USP7 mRNA expression in glioblastoma multiforme, renal clear cell carcinoma, renal papillary cell carcinoma, and thyroid carcinoma was significantly lower than that in corresponding paracancular normal tissue ( P<0.05). In addition, USP7 mRNA expression in SKCM metastases was much higher than that in primary tumor tissue ( P<0.05). Survival curves showed no significant difference in survival rate between patients with high USP7 expression and patients with low USP7 expression in CESC, HNSC, LUSC, and SKCM (Log-rank P>0.05, with hazard ratios of 1.00, 0.99, 1.00, and 1.30, respectively). USP7 expression in colon cancer, colorectal cancer, thymic cancer, and thyroid cancer was negatively correlated with TMB (with Pearson correlation coefficients of -0.26, -0.19, -0.19, and 0.11, respectively, P<0.05). USP7 expression in glioma, CESC, lung adenocarcinoma, mixed renal carcinoma, and LUSC was positively correlated with MSI expression (with Pearson correlation coefficients of 0.22, 0.14, 0.15, 0.08, and 0.14, respectively, P<0.05), and USP7 expression in colon cancer, colorectal cancer, invasive breast cancer, prostate cancer, HNSC, thyroid cancer, and diffuse large B-cell lymphoma were significantly negatively correlated with MSI expression (with Pearson correlation coefficients of -0.31, -0.27, -0.13, -0.19, -0.16, -0.18, and -0.53, respectively, P<0.05). The expression of USP7 in CESC was positively correlated with that of both MSH2 and MSH6 (with Spearman correlation coefficients of 0.51 and 0.44, respectively, P<0.05), and the expression of USP7 in HNSC was positively correlated with the expression of EPCAM, MLH1, MSH2, MSH6, and PMS2 (with Spearman correlation coefficients of 0.39, 0.14, 0.49, 0.54, and 0.41, respectively, P<0.05), and the expression of USP7 in LUSC was positively correlated with the expression of EPCAM, MSH2, MSH6, and PMS2 (with Spearman correlation coefficients of 0.20, 0.36, 0.40, and 0.34, respectively, P<0.05), and the expression of USP7 in SKCM was positively correlated with the expression of EPCAM, MLH1, MSH2, MSH6, and PMS2 (with Spearman correlation coefficients of 0.11, 0.33, 0.42, 0.55, and 0.34, respectively, P<0.05). The expression of USP7 in CESC, HNSC, LUSC, and SKCM was significantly positively correlated with the expression of DNMT1, DNMT3A, and DNMT3B (with Spearman correlation coefficients of 0.42, 0.34, 0.22, 0.45, 0.52, 0.22, 0.36, 0.36, 0.22, 0.38, 0.46, and 0.21, respectively, P<0.05). The expression of USP7 in CESC, HNSC, LUSC, and SKCM was positively correlated with CD4 + T cell infiltration (with Partial correlation coefficients of 0.14, 0.22, 0.13, and 0.16, respectively, P<0.05). Being similar to the pattern of USP7 expression and ranked among top 100 protein sets, the top 5 proteins were C16orf72, BCLAF1, UBN, GSPT1, ERI2 (with Spearman correlation coefficients of 0.83, 0.74, 0.73, and 0.72, respectively, all P values<0.05). The top 50 protein sets that directly physically bind to USP7 overlapped with the aforementioned protein set by only one protein, thyroid hormone receptor interaction factor 12. KEGG enrichment analysis showed that USP7 related genes were involved in cell cycle, spliceosome, cell senescence, and p53 signal pathway. GO enrichment analysis showed that USP7 related genes were involved in transcriptional regulation, protein ubiquitination, DNA repair, and cytoplasmic pattern recognition receptor signal pathways. Analysis of clinical samples showed that USP7 expression was significantly higher in hypertrophic scars (0.35±0.05), scar ulcers (0.43±0.04), and scar cancers (0.61±0.03) than in normal skin (0.18±0.04), P<0.05.   Conclusions   USP7 may be a clinical biomarker for the progression of cicatricial ulcer cancer.

