全身性感染与感染性休克课件_2

全身性感染与感染性休克 What is New? 北京协和医院 杜斌 全身性感染(sepsis): 定义 确证或可疑的感染, 以及 某些下列指标 n一般指标 n炎症指标 n血流动力学指标 n器官功能不全指标 n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 全身性感染(sepsis): 定义 一般指标发热(核心体温 38.3C) 体温过低(核心体温 90 bpm或超过按年龄校正的正常值 2SD 呼吸频数 神志改变 明显水肿或液体正平衡( 20 ml/kg/24 hr) 无糖尿病患者出现高血糖( 120 mg/dl) 炎症指标白细胞增加( 12 x 109/L) 白细胞缺乏(10% 血浆CRP超过正常值 2SD 血浆PCT超过正常值 2SD 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 血流动力学指标 低血压(SBP 40 mmHg) SvO2 3.5 L/min/m2 器官功能不全指标低氧血症(PaO2/FiO2 0.5 mg/dl 凝血障碍(INR 1.5或aPTT 60 sec) 肠梗阻(无肠鸣音) 血小板缺乏( 4 mg/dl或70 mmol/L) 组织灌注指标高乳酸血症( 1 mmol/L) 毛细血管充盈差或皮肤花斑 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): 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 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; 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 n平均每年 增加26.3% 真菌 n1979年 5,231例 n2000年 16,042例 n增加 207%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 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. 全身性感染流行病学: USA 1979 2000 ICD-9有关全身性感染的编码 500家急性病医院 750,000,000住院患者 10,319,418例全身性感染/22年 全身性感染发病率的推算 平均每年增加1.5%; 相当于年增新发病例约22,875例 Angus DC, et al. The epidemiology of severe sepsis in the United States: Analysis of incidence, outcome and associated costs of care. 全身性感染临床试验对照组的病死率 全身性感染与严重全身性感染 国家年份发病率死亡率病死率费用 全身性感染 USA197982.721.926.5% USA2000240.443.918.3% 严重全身性感染 USA19953000.8628.6%22100 UK1997512447% 3801 17963 Australia20037737.5% 严重全身性感染: 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). 严重全身性感染与其他死因 2001年死亡人数 心血管疾病931,108 恶恶性肿肿瘤553,768 严严重全身性感染215,000 意外101,537 Alzeimer氏病53,852 HIV/AIDS14,175 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 1.Davies A et al. Abstract 581. 14th Annual Congress of the European Society of Intensive Care Medicine, Geneva, Switzerland, 30 September-3 October 2001 2.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 Sepsis Campaign: Why? 过去5年间阳性结果的干预措施 n严重全身性感染与感染性休克 uEGDT u激素 uAPC u小潮气量通气策略 n危重病患者的一般治疗 u镇静 u严格血糖控制 u脱机方案 严重全身性感染 循证医学指南 干预措施NNT 小潮气量通气策略11 早期目标指导治疗6 8 活化蛋白C16 (whole trial) 8 (APACHE II 25) 强化胰岛素治疗29 ACTH刺激试验 无反应者小剂量激素治疗7 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 MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM and the SSC Management Guidelines Committee Crit Care Med 2004; 32: 858-873 Intensive Care Med 2004; 30: 536-555 available online at The guidelines were published in both Critical Care Medicine and in Intensive care Medicine, and are available on-line Surviving Sepsis Campaign Guidelines For Management Of Severe Sepsis / Septic Shock The First Revision A Preliminary Report 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) ARDS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) 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) ARDS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) 推荐意见的评级系统 推 荐 级 别 1.至少两项I级研究支持 2.一项I级研究支持 3.仅有II级研究支持 4.