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1 C cortisol Zona fasciculata Zona Reticularis 2008 Surviving Sepsis Campaign catecholamine C VIIIa Va ; PAI-1 C sepsissevere sepsisseptic shock shoalin01@gmail.com 1 27

2 1 American College of Chest Physicians ACCP Society of Critical Care Medicine SCCM systemic inflammatory response syndrome / 20 / PaCO2 32mmHg 12,000/mm 3 4,000/mm 3 10% Severe sepsis 90mm Hg 70mm Hg 0.5ml/kg PaO2/FiO2 250 PaO2/FiO /mm 3 ph base deficit 5mEq/ LSeptic shock 90 mmhg 40mmHg C C cortisol Zona fasciculata Zona Reticularis Adrenocorticotropic hormone ACTH 5-24 corticosteroid binding globulin CBG CBG acute stress Cronin meta-analysis 28

3 methylprednisolone 30mg/kg Annane vasopressin ACTH cortisol ACTH ACTH 4 Cortisol immunoassays measurement mass spectrometry 2002 JAMA hydrocortisone 50mg fludrocortisone 50 g adverse event Minneci meta-analysis 1989 hydrocortisone 25000mg/day mg hydrocortisone multicenter corticortropin 50mg hydrocortisone corticortropin 7 the Corticosteroid Therapy of Septic Shock CORTICUS study ACTH stimulation test vessopressin Surviving Sepsis Campaign guideline 9 hydrocortisone vessopressin ACTH stimulation test hydrocortisone hydrocortisone dexamethasone dexamethasone 29

hypothalamic-pituitary-adrenal axis hydrocortisone fludrocortisone vessopressin 300mg 10-12 C C Protein C K plasma serine protease zymogen Va VIIIa Protein S C factor VII IX X thrombin thrombomodulin

4 hypothalamic-pituitary-adrenal axis hydrocortisone fludrocortisone vessopressin 300mg C C Protein C K plasma serine protease zymogen Va VIIIa Protein S C factor VII IX X thrombin thrombomodulin thrombin thrombomodulin protein C C activated protein C APC protein S factor Va VIIIa thrombin fibrin APC PAI-1 Plasminogen-activator inhibitor 1 TAFI thrombin-activatable fibrinolysis inhibitor 13 thrombomodulin APC APC C Russell JA. Management of sepsis. N Engl J Med 2006;355:

C Bernard GR, et al. Recombinant human protein C Worldwide Evaluation in Severe Sepsis PROWESS study group. Efficacy and safety of recombinant human activated protein C for severe sepsis.

5 C Bernard GR, et al. Recombinant human protein C Worldwide Evaluation in Severe Sepsis PROWESS study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344: C Innate immunity adaptive immunity procoagulation factor anticoagulation factor 14 IL-1 IL-6 TNF- tissue factor coagulation cascadeviiia Va fibrinogen thrombin fibrin thrombin PAI-1 Plasminogen-activator inhibitor 1 tpa tissue plasminogen activator 15 C VIIIa Va ; PAI

6 C 20 PROWESS the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis 2001 C g/kg/hr rhapc recombinant human activated protein C Dortrecogin alfa Xigris % 24.7% C 1.5% 15 Acute Physiology and Chronic Health Evaluation APCHE C 17 C APCHE II 25 U.S. Food and Drug Administration 2005 ADDRESS C Dortrecogin alfa APCHE II C C C 18 C Dortrecogin alfa C XPRESS Xigris and Prophylactic Heparin Evaluation in Severe Sepsis Study Group Heparin 15 g/kg/hr rhapc Dortrecogin alfa Xigris rhapc C Dortrecogin alfa C 2008 Surviving Sepsis Campaign APACHE score 25 Dortrecogin alfa APACHE II score C Dortrecogin alfa Dortrecogin alfa Dortrecogin alfa APTT activated partial thromboplastin time PT prothrombin time D-dimer 32

7 Dortrecogin alfa Heparin 15 IU/kg/hr 4 5 INR /L 7 catecholamine C 01. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29: American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20: Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, Fisher CJ Jr. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med 1995;23: Annane D. Corticosteroids for septic shock. Crit Care Med 2001;29:S117-S Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troché G, Chaumet-Riffaud P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288: Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 2004;141: Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358: Sprung CL, Annane D, Briegel J, Keh D, Moreno R, Singer M, Weiss Y, Sorenson F. Corticosteroid therapy of septic shock (CORTICUS) (abstract). Am Rev Resp Crit Care Med 2007;175:A Bion J, Jaeschke R, Thompson BT, Levy M, Dellinger RP. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: Intensive Care Med 2008;34: Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987;317: Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, Fisher CJ Jr. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med 1995;23: The Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med 1987;317:

