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摘 要 Abstract Septic-associated encephalopathy (SAE) is a key manifestation of sepsis, ranging from delirium to coma and occurring in up to 70% of patients admitted to the ICU. SAE is associated with higher ICU and hospital mortality, and also with poorer long-term outcomes, including cognitive and functional outcomes. The pathophysiology of SAE is complex, and it may involve neurotransmitter dysfunction, inflammatory and ischemic lesions to the brain, microglial activation, and blood–brain barrier dysfunction. Delirium (which is included in the SAE spectrum) is mostly diagnosed with validated scales in the ICU population. There is no established treatment for SAE; benzodiazepines should generally be avoided in this setting. Nonpharmacological prevention and management is key for treating SAE; it includes avoiding oversedation (mainly with benzodiazepines), early mobilization, and sleep promotion. 脓毒症脑病（SAE）是脓毒症的主要表现，症状表现从谵妄到昏迷，在ICU患者中发病率高达70%。在ICU和医院中，SAE与较高的死亡率相关，也与较差的长期结果(包括认知和功能结果)相关。脓毒症的发病机制十分复杂，涉及多方面，可能涉及神经递质功能障碍、大脑炎症和缺血性损伤、小胶质细胞活化和血脑屏障功能障碍等。在ICU，患者主要通过有效的量表被诊断为谵妄。脓毒症脑病目前还没有确切的治疗方法，但应避免使用苯二氮卓类药物。非药物处理和干预是治疗脓毒症脑病的关键：包括避免过度镇静（主要是苯二氮卓类药物），早期活动和促进睡眠。 Keywords: Sepsis. neuroinflammation. sepsis-associated. encephalopathy. microglia. blood–brain barrier. neuroanatomy 关键词：脓毒症、神经炎症、脓毒症脑病、小神经胶质细胞、血脑屏障、神经解剖学 前 言 Introduction Since ancient times, physicians have recognized that the central nervous system (CNS) is one of the first organs affected in sepsis, and its clinical manifestation is the so-called sepsis-associated encephalopathy (SAE) [1]. Sepsis, defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection [2], is a leading cause of ICU admission and death worldwide [3]. The incidence of SAE is about 50%. It varies from 8% to more than 70% of septic patients, according to the sepsis severity, patients’ profile, and SAE diagnostic criteria [4–6]. It can be the revealing manifestation of sepsis, and alteration in mental status has been identified as 1 of the 3 screening items for detecting sepsis [7]. Its pathophysiology comprises neuroinflammation, vascular changes, and metabolic failure leading to tissue lesions seen in animal models and observed in humans [1]. These mechanisms are not homogeneous in the brain and may lead to region-specific lesions. The centers involved in autonomic controls, arousal, awareness, and behavior are particularly affected, accounting for the clinical features of SAE varying from sickness behavior to consciousness impairment (i.e., ranging from delirium to coma) [1, 8]. SAE is characterized by changes in the electroencephalogram (EEG), with a nonconvulsive status epilepticus that can be detected in up to 20% of cases [9]. The radiologic lesions are uncommon, but white matter hypersignal and ischemic stroke can be observed in the subgroup of patients with septic shock ischemic lesions in about 30% of patients [10–12]. SAE is associated with increased mortality [4, 13] as well as long-term cognitive impairment—mainly affecting memory, attention, and verbal fluency [14, 15]—and psychological disorders, including depression, anxiety, and posttraumatic stress disorder (PTSD) [16, 17]. Its management relies mainly on general ICU good practices as specific treatment is still lacking. 