至少一项III级研究支持 5.IV或V级研究支持 证 据 级 别 I.结果明确的大规模随机临床试验; 假阳性或假阴性错误危险小 II.结果不确定的小规模随机临床试验; 假阳性或假阴性错误危险中 等 III.非随机同期对照 IV.非随机历史对照及专家意见 V.病例报告, 非对照研究及专家意见 Sackett DL. Chest 1989; 95: 2S-4S Sprung CL, Bernard GR, Dellinger RP. Intensive Care Med 2001; 27(Suppl): S1-S2 推荐意见的评级系统 GRADE 证据的质量 评估指标 n试验设计 n一致性 n直接性(对所研究 的问题) n偏倚的报告 评估级别 nA 高质量 nB 中等质量 nC 低质量 nD 极低质量 推荐的强度 1: 强烈推荐 n方法学缺陷较少 n作用较大 n副作用较少 2: 一般推荐 n方法学缺陷较多 n评价不确切 n作用较小 n明显增加危害, 工 作负担, 医疗费用 Surviving Sepsis Campaign Guideline 推荐意见(n = 46) 最初的复苏治疗 发生全身性感染诱发的低血压时 n低血压 n乳酸酸中毒 乳酸清除率与感染性休克预后 乳酸清除率 = (乳酸ED Presentation 乳酸Hour 6) x 100 乳酸ED Presentation 严重全身感染与感染性休克预后的独立危险因素 乳酸清除率OR 0.989 95%CI 0.978 0.999 p = .04 Nguyen HB, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A, Ressler JA, Tomlanovich MC. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004; 32:1637-1642. 隐性低灌注与创伤预后 The Golden Hour and the Silver Day 入选标准: n成年创伤患者 n存活时间 24小时 nISS 20 n血流动力学稳定 uSBP 100 uHR 1 mL/kg/h n乳酸 2.5 mmol/L或其他灌注不足表现 Blow O, Magliore L, Claridge J, Butler 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 Correction 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 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 全身性感染的诊断 适当的培养 至少留取2个血培养 n1个外周血培养 n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 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 Therapy. 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 Infect Dis 2001; 32: 1651-5 抗生素治疗 确诊严重全身性感染后1小时内开始静 脉抗生素治疗 1C (Grade E) 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 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 持续低血压或乳酸 4 mmol/L 最初的复苏治疗 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 (Grade B) 感染性休克: 灌注压与组织灌注 MAP 65MAP 75MAP 85F/LT 尿量(ml)49 1856 2143 13.60/.71 毛细血管血流 (ml/min/100 g) 6.0 1.65.8 1.15.3 0.9.59/.55 红细 胞速度(au) 0.42 0.06 0.44 0.16 0.42 0.06 .74/.97 PiCO2 (mmHg)41 247 246 2.11/.12 Pa PiCO2 (mmHg)13 317 316 3.27/.40 LeDoux, Astiz ME, Carpati CM, Rackow ED. Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med 2000; 28:2729-2732 影响感染性休克预后的循环指标 目的: 确定与预后相关的血流动力学指标的适当阈值 设计: 回顾性队列研究 n1999 2002年, 治疗的最初48小时, 分析6和48小时 结果: n病死率33% n单因素分析及逻辑回归分析 u入院时的MAP和乳酸水平 u48小时的MAP, SvO2 34 g/dl或上升 9 g/dl n血浆皮质醇 926% = 34 34 967% 34 38.3C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 n氢化可的松50 mg iv q6h n9-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 No. (%) 指标标安慰剂剂激素校正OR (95%CI)P值值 无反应应者 患者数115114 28天病死率73 (63)60 (53)0.54 (0.31 0.97).04 ICU病死率81 (70)66 (58)0.50 (0.28 0.89).02 住院病死率83 (72)70 (61)0.53 (0.29 0.96).04 1年病死率88 (77)77 (68)0.57 (0.31 1.04).07 反应应者 患者数3436 28天病死率18 (53)22 (61)0.97 (0.32 2.99).96 ICU病死率20 (59)24 (67)0.99 (0.31 3.16).99 住院病死率20 (59)25 (69)1.20 (0.38 3.76).75 1年病死率24 (71)25 (69)0.70 (0.20 2.40).57 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 病例数 (%) 指标标安慰剂剂激素 校正OR (95%CI) P值值 所有患者 患者数150149 28天病死率91 (61)82 (55) 0.65 (0.39 1.07) .09 ICU病死率101 (68)90 (60) 0.61 (0.37 1.02) .06 住院病死率103 (69)95 (63) 0.67 (0.40 1.12) .12 1年病死率112 (75)102 (68) 0.62 (0.36 1.05) .08 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 hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 862-71. 