切换至 "中华医学电子期刊资源库"

中华危重症医学杂志(电子版) ›› 2023, Vol. 16 ›› Issue (02) : 123 -129. doi: 10.3877/cma.j.issn.1674-6880.2023.02.006

荟萃分析

重组人可溶性血栓调节蛋白治疗脓毒症合并弥散性血管内凝血临床疗效的Meta分析
卢鑫, 魏昕, 王志斌()   
  1. 200433 上海,海军军医大学麻醉系危重病医学教研室
    200092 上海,上海交通大学医学院附属新华医院临床药学部
  • 收稿日期:2022-12-29 出版日期:2023-04-30
  • 通信作者: 王志斌
  • 基金资助:
    国家自然科学基金面上项目(81872880); 国家自然科学基金青年科学基金项目(82104269)

Clinical efficacy of recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a meta-analysis

Xin Lu, Xin Wei, Zhibin Wang()   

  1. Department of Critical Care Medicine, School of Anesthesiology, Naval Medical University, Shanghai 200433, China
    Department of Clinical Pharmacy, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
  • Received:2022-12-29 Published:2023-04-30
  • Corresponding author: Zhibin Wang
引用本文:

卢鑫, 魏昕, 王志斌. 重组人可溶性血栓调节蛋白治疗脓毒症合并弥散性血管内凝血临床疗效的Meta分析[J/OL]. 中华危重症医学杂志(电子版), 2023, 16(02): 123-129.

Xin Lu, Xin Wei, Zhibin Wang. Clinical efficacy of recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a meta-analysis[J/OL]. Chinese Journal of Critical Care Medicine(Electronic Edition), 2023, 16(02): 123-129.

目的

系统评价重组人可溶性血栓调节蛋白(rhTM)治疗脓毒症合并弥散性血管内凝血(DIC)的临床疗效。

方法

检索PubMed、Embase、Cochrane Library、Sinomed、中国知网、万方数据库、维普数据库自建库至2022年7月发表的关于rhTM治疗脓毒症合并DIC患者的临床研究。对照组使用肝素、安慰剂治疗或空白对照;试验组使用rhTM治疗。由2名研究人员独立筛选文献、数据提取及质量评价后,使用RevMan 5.4软件进行Meta分析。

结果

共纳入7篇文献、合计1 913例患者,其中试验组937例,对照组976例。Meta分析显示,试验组患者28 d病死率显著低于对照组[相对危险度(RR)= 0.83,95%置信区间(CI)(0.71,0.97),Z = 2.40,P = 0.02],DIC缓解率显著高于对照组[RR = 1.34,95%CI(1.09,1.66),Z = 2.75,P = 0.006],而两组患者间不良事件数比较差异没有统计学意义[RR = 1.01,95%CI(0.58,1.75),Z = 0.02,P = 0.98]。

结论

rhTM能够降低脓毒症合并DIC患者的28 d病死率,提高DIC缓解率,且不会增加不良事件的发生,具有较好的临床使用价值。

Objective

To systematically evaluate the clinical efficacy of recombinant human soluble thrombomodulin (rhTM) in sepsis-induced disseminated intravascular coagulation (DIC).

Methods

Clinical studies on rhTM for the treatment of sepsis-induced DIC were searched in PubMed, Embase, Cochrane Library, Sinomed, China National Knowledge Infrastructure, Wanfang database and VIP database published up to July 2022. The control group was treated with heparin, placebo or blank control. The experimental group was treated with rhTM. Two reviewers independently screened articles, extracted data and evaluated the quality of included studies. The RevMan 5.4 software was used to perform meta-analysis.

Results

Seven clinical studies involving 1 913 patients were included, with 935 patients in the experimental group and 978 patients in the control group. Meta-analysis showed that the 28-day mortality in the experimental group was much lower than that in the control group [relative risk (RR) = 0.83, 95% confidence interval (CI) (0.71, 0.97), Z = 2.40, P = 0.02], the remission rate of DIC was much higher [RR = 1.34, 95%CI (1.09, 1.66), Z = 2.75, P = 0.006], and no significant difference in the number of adverse events was found between the two groups [RR = 1.01, 95%CI (0.58, 1.75), Z = 0.02, P = 0.98].