一直以来，内科医生们早就认识到中枢神经系统是脓毒症最早受累的器官之一，其临床表现即所谓的脓毒症相关性脑病。脓毒症的定义是宿主对感染反应失调引起的危及生命的器官功能障碍，是全球ICU入院和死亡的主要原因。脓毒症的发病率大概为50%，而根据脓毒症的严重程度、患者情况和脓毒症脑病的诊断标准，脓毒症患者的死亡率从8%到70%以上不等。脓毒症脑病是脓毒症的显著性变化，精神状态的改变已被确定为检测脓毒症的3个筛查项目之一。脓毒症的病理生理学机制涉及神经炎症、血管变化和代谢衰竭，进而能在动物模型和患者体内观察到组织损伤。这些机制在大脑中不是同质的，可能导致区域特异性损伤。主要受损伤的是涉及自主控制、觉醒、意识和行为的中心，这也就解释了脓毒症脑病从疾病行为到意识障碍不等的临床特征（即从谵妄到昏迷）。脓毒症脑病的特征性改变是脑电图(EEG)的变化，在20%的病例中可以检测到非惊厥性癫痫持续状态。脓毒症脑病的影像学病变并不常见，但在约30%的脓毒性休克缺血性病变患者的亚组中可以观察到脑白质的高信号和缺血性卒中。脓毒症脑病导致死亡率增加、长期认知障碍（主要影响记忆、注意力和言语流利度）和心理障碍，包括抑郁、焦虑和创伤后应激障碍(PTSD)。其处理主要依赖于ICU的良好监护，目前仍缺乏具体的治疗措施。 The brain is an immune-privileged organ as it is less subject to the immune response, with consequences to make it tolerant to tumors and graft. Now the current thinking is that the CNS can be profoundly affected by severe systemic infections. Therefore, in this chapter, we will review the main characteristics of SAE and its pathophysiology, as well as its therapeutics and prognosis. 大脑是一个享有免疫特权的器官，因为它较少受到免疫反应的影响，对肿瘤和移植物具有耐受性。目前认为严重的全身感染可对中枢神经系统造成极大损害。因此，在本综述中，我们将论述脓毒症脑病的主要特征和病理生理机制以及治疗和预后。 流行病学 Epidemiology Because of the absence of consensual definition of SAE, there is a great variation in its incidence across studies. Thus, 20 to 40% of septic patients admitted to the ICU will develop an encephalopathy. It has been reported that delirium is observed in up to 70% of elderly mechanically ventilated patients [14,18]. The most consistent risk factors are age, previous cognitive impairment, kidney and liver failure, and sepsis severity [4, 14]. Similarly, bacteremia is accompanied by changes in neurological status, ranging from lethargy to coma, in about 70% of cases [4]. Finally, only 19% of the patients admitted to the ICU showed a normal EEG with alpha rhythm and 80% present EEG background or epileptic anomalies [19, 20]. 由于缺乏对脓毒症脑病的确切定义，各研究之间的发病率差异很大，ICU的病人20%至40%会出现脑病。据报道，高达70%的老年机械通气患者会出现谵妄。主要风险因素包括年龄、既往认知障碍、肝肾功能衰竭和脓毒症严重程度。同时，大约70%的病例中，脓毒症患者存在神经精神状态的改变，从嗜睡到昏迷不等。在入住ICU的患者中，只有19%的患者表现出正常的α节律脑电图，80%的患者表现出脑电图背景异常或癫痫。 It has been clearly shown that occurrence of encephalopathy increases the risk of death in septic patients, although themechanisms underlying the relationships between SAE andmortality are not elucidated yet. Mortality rate is mainly associated with the clinical and electrophysiological severity of SAE. 尽管脓毒症脑病和死亡率相关性的潜在机制尚未阐明，但早有事实表明脑病的发生增加了脓毒症患者的死亡率。死亡率的高低主要与脓毒症脑病的临床和电生理严重程度有关。 Septic patients are at risk also of developing longterm cognitive impairment and psychological disorders. Thus, hospitalization for sepsis is associated with a 10% increase in the prevalence of cognitive impairment during 8 years [14, 21]. Attention, verbal fluency, executive function, verbal memory, and quick mental processing are the main cognitive functions impaired, whereas visual memory and visuoconstructive ability are usually spared [15, 22]. The psychological disorders include anxiety, depression, and PTSD [17, 23]. Sepsis even increases the risk for suicide within 2 years after its recovery [24]. These psychological and cognitive disorders dramatically impact quality of life and functional status [15]. At 1 year, up to 51% of septic patients have not returned to full-time employment [25]. It is considered that the cognitive dysfunction results from early sepsis-related insults of the hippocampus and frontal lobe [21, 26] and the psychological disorders from those involving the limbic system [1]. 脓毒症患者有发展为长期认知功能障碍和心理障碍的风险，在8年内，因脓毒症住院与认知障碍患病率增加10%有关。认知功能受损主要包括注意力、言语流畅性、执行功能、言语记忆和快速思维处理的能力下降，而视觉记忆和视觉建构能力通常被保留。心理障碍则包括焦虑、抑郁和创伤后应激障碍。脓毒症甚至会增加康复后2年内自杀的风险。这些心理和认知障碍极大地影响了生活质量和功能状态。一年内，高达51%的脓毒症患者没有恢复全职工作。认知功能障碍是由于脓毒症早期海马和额叶损伤导致，而心理障碍则涉及边缘系统。 病理生理学 Pathophysiology Systemic inflammation leads to deleterious effects on the brain parenchyma resulting in SAE. SAE can be evidenced clinically, electrophysiologically, or radiologically and can be modeled in animal studies. 全身炎症反应对脑实质产生影响导致脓毒症脑病。可通过动物建立脓毒症脑病模型，从而证实其临床、电生理或影像学改变。 Specific pathways mediate this signal to the brain and triggers 3 processes which are neuroinflammation, ischemia, and cellular metabolic stress [27]. It is likely that complement system activation contributes to the BBB dysfunction [28]. Macro- and microcirculatory dysfunctions induce ischemia; the dysfunction of the vascular complex (which includes the endothelial cells, astrocytes, and blood–brain barrier) and the activation of microglia lead to neuroinflammation. These 2 processes add to other systemic factors (i.e., drug neurotoxicity, hypoxia, dysglycemia, renal or liver failure) and induce metabolic stress (Fig. 1). Oxidative stress closely linked to dysfunction of the mitochondria alters neuronal function and vitality [26, 29]. Specific brain regions are particularly sensitive to these processes, those involved in autonomic control, arousal, defining behavioral response to stress, and more complex cognitive functions such as memory and attention [30]. Strong neuronal activation is consistently evidenced in the hippocampus, the amygdala, the nucleus tractus solitarii, and the locus coeruleus [31]. An increased neuronal apoptosis associated with microglial activation has been specifically evidenced in these areas by the neuropathological study of the brain from patients who died from sepsis [32]. These findings provide the anatomic substrate of acute and long-term consequences of SAE. 特定的通路将炎症信号传递给大脑，并触发三个过程，即神经炎症、局部缺血、和细胞代谢应激。补体系统的激活很可能是导致血脑屏障功能障碍的原因。大循环和微循环功能障碍导致缺血；血管复合体(包括内皮细胞、星形胶质细胞和血脑屏障)功能障碍和小胶质细胞激活导致神经炎症。这两个过程与其他系统性因素相辅相成，强化了其他系统性因素(即药物神经毒性、缺氧、血糖紊乱、肾功能衰竭或肝功能衰竭)，并导致代谢应激。氧化应激与线粒体功能障碍密切相关，会改变神经元的功能和活力。大脑的特定区域对这些病理过程特别敏感，涉及自主神经调节、兴奋、唤醒、对压力行为反应，以及更复杂的认知功能，比如记忆和注意力。在海马、杏仁核、孤束核和蓝斑都有强烈的神经元激活。通过对死于脓毒症患者的脑部进行的神经病理学研究显示，已有明确的证据证明这些区域中神经细胞凋亡的增加与小胶质细胞激活相关。这些发现为脓毒症脑病的急性和长期结果提供了解剖学基础。  图1.不同病理生理过程的示意图 在脓毒症相关脑病期间观察到或推断。 血管变化包括血脑屏障功能障碍、神经血管分离和中风。神经炎症包括小胶质细胞和星形细胞的激活，增强兴奋性毒性和代谢失衡，诱发神经元细胞死亡。 