8 13. Perera L. Modeling Zymogen Proptein C. Biophys J 2000;6: Russell JA. Management of sepsis. N Engl J Med 2006; 355: Siegel JP. Assessing the use of activated protein C in the treatment of severe sepsis. N Engl J Med 2002; 347: Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344: Ely EW, Laterre PF, Angus DC, Helterbrand JD, Levy H, Dhainaut JF, Vincent JL, Macias WL, Bernard GR; PROWESS Investigators. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med 2003;31: Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, François B, Guy JS, Brückmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL; 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: Levy H, Laterre PF, Bates B, Qualy RL. Steroid use in PROWESS severe sepsis patients treated with drotrecogin alfa (activated). Crit Care 2005;9:R Levi M, Levy M, Williams MD, Douglas I, Artigas A, Antonelli M, Wyncoll D, Janes J, Booth FV, Wang D, Sundin DP, Macias WL; Xigris and Prophylactic Heparin Evaluation in Severe Sepsis (XPRESS) Study Group. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med 2007;176:

9 THE CLINICAL APPLICATIONS OF CORTICOSTEROIDS AND RECOMBINANT HUMAN ACTIVATED PROTEIN C IN PATIENTS WITH SEVERE SEPSIS Yu-Tzu Tsao 1, Shoa-Lin Lin 2 Abstract Although sepsis is one of the most common causes of death on a global basis and is also the main leading cause of death in intensive care units, the management sometimes remains challenging, thereby portending a significant barrier of prognosis. How to improve the therapeutic efficacy and mortality in patients with sepsis is of paramount importance and particular emphasis should be given to insights derived from the current treatment protocols. Notably, the therapeutic outcomes of hydrocortisone and recombinant human activated protein C in patients with severe sepsis and septic shock are promising. Since cortisol has a powerful anti-inflammatory role by suppressing innate and adaptive immune systems, recommendation of hydrocortisone therapy is only reserved for adult septic shock patients after blood pressure is identified to be poorly responsive to fluid resuscitation and vasopressor institution or in pediatric septic shock patients with catecholamine resistance and suspected or proven adrenal insufficiency. Recombinant human activated protein C exerts an antithrombotic effect by inactivating factors Va, VIIIa, decreasing the synthesis of plasminogen-activator inhibitor 1, inhibiting tissue factors released from monocytes and endothelial cell, and reducing the rolling of neutrophils on injured endothelium in order to limit the generation of thrombin and prevent further coagulation cascade. Adult patients with sepsis induced organ dysfunction associated with high risk of death, APACHE II 25 or multiple organ failure are suggested to receive recombinant human activated protein C. The aim of this article is to address the clinical applications and review the mechanistic basis of hydrocortisone and recombinant human activated protein C therapy. Key words: Corticosteroids, Recombinant human activated protein C; Sepsis Correspondence: Dr. Shoa-Lin Lin Intensive Care Unit, Kaohsiung Veterans General Hospital, No.386, Ta-Chung 1 st Rd., Kaohsiung City 813, Taiwan Phone: ; Fax: ; shoalin01@gmail.com 1 Department of Critical Care Medicine, and Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, Taipei 35

曹国辉等 : 休克诊治中应注意的几个问题 2014 年毒性休克等梗阻性休克由心血管管路中血流发生梗阻所致, 特点为舒张期充盈异常或后负荷过高, 此类休克常见病因为心包填

曹国辉等 : 休克诊治中应注意的几个问题 2014 年毒性休克等梗阻性休克由心血管管路中血流发生梗阻所致, 特点为舒张期充盈异常或后负荷过高, 此类休克常见病因为心包填第 31 卷第 5 期 2014 年 10 月综述医学研究与教育 Medical Research and Education Vol. 31 No. 5 Oct., 2014 休克诊治中应注意的几个问题曹国辉, 王新平 ( 河北大学附属医院急诊医学科, 河北保定 071000) 摘要 : 休克是危重病