     

  • (1)通过吲哚菁绿荧光造影观察皮瓣血流灌注情况并绘制皮肤微循环动态色阶图,可快速、有效评价游离皮瓣血流灌注强度及范围。

    (2)证实多巴酚丁胺可快速、有效提升糖尿病足患者平均动脉压且不收缩外周血管,解决了糖尿病足患者行游离皮瓣修复术中皮瓣低灌注的问题。

    糖尿病足溃疡具有愈合困难、复发率高、致残率高等特点 1,当存在肌腱、骨、关节、大血管、神经等组织裸露时,采用游离皮瓣移植修复可大大降低因溃疡导致截肢等恶性事件的发生率。但糖尿病患者全身动脉易发生血管粥样硬化和狭窄,故对糖尿病足创面行游离皮瓣修复术时,如何提升皮瓣血流灌注压力从而改善皮瓣活力是临床亟待解决的问题。多巴酚丁胺作为一种强心药,通过加强心脏收缩力提升患者全身平均动脉压(MAP)且不收缩外周血管。因此,本课题组对接受游离皮瓣移植修复的糖尿病足患者,术中使用多巴酚丁胺提升血压,观察该药对术中皮瓣血流灌注及患者生命体征的影响。

    本前瞻性自身对照研究通过遵义医科大学附属医院(下称本单位)生物医学研究伦理委员会审批,批号:KLL-2022-765。患者或患者委托人签署研究知情同意书。

    纳入标准:(1)年龄18~75岁;(2)需行全身麻醉下游离皮瓣移植修复创面的糖尿病足患者;(3)常规术前下肢主要动脉CT血管造影(CTA)结果显示,胫前动脉、胫后动脉和腓动脉中至少有1条动脉通畅;(4)Wagner分级Ⅲ级或Ⅳ级。排除标准:(1)有胸痛、胸闷症状;(2)常规术前心脏彩超提示,左室流出道梗阻或严重心脏器质性病变;(3)严重心律失常;(4)尿毒症;(5)收缩压≥160 mmHg(1 mmHg=0.133 kPa)和/或舒张压≥100 mmHg;(6)碘过敏。

    2022年1—11月,本单位烧伤整形外科收治20例符合入选标准的糖尿病足患者,其中男9例、女11例,年龄44~75(58±10)岁,体重指数(24.5±1.6)kg/m 2。常规术前下肢主要动脉CTA结果显示,仅1条动脉通畅者3例、2条动脉通畅者17例。足部创面大小5 cm×4 cm~20 cm×10 cm[(156±30)cm 2],均拟采用游离股前外侧皮瓣修复。

    盐酸戊乙奎醚购自锦州奥鸿药业有限责任公司,咪达唑仑、舒芬太尼、瑞芬太尼购自宜昌人福药业有限责任公司,苯磺酸顺阿曲库铵注射液购自江苏恒瑞医药股份有限公司,依托咪酯、丙泊酚购自江苏恩华药业股份有限公司,盐酸多巴酚丁胺注射液购自广东南国药业有限公司,吲哚菁绿购自丹东医创药业有限责任公司。

    MI-4型红外显像仪购自济南显微智能科技有限公司,Aelite NXT型麻醉机购自通用电气医疗系统(中国)有限公司,BeneVision N15型心电监护仪购自深圳迈瑞生物医疗电子股份有限公司,3M TM Bair Hugger 775型升温仪购自美国3M公司,MIR-H263-PC型液体加温箱购自日本Panasonic公司,GEM 3500型血气分析仪购自美国IL公司,微量注射泵购自深圳麦科田生物医疗技术有限公司。

