1、全身性感染与感染性休克 What is New?,北京协和医院 杜 斌,严重全身性感染与感染性休克,非特异性损伤引 起的临床反应, 满足 2条标准: T 38C or 90 bpm RR 20 bpm WCC 12,000/mm3 or 10%杆状核,SIRS = systemic inflammatory response syndrome,SIRS及可疑或 明确的感染,Chest 1992;101:1644.,全身性感染 伴器官衰竭,顽固性低血压,SIRS,Sepsis,Severe Sepsis,Septic Shock,全身性感染(sepsis): 定义,确证或可疑的感染, 以及 某些
2、下列指标 一般指标 炎症指标 血流动力学指标 器官功能不全指标 组织灌注指标,Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G, For the International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31: 1250-1256,全
3、身性感染(sepsis): 定义,Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G, For the International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31: 1250-1256,全身性感染(sepsis): 定义,Levy
4、MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G, For the International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31: 1250-1256,全身性感染(sepsis): 改变定义的原因,诊断标准应当 普遍适用于临床医疗及临床试验
5、具有较高的敏感性和特异性 避免过于复杂以至难以记忆或应用 采用普遍应用的试验指标 适用于成人, 儿童和新生儿,Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G, For the International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003;
6、 31: 1250-1256,全身性感染(sepsis): 流行病学,Martin GS, Mannino DM, Stephanie Eaton S, et al. The Epidemiology of Sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348: 1546-54.,全身性感染(sepsis): 流行病学,致病菌 革兰阳性菌 平均每年增加26.3% 真菌 1979年5,231例 2000年16,042例 增加207%,Martin GS, Mannino DM, Stephanie E
7、aton S, et al. The Epidemiology of Sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348: 1546-54.,全身性感染(sepsis): 流行病学,Martin GS, Mannino DM, Stephanie Eaton S, et al. The Epidemiology of Sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348: 1546-54.,严重全身性感
8、染: 与常见病的比较,National Center for Health Statistics, 2001. American Cancer Society, 2001. *American Heart Association. 2000. Angus DC et al. Crit Care Med. 2001 (In Press).,全身性感染的医疗费用,2000年 ICU医疗费用的40% 欧洲每年花费 7,600,000,0001 美国每年花费 $16,700,000,0002,Davies A et al. Abstract 581. 14th Annual Congress of t
9、he European Society of Intensive Care Medicine, Geneva, Switzerland, 30 September-3 October 2001 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; 29:13031310,Surviving
10、Sepsis Campaign: Why?,过去5年间阳性结果的干预措施 严重全身性感染与感染性休克 EGDT 激素 APC 小潮气量通气策略 危重病患者的一般治疗 镇静 严格血糖控制 脱机方案,Surviving Sepsis Campaign (SSC) Guidelines for Management of Severe Sepsis and Septic Shock,Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker
11、 MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM and the SSC Management Guidelines CommitteeCrit Care Med 2004; 32: 858-873 Intensive Care Med 2004; 30: 536-555 available online at www.sccm.org The guidelines were published in both Critical Care Medicine and in Intensive care Medicine, and are ava
12、ilable on-line,Surviving Sepsis Campaign Guideline,最初复苏(initial resuscitation) 诊断(diagnosis) 抗生素治疗(antibiotic therapy) 感染源控制(source control) 液体治疗(fluid therapy) 升压药物(vasopressors) 强心药物(inotropic therapy) 激素(steroids) 活化蛋白C (recombinant human activated protein C) 血液制品(blood product administration),AR
13、DS机械通气(mechanical ventilation of sepsis-induced ALI/ARDS) 镇静(sedation, analgesia, and NMB in sepsis) 血糖控制(glucose control) 肾脏替代(renal replacement) 碳酸氢钠(bicarbonate therapy) DVT预防(DVT prophylaxis) 应激性溃疡预防(stress ulcer prophylaxis) 考虑限制支持治疗水平(consideration for limitation of support),严重全身性感染与感染性休克的治疗,S
14、IRS,Sepsis,Severe Sepsis,Septic Shock,血糖控制非常重要: 最初病情稳定后静脉输注胰岛素 1B 目标范围? 血糖 150 mg/dL 2C血糖控制方案 2C葡萄糖热卡及监测 1B,强化胰岛素治疗严格控制血糖,外科患者的强化胰岛素治疗,Van Den Berghe G, Wouters P, Weekers F, et al.: Intensive insulin therapy in the critically ill patients. N Engl J Med 2001, 345:1359-1367,外科患者的强化胰岛素治疗,至随访第12个月, 强化胰
15、岛素治疗可以降低病死率3.4% (p 0.04) 强化胰岛素治疗还可以 住院病死率 34% 血行性感染率 46% 需要肾脏替代治疗的急性肾功能衰竭 41% 输血的中位数 50%,Van Den Berghe G, Wouters P, Weekers F, et al.: Intensive insulin therapy in the critically ill patients. N Engl J Med 2001, 345:1359-1367,危重病患者的强化胰岛素治疗,平均血糖水平下降 152.3 vs. 130.7 mg/dL (P .001) 高血糖( 200 mg/dL)者减少
16、56.3% 低血糖患者比例未增加 新发肾脏功能不全减少75% (P=.03) 需要输注红细胞的患者比例减少18.7% (P=.04) 住院病死率下降29.3% (P=.002),Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc. 2004;79:992-1000,内科患者的强化胰岛素治疗,van den Berghe G, Wilmer A, Hermans G, Meersseman
17、W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive Insulin Therapy in the Medical ICU. N Engl J Med 2006; 354: 449-61,内科患者的强化胰岛素治疗,van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive Insulin Ther
18、apy in the Medical ICU. N Engl J Med 2006; 354: 449-61,内科患者的强化胰岛素治疗,van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive Insulin Therapy in the Medical ICU. N Engl J Med 2006; 354: 449-61,强化胰岛素治疗: 尚未阐明的问题,血糖控制抑或应用胰岛素的结果 血糖控制
19、的最佳范围 血糖水平越低, 患者预后越好 80 110 mg/dl vs. 80 150 mg/dl 警惕低血糖的发生 德国感染学会的多中心试验(GLUCONTROL)被迫终止,强化胰岛素治疗: 低血糖发生率,最初的复苏治疗,发生全身性感染诱发的低血压时 低血压 乳酸酸中毒,隐性低灌注与创伤预后,The Golden Hour and the Silver Day 入选标准: 成年创伤患者 存活时间 24小时 ISS 20 血流动力学稳定 SBP 100 HR 1 mL/kg/h 乳酸 2.5 mmol/L或其他灌注不足表现,Blow O, Magliore L, Claridge J, Bu
20、tler K, Young J. The Golden Hour and the Silver Day: Detection and Correction of Occult Hypoperfusion within 24 Hours Improves Outcome from Major Trauma. J Trauma 1999; 47(5): 964,隐性低灌注与创伤预后,Blow O, Magliore L, Claridge J, Butler K, Young J. The Golden Hour and the Silver Day: Detection and Correcti
21、on of Occult Hypoperfusion within 24 Hours Improves Outcome from Major Trauma. J Trauma 1999; 47(5): 964,严重创伤患者两次LA 2.5,输注液体或血液制品,重复LA 2.5,Swan-Ganz, 动脉插管, 肾脏剂量多巴胺,将PCWP提高到12 15 将Hct提高到30%,重复LA 2.5,升压药物(多巴酚丁胺) 心脏超声检查,若LA仍 2.5,隐性低灌注与创伤预后,Blow O, Magliore L, Claridge J, Butler K, Young J. The Golden H
22、our and the Silver Day: Detection and Correction of Occult Hypoperfusion within 24 Hours Improves Outcome from Major Trauma. J Trauma 1999; 47(5): 964,全身性感染的诊断,适当的培养 至少留取2个血培养 1个外周血培养 每个留置 48 h的血管通路留取1个血培养(Grade D),抗生素治疗前后血培养的阳性率,139名患者,抗生素治疗前,抗生素治疗过程中,开始抗生素治疗,83名患者(60%)血培养阴性或分离出污染菌,0/83 (0%)分离到致病菌,
23、56名患者(40%)分离到致病菌,26/56 (45%)分离到致病菌,25名患者(45%)分离到致病的葡萄球菌,19/25 (76%)分离到葡萄球菌,14名患者(25%)分离到致病的链球菌,5/14 (36%)分离到链球菌,17名患者(30%)分离到革兰阴性杆菌,2/17 (12%)分离到革兰阴性杆菌,1/139 (0.72%)分离到新的致病菌,Grace CJ, Lieberman J, Pierce K, et al. Usefulness of Blood Culture for Hospitalized Patients Who Are Receiving Antibiotic The
24、rapy. Clin Infect Dis 2001; 32: 1651-5,临床意义,应用抗生素前进行血培养分离到致病菌的可能性增加2.2倍 在开始抗生素治疗最初72小时内, 连续进行血培养的结果, 可以根据应用抗生素前血培养的结果预测 极少分离到新的致病菌 医生可以等待应用抗生素前的血培养结果回报后, 再进行新的血培养,Grace CJ, Lieberman J, Pierce K, et al. Usefulness of Blood Culture for Hospitalized Patients Who Are Receiving Antibiotic Therapy. Clin
25、Infect Dis 2001; 32: 1651-5,严重全身性感染与感染性休克的治疗,SIRS,Sepsis,Severe Sepsis,Septic Shock,抗生素治疗与感染灶控制,确诊严重全身性感染后1小时内开始静脉抗生素治疗1C,强化胰岛素治疗严格控制血糖,早期应用抗生素与感染患者病死率,Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of surv
26、ival in human septic shock. Crit Care Med 2006; 34: 1589-1596,早期应用抗生素与感染患者病死率,Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34: 1589-1596,严重全身性感染与感染性休
27、克的治疗,SIRS,Sepsis,Severe Sepsis,Septic Shock,抗生素治疗与感染灶控制,早期目标指导治疗,持续低血压或乳酸 4 mmol/L 最初6小时内达到的目标 CVP 8 12 mmHg MAP 65 mmHg UO 0.5 ml/kg/hr ScvO2 70% 1B,强化胰岛素治疗严格控制血糖,全身性感染: 早期目标指导治疗,Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N
28、Engl J Med 2001, 345:1368-1377,全身性感染: 早期目标指导治疗,Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001, 345:1368-1377,EGDT组患者输液更多,Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of seve
29、re sepsis and septic shock. N Engl J Med 2001, 345:1368-1377,EGDT组输血及应用多巴酚丁胺更多,Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001, 345:1368-1377,EGDT与感染性休克的预后,Rivers E, Nguyen B, Havstad S, et al. Early goal-directe
30、d therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001, 345:1368-1377,心血管猝死 21% vs. 10% P = 0.02 MODS 22% vs. 16% P = 0.27,EGDT与感染性休克的预后,Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001, 3
31、45:1368-1377,严重全身性感染与感染性休克的治疗,SIRS,Sepsis,Severe Sepsis,Septic Shock,抗生素治疗与感染灶控制,早期目标指导治疗,死亡高危: APACHE II 25感染诱发的MOF感染性休克感染诱发的ARDS 无绝对禁忌症 权衡相对禁忌症 B,活化蛋白C治疗,强化胰岛素治疗严格控制血糖,全身性感染: 活化蛋白C,Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe se
32、psis. N Engl J Med 2001; 344: 699-709.,安慰剂 (n = 840),活化蛋白C (n = 850),绝对病死率下降6.1%,全身性感染: 活化蛋白C,Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.,APACHE II四分位与病死率,Bernard GR, Vincent JL, Laterre P
33、F, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.,26:33,57:49,58:48,118:80,全身性感染: 活化蛋白C,PROWESS Randomized, double-blinded, placebo-controlled Known or suspected infection, SIRS criteria 3; organ dysfunction 1 28-day mortality
34、rate: 30.8% vs.24.7% (p = 0.005) ADDRESS Randomized, double-blinded, placebo-controlled Severe sepsis, APACHE II 25, or single-organ failure 28-day mortality rate: 17.0% vs. 18.5% (p = 0.34) ENHANCE Single-arm, open-label Known or suspected infection, SIRS criteria 3; organ dysfunction 1 28-day mort
35、ality rate: 25.3%,严重全身性感染与感染性休克的治疗,SIRS,Sepsis,Severe Sepsis,Septic Shock,抗生素治疗与感染灶控制,早期目标指导治疗,应用氢化可的松200 300 mg/d, 分为3 4次给药或持续静脉输注, 疗程7天 经过液体复苏和升压药物治疗低血压持续1小时 1B 充分液体复苏后仍需升压药物至少1小时 2C,活化蛋白C治疗,激素替代治疗,强化胰岛素治疗严格控制血糖,全身性感染: 相对性肾上腺皮质功能不全(RAI),ACTH刺激试验 步骤 ACTH 250 g im或iv 用药后0, 30和60分钟测定血浆皮质醇水平 诊断标准 血浆皮质
36、醇 34 g/dl或上升 9 g/dl 血浆皮质醇 15 g/dl或上升 9 g/dl,全身性感染: 相对性肾上腺皮质功能不全(RAI),相对性肾上腺皮质功能不全与病死率,Annane D, Sbille V, Troch G, et al.: A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 2000, 283:1038-1045,感染性休克的激素替代治疗,入选标准 明确的感染灶 休克发生 38.3C
37、或 90 bpm SBP 5 g/kg/min)或NE或Epi UO 2 mmol/L 机械通气,治疗 治疗组 氢化可的松50 mg iv q6h 9-氟氢可的松50 g qd 安慰剂组 疗程 7天,Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 862-71.,感染性休克的激素替代治疗,Ann
38、ane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 862-71.,ACTH test 8 hours,SEPTIC SHOCK,placebo,HC 50 mg/6 hours + FC 50 mcg/day p.o.,N = 150,N = 149,28-day mortality,7 days,感染
39、性休克的激素替代治疗,Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 862-71.,感染性休克的激素替代治疗,Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortis
40、one and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 862-71.,P = 0.04,P = 0.96,感染性休克的激素替代治疗,Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 8
41、62-71.,激素与感染: 尚待阐明的问题,患者选择 严重感染 vs. 感染性休克 用药时机 发病 8小时 vs. 72小时 激素疗程 是否减量 预后指标 休克逆转 vs. 病死率,严重全身性感染 循证医学指南,Sepsis Bundle,集束化治疗的定义 与疾病相关的一组治疗措施 (集束化治疗的各个组成部分) 共同实施可较分别实施改善预后,Sepsis Resuscitation Bundle (应在最初6小时内达到),测定血清乳酸水平 应用抗生素前留取血培养 入急诊室3小时或入ICU1小时内应用抗生素 低血压和(或)乳酸 4 mmol/L (36 mg/dl)时: 最初应用晶体液至少20
42、ml/kg(或等量的胶体液) 最初液体复苏无效时应用升压药物以维持MAP 65 mmHg 经过液体复苏后仍持续低血压(感染性休克)和(或)乳酸 4 mmol/L (36 mg/dl): 使CVP 8 mmHg 使ScvO2 70%,Sepsis Management Bundle (应在最初24小时内达到),对感染性休克患者根据ICU标准化规定应用小剂量激素 根据ICU标准化规定应用活化蛋白C 控制血糖水平正常值下限, 且 150 mg/dl (8.3 mmol/L) 维持机械通气患者吸气平台压力 30 cmH2O,Surviving Sepsis Campaign Initial Resul
43、ts Reporting the Gap between Perception and Practice,What We Think We Do vs. What We Actually Do,ARDS保护性通气策略 ARDSnet,The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distre
44、ss syndrome. N Engl J Med 2000; 342:1301-1308,P = 0.007,Adhere to “Best Practice”?,Do you use lung protective strategy in ventilating acute lung injury patients?,Brunkhorst FM, et al, for the German Competence Network Sepsis SepNet. The gap between perception and practice of sepsis therapy. (submitt
45、ed),Adhere to “Best Practice”?,Results of Non-Scripted Care Processes,Brunkhorst FM, et al, for the German Competence Network Sepsis SepNet. The gap between perception and practice of sepsis therapy. (submitted),Supportive and Adjunctive Therapies Results of the German “Prevalence” Study,Brunkhorst
46、FM, et al, for the German Competence Network Sepsis SepNet. The gap between perception and practice of sepsis therapy. (submitted),为何循证治疗在ICU中应用并不普遍,缺乏相关知识 医疗费用报销的限制, 繁忙的工作安排 ICU医生的怀疑 危重病领域众多的阴性试验结果 对证据的主观选择 临床惰性 不能正确鉴别患者 医疗资源的配置,VHA 19-ICU Sepsis Bundles,69% Reduction (p 0.001),36% Reduction (NS),P
47、ronovost P, 2005,EGDT in ED,Trzeciak S, Dellinger RP, Abate NL, Cowan RM, Stauss M, Kilgannon JH, Zanotti S, Parrillo JE. Translating Research to Clinical Practice: A 1-Year Experience With Implementing Early Goal-Directed Therapy for Septic Shock in the Emergency Department. Chest 2006; 129: 225-23
48、2,EGDT in ED,Trzeciak S, Dellinger RP, Abate NL, Cowan RM, Stauss M, Kilgannon JH, Zanotti S, Parrillo JE. Translating Research to Clinical Practice: A 1-Year Experience With Implementing Early Goal-Directed Therapy for Septic Shock in the Emergency Department. Chest 2006; 129: 225-232,Sepsis Bundle
49、,101名严重全身性感染患者符合6小时Bundle 普通病房: 90 (89%) 急诊科: 11 (11%),71名收入ICU 符合24小时Bundle: 69 (98%),43 (61%)转出ICU,28 (39%)死于ICU,35 (81%)存活,8 (19%)死亡,65 (64%)存活,36 (36%)死亡,Gao F, Melody T, Daniels DF, Giles S, Fox S. The impact of compliance with 6-hour and 24-hour sepsis bundles on hospital mortality in patients with severe sepsis: a prospective observational study. Critical Care 2005, 9:R764-R770 (DOI 10.1186/cc3909),Sepsis Bundle,符合6小时Bundle (n = 101),符合24小时Bundle (n = 69),