Conclusion

rhTM can reduce the 28-day mortality and improve the remission rate of DIC in patients with sepsis-induced DIC, and it does not increase the occurrence of adverse events, showing good clinical application value.

图1 纳入研究的偏倚风险评估图注:a图为偏倚风险构成比;b图为各纳入研究的偏倚风险
表1 纳入研究的基本信息
图2 rhTM对脓毒症合并DIC患者28 d病死率影响的森林图注:rhTM.重组人可溶性血栓调节蛋白;DIC.弥漫性血管内凝血;RR.相对危险度;CI.置信区间;试验组予以rhTM治疗,对照组予以肝素、安慰剂治疗或空白对照
图3 rhTM对脓毒症合并DIC患者DIC缓解率影响的森林图注:rhTM.重组人可溶性血栓调节蛋白;DIC.弥漫性血管内凝血;RR.相对危险度;CI.置信区间;试验组予以rhTM治疗,对照组予以肝素、安慰剂治疗或空白对照
图4 rhTM对脓毒症合并DIC患者不良事件发生影响的森林图注:rhTM.重组人可溶性血栓调节蛋白;DIC.弥漫性血管内凝血;RR.相对危险度;CI.置信区间;试验组予以rhTM治疗,对照组予以肝素、安慰剂治疗或空白对照
图5 rhTM对脓毒症合并DIC患者28 d病死率影响的Meta分析文献发表偏倚漏斗图注:rhTM.重组人可溶性血栓调节蛋白;DIC.弥漫性血管内凝血;RR.相对危险度
1
Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3)[J]. JAMA, 2016, 315 (8): 801-810.
2
Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study[J]. Lancet, 2020, 395 (10219): 200-211.
3
Xie J, Wang H, Kang Y, et al. The epidemiology of sepsis in Chinese ICUs: a national cross-sectional survey[J]. Crit Care Med, 2020, 48 (3): e209-e218.
4
中华医学会急诊医学分会,中华危重病急救医学杂志编辑委员会,脓毒症并发弥散性血管内凝血诊治急诊专家共识专家组.脓毒症并发弥散性血管内凝血诊治急诊专家共识[J].实用检验医师杂志20179(3):129-132.
5
宋立成,韩志海.脓毒症相关凝血功能障碍机制及治疗的研究进展[J/CD].中华危重症医学杂志(电子版)201710(2):125-129.
6
Iba T, Nagaoka I, Boulat M. The anticoagulant therapy for sepsis-associated disseminated intravascular coagulation[J]. Thromb Res, 2013, 131 (5): 383-389.
7
Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012[J]. Intensive Care Med, 2013, 39 (2): 165-228.
8
Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016[J]. Intensive Care Med, 2017, 43 (3): 304-377.
9
Ito T, Thachil J, Asakura H, et al. Thrombomodulin in disseminated intravascular coagulation and other critical conditions-a multi-faceted anticoagulant protein with therapeutic potential[J]. Crit Care, 2019, 23 (1): 280.
10
Levi M, Van Der Poll T. Thrombomodulin in sepsis[J]. Minerva Anestesiol, 2013, 79 (3): 294-298.
11
Yamakawa K, Aihara M, Ogura H, et al. Recombinant human soluble thrombomodulin in severe sepsis: a systematic review and meta-analysis[J]. J Thromb Haemost, 2015, 13 (4): 508-519.
12
Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine[J]. Chest, 1992, 101 (6): 1644-1655.
13
Kobayashi N, Maekawa T, Takada M, et al. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the Research Committee on DIC in Japan[J]. Bibl Haematol, 1983 (49): 265-275.
14
Taylor FB Jr, Toh CH, Hoots WK, et al. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation[J]. Thromb Haemost, 2001, 86 (5): 1327-1330.
15
Gando S, Iba T, Eguchi Y, et al. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria[J]. Crit Care Med, 2006, 34 (3): 625-631.
16
Aikawa N, Shimazaki S, Yamamoto Y, et al. Thrombomodulin alfa in the treatment of infectious patients complicated by disseminated intravascular coagulation: subanalysis from the phase 3 trial[J]. Shock, 2011, 35 (4): 349-354.
17
Ogawa Y, Yamakawa K, Ogura H, et al. Recombinant human soluble thrombomodulin improves mortality and respiratory dysfunction in patients with severe sepsis[J]. J Trauma Acute Care Surg, 2012, 72 (5): 1150-1157.
18
Vincent JL, Ramesh MK, Ernest D, et al. A randomized, double-blind, placebo-controlled, phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation[J]. Crit Care Med, 2013, 41 (9): 2069-2079.
19
Vincent JL, Francois B, Zabolotskikh I, et al. Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: the SCARLET randomized clinical trial[J]. JAMA, 2019, 321 (20): 1993-2002.
20
Yamakawa K, Fujimi S, Mohri T, et al. Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study[J]. Crit Care, 2011, 15 (3): R123.
21
Hagiwara A, Tanaka N, Uemura T, et al. Can recombinant human thrombomodulin increase survival among patients with severe septic-induced disseminated intravascular coagulation: a single-centre, open-label, randomised controlled trial[J]. BMJ Open, 2016, 6 (12): e12850.
22
Ushizawa H, Isotani E, Sera T, et al. Randomized controlled trial of novel recombinant human soluble thrombomodulin for sepsis with DIC patients in Japan[J]. Crit Care Med, 2011, 39 (12): 108.
23
刘小荣.儿童血栓性微血管病的诊断及治疗进展[J].中华实用儿科临床杂志201631(17):1292-1295.
24
Thompson EA, Salem HH. Inhibition by human thrombomodulin of factor Xa-mediated cleavage of prothrombin[J]. J Clin Invest, 1986, 78 (1): 13-17.
25
Abeyama K, Stern DM, Ito Y, et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism[J]. J Clin Invest, 2005, 115 (5): 1267-1274.
26
Nagato M, Okamoto K, Abe Y, et al. Recombinant human soluble thrombomodulin decreases the plasma high-mobility group box-1 protein levels, whereas improving the acute liver injury and survival rates in experimental endotoxemia[J]. Crit Care Med, 2009, 37 (7): 2181-2186.
27
Suzuki K, Kusumoto H, Deyashiki Y, et al. Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation[J]. EMBO J, 1987, 6 (7): 1891-1897.
28
Mohri M, Sugimoto E, Sata M, et al. The inhibitory effect of recombinant human soluble thrombomodulin on initiation and extension of coagulation-a comparison with other anticoagulants[J]. Thromb Haemost, 1999, 82 (6): 1687-1693.
29
Umemura Y, Yamakawa K, Ogura H, et al. Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta-analysis of randomized controlled trials[J]. J Thromb Haemost, 2016, 14 (3): 518-530.
30
Moll S, Lindley C, Pescatore S, et al. Phase Ⅰ study of a novel recombinant human soluble thrombomodulin, ART-123[J]. J Thromb Haemost, 2004, 2 (10): 1745-1751.
31
Tsuruta K, Yamada Y, Serada M, et al. Model-based analysis of covariate effects on population pharmacokinetics of thrombomodulin alfa in patients with disseminated intravascular coagulation and normal subjects[J]. J Clin Pharmacol, 2011, 51 (9): 1276-1285.
32
Yamakawa K, Murao S, Aihara M. Recombinant human soluble thrombomodulin in sepsis-induced coagulopathy: an updated systematic review and meta-analysis[J]. Thromb Haemost, 2019, 119 (1): 56-65.
33
高洁,靳英辉,吴荷宁,等.脓毒症相关弥漫性血管内凝血患者使用重组人可溶性血栓调节蛋白疗效的Meta分析[J/CD].中华危重症医学杂志(电子版)20158(6):361-365.
34
Saito H, Maruyama I, Shimazaki S, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase Ⅲ, randomized, double-blind clinical trial[J]. J Thromb Haemost, 2007, 5 (1): 31-41.
[1] 蚁淳, 袁冬生, 熊学军. 系统免疫炎症指数与骨密度降低和骨质疏松的关联[J/OL]. 中华关节外科杂志(电子版), 2024, 18(05): 609-617.
[2] 李志文, 李远志, 李华, 方志远. 糖皮质激素治疗膝骨关节炎疗效的网状Meta分析[J/OL]. 中华关节外科杂志(电子版), 2024, 18(04): 484-496.
[3] 庄燕, 戴林峰, 张海东, 陈秋华, 聂清芳. 脓毒症患者早期生存影响因素及Cox 风险预测模型构建[J/OL]. 中华危重症医学杂志(电子版), 2024, 17(05): 372-378.
[4] 吴姗姗, 潘裕民, 刘晋, 张劲松, 乔莉. 睡眠呼吸暂停综合征患者静脉血栓栓塞症发生率的Meta分析[J/OL]. 中华危重症医学杂志(电子版), 2024, 17(04): 312-317.
[5] 杨瑾, 刘雪克, 张媛媛, 金钧, 韦瑶. 肠道微生物来源石胆酸对脓毒症相关肝损伤的保护作用[J/OL]. 中华危重症医学杂志(电子版), 2024, 17(04): 265-274.
[6] 张霞, 张瑞, 郑志波, 张勤. 紫草素调控乳酸化修饰和线粒体功能改善脓毒症心肌病小鼠的预后[J/OL]. 中华危重症医学杂志(电子版), 2024, 17(04): 275-284.
[7] 张婧琦, 江洋, 孙佳璐, 唐兴喆, 赵宇飞, 崔颖, 李信响, 戴景月, 傅琳, 彭新桂. 基于肾周CT特征结合血清肌酐水平探讨脓毒症伴急性肾损伤的早期识别[J/OL]. 中华危重症医学杂志(电子版), 2024, 17(04): 285-292.
[8] 李振翮, 魏长青, 甄国栋, 李振富. 脓毒症并发急性呼吸窘迫综合征患者血清S1P、Wnt5a变化及其临床意义[J/OL]. 中华危重症医学杂志(电子版), 2024, 17(04): 293-300.
[9] 马振威, 宋润夫, 王兵. ERCP胆道内支架与骑跨十二指肠乳头支架置入治疗不可切除肝门部胆管癌疗效的Meta分析[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(06): 807-812.
[10] 龚财芳, 赵俊宇, 游川. 围手术期肠内营养在肝癌肝切除患者中有效性及安全性的Meta分析[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(04): 551-556.
[11] 王芳, 刘达, 左智炜, 盛金平, 陈庭进, 蒋锐. 定量CT与双能X线骨密度仪对骨质疏松诊断效能比较的Meta分析[J/OL]. 中华老年骨科与康复电子杂志, 2024, 10(06): 363-371.
[12] 成人脓毒症患者β-内酰胺类抗生素延长输注专家共识编写组. 成人脓毒症患者β-内酰胺类抗生素延长输注专家共识[J/OL]. 中华重症医学电子杂志, 2024, 10(04): 313-324.
[13] 陈惠英, 邱敏珊, 邵汉权. 脓毒症诱发肠黏膜屏障功能损伤的风险因素模型构建与应用效果[J/OL]. 中华消化病与影像杂志(电子版), 2024, 14(05): 448-452.
[14] 周倩妹, 王宪娥, 徐筱, 老慧琳, 赵欣悦, 胡菁颖. 多元化系统护理对老年人群牙周健康指标影响的系统评价[J/OL]. 中华临床医师杂志(电子版), 2024, 18(05): 500-506.
[15] 傅新露, 李之岳, 卢丹. 妊娠合并结肠癌穿孔致脓毒症休克一例并文献复习[J/OL]. 中华产科急救电子杂志, 2024, 13(04): 227-231.
阅读次数
全文


摘要