全身性感染与感染性休克全身性感染与感染性休克What is New?安顺市人民医院严重全身性感染与感染性休克严重全身性感染与感染性休克非特异性损伤引非特异性损伤引起的临床反应起的临床反应, 满足满足 2条标准条标准: T 38 C or 90 bpmRR 20 bpmWCC 12,000/mm3or 10%杆状核杆状核SIRS = systemic inflammatory response syndrome SIRS及可疑或及可疑或明确的感染明确的感染Chest 1992;101:1644. 全身性感染全身性感染伴器官衰竭伴器官衰竭顽固性低血压顽固性低血压SIRSSepsisSevere Sepsis Septic Shock全身性感染全身性感染(sepsis): 流行病学流行病学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.全身性感染发病率的推算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临床试验对照组的病死率全身性感染的医疗费用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$16,700,000,00021.Davies A et al. Abstract 581. 14th Annual Congress of the European Society of Intensive Care Medicine, Geneva, Switzerland, 30 September-3 October 20012.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; 29:13031310Surviving 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uEGDTu激素uAPCu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Surviving Sepsis Campaign (SSC) Guidelines for Management of Severe Sepsis and Septic ShockDellinger 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 CommitteeCrit Care Med 2004; 32: 858-873Intensive Care Med 2004; 30: 536-555available online atwww.springerlink.comwww.sccm.orgwww.sepsisforum.comThe guidelines were published in both Critical Care Medicine and inIntensive care Medicine, and are available on-lineSurviving 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)严重全身性感染与感染性休克的治疗严重全身性感染与感染性休克的治疗SIRSSepsisSevere 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 215 mg/dL 110 mg/dL胰岛素治疗维持葡萄糖水平180 200 mg/dL(10.0 11.1 mmol/L)80 110 mg/dL(4.4 6.1 mmol/L)39%应用胰岛素99%应用胰岛素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外科患者的强化胰岛素治疗至随访第12个月, 强化胰岛素治疗可以降低病死率3.4% (p 24小时nISS 20n血流动力学稳定uSBP 100uHR 1 mL/kg/hn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严重创伤患者两次严重创伤患者两次LA 2.5输注液体或血液制品输注液体或血液制品重复重复LA 2.5Swan-Ganz, 动脉插管动脉插管, 肾脏剂量多巴胺肾脏剂量多巴胺将将PCWP提高到提高到12 15将将Hct提高到提高到30%重复重复LA 2.5升压药物升压药物(多巴酚丁胺多巴酚丁胺)心脏超声检查心脏超声检查若若LA仍仍 2.5隐性低灌注与创伤预后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抗生素治疗前后血培养的阳性率139名患者名患者抗生素治疗前抗生素治疗前抗生素治疗过程中抗生素治疗过程中开始抗生素治疗开始抗生素治疗83名患者名患者(60%)血培养阴性或血培养阴性或分离出污染菌分离出污染菌0/83 (0%)分离到致病菌分离到致病菌56名患者名患者(40%)分离到致病菌分离到致病菌26/56 (45%)分离到致病菌分离到致病菌25名患者名患者(45%)分离到致分离到致病的葡萄球菌病的葡萄球菌19/25 (76%)分离到葡萄球菌分离到葡萄球菌14名患者名患者(25%)分离到致分离到致病的链球菌病的链球菌5/14 (36%)分离到链球菌分离到链球菌17名患者名患者(30%)分离到革分离到革兰阴性杆菌兰阴性杆菌2/17 (12%)分离到革兰阴性杆菌分离到革兰阴性杆菌1/139 (0.72%)分离到新的致病菌分离到新的致病菌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严重全身性感染与感染性休克的治疗严重全身性感染与感染性休克的治疗SIRSSepsisSevere Sepsis Septic Shock抗生素治疗与感染灶控制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克的治疗严重全身性感染与感染性休克的治疗SIRSSepsisSevere Sepsis Septic Shock抗生素治疗与感染灶控制抗生素治疗与感染灶控制早期目标指导治疗早期目标指导治疗持续低血压或乳酸持续低血压或乳酸 4 mmol/L最初6小时内达到的目标CVP 8 12 mmHgMAP 65 mmHgUO 0.5 ml/kg/hrScvO2 70%1B强化胰岛素治疗严格控制血糖强化胰岛素治疗严格控制血糖全身性感染全身性感染: 早期目标指导治疗早期目标指导治疗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全身性感染全身性感染: 早期目标指导治疗早期目标指导治疗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, 345:1368-1377EGDT组患者输液更多组患者输液更多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, 345:1368-1377EGDT组输血及应用多巴酚丁胺更多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, 345:1368-1377EGDT与感染性休克的预后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, 345:1368-1377心血管猝死心血管猝死21% vs. 10%P = 0.02MODS22% vs. 16%P = 0.27严重全身性感染与感染性休克的治疗严重全身性感染与感染性休克的治疗SIRSSepsisSevere Sepsis Septic Shock抗生素治疗与感染灶控制抗生素治疗与感染灶控制早期目标指导治疗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活化蛋白活化蛋白C治疗治疗强化胰岛素治疗严格控制血糖强化胰岛素治疗严格控制血糖全身性感染全身性感染: 活化蛋白活化蛋白CBernard 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.安慰剂安慰剂(n = 840)活化蛋白活化蛋白C(n = 850)绝对病死率下降6.1%主要分析结果主要分析结果双尾双尾P值值0.005校正后的相对危险度降低校正后的相对危险度降低19.4%存活比数增加存活比数增加38.1%严重全身性感染与感染性休克的治疗严重全身性感染与感染性休克的治疗SIRSSepsisSevere Sepsis Septic Shock抗生素治疗与感染灶控制抗生素治疗与感染灶控制早期目标指导治疗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活化蛋白活化蛋白C治疗治疗激素替代治疗激素替代治疗强化胰岛素治疗严格控制血糖强化胰岛素治疗严格控制血糖感染性休克的激素替代治疗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.ACTH test8 hoursSEPTICSHOCKplaceboHC 50 mg/6 hours+ FC 50 mcg/day p.o.N = 150N = 14928-daymortality7 days感染性休克的激素替代治疗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.P = 0.04P = 0.96严重全身性感染严重全身性感染 循证医学指南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29ACTH刺激试验无反应者小剂量激素治疗7Sepsis Resuscitation Bundle(应在最初应在最初6小时内达到小时内达到)1.测定血清乳酸水平2.应用抗生素前留取血培养3.入急诊室3小时或入ICU1小时内应用抗生素4.低血压和(或)乳酸 4 mmol/L (36 mg/dl)时:a)最初应用晶体液至少20 ml/kg(或等量的胶体液)b)最初液体复苏无效时应用升压药物以维持MAP 65 mmHg5.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):a)使CVP 8 mmHgb)使ScvO2 70%Sepsis Management Bundle(应在最初应在最初24小时内达到小时内达到)1.对感染性休克患者根据ICU标准化规定应用小剂量激素2.根据ICU标准化规定应用活化蛋白C3.控制血糖水平正常值下限, 且 150 mg/dl (8.3 mmol/L)4.维持机械通气患者吸气平台压力 30 cmH2OSurviving Sepsis Campaign Initial ResultsReporting the Gap betweenPerception and PracticeWhat We Think We Dovs.What We Actually DoARDS保护性通气策略保护性通气策略 ARDSnetThe 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; 342:1301-1308P = 0.007研究结果的发表对日常工作并无影响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: A295P = 0.11P = 0.02Adhere 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 ProcessesBrunkhorst FM, et al, for the German Competence Network Sepsis SepNet. The gap between perception and practice of sepsis therapy. (submitted)Supportive and Adjunctive TherapiesResults of the German “Prevalence” StudyBrunkhorst FM, et al, for the German Competence Network Sepsis SepNet. The gap between perception and practice of sepsis therapy. (submitted)为何循证治疗在为何循证治疗在ICU中应用并不普遍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 Bundles69% Reduction (p 0.001)36% Reduction (NS)Pronovost P, 2005EGDT in EDMean SDMedianRangeCentral line inserted2.1 1.71.51 8CVP goal achieved6.3 3.86.01 14MAP goal achieved5.6 3.24.02 13ScvO2 measured2.4 1.82.01 8ScvO2 goal achieved6.4 4.05.02 16Trzeciak 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: 225-232EGDT in EDBefore EGDTEGDTP value输注晶体液ED3509 23125685 30210.02ICU第一个24小时5548 48782752 17310.03PAC应用7 (43.8)2 (9.1)0.01ICU住院日(d)4.2 (0.5 14.3)1.8 (0.0 34.9)0.12住院病死率7 (43.8)4 (18.2)0.09住院费用(USD)135,19982,2330.14Trzeciak 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: 225-232Sepsis Bundle101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ICU35 (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 = 0.01NNT = 3.9Gao 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 = 0.16Gao 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)感染性休克感染性休克标准治疗程序(SOP)EGDT强化胰岛素治疗应激剂量激素rhAPC肺保护性通气策略经验性抗生素治疗感染灶控制Kortgen A, Niederprm P, Bauer M. Implementation of an evidence-based “standard operating procedure” and outcome in septic shock. Crit Care Med 2006 (in press)感染性休克感染性休克对照组(n = 30)治疗组(n = 30)最初24小时应用多巴酚丁胺212应用胰岛素1830应用氢化可的松1330应用活化蛋白C07NE最大剂量(g/kg/min)0.910.365至开始控制血糖时间(hr)10 (2, 26)0 (0, 1)Kortgen A, Niederprm P, Bauer M. Implementation of an evidence-based “standard operating procedure” and outcome in septic shock. Crit Care Med 2006 (in press)感染性休克感染性休克Kortgen A, Niederprm P, Bauer M. Implementation of an evidence-based “standard operating procedure” and outcome in septic shock. Crit Care Med 2006 (in press)全身性感染与感染性休克全身性感染与感染性休克发病率逐年增加病死率高居不下多项临床试验结果令人鼓舞nEGDTn激素nAPCn小潮气量通气策略n严格血糖控制综合治疗措施可能改善预后