人类重组活化蛋白C治疗严重脓毒症的Meta分析_《中国循证医学杂志》

作者：

王倩 ¹ , 赵阳 ² ,  朱杰 ¹

1. 中国医科大学附属第四医院急诊科（沈阳　110032）；2. 中国医科大学附属盛京医院ICU（沈阳　110004）;

关键词：

人类重组活化蛋白C 严重脓毒症系统评价 Meta分析随机对照试验

DOI：

10.7507/1672-2531.20130229

视频：

导出 下载 收藏 扫码 引用

摘要 全文 图表 视频 参考文献 施引文献 补充材料

目的　系统评价人类重组活化蛋白C（rhAPC）治疗严重脓毒症的有效性及安全性。
方法　计算机检索MEDLINE、EMbase、The Cochrane Library、VIP、CNKI、CBM和WanFang Data等数据库，全面收集rhAPC治疗严重脓毒症的随机对照试验（RCT），检索时限均为建库至2012年7月，并追溯纳入研究的参考文献。由两位研究者按照纳入与排除标准独立筛选文献、提取资料和评价质量后，采用RevMan 5.0软件进行Meta分析。
结果　共纳入5个RCT，6 307例患者。Meta分析结果显示：rhAPC组同安慰剂组相比，两者在严重脓毒症患者28天病死率［RR=1.00， 95%CI（0.84，1.19），P=1.00］和90天病死率［RR=1.00， 95%CI（0.87，1.14），P=0.96］方面差异均无统计学意义。对不同急性生理及慢性健康评分Ⅱ（Acute Physiology and Chronic Health EvaluationⅡ，APACHEⅡ）严重脓毒症患者的28天病死率进行亚组分析，结果显示两组差异也无统计学意义［APACHEⅡ评分 lt;25分：RR=1.06，95%CI（0.93，1.21），P=0.37；APACHEⅡ评分≥25分：RR=0.93，95%CI（0.69，1.24），P=0.60］。不同活化蛋白C缺乏程度患者28天病死率的亚组分析结果显示，两组差异也无统计学意义［APC缺乏 lt;80%：RR=0.96，95%CI（0.56，1.65），P=0.89；APC缺乏 gt;80%：RR=0.61，95%CI（0.34，1.08），P=0.09］。此外，rhAPC能使严重脓毒症患者严重出血事件发生的风险增加1.62倍［RR=1.62， 95%CI（1.17，2.23），P=0.004］，但两组在严重不良反应总发生率方面，差异无统计学意义［RR=1.04， 95%CI（0.92，1.18），P=0.53］。
结论　现有证据表明，rhAPC并不能改善严重脓毒症患者的预后，反而会增加出血风险。

引用本文： 王倩,赵阳,朱杰. 人类重组活化蛋白C治疗严重脓毒症的Meta分析. 中国循证医学杂志, 2013, 13(11): 1333-1339. doi: 10.7507/1672-2531.20130229 复制

1.	Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med, 2003, 348(12): 1546-1554.
2.	Hall MJ, Williams SN, DeFrances CJ, et al. Inpatient care for septicemia or sepsis: a challenge for patients and hospitals. NCHS Data Brief, 2011, (62): 1-8.
3.	Brun-Buisson C. Epidemiology of severe sepsis. Presse Médicale, 2006, 35(3 Pt 2): 513-520.
4.	Danai PA, Sinha S, Moss M, et al. Seasonal variation in the epidemiology of sepsis. Critical Care Medicine, 2007, 35(2): 410-415.
5.	Das UN. Critical advances in septicemia and septic shock. Criti Care, 2000, 4(5): 290-296.
6.	Khwannimit B, Bhurayanontachai R. The epidemiology of, and risk factors for, mortality from severe sepsis and septic shock in a tertiary-care university hospital setting. Epidemiology and Infection, 2009, 137(9): 1-9.
7.	Linde-Zwirble WT, Angus DC. Severe sepsis epidemiology: sampling, selection, and society. Crit Care, 2004, 8(4): 222-226.?.
8.	Brun-Buisson C, Meshaka P, Pinton P, et al. EPISEPSIS: a reappraisal of the epidemiology and out- come of severe sepsis in French intensive care units. Intensive Care Med, 2004, 30(4): 580-588.
9.	Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med, 2001, 29(7): 1303-1313.
10.	Cheng B, Xie G, Yao S, et al. Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China. Critical Care Medicine, 2007, 35(11): 2538-2546.
11.	Paul M. Is there a treatment for sepsis other than antibiotics? Clinical Microbiology and Infection, 2009, 15(4): 297.
12.	Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med, 2003, 348(2): 138-150.
13.	Grey ST, Hancock WW. Inhibition of LPS-induced activation of human monocytes by activated protein C (APC) occurs through a novel mechanism. J Leukoc Biol, 1993, 114(6): A487.
14.	Bernard GR, Vincent JL, Laterre PF, et al, and the Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. E?cacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med, 2001, 344(5): 699-709.
15.	Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0[updated March 2011]. The Cochrane Collaboration, 2011, Available from: www.cochrane-handbook.org.
16.	Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002, 21(11): 1539-1558.
17.	Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ, 2003, 327()7414: 557-560.
18.	Egger M, Altman DG, Smith GD. Systematic reviews in health-care: meta-analysis in context. 2nd Ed. BMJ Books, Wiley: London, 2001.
19.	. Bernard GR, Ely EW, Wright TJ, et al. Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit Care Med, 2001, 29(11): 2051-2059.
20.	Angus DC, Laterre PF, Helterbrand J, et al, and PROWESS Investigators. The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis. Crit Care Med, 2004, 32(11): 2199-2206.
21.	Abraham E, Laterre PF, Garg R, et al, and Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med, 2005, 353(13): 1332-1341.
22.	Dhainaut JF, Antonelli M, Wright P, et al. Extended drotrecogin alfa (activated) treatment in patients with prolonged septic shock. Intensive Care Med, 2009, 35(7): 1187-1195.
23.	Ranieri VM, Thompson BT, Barie PS, et al, and PROWESS-SHOCK Study Group. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med, 2012, 366(22): 2055-2064.
24.	Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet, 2005, 365(9453): 63-78.
25.	Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood, 2007, 109(8): 3161-3172.
26.	Shorr AF, Bernard GR, Dhainaut JF, et al. Protein C concentrations in severe sepsis: An early directional change in plasma levels predicts outcome. Crit Care, 2006, 10(6): R92.
27.	MammenE. Thehaematological manifestations of sepsis. J Antimicrob Chemother, 1998, 41(Suppl A): S17-S24.
28.	Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med, 2008, 36(12): 296-327.
29.	Casserly B, Gerlach H, Phillips GS, et al. Evaluating the use of recombinant human activated protein C in adult severe sepsis: results of the Surviving Sepsis Campaign. Crit Care Med, 2012, 40(5): 1417-1426.
30.	Kalil AC, Larosa SP. Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression. Lancet Infect Dis, 2012, 12(9): 678-686.
31.	Rimmer E, Kumar A, Doucette S, et al, and Cooperative Antimicrobial Therapy of Septic Shock Database Research Group. Activated protein C and septic shock: A propensity-matched cohort study. Crit Care Med, 2012, 40(11): 2974-2981.
32.	Martí-Carvajal AJ, Solà I, Lathyris D, et al. Human recombinant activated protein C for severe sepsis. Cochrane Database Syst Rev, 2012, 3: CD004388.
33.	Nadel S, Goldstein B, Williams MD, et al, and Researching severe Sepsis and Organ dysfunction in children: a global perspective (RESOLVE) study group. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet, 2007, 369(9564): 836-843.
34.	University of Versailles: Activated protein C and corticosteroids for human septic shock (APROCCHS). Available from: http://clinicaltrials.gov/ct2/show/NCT00625209. Accessed Oct 3, 2012.
35.	University of Versailles: Pharmacogenomic Biomarker Study for Recombinant Human Activated Protein C Treatment in Severe Sepsis. Available from: http://clinicaltrials.gov/ct2/show/NCT01486524. Accessed Oct 3, 2012.
36.	Guyatt G, Oxman A, Montori V, et al. GRADE指南: Ⅴ.证据质量评价—发表偏倚. 中国循证医学杂志, 2011, 11(12): 1430-1434.

1. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med, 2003, 348(12): 1546-1554.
2. Hall MJ, Williams SN, DeFrances CJ, et al. Inpatient care for septicemia or sepsis: a challenge for patients and hospitals. NCHS Data Brief, 2011, (62): 1-8.
3. Brun-Buisson C. Epidemiology of severe sepsis. Presse Médicale, 2006, 35(3 Pt 2): 513-520.
4. Danai PA, Sinha S, Moss M, et al. Seasonal variation in the epidemiology of sepsis. Critical Care Medicine, 2007, 35(2): 410-415.
5. Das UN. Critical advances in septicemia and septic shock. Criti Care, 2000, 4(5): 290-296.
6. Khwannimit B, Bhurayanontachai R. The epidemiology of, and risk factors for, mortality from severe sepsis and septic shock in a tertiary-care university hospital setting. Epidemiology and Infection, 2009, 137(9): 1-9.
7. Linde-Zwirble WT, Angus DC. Severe sepsis epidemiology: sampling, selection, and society. Crit Care, 2004, 8(4): 222-226.?.
8. Brun-Buisson C, Meshaka P, Pinton P, et al. EPISEPSIS: a reappraisal of the epidemiology and out- come of severe sepsis in French intensive care units. Intensive Care Med, 2004, 30(4): 580-588.
9. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med, 2001, 29(7): 1303-1313.
10. Cheng B, Xie G, Yao S, et al. Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China. Critical Care Medicine, 2007, 35(11): 2538-2546.
11. Paul M. Is there a treatment for sepsis other than antibiotics? Clinical Microbiology and Infection, 2009, 15(4): 297.
12. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med, 2003, 348(2): 138-150.
13. Grey ST, Hancock WW. Inhibition of LPS-induced activation of human monocytes by activated protein C (APC) occurs through a novel mechanism. J Leukoc Biol, 1993, 114(6): A487.
14. Bernard GR, Vincent JL, Laterre PF, et al, and the Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. E?cacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med, 2001, 344(5): 699-709.
15. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0[updated March 2011]. The Cochrane Collaboration, 2011, Available from: www.cochrane-handbook.org.
16. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002, 21(11): 1539-1558.
17. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ, 2003, 327()7414: 557-560.
18. Egger M, Altman DG, Smith GD. Systematic reviews in health-care: meta-analysis in context. 2nd Ed. BMJ Books, Wiley: London, 2001.
19. . Bernard GR, Ely EW, Wright TJ, et al. Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit Care Med, 2001, 29(11): 2051-2059.
20. Angus DC, Laterre PF, Helterbrand J, et al, and PROWESS Investigators. The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis. Crit Care Med, 2004, 32(11): 2199-2206.
21. Abraham E, Laterre PF, Garg R, et al, and Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med, 2005, 353(13): 1332-1341.
22. Dhainaut JF, Antonelli M, Wright P, et al. Extended drotrecogin alfa (activated) treatment in patients with prolonged septic shock. Intensive Care Med, 2009, 35(7): 1187-1195.
23. Ranieri VM, Thompson BT, Barie PS, et al, and PROWESS-SHOCK Study Group. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med, 2012, 366(22): 2055-2064.
24. Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet, 2005, 365(9453): 63-78.
25. Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood, 2007, 109(8): 3161-3172.
26. Shorr AF, Bernard GR, Dhainaut JF, et al. Protein C concentrations in severe sepsis: An early directional change in plasma levels predicts outcome. Crit Care, 2006, 10(6): R92.
27. MammenE. Thehaematological manifestations of sepsis. J Antimicrob Chemother, 1998, 41(Suppl A): S17-S24.
28. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med, 2008, 36(12): 296-327.
29. Casserly B, Gerlach H, Phillips GS, et al. Evaluating the use of recombinant human activated protein C in adult severe sepsis: results of the Surviving Sepsis Campaign. Crit Care Med, 2012, 40(5): 1417-1426.
30. Kalil AC, Larosa SP. Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression. Lancet Infect Dis, 2012, 12(9): 678-686.
31. Rimmer E, Kumar A, Doucette S, et al, and Cooperative Antimicrobial Therapy of Septic Shock Database Research Group. Activated protein C and septic shock: A propensity-matched cohort study. Crit Care Med, 2012, 40(11): 2974-2981.
32. Martí-Carvajal AJ, Solà I, Lathyris D, et al. Human recombinant activated protein C for severe sepsis. Cochrane Database Syst Rev, 2012, 3: CD004388.
33. Nadel S, Goldstein B, Williams MD, et al, and Researching severe Sepsis and Organ dysfunction in children: a global perspective (RESOLVE) study group. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet, 2007, 369(9564): 836-843.
34. University of Versailles: Activated protein C and corticosteroids for human septic shock (APROCCHS). Available from: http://clinicaltrials.gov/ct2/show/NCT00625209. Accessed Oct 3, 2012.
35. University of Versailles: Pharmacogenomic Biomarker Study for Recombinant Human Activated Protein C Treatment in Severe Sepsis. Available from: http://clinicaltrials.gov/ct2/show/NCT01486524. Accessed Oct 3, 2012.
36. Guyatt G, Oxman A, Montori V, et al. GRADE指南: Ⅴ.证据质量评价—发表偏倚. 中国循证医学杂志, 2011, 11(12): 1430-1434.

《中国循证医学杂志》

人类重组活化蛋白C治疗严重脓毒症的Meta分析

摘要 全文 图表 视频 参考文献 施引文献 补充材料

上一篇

下一篇

Format

Content

《中国循证医学杂志》

人类重组活化蛋白C治疗严重脓毒症的Meta分析

摘要 全文 图表 视频 参考文献 施引文献 补充材料

上一篇

下一篇

Format

Content

摘要全文图表视频参考文献施引文献补充材料