大脑信号 Brain Signaling The inflammatory signal in the brain involves the humoral and neural pathways. For example, the intraperitoneal inflammation signal is conveyed by vagal afferents to the medullary autonomic nuclei and the vagus nerve is able to modulate local and systemic inflammation (by its peritoneal and splenic innervations respectively). The neural pathways could also comprise other nerves and nuclei such as the trigeminal nerve and nucleus. The medullary autonomic nuclei can modulate more widely the response to the sepsis by their connections to other autonomic neuroendocrine and behavioral centers [32]. Areas deprived of BBB form the humoral pathway involving circumventricular organs and the area postrema. Inflammatory mediators are then allowed to traffic towards the local neuroendocrine and autonomic centers [33]. These 2 pathways orchestrate the inflammatory stress response clin-ically observable as the sickness behavior. 大脑中的炎症信号涉及体液和神经两个通路。例如，腹膜内炎症信号由迷走神经传入延髓，迷走神经能够调节局部和全身炎症(分别通过腹膜和脾脏神经)。神经通路也由其他神经或神经核组成，如三叉神经和三叉神经核。延髓自主神经核团可以通过其他自主神经、内分泌和行为中枢的联系来更广泛地调节对脓毒症的反应。缺乏血脑屏障的区域形成涉及脑室周围器官和延髓最后区的体液通路。然后，炎症介质流向各部分神经内分泌和自主神经中心。这两条途径共同作用产生临床上可观察到的炎症应激反应，导致疾病的发生。 Blood–brain barrier (BBB) dysfunction is also observed during sepsis. It controls the blood–brain water, molecule, and ion balance and restrains immune cell, toxin, and pathogen crossing [34, 35]. Astrocytes and pericytes maintain its integrity. In septic shock, the neuropathological, electron mi-crograph examination and MRI studies confirm the BBB impairment, responsible for vasogenic edema in the white matter [11, 36]. Posterior reversible encephalopathy syndromes are evidenced in septic patients, corroborating these findings [37]. BBB impairment is also experimentally modeled, reproducing endothelial activation, complement activation, and the decrease in tight junction protein expression, namely occludin, ZO-1, ZO-2, claudin-3, and claudin-5 [38]. Also, an upregulation of aquaporine 4 has been evidenced, probably favoring brain edema in patients [36]. 脓毒症伴有血脑屏障的功能障碍。血脑屏障控制着血脑水、分子和离子平衡，抑制免疫细胞、毒素和病原体的交叉，星形胶质细胞和周围细胞维持其完整性。当脓毒症性休克时，神经病理学、电子显微镜检查和MRI都证实了血脑屏障功能的受损导致脑白质发生血管源性水肿，以及脓毒症患者出现可逆性脑病综合征。实验室可以模拟血脑屏障损伤模型，再现内皮激活、补体激活和紧密连接蛋白（即occludin、ZO-1、ZO-2、claudin-3和claudin-5）表达的减少。此外，已有证据表明水通道蛋白4表达上调，可能加重脓毒症患者的脑水肿。 神经炎症与小胶质细胞活化 Neuroinflammation and Microglial Activation In the brain, microglial cells are the main macrophage cells, representing most of the brain immune system. They also prune unused synapses and secrete neurotrophic factors contributing to synaptic plasticity. They also present phagocytic, migration, proliferation, and various mediator release capaci-ties. Most of their various surface receptors interact with the peripheral immune system notably through cytokine ligation but can also sense damage- and pathogen-associated molecular patterns (DAMPs and PAMPs) [39]. 在大脑中，小胶质细胞是主要的巨噬细胞，是大脑免疫系统的主要组成部分。小胶质细胞还可以修剪未启用的突触，并分泌有助于突触可塑性的神经营养因子。它们还具有吞噬、迁移、增殖和释放各种介质的能力。大多数小胶质通过不同的表面受体与外周免疫系统相互作用，特别是通过细胞因子连接，同时也可以感知到损伤和病原体相关的分子模式(DAMPS和PAMPs)。 Upon stimulation through circulating endotoxins or tolllike receptor pathways, microglial cells activate and present morphological, immunological, and metabolic changes. Morphological changes are mostly characterized by a shortening of their processes called deramification, up to an amoeboid form to the extreme. Various immunological phenotypes of microglia activation are observed in response to such activation, ranging from proinflammatory (M1) releasing proinflammatory cytokines (such as gamma interferon or tumor necrosