脓毒症相关性脑病课件.ppt

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1、,今天讨论内容：脓毒症相关性脑病,SAE的诊断与治疗,什么是SIRS 什么是SEPSIS 什么是 SAE SAE的诊断与治疗,Todays knowledge will be a killer tomorrow !,Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or

2、 appropriate,儿科领域的知识和实践在持续不断地 变 化，因为新的研究和经验在不断拓展、 丰富 我们的知识，因此，我们在治疗技术、 药物应用方面作出相应改变是必须的或者 说是合适的。 Nelson儿科学第18 版,相关基础知识,SIRS、Sepsis、MODS、SAE,感染性疾病和传染性疾病都是炎症反应和脓毒症,SIRS、Sepsis、MODS、SAE,What is SIRS？ 全身炎症反应综合征,SIRS的诊断标准: 1、 呼吸加快: 20/分钟,或 PCO2 90/分、体温升高： 、白细胞升高或降低:4109 /L109 /L,SCCM ESICMACCP ATS SIS,时间

3、： 2001年（2002年公布）专题：重新审定 SIRS, Sepsis, MODS.定义: SIRS, Sepsis, Severe Sepsis, Septic Shock, MODS,What is sepsis？ 脓 毒 血 症,What is sepsis？ 感染引起的SIRS ? !,ACCP SCCM 联席会 议 定 义,时间： 1991年（1992公布） SIRS: 机体对炎性损伤的反应 Sepsis： SIRS+感染 Severe Sepsis： Sepsis+MODS Septic Shock ： Sepsis+顽固性低灌注,What is SAE ？ 什么是脓毒症性脑病？

4、,脓毒症相关性脑病Sepsis Associated Encephalopathy(SAE),内容: 概述病因和发病机理诊断和治疗,脓毒症性脑病（SAE）概念,是指缺乏中枢神经系统感染的临床或实验室证据，由全身炎性反应(SIRS)或脓毒症（Sepsis）引起的弥散性脑功能障碍。SAE是重症监护病房最常见的脑病之一，因其临床表现缺乏特征性而常被漏诊。SAE的发病机制尚未完全清楚，可能与多种因素有关。晚期SAE常并多脏器衰竭，早期SAE则在多脏器衰竭发生前出现；意识障碍是SAE的主要表现，诊断要首先排除其他病因。,脓毒症性脑病（SAE）概念,脑电图和诱发电位等检查有助于早期诊断和评估脑功能障碍的严

5、重性及预后。目前针对SAE还缺乏特效治疗，是否对SAE采取及时、有效的整体治疗是影响患者预后的主要因素。,Features of Pathophysiology Hypermetabolism 高代谢状态 Hyperhemodynamic 高动力循环状态 Uncontrolled mediators release 炎症介质释放 Tissue injury & Organ disfunction 组织细胞损伤,What is sepsis?Host Auto-immunol injury机体对免疫原性物质、创伤和高度应激产生的免疫应答性反应导致宿主自身免疫损伤的病理生理过程,Sepsis的本质

6、之一 宿主自身免疫损伤,细胞因子风暴 炎症介质瀑布 呼吸爆发 级联反应 肠道细菌移位肠源性内毒素血症 肠道中心说,Sepsis的本质之二 微循环障碍,Sepsis is a disease of Microcirculatory dysfunction!,Sepsis的本质之二 微循环障碍,Examples of high and low capillary density. The capillary density was calculated similar to the technique of De Backer et al.1 A grid of equidistant verti

7、cal and horizontal lines was superimposed on the image. The vessel density was calculated as the number of smallvessels (20 m) intersecting the lines of the grid divided by the total length of the lines yielding the number of small vessels per millimeter. The image in A represents a high capillary d

8、ensity, and the image in B represents a low capillary density. Real-time video sequences of orthogonal polarization spectral imaging in severe sepsis and septic shock are available from the authors through a file download.,Sepsis的本质之三 亚细胞结构损伤与内呼吸障碍,MMDS-对sepsis的新认识Microcirculatory and Mitochondrial

9、Distress Syndrome 微循环和线粒体窘迫综合征内呼吸窘迫综合征?,Sepsis的本质之三亚细胞结构损伤与内呼吸障碍,MMDS - -对sepsis的新认识Microcirculatory and Mitochondrial Distress Syndrome 微循环和线粒体窘迫综合征内呼吸窘迫综合征?,人体供氧过程,肺-肺循环 体循环 毛细血管-组织细胞 气体交换 氧输送 气体交换 DO2 DO2 VO2，AO2 外呼吸 内呼吸 ARDS SHOCK MMDS,决定sepsis发展的因素内因,基因多态性 : PIRO系统同一基因的基因状态细胞内环境细胞内生理内分泌、代谢,脓毒症相

10、关性脑病Sepsis Associated EncephalopathySAE,12/21/2022,Free template from ,30,SAE定义1： SAE is an encephalopathy attributed primarily to sepsis or systemic inflammatory response syndrome (SIRS) and has often been a diagnosis of exclusion.,SIRS Associated Encephalopathy (SIRSAE) Septic Encephalopathy (SE)

11、Sepsis Associated Encephalopathy (SAE),12/21/2022,Free template from ,32,SAE定义2： It is better defined as Sepsis associated encephalopathy (SAE) in order to stress the absence of direct infection of the central nervous system.,脓毒症相关性脑病（SAE）是ICU病人最常发生的脑病。,12/21/2022,Free template from ,33,炎 性 脑 病 （Sep

12、tic Encephalopathy),概念： 1、即脓毒症相关性脑病( SAE, SIRS-SAE ) （Sepsis Associated Encephalopathy SAE） 、SIRS-Associated Encephalopathy (SIRS-SAE) 3、SIRS-Associated Septic Encephalopathy,炎 性 脑 病（septic encephalopathy SAE),、 具体发病机制不清 ，可能与多种因素有关，与炎症介质和细胞因子释放，对中枢神经损伤有关；3、临床特征：从轻微意识障碍到弥散性非局灶性中枢损伤所致的软瘫；、严重者可留下终身残疾。症

13、状在sepsis病程中出现早、进展迅速、发生率高，与患者预后密切相关。,炎 性 脑 病 （septic encephalopathy SAE),TNF-a与SAE的发病密切相关，目前认为是通过TNFR-1起作用，早期未得到合理治疗会产生严重后遗症，治疗在于对Sepsis早期识别，避免不合理的治疗，和支持疗法。 无有效的针对性治疗方法，预后与是否积极、有效的治疗sepsis有关。,SAE发病率高:50%-70%脓毒症病人发生SAE,SAE 的临床特征:精神意识状态改变The main sign of SAE is an altered mental status 弥散性大脑功能障碍出现在其他器官

14、衰竭前A diffuse cerebral dysfunction is often present in sepsis and before signs of other organ failure,诊断SAE需排除： 肝肾功能障碍 电解质紊乱和酸碱平衡失调 呼吸和体温干扰 低血压 机体其它功能紊乱,病因: Not well understood Related to following: Micro-organism toxin Inflammatory mediators (SIRS-SAE) Metabolic alteration Abnormality of cerebral ci

15、rculation BCAA/AAA Unbalance,病因:发病机理未祥，与下列因素有密切关系：微生物毒素炎症介质作用代谢紊乱脑循环功能障碍支链氨基酸芳香氨基酸比例失调,Sepsis associated encephalopathy,Cerebral hypoperfusion,Loss of CBF autoregulation,BBB alteration,BCAA/AAAUnbalanceFalse neuro transmittersincrease,Free radicalsOxydative stressCytokines ExitotoxicityApotosis,Iatr

16、ogenicDamage医源性,炎 性 脑 病 （septic encephalopathy SAE),TNF-a与SAE的发病密切相关，目前认为是通过TNFR-1起作用，早期未得到合理治疗会产生严重后遗症，治疗在于对Sepsis早期识别，避免不合理的治疗，和支持疗法。 无有效的针对性治疗方法，预后与是否积极、有效的治疗sepsis有关。,临床表现,意识障碍为主要临床表现，脑组织弥散性损伤致非局灶性软瘫。 脑电图检查灵敏度高，可作早期诊断依据及对病情严重程度做出评估,TNF-a,1、 机体受到有害刺激后最早分泌的细胞因子2、sepsis病程中导致组织损伤的关键促炎因子3、 体内存在TNFR-1

17、和TNFR-2两种受体4、 脑内以TNFR-1为主，并且TNFR-1组成性 表达于星形胶质细胞和微血管系统5 、LPS可使小胶质细胞和星形胶质细胞 产生和分泌TNF-a,TNF-a在炎性脑病中发挥了怎样的作用,？,2 0 0 7 年美国芝加哥大学Alexander JJ等就TNF-a在炎性脑病中的作用做了如下研究：,实验设计,实验动物,THF-a+/+小鼠,THF-a+/+小鼠,THF-a-/-小鼠,0.15mg salineip,0.15mg LPSip,0.15mg LPSip,8h后，处死动物收集脑组织和其它标本,实 验 设 计,检测指标1 血清TNF-a浓度2 脑组织TNF-a和TNF

18、R-1 mRNA表达水平3 脑组织TNFR-1表达水平4 脑组织中性粒细胞浸润程度与TNFR-1关系5 脑组织iNOS mRNA表达水平6 脑组织星形胶质细胞活性与TNFR-1关系,实 验 设 计,检测指标7 海马组织损伤程度8 脑组织凋亡程度9 脑组织caspase-3活性10 脑组织水含量11 血脑屏障通透性检测12 AQP4表达与TNFR-1关系,实 验 结 果,1 TNF-a通过作用于TNFR1引起炎性脑病,实验结果,通过免疫荧光检验法观察LPS腹腔注射对小鼠脑组织TNFR-1表达的影响：(a)TNFR1+/+salinetreated,荧光强度较弱,TNFR-1表达减少,实验结果,通

19、过免疫荧光检验法观察LPS腹腔注射对小鼠脑组织TNFR1表达的影响(b)TNFR1+/+ LPS-treated,荧光主要集中于海马和皮质,TNFR-1表达增加；,实验结果,(c)TNFR1-/-LPS-treated, 荧光微弱, 几乎无TNFR1表达(d)对着色区域评分（0-4分)1 TNFR1+/+saline-treated2 TNFR1+/+ LPS-treated3 TNFR1-/-LPS-treated,实验结果,对胶质细胞原纤维酸性蛋白（GFAP)（a）、TNFR1（b）和两者同时(c) , 染色TNFR-1表达与星形胶质细胞表面,实验结果,2 TNFR1介导LPS诱导的中性粒

20、细胞在脑组织中的浸润,中性粒细胞通过TNFR1浸润于脑组织(A)TNFR1+/+saline-treated,脑组织中几乎无中性粒细胞(B)TNFR1+/+LPS-treated,大量中性粒细胞浸润于脑组织， 主要集中于脑皮质(C) TNFR1-/-LPS-treated,少量中性粒细胞浸润,实验结果,3 LPS导致TNFR1依赖的iNOS表达上调,每个数据点代表一个独立的动物,实验结果,4 TNFR1缺失小鼠可抵抗LPS诱导的星形胶质细胞增生,LPS通过TNFR1使星形胶质细胞部分活化(A) TNFR1+/+saline-treated,几乎无星形胶质细胞的活化(B) TNFR1+/+LPS

21、-treated,海马和皮质有大量星形胶质细胞活化(C) TNFR1-/-LPS-treated,星形胶质细胞活化显著减少,实验结果：,5 TNFR1缺陷小鼠可抵抗炎性脑病病程中脑细胞的凋亡,A、C：TNFR1+/+saline-treated（200）B、D：TNFR1+/+LPS-treated（400 ）箭头所指为细胞损伤处,实验结果,TNFR1缺失显著减少LPS诱导的脑细胞凋亡,实验结果,TNFR1调节LPS诱导的caspase 3在脑内的活化,实验结果,6 内毒素血症增加脑组织AQP4表达和水分含量,实验结果,LPS引起血脑屏障通透性改变(A) TNFR1+/+saline-trea

22、ted,可见埃文斯蓝渗出(B) TNFR1+/+LPS-treated,与(A)图相比，较多埃文斯蓝渗出(C) TNFR1-/-LPS-treated,与(A)图相比，较少埃文斯蓝渗出,实验结果：,TNFR1缺失可抑制内毒素血症时AQP4表达增加(A) TNFR1+/+saline-treated,荧光微弱，AQP4表达较少(B) TNFR1+/+LPS-treated,荧光强度高，AQP4表达显著增加(C) TNFR1-/-LPS-treated,荧光强度较弱，AQP4表达有所减少(D)着色部分评分（0-4分），图中1、2、3与前述A、B、C相对应,讨 论：,尽管已经确定TNF-a是seps

23、is病程中的关键因子，并且TNF-a在炎性脑病中的作用也被检测，但TNF-a导致炎性脑病的确切机制还未明确。,讨 论 ：,腹腔注射LPS后，可观察到整体性TNF-a水平升高。脑组织中，TNF-a和TNFR1表达增加。TNF-a可通过增加血脑屏障通透性、过度活化星形胶质细胞和诱导脑细胞凋亡等引起脑组织损伤，脑功能受损。,讨 论：,TNF-a引起血脑屏障通透性改变和脑损伤TNF-a不仅可直接损伤无血脑屏障区域(如:CVO)、 血脑屏障不完整区域的脑组织，而且还可通过作 用于TNFR1，使血脑屏障通透性改变，损伤脑组织 血脑屏障通透性改变，有利于中性粒细胞浸润和 炎性脑损伤，在脑细胞凋亡中发挥了重要

24、作用血脑屏障通透性改变，使过量液体进入脑组织， 引起脑水肿。,讨 论 :,TNF-a引起胶质细胞活化和脑损伤TNF-a可直接激活胶质细胞，也可通过浸润的中性粒细胞间接激活胶质细胞。激活的胶质细胞可分泌神经毒性物质，如兴奋性氨基酸，引起细胞凋亡；也可产生和释放TNF-a、NO，TNF-a又可通过TNFR1增加NO的产生激活的胶质细胞AQP4表达增加，过多的水分进入脑细胞，引起脑水肿。,讨 论 :,TNF-a引起细胞凋亡和脑损伤TNF-a直接作用于TNFR1，通过死亡受体途径，引起caspase-8、caspase-3顺序激活，最终引起胶质细胞凋亡TNF-a还可通过刺激胶质细胞产生神经毒性物质和浸

25、润的中性粒细胞引起细胞凋亡,结 论 :,Alexander JJ等的实验证明：1 TNFR-1介导的信号传递是LPS诱导的炎症反应的重要途径2 抑制TNF-a/TNFR-1信号传递途径可减轻炎性脑病病程中的细胞凋亡、中性粒细胞浸润、胶质细胞增生及脑水肿。,病理生理：微生物毒素直接脑损伤炎症使损伤内皮细胞、星型细胞和神经元受损伤使脑功能障碍比例失调,SAE发病机制：- 细菌对中枢神经系统直接损害- 内毒素或炎症介质对中枢神经系统的损害- 脑血流或脑代谢受损- 氨基酸或神经递质改变- 白细胞激活和破坏血脑屏障,Table 1: Encephalopathy in the ICUInfection

26、associated Meningoencephalitis Sepsis associated encephalopathy (SAE)Vascular Ischemic stroke Intracerebral hemorrhage Subarachnoid hemorrhage Cerebral vasospasmDemyelination Pontine and extra pontine myelinolysis Acute disseminated encephalomyelitis (ADEM)Metabolic Liver failure Renal failure Endoc

27、rine dysfunction Glucemic disturbances Electrolyte imbalance Hypoxia HypercarbiaTraumatic Traumatic brain injuryHypoxic Post-cardiac arrestToxic Drug intoxication Toxin exposure Neuroleptic malignant syndromeNutritional Wernickes encephalopathyNeoplastic Gliomatosis cerebriSeizures Status epilepticu

28、sGenetic Mitochondrial cytopathy Acute intermittent porphyriMultifactorial ,12/21/2022,Free template from ,73,临床表现：非特异性弥散性脑功能障碍，从意识改变到昏迷。软瘫和非抽搐性神经系统损伤性表现诊断：, CT扫描和有助于确诊和严重程度分级。腰穿有助于排除其他中枢神经系统感染疾病,临床表现诊断： 、非特异性弥散性脑功能障碍，从意识改变到昏迷。、软瘫和非抽搐性神经系统损伤性表现。临床分期： 早期：意识改变不拌有 晚期：昏迷拌多器官损伤（）,Freund et al. 0 = 清醒 Con

29、fusion ; 2= somnolence ; 3 = stipor ; 4= comaGlasgow Scale : 分值 Mortality 1314 20% 912 50 3 8 63,、：theta , delta , triphasic wave，burst suppression. EEG与死亡率关系：Theta波优势死亡率delta波优势死亡率triphasic wave优势死亡率Burst Suppresion 死亡率,SAE与MODS关系：相关：SAE可以是MODS的一部分无关：SAE可发生于sepsis早期阶段， MODS出现前,脓毒症病人器官功能障碍发生率:肺 18%肾

30、 15% 心血管系统 7% 血液系统 6% 代谢失调 4% 神经系统 2%,影响神经系统功能障碍诊断的因素： 镇静剂 神经肌肉阻滞剂 机械通气,SAE临床特征： SAE是一种非局限性、弥散性脑病，可表现为从轻度注意力受损、意识改变、直至深昏迷。 早期阶段：注意力受损、书写障碍、定向力障碍,SAE辅助检查： CSF：蛋白升高，细胞数正常， 细菌培养 通常阴性 EEG：灵敏度高，特异度差,SAE影像学检查：SAE较少见影像学异常,SAE影像学检查： 轻者 : CT正常 重者 : MRI 弥散性改变,SAE 治疗: 1、不存在特殊治疗方法 Specific treatment dose not ex

31、ist! 、治疗依赖于早期对脓毒血症积极合理 的整体治疗 It relies on prompt and appropriate treatment of sepsis as a whole!,、避免大剂量激素治疗 Avoidance of high dose steroid treatment 、氧疗法和支持疗法Oxygen & Supportive Therapy,人体内稳态与内环境平衡,血液内稳态：循环、携氧能力 内环境平衡: 晶体环境电生理稳态 胶体环境白蛋白水稳态 酸硷环境生化稳态生物代谢,现代医学证实： SAE 的主要病理生理是: 内 环 境 和 免 疫 失 衡 导 致 自身免疫损

32、伤！!,感染性疾病和传染病的病理生理本质,病原微生物机体免疫反应相互作用 1、机体战胜疾病-同时造成免疫损伤急性-SIRS 2、病原摧毁机体- 衰竭- 死 亡 - CARS 3、机体与致病因素相持- 病情亚急性 慢 性 化 -MARS,全身炎症反应综合征(SIRS) : - 急性期表现，病情早期，免疫功能亢进。 代偿性抗炎反应综合征（CARS）: - 晚期表现 机体衰弱、器官严重损伤， - 免疫功能低下，麻痹。 混合性抗炎反应综合征（MARS） : - 急性、亚急性、慢性表现同时存在， - 免疫混合性功能障碍,SIRS与CARS,细胞因子风暴和炎症介质瀑布,结论： 早期发现对SAE治疗和预后有

33、十分重要的意义 SAE使ICU病人病死率增加 绝大多数治疗核心在于积极控制潜在的感染,SAE 预后：本病大多数预后良好，迁延治疗或错误治疗会导致中枢神经系统不可逆损伤，留下神经系统后遗症。,Sepsis is a disease of microcirculation dysfunction ! 脓毒症是微循环病 Coagulopathies disorders are also the feature of sepsis ! 凝血功能障碍也是脓毒症的特征,Sepsis :- Sepsis associated encephalopathy (SAE)脑- Sepsis induced car

34、diac dysfunction心脏- Inflammation- coagulation cross talk 凝血机制- Bacterial Translocation ( from gut to the lung)胃肠道- SIRS Sepsis MODS( kidney, heart, lung,liverGastric intestine, Blood system & brain ect.) 多器官Antibiotics induced sepsis !Antibiotics mediated sepsis !,whereas SAE is considered a diffuse

35、 cerebral dysfunction as a consequence of the systemic inflammatory response to an infection with no direct central nervous system infestation.sepsis-associated encephalopathy (SAE), sepsis-associated delirium, or brain dysfunctionSepsis associated encephalopathy (SAE) is a severe complication of se

36、psis with an incidence ranging from 9% to 71%.,Reciprocal interactions between the immune and central nervous systems(CNS) are now considered to be major components of the host response in septic shock. Because the CNS controls a wide range of physiological functions that are crucial to maintain hom

37、eostasis and orchestrate the host response at behavioral, neuroendocrine and autonomic levels, disturbances in any of these adaptive functions may deleteriously influence the course of septic shock.,Contributing factors for the compromise of the BBB include cytokines and chemokines, activation of th

38、e complement cascade, phagocyte-derived toxic mediators, and bacterial products. Recent studies suggest that bacterial proteins may readily cross the functional BBB and trigger an inflammatory response in the subarachnoid space, in absence of a bacterial invasion.,Experimental studies have shown tha

39、t microcirculatory dysfunction, a consequence of endothelial activation, is an early pathogenic step.,In 2006, the California encephalitis project, which evaluated 1570 patients with encephaliti, identified an infectious causative agent in approximately 30% of cases and a postinfectious disease proc

40、ess in 8% of cases. Of note, no cause was identified in 63% of the patients.Postinfectious encephalitis differs from acute infectious encephalitis by the usual failure to isolate infectious agents from neural tissue and by the predominance of inflammation and demyelination.,ADEM is classified under

41、demyelinating diseases of the central nervous system with a monophasic course and its diagnosis can only be made after all of the other possible diseases are ruled out. Although the etiology of both ADEM,Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder of the c

42、entral nervous system (CNS) characterized by a widespread demyelination involving the white matter of the brain and spinal cord . Antecedent infections have been associated with a subsequent immunological trigger of ADEM.,Acute disseminated encephalomyelitis is usually a monophasic inflammatory demy

43、elinating disorder of the CNS that occurs within days to weeks of a viral illness or a vaccination. The preceding infection is typically a benign upper respiratory tract infection or a nonspecific febrile illness. Historically, most cases were associated with exanthematous diseases (measles, varicel

44、la and rubella). ADEM has also been described after various definiteinfections or vaccinations.,Acute disseminated encephalomyelitis is thought to be an auto-immune disease and two pathogenetic mechanisms have been advanced. The first mechanism implies the molecular mimicry phenomenon, consisting of

45、 structural homology between a pathogen and myelin proteins of the host leading to T-cell activation and specific autoimmune CNS response against the brain and spinal cord. The second mechanism is the direct aggression of the CNS by a pathogen that may cause brain tissue damage and an infection-indu

46、ced myelin antigen release associated with bloodbrain barrier rupture.,Acute disseminated encephalomyelitis is clinically characterized by the acute onset (maximal neurological deficit reached within hours to days of onset) of focal neurological signs and encephalopathy (early evidence of behavioral

47、 impairment, delirium, fluctuations of vigilance). It usually follows a minor infection or vaccination, with a latency period of 230 days. Patients can present with a clinical picture of severe CNS infection with impaired consciousness, fever and sometimes nuchal rigidity. Both focal and generalized

48、 seizures have been reported with an incidence ranging from 4 to 30% in adults.,ADEM is predominantly a pediatric disease, with recent studies reporting an incidence of 0.4 to 0.9 per 100 000Immune-mediated disease of brain. It usually occurs following a viral infection or vaccination, but it may al

49、so appear spontaneously. Abrupt onset and a monophasic course. Symptoms usually begins 1-3 weeks after infection or vaccination. Major symptoms are fever, headache, drowsiness, seizures and coma.,Edematous white-matter T2 hyperintense lesions occurring at the same time is the classical picture of AD

50、EM.Asymmetrical distributed lesions affect the central white matter and cortical graywhite junction of both cerebral hemispheres and infratentorial areas.Deep gray matter (thalami and basal ganglia) involvement is reported in 1560% of cases in adults 5, which may help differentiate ADEM from mutiple