    1.4.1   麻醉管理方法

    所有患者均由同一组麻醉医师实施气管插管全身麻醉。麻醉前30 min肌内注射1 mg/mL盐酸戊乙奎醚0.01 mg/kg以抑制腺体分泌,进入手术室后监测心电图、脉搏血氧饱和度。在局部麻醉下行桡动脉穿刺,监测MAP,同时记录此时患者收缩压(基础值),行动脉血气分析,行右颈内静脉穿刺置管监测中心静脉压(CVP)。以麻醉诱导前(患者所有监测准备就绪,准备行静脉推注全身麻醉药物之前)MAP为基础血压(称为MAP 0)。麻醉诱导的用药方案:静脉推注1 mg/mL咪达唑仑0.1 mg/kg、50 μg/mL舒芬太尼0.3~0.4 μg/kg、2 mg/mL苯磺酸顺阿曲库铵0.15 mg/kg、2 mg/mL依托咪酯0.15~0.30 mg/kg,面罩给氧去氮后气管插管行机械通气,采用容量模式控制呼吸,潮气量6~8 mL/kg、吸呼比1.0∶1.5~1.0∶2.0、呼气末正压3~6 cmH 2O(1 cmH 2O=0.098 kPa)、吸入气氧浓度50%~60%,调整呼吸频率,使呼气末二氧化碳分压稳定于35~45 mmHg。使用丙泊酚联合瑞芬太尼维持麻醉,将脑电双频谱指数控制在40~60。放置鼻咽温度探头测量体温,使用升温仪或液体加温箱加热液体,维持口咽温度在36.0~37.0 ℃。术中输入电解质溶液为生理盐水,胶体液为羟乙基淀粉130/0.4电解质注射液,将CVP维持在8~12 cmH 2O。术中根据血气分析结果调整电解质及酸碱平衡,将血糖控制在5.5~10.0 mmol/L,使血红蛋白≥70 g/L,吻合血管前不使用任何血管活性药物。

    1.4.2   股前外侧皮瓣移植方案及皮瓣血流灌注的判断方法

    皮瓣移植手术均由同一组医师完成,皮瓣蒂部动脉为旋股外侧动脉,受区动脉选择胫前动脉(8例)或胫后动脉(12例),动脉均行端侧吻合;蒂部2条静脉均为旋股外侧动脉伴行静脉,受区静脉选择胫前静脉(8例)或胫后静脉(12例),静脉均行端端吻合,保证足远端血供。

    血管吻合完成,观察皮瓣血运10 min,排除血管痉挛及吻合口栓塞(此时即血管再通后10 min)。静脉推注造影剂2.5 mg/mL吲哚菁绿3 mL,立即使用红外显像仪观察皮瓣血流灌注情况,并使用仪器自带系统软件进行分析。根据皮瓣血流灌注高低不同反映的颜色差异进行区分,红色是高灌注区域,蓝色是低灌注区域。利用透明网格坐标纸覆盖皮瓣表面,勾画并测量皮瓣整体面积及红色区域达最大时皮瓣高、低灌注面积,计算皮瓣高、低灌注面积比。皮瓣高灌注面积比=皮瓣高灌注区域面积÷皮瓣整体面积,皮瓣低灌注面积比=皮瓣低灌注区域面积÷皮瓣整体面积。推注第1次造影剂30 min后由中心静脉泵注多巴酚丁胺,初始剂量3 μg·kg -1·min -1,每隔30 s增加1 μg·kg -1·min -1,直到MAP达到目标血压,即MAP较MAP 0高6~10 mmHg 2(此时即泵注多巴酚丁胺后达目标血压时)。同前推注第2次造影剂,使用相同方法观察皮瓣血流灌注及分析图像,之后调整多巴酚丁胺泵注剂量,将患者MAP维持在麻醉诱导前水平并持续至术毕。待患者清醒、自主呼吸恢复后,拔出气管导管,10 min后测量患者的心率及MAP。若在泵注多巴酚丁胺时患者出现以下任意一种情况,立即停止泵注多巴酚丁胺 3, 4:(1)已达到最大心率,即(220-年龄)×85%;(2)多巴酚丁胺使用达最大剂量15 μg·kg -1·min -1;(3)收缩压较基础值降低20 mmHg以上;(4)心电图ST段抬高或降低2 mm以上;(5)出现任何频发(≥5次/min)心律失常。