激素与感染: 尚待阐明的问题 患者选择 n严重感染 vs. 感染性休克 用药时机 n发病 2501.62 (1.01 2.60) Krinsley n持续肾脏替代治疗 14 Pittas n胰岛素治疗3.4 (1.9 6.3) n糖尿病史 n全身性感染 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 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 Resuscitation Bundle (应在最初6小时内达到) B. 测定血清乳酸水平 D. 应用抗生素前留取血培养 E. 入急诊室3小时或入ICU1小时内应用抗生素 E. 低血压和(或)乳酸 4 mmol/L (36 mg/dl)时: 最初应用晶体液至少20 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 mm Hg B. 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 mm Hg 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 Sepsis Management Bundle (应在最初24小时内达到) C.对感染性休克患者根据ICU标准化规定 应用小剂量激素 B.根据ICU标准化规定应用活化蛋白C D.控制血糖水平正常值下限, 且 150 mg/dl (8.3 mmol/L) B.维持机械通气患者吸气平台压力 30 cmH2O Surviving Sepsis Campaign Initial Results 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 小潮气量传统 潮气量P值 患者数387405NA Vt (ml/kg)6.2 0.911.8 0.8 .05 Pplat (cmH2O)25 733 9 .05 PIP (cmH2O)32 839 10 .05 RR (bpm)29 716 6 .05 MV (lpm)12.9 3.612.6 4.5NS PEEP (cmH2O)9.4 3.68.6 3.6 .05 PaO2 / FiO2158 73176 76 .05 PaO2 (mmHg)76 2377 19NS PaCO2 (mmHg)40 1035 8 .05 pH7.38 0.087.41 0.07 .05 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 distress syndrome. N Engl J Med 2000; 342:1301-1308 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 distress syndrome. N Engl J Med 2000; 342:1301-1308 P = 0.007 研究结果的发表对日常工作并无影响 Rubenfeld GD, et al. Am J Respir Crit Care Med 2001; 163: A295 P = 0.11 P = 0.02 研究结果的发表对日常工作并无影响 Brower RG, et al. Am J Respir Crit Care Med 2004; 169(suppl): A256 ARDS Network Paper Published NEJM 实施保护性通气策略的障碍 开始保护性通气策略的障碍继续 保护性通气策略的障碍 医生不希望放弃对呼吸机的控制40%对患者不舒适及呼吸频数的顾虑69% 医生未认识 到患者为ALI/ARDS43%对CO2潴留及酸中毒的顾虑69% 医生认为 患者有小潮气量的禁忌40%对氧合恶化的顾虑35% 医生喜好使用定压通气方式27%护士不喜欢使用小潮气量38% RT不希望放弃对呼吸机的控制23%RT不喜欢使用小潮气量34% Rubenfeld GD, Cooper C, Carter G, Thompson BT, Hudson LD. Barriers to providing lung-protective ventilation to patients with acute lung injury. Crit Care Med 2004; 32:1289 -1293 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. (submitted) 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 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 n医疗费用报销的限制, 繁忙的工作安排 ICU医生的怀疑 n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) Pronovost P, 2005 Sepsis Bundle 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ICU28 (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) 52% (52/101) 30% (21/69) 依从率 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 (6 hour) RR 2.12 (1.20 3.76) P = 0.01 NNT = 3.9 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 (6 hour) 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 (24 hour) RR 1.76 (0.84 3.64) P = 0.16 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/cc