1、孙仁华浙江省人民医院ICU2016-10,脓毒症3.0“面面观”,严重脓毒症及脓毒性休克流行病学,严重脓毒症患者死亡风险为34%，脓毒性休克患者死亡风险为50%。,新近流调显示脓毒性休克死亡率下降,结果发现，重症感染患者的绝对死亡率从 35.0% 下降到了 18.4%，总死亡率下降了 16.6%，年绝对死亡率下降了 1.3%，相对风险下降了 47.5%。,JAMA. 2014 Apr 2;311(13):1308-16.,脓毒症定义变迁（1.0）,Sepsis 1.0=感染SIRS,Chest 1992 Jun; 101(6):1644-55,脓毒症定义变迁（2.0）,Intensive Ca
2、re Med. 2003 Apr;29(4):530-8. Epub 2003 Mar 28.,Sepsis 2.0=感染SIRS会议提出了包括20余条临床症状和体征评估指标构成的诊断标准，即Sepsis 2.0。然而该标准过于复杂，且缺乏充分的研究基础和科学研究证据支持，并未得到临床认可和应用。,Diagnostic criteria for sepsis,The PIRO system for staging sepsis,2012,SSC指南发展,Critical care medicine 2004 Mar; 32(3):858-73.Critical care medicine 20
3、08 Jan; 36(1):296-327.Crit Care Med. 2013 Feb;41(2):580-637.,2008,2004,脓毒症诊断标准的“争议”,方法：通过对2000 年至2013 年澳大利亚和新西兰172 个重症加强治疗病房(ICU)近120 万例患者的数据分析，根据是否满足2条全身炎症反应综合征(SIRS)的诊断标准将感染伴器官功能障碍的患者分为SIRS 阳性和SIRS 阴性两组。结果：在近11万例感染伴器官功能障碍的患者中，87.9%为SIRS阳性，12.1%为SIRS 阴性，在14年内两组患者的临床特征和病死率变化相似。校正分析显示，患者病死率随着满足SIRS标准
4、项目的增加呈线性增高。结论：该研究说明现有脓毒症标准有可能遗漏约 1/8 的感染伴器官功能障碍患者，且该标准不能确定病死率增加的临界点，这提示当前脓毒症的筛查标准的特异性不佳。,N Engl J Med, 2015, 372 (17): 1629-1638.,Do we need a new definition of sepsis?,the definition of septic shock currently revolves around variable blood pressure and/or lactate levels, with loosely termed or unde
5、fined adequacy of fluid resuscitation and persistent hypotension. Defining sepsis must, however, be an ongoing iterative process requiring minor or major revisions as new findings come to light. In much the same way that software enhancements move from version 1.0 to 1.1 or to 2.0 depending on the m
6、agnitude of change, so a new sepsis 3.0 definition must be refined into versions 3.1, 3.2, and so on until an eventual complete overhaul generates the development of sepsis 4.0.,Intensive Care Med, 2015, 41 (5): 909-911.,脓毒症的诊断标准于1991年发布（脓毒症1.0）,但过于敏感，可能导致脓毒症的过度诊断和治疗；2001年更新版（脓毒症2.0）又过于复杂，未被广泛应用。,脓毒
7、症3.0. 2016年,Sepsis 3.0“应运而生”,JAMA. 2016 Feb 23;315(8):801-10,Sepsis 3.0定义,JAMA. 2016 Feb 23;315(8):801-10,Mortality 10%,Sepsis 3.0InfectionSOFA2,Sepsis 3.0诊断标准,JAMA. 2016 Feb 23;315(8):801-10,Septic shock 定义及诊断标准,JAMA. 2016 Feb 23;315(8):801-10,Mortality 40%,Septic shock=Sepsis+输液无反应低血压+使用缩血管药物维持MAP
8、65mmHg）+乳酸则2mmol/L。,Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality.,脓毒症3.0诊断流程,JAMA. 2016 Feb 23;315(8):801-10,Sepsis 3.0,ACCP反对Sepsis 3.0,1.Given that use of the current definitions resu
9、lts in saving lives, it seems unwise to change course in midstream by shifting the definition. This is especially true because there is still no known precise pathophysiological feature that defines sepsis.,2.Abandoning the use of SIRS to focus on findings that are more highly predictive of death co
10、uld encourage waiting, rather than early, aggressive intervention. This is a mistake that we cannot make.,3.To abandon one system of recognizing sepsis because it is imperfect and not yet in universal use for another system that is used even less seems unwise without prospective validation of the ne
11、w systems utility.,Chest 2016 Feb,ACCP反对Sepsis 3.0,4. What patients need is that we continue to build on the momentum of the last two decades and that we not disrupt it by conflating change with progress.,5. Our principal concern is that the new definition de-emphasizes intervention at earlier stage
12、s of sepsis when the syndrome is actually at its most treatable. We believe that adopting a more restrictive definition that requires further progression along the sepsis pathway may delay intervention in this highly time-dependent condition, with additional risk to patients.,Chest 2016 Feb,精准医学下的Se
13、psis 3.0不足,“Definition” versus “Clinical Criteria”. (1)Sepsis researchers, both bench and clinical, should consider how their findings might validate or invalidate the new definition; (2)Clinicians should determine if the clinical criteria are useful in their own practices and consider what addition
14、al elements ought to be tested; (3)sooner rather than later.,Critical care medicine 2016 May; 44(5):857-8.,“Dependent and Independent Variables”. Sepsis = (life-threatening)(organ dysfunction)(dysregulated host response)(infection). (1) Dont assume that the sequence of events identified in the new d
15、efinition reflects pathobiological reality, because no one really knows how things are ordered and connected; (2) Dont assume that the predominant abnormality in sepsis is immunologicalthat hypothesis has dominated both mechanistic and therapeutic investigation for over two decades, and has yet to b
16、ear fruit.,Critical care medicine 2016 May; 44(5):857-8.,精准医学下的Sepsis 3.0不足,精准医学下的Sepsis 3.0不足,“Appropriate comparators”. (1)We need to reconsider just what constitutes an appropriate control for sepsis research; (2) At the very least, we ought to make sure that studies characterizing sepsis in anim
17、al models and in patients use similar controls. “What comes next? ”. Howand how soondo we initiate Sepsis-4.0? I dont knowbut lets not wait a decade and a half this time.,Critical care medicine 2016 May; 44(5):857-8.,Problem #1: Sepsis-III remains subjective,Sepsis 3.0的10个疑问（一）,所有定义都包含了“suspected in
18、fection”，但怎么去界定“suspected infection”却很难。,Problem #2: qSOFA & SOFA are mortality predictors, not tests for sepsis,Sepsis 3.0的10个疑问（二）,qSOFA & SOFA 评分多用于死亡预测，而非用于检测sepsis。,Problem #3: Sepsis-III is less specific for infection than Sepsis-II,Sepsis 3.0的10个疑问（三）,Sepsis 3.0 对诊断感染特异性低于Sepsis 2.0 。,Problem
19、 #4: qSOFA has similar performance compared to SIRS for mortality prediction,Sepsis 3.0的10个疑问（四）,事实上，qSOFA与SIRS对死亡预测价值相当 。,Problem #5: qSOFA may be less specific in diseases that directly cause hypotension, tachypnea, or delirium,Sepsis 3.0的10个疑问（五）,Sepsis 3.0的10个疑问（六）,Problem #6: qSOFA is inconsist
20、ent with a validated prognostic model (CURB65),CURB65模型被认为肺炎诊断经典模型。qSOFA与之比较，会高估肺炎的死亡率。,Sepsis 3.0的10个疑问（七）,Problem #7: Combining qSOFA and SOFA scores is not evidence-based among patients outside the ICU,SOFA 比qSOFA特异性更低，似乎不符合逻辑。,Sepsis 3.0的10个疑问（八）,Problem #8: The combined performance of qSOFA + S
21、OFA for mortality is not reported.,Sepsis 3.0的10个疑问（九）,Problem #9: The overall sensitivity of Sepsis-III for sepsis might be 50% outside of the ICU,Sepsis 3.0的10个疑问（十）,Problem #10: Sepsis-III is not a consensus guideline in the United States,支持团体：Society of Critical Care Medicinethe American Thoraci
22、c Societythe American Association of Critical Care Nurses,暂未支持团体：American College of Chest Physiciansthe Infectious Disease Society of America the Emergency Medicine societies the hospital medicine societies,脓毒症未来发展,机制、诊治发展,定义更新：脓毒症3.0,BMJ：Sepsis的病理生理及临床治疗,作者综述5000多篇文献（引文217篇），复习了近35年来脓毒症的流行病学，危险因素、
23、微生物学以及病因学及其治疗的研究成果，。综述对最新的Sepsis3.0也做了介绍和归纳，根据Sepsis3.0 定义规定，脓毒症是由于对感染的不适当的宿主反应而产生的危及生命的脏器功能障碍，而Sepsis1.0或2.0说的是全身炎症反应，两者的差别决定了其病理生理的机制是不一致的。,BMJ (Clinical research ed.) 2016 353:i1585.,BMJ:当前证据下的脓毒症诊治“取舍”,BMJ (Clinical research ed.) 2016 353:i1585.,脓毒症未来发展方向,What is the optimal fluid and vasopresso
24、r resuscitation strategy in the early phase of septic shock? 感染性休克早期阶段理想的液体与缩血管药物复苏策略？Will lung protective ventilation in patients with sepsis reduce the development of acute respiratory distress syndrome? 肺保护通气降低SEPSIS患者ARDS发展？ Will new treatments reduce the incidence of acute kidney injury in pati
25、ents with sepsis? 新疗法降低SEPSIS患者AKI发生率？发展方向Can rapid, inexpensive, and specific microbiologic tests for defining causative pathogens be developed using genetic and other approaches? 快速、廉价、特异的方法如基因检测等可行吗？Will we develop new effective and safe antibiotics in an era of increasingly common drug resistant
26、 pathogens? 耐药时代的新抗菌药物？,BMJ (Clinical research ed.) 2016 353:i1585.,How does the microbiome change in sepsis and how might this be leveraged therapeutically? SEPSIS中微生物如何变化及如何因此调整治疗？What are the long term physical, cognitive, and psychosocial changes in patients who survive sepsis, and can we develo
27、p effective rehabilitative techniques?SEPSIS存活者长期 的躯体、认知、心里有何变化？有效康复技术？Can we improve the ability of preclinical models of sepsis to predict therapeutic efficacy? 改善SEPSIS临床前模型能力，预测治疗效果Can we develop a range of point-of-care biomarkers to group patients with sepsis into pathophysiologic categories?
28、This would improve our understanding of the biology and may enhance clinical trial design 能通过生物标志物对SEPSIS患者进行病理生理归类，从而加深认识提高临床研究的设计？How will the recently released definitions and clinical criteria for sepsis shape its clinical detection, treatment, and research? 新标准对诊断、治疗、研究的影响？,脓毒症未来发展方向,BMJ (Clini
29、cal research ed.) 2016 353:i1585.,小 结,Sepsis 3.0支持者：1. 较之旧定义，新定义简单明了，易于教学及理解；2. qSOFA 专注于具有提示意义的主要脏器系统的症状和体征；3. qSOFA 已经回顾性的大数据分析证明可信有效；4. qSOFA的敏感性与特异性优于既往的ICU环境之外应用的标准；5. 新定义的发布及所引起的讨论有助于提高对该疾病的关注度。,Sepsis 3.0反对者：1. 新定义强调的标准为“已知或疑似感染的患者”，但显然感染并非总能被发现，即使使用血培养；2.qSOFA 在非ICU环境的应用有可能过于敏感；3.qSOFA与SOFA严格而言并非Sepsis的筛查工具，而应该是提示病死率增加的标志物；4. 美国医疗保险中心（CMS）目前也尚未通过新的定义，而继续沿用Sepsis2.0；5. 以上内容和定义不涉及第二科，换句话说，儿科目前缺乏相应应用。,3.0未来发展,1、有待临床进一步论证2、SIRS是该“say baybay”吗？,谢 谢,