    麻醉诱导前、血管再通后10 min、泵注多巴酚丁胺后达目标血压时、拔出气管导管后10 min的心率及MAP,血管再通后10 min、泵注多巴酚丁胺后达目标血压时的皮瓣高、低灌注面积比,皮瓣切取面积、手术时长、输液总量、多巴酚丁胺的泵注剂量及使用总量,术中不良事件、术后皮瓣并发症及随访情况。

    采用SPSS 22.0统计软件进行数据分析,计量资料数据中符合正态分布者,采用 x ¯ ± s 表示,仅设2个时间点的指标比较采用配对样本 t检验;多个时间点间总体比较采用重复测量方差分析,两两比较采用Bonferroni法。计量资料数据中不符合正态分布者,采用 MQ 1 ,Q 3)表示,多个时间点间总体比较采用广义估计方程法,并进一步进行两两比较。 P<0.05为差异有统计学意义。

    与麻醉诱导前比较,患者血管再通后10 min心率与MAP均明显降低( P<0.05),泵注多巴酚丁胺后达目标血压时心率与MAP均明显升高( P<0.05);与血管再通后10 min比较,患者泵注多巴酚丁胺后达目标血压时、拔出气管导管后10 min心率与MAP均明显升高( P<0.05);与泵注多巴酚丁胺后达目标血压时比较,患者拔出气管导管后10 min心率与MAP均明显降低( P<0.05)。见 表1

    表1  20例行股前外侧皮瓣游离移植修复术的糖尿病足患者各时间点部分生命体征的比较
    时间点 心率(次/min, x ¯ ± s MAP[mmHg, MQ 1 ,Q 3)]
    麻醉诱导前 83±10 101.5(88.5,104.5)
    血管再通后10 min 66±9 64.5(60.0,66.0)
    泵注多巴酚丁胺后达目标血压时 94±15 106.0(96.0,110.0)
    拔出气管导管后10 min 78±11 99.5(91.5,105.5)
    统计量值 F=25.55 Wald χ 2=595.10
    P <0.001 <0.001
    P 1 <0.001 <0.001
    P 2 0.001 <0.001
    P 3 0.066 0.764
    P 4 <0.001 <0.001
    P 5 0.004 <0.001
    P 6 <0.001 <0.001
    注:目标血压指平均动脉压(MAP)较麻醉诱导前高6~10 mmHg(1 mmHg=0.133 kPa);统计量值、 P值为各时间点间总体比较所得; P 1值、 P 2值、 P 3值分别为血管再通后10 min、泵注多巴酚丁胺后达目标血压时、拔出气管导管后10 min与麻醉诱导前的各指标比较所得, P 4值、 P 5值分别为泵注多巴酚丁胺后达目标血压时、拔出气管导管后10 min与血管再通后10 min各指标比较所得, P 6值为拔出气管导管后10 min与泵注多巴酚丁胺后达目标血压时各指标比较所得
    下载: 导出CSV 
    | 显示表格

    患者泵注多巴酚丁胺后达目标血压时皮瓣高灌注面积比为0.63±0.11,明显高于血管再通后10 min的0.31±0.09( t=-9.92, P<0.001);患者泵注多巴酚丁胺后达目标血压时皮瓣低灌注面积比为0.12±0.05,明显低于血管再通后10 min的0.45±0.10( t=17.05, P<0.001)。

    患者皮瓣切取面积为6 cm×5 cm~22 cm×11 cm[(174±35)cm 2],手术时长为305~465(372±52)min,输液总量为1 850~3 250(2 485±361)mL,术中所有患者均未出现吲哚菁绿造影相关并发症,多巴酚丁胺泵注剂量为3~13 μg·kg -1·min -1、使用总量为1.8~14.0[5.7(2.1,9.7)]mg。2例患者泵注多巴酚丁胺期间MAP较血管再通后10 min明显升高,但在还未达到比麻醉诱导前高6 mmHg时,已达最大心率(130 次/min以上),停止泵注多巴酚丁胺后心率逐渐恢复至90 次/min左右。术后 2 d,1例患者皮瓣远端部分坏死,考虑为皮瓣边缘距离血管蒂部较远、供血不足所致,清除坏死部分皮瓣,移植对侧大腿薄中厚皮片修复残留的创面,5 d后,皮片成活。术后随访3~6个月,皮瓣均存活良好,质地柔软、形态饱满,患者未发生不良心血管意外事件。

    患者男,49岁。因糖尿病足溃疡1年余入院。专科检查:右足第2~5趾缺失,仅残存第1足趾,足部创面大小为20 cm×7 cm,伴跖骨及跟骨外露;下肢血管CTA显示右下肢胫前动脉及腓动脉连续性中断,胫后动脉通畅。于全身麻醉下游离移植股前外侧皮瓣修复糖尿病足溃疡创面。麻醉诱导前心率为88 次/min、MAP为101 mmHg。术中切取股前外侧皮瓣面积约为22 cm×8 cm,将皮瓣蒂部动脉与受区胫后动脉吻合,皮瓣蒂部2条静脉与受区胫后静脉吻合。血管再通后10 min心率为69 次/min、MAP为66 mmHg,同前静脉推注吲哚菁绿,此时皮瓣高灌注面积比为0.29、低灌注面积比为0.42。泵注多巴酚丁胺2 min后心率为89 次/min、MAP达107 mmHg(即泵注多巴酚丁胺后达目标血压时),皮瓣高灌注面积比为0.77、低灌注面积比为0.07,皮瓣红润、外观饱满。术中,根据血压动态调整多巴酚丁胺泵注剂量,维持在3~7 μg·kg -1·min -1之间,使用总量为5.0 mg。手术时长为320 min,输液总量为1 900 mL。拔出气管导管后10 min,心率为80 次/min、MAP为98 mmHg,皮瓣血运良好。术后随访5个月,皮瓣红润,形态饱满,质地柔软。见 图1

    注:目标血压指平均动脉压较麻醉诱导前高6 mmHg(1 mmHg=0.133 kPa)

    中国有近1.14亿成年人患糖尿病,是世界上糖尿病患者人数最多的国家 5,约6.3%的糖尿病患者会出现下肢感染形成创面,预后差,大大降低了患者生活质量,而游离皮瓣修复术有利于下肢创面恢复,改善患者生存质量 6, 7, 8。皮瓣血运状态是决定手术成功与否的关键因素,用游离皮瓣修复糖尿病足创面时,主要通过借助下肢主干血管血流同时供应足部及远端皮瓣 9,因此需要足够的血流灌注压力和灌注量。MAP是皮瓣组织压力梯度的主要决定因素,术中全身麻醉或区域阻滞均会不同程度降低MAP。糖尿病患者血管基层增生,脂质沉积,全身动脉存在不同程度狭窄,且支配下肢微循环的神经长期暴露在高糖环境导致神经营养障碍而变性,血管调节机制受损,故麻醉过程中较非糖尿病患者更容易发生低血压 10。因此,如何提高皮瓣血流灌注压力且增加灌注量是糖尿病足患者临床治疗中迫切需要解决的问题。

    在开展本研究前,为降低围手术期风险,需排除术前严重心脏器质性病变的患者。多巴酚丁胺是一种强心药,直接作用于β 1受体,通过增加心输出量调节MAP。本研究显示,泵注多巴酚丁胺后达目标血压时患者MAP较其他时间点明显升高,同时心率轻度增快。与其他血管活性药物如麻黄碱、去甲肾上腺素等相比较,多巴酚丁胺还激动血管平滑肌细胞上的β 2受体,泵注剂量<15 μg·kg -1·min -1时,不会收缩外周血管,特别是在低剂量(<5 μg·kg -1·min -1)时可引发外周血管轻度扩张;若泵注剂量超过15 μg·kg -1·min -1,则会刺激α 1受体引起强烈的血管收缩 11。既往Scholz等 12的研究也证实了多巴酚丁胺在头颈外科皮瓣手术中的应用安全有效,并观察到在多巴酚丁胺泵注剂量为4~6 μg·kg -1·min -1时,吻合口动脉血流平均流量和最大流量较基线有明显提高。故本试验中所有患者的多巴酚丁胺的泵注剂量维持在3~13 μg·kg -1·min -1,均<15 μg·kg -1·min -1。在游离皮瓣修复术的管理中,有学者认为早期应用多巴酚丁胺联合适度液体输注不会增加皮瓣移植失败率,反而可降低大量输液(>7 L)所致并发症的风险 13, 14。本试验中为避免容量超负荷,将CVP控制在8~12 cmH 2O,保持轻度高血容量,术中输液总量为1 850~3 250 mL,后期随访未见皮瓣水肿等并发症。

    吲哚菁绿荧光造影技术现已被广泛应用于皮瓣外科评估皮瓣活力 15, 16, 17, 18。Bigdeli等 19总结分析了88例行游离皮瓣移植患者术中使用该技术判断组织灌注的情况,得出该技术预测组织坏死的敏感度为100%、特异度为98.8%、阳性预测值为87.5%、阴性预测值为100%。由于前期血管吻合过程中手术刺激较小,加上糖尿病患者全身血管及神经受到不同程度损害,本研究中患者血管再通后10 min MAP明显低于MAP 0。本试验利用红外显像仪自带软件,绘制皮肤微循环动态色阶图,证实了在低MAP状态下,皮瓣低灌注区域较大;使用多巴酚丁胺后MAP明显提高,皮瓣高灌注区域明显扩大,中心区域灌注强度更高(部分呈暗红色),低灌注区域明显缩小。说明多巴酚丁胺可有效提升糖尿病足创面游离皮瓣修复术中皮瓣的血流灌注,使高灌注区域灌注压力更强、范围更广,有效缩小低灌注区域,增强皮瓣活力。虽然吲哚菁绿的半衰期很短,为3~4 min,但实践显示,注射吲哚菁绿20~25 min后皮瓣内才完全检测不到荧光效应,故本试验2次造影时间间隔30 min,以严格避免上一次造影剂残留对下一次造影产生影响。

    本课题组前期研究结果表明,高于基础血压6~10 mmHg即可明显改善游离皮瓣血运,但随着血压继续升高,游离皮瓣血运评分并不能随之增高 2。本试验在泵注多巴酚丁胺期间,有2例患者在MAP未达到MAP 0+6 mmHg时心率已达到最大,但患者的血压较吻合口再通时有明显提高,同时皮瓣血流灌注也明显增加,停止泵药后症状消失,后续无恶性心血管事件发生。分析术中出现心血管事件的原因可能与糖尿病患者机体动脉硬化 20和心脏自主神经功能受损 21有关,提示此类患者可能存在心脏储备功能下降及心肌细胞受损的情况,使用多巴酚丁胺期间需严密监护。同时还提示,糖尿病患者行游离皮瓣移植术时,血管再通期间血压的调控目标可能低于非糖尿病患者的血压目标值,具体血压范围的界定需进一步研究。本研究中无其他不良事件,术后随访20例患者皮瓣均存活良好。

    综上所述,将多巴酚丁胺应用于糖尿病足创面游离皮瓣修复术中,可以提高术中皮瓣血流灌注压力,明显扩大高灌注区域,缩小低灌注范围,增加皮瓣活力,降低此类患者术中全身重要器官低灌注的风险。但本研究存在一定的局限性:(1)样本量较小,且为同一医院的患者,研究结果仍需大样本、多中心、随机对照临床研究验证。(2)受临床因素限制,没有在血管再通期间设定不同目标血压观察皮瓣血流灌注情况,故未能确定此类手术的最佳目标血压调控范围。因此,后续需进一步研究,寻找此类手术安全、适宜的目标血压范围。

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    Created with Highcharts 5.0.7Chart context menuAccess Area Distribution其他: 6.2 %其他: 6.2 %其他: 0.5 %其他: 0.5 %Arlington: 0.1 %Arlington: 0.1 %Falls Church: 0.2 %Falls Church: 0.2 %Seattle: 0.1 %Seattle: 0.1 %United States: 0.2 %United States: 0.2 %三明: 0.4 %三明: 0.4 %三门峡: 0.2 %三门峡: 0.2 %上海: 0.5 %上海: 0.5 %东莞: 0.5 %东莞: 0.5 %丽水: 0.4 %丽水: 0.4 %乌鲁木齐: 0.2 %乌鲁木齐: 0.2 %六安: 0.1 %六安: 0.1 %内江: 0.1 %内江: 0.1 %包头: 0.2 %包头: 0.2 %北京: 0.7 %北京: 0.7 %十堰: 0.1 %十堰: 0.1 %南京: 0.2 %南京: 0.2 %南宁: 0.4 %南宁: 0.4 %南平: 0.2 %南平: 0.2 %南昌: 0.4 %南昌: 0.4 %南通: 0.1 %南通: 0.1 %厦门: 0.6 %厦门: 0.6 %台州: 2.2 %台州: 2.2 %合肥: 0.1 %合肥: 0.1 %吉林: 0.6 %吉林: 0.6 %咸阳: 1.6 %咸阳: 1.6 %嘉兴: 0.9 %嘉兴: 0.9 %嘉峪关: 0.1 %嘉峪关: 0.1 %夏延: 0.2 %夏延: 0.2 %多伦多: 0.2 %多伦多: 0.2 %大连: 1.8 %大连: 1.8 %天津: 0.3 %天津: 0.3 %孟买: 0.2 %孟买: 0.2 %宁德: 0.2 %宁德: 0.2 %宁波: 0.5 %宁波: 0.5 %安康: 0.1 %安康: 0.1 %宜春: 0.3 %宜春: 0.3 %宿迁: 1.2 %宿迁: 1.2 %山景城: 0.5 %山景城: 0.5 %巴黎: 0.3 %巴黎: 0.3 %常州: 0.1 %常州: 0.1 %常德: 0.5 %常德: 0.5 %广安: 0.1 %广安: 0.1 %广州: 2.4 %广州: 2.4 %廊坊: 0.2 %廊坊: 0.2 %张家口: 1.2 %张家口: 1.2 %徐州: 0.9 %徐州: 0.9 %德州: 0.1 %德州: 0.1 %成都: 0.2 %成都: 0.2 %扬州: 0.2 %扬州: 0.2 %抚州: 1.2 %抚州: 1.2 %斯劳: 0.1 %斯劳: 0.1 %新乡: 0.2 %新乡: 0.2 %无锡: 0.7 %无锡: 0.7 %日照: 0.3 %日照: 0.3 %昆明: 0.4 %昆明: 0.4 %晋城: 0.1 %晋城: 0.1 %朝阳: 1.5 %朝阳: 1.5 %杭州: 2.7 %杭州: 2.7 %枣庄: 0.2 %枣庄: 0.2 %格兰特县: 0.1 %格兰特县: 0.1 %梧州: 0.3 %梧州: 0.3 %榆林: 0.8 %榆林: 0.8 %武汉: 1.5 %武汉: 1.5 %汕头: 0.6 %汕头: 0.6 %江门: 0.1 %江门: 0.1 %池州: 0.5 %池州: 0.5 %沃思堡: 0.1 %沃思堡: 0.1 %沈阳: 1.2 %沈阳: 1.2 %泉州: 0.2 %泉州: 0.2 %泰州: 0.3 %泰州: 0.3 %泸州: 0.1 %泸州: 0.1 %洛阳: 0.3 %洛阳: 0.3 %济南: 1.2 %济南: 1.2 %济宁: 0.2 %济宁: 0.2 %海得拉巴: 0.2 %海得拉巴: 0.2 %海西: 0.3 %海西: 0.3 %淮北: 0.4 %淮北: 0.4 %淮安: 0.2 %淮安: 0.2 %深圳: 0.2 %深圳: 0.2 %温州: 0.5 %温州: 0.5 %渭南: 0.6 %渭南: 0.6 %湖州: 0.9 %湖州: 0.9 %湘西: 0.5 %湘西: 0.5 %漯河: 0.5 %漯河: 0.5 %漳州: 1.4 %漳州: 1.4 %潍坊: 0.1 %潍坊: 0.1 %烟台: 0.1 %烟台: 0.1 %盐城: 0.5 %盐城: 0.5 %盘锦: 0.5 %盘锦: 0.5 %石家庄: 1.0 %石家庄: 1.0 %福州: 0.6 %福州: 0.6 %纽约: 0.3 %纽约: 0.3 %绍兴: 0.6 %绍兴: 0.6 %绵阳: 0.3 %绵阳: 0.3 %自贡: 0.2 %自贡: 0.2 %舟山: 0.5 %舟山: 0.5 %芒廷维尤: 22.8 %芒廷维尤: 22.8 %芝加哥: 0.6 %芝加哥: 0.6 %苏州: 0.5 %苏州: 0.5 %苏黎世: 0.1 %苏黎世: 0.1 %荆州: 0.1 %荆州: 0.1 %荆门: 1.3 %荆门: 1.3 %莆田: 0.2 %莆田: 0.2 %营口: 0.9 %营口: 0.9 %葫芦岛: 0.3 %葫芦岛: 0.3 %衡水: 0.2 %衡水: 0.2 %衡阳: 0.1 %衡阳: 0.1 %衢州: 0.6 %衢州: 0.6 %襄阳: 0.2 %襄阳: 0.2 %西宁: 1.4 %西宁: 1.4 %西安: 0.1 %西安: 0.1 %辽阳: 0.2 %辽阳: 0.2 %达州: 0.2 %达州: 0.2 %运城: 0.2 %运城: 0.2 %连云港: 0.7 %连云港: 0.7 %邵阳: 0.2 %邵阳: 0.2 %郑州: 0.1 %郑州: 0.1 %郴州: 1.2 %郴州: 1.2 %重庆: 3.4 %重庆: 3.4 %金华: 0.8 %金华: 0.8 %铁岭: 1.1 %铁岭: 1.1 %银川: 0.1 %银川: 0.1 %锦州: 0.2 %锦州: 0.2 %长春: 0.3 %长春: 0.3 %长沙: 0.8 %长沙: 0.8 %随州: 0.8 %随州: 0.8 %雅安: 0.6 %雅安: 0.6 %青岛: 0.3 %青岛: 0.3 %鞍山: 1.6 %鞍山: 1.6 %香港: 0.2 %香港: 0.2 %驻马店: 0.2 %驻马店: 0.2 %鹰潭: 0.2 %鹰潭: 0.2 %黄冈: 1.4 %黄冈: 1.4 %黄南: 0.2 %黄南: 0.2 %黄山: 0.1 %黄山: 0.1 %黄石: 0.5 %黄石: 0.5 %其他其他ArlingtonFalls ChurchSeattleUnited States三明三门峡上海东莞丽水乌鲁木齐六安内江包头北京十堰南京南宁南平南昌南通厦门台州合肥吉林咸阳嘉兴嘉峪关夏延多伦多大连天津孟买宁德宁波安康宜春宿迁山景城巴黎常州常德广安广州廊坊张家口徐州德州成都扬州抚州斯劳新乡无锡日照昆明晋城朝阳杭州枣庄格兰特县梧州榆林武汉汕头江门池州沃思堡沈阳泉州泰州泸州洛阳济南济宁海得拉巴海西淮北淮安深圳温州渭南湖州湘西漯河漳州潍坊烟台盐城盘锦石家庄福州纽约绍兴绵阳自贡舟山芒廷维尤芝加哥苏州苏黎世荆州荆门莆田营口葫芦岛衡水衡阳衢州襄阳西宁西安辽阳达州运城连云港邵阳郑州郴州重庆金华铁岭银川锦州长春长沙随州雅安青岛鞍山香港驻马店鹰潭黄冈黄南黄山黄石

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      沈阳化工大学材料科学与工程学院 沈阳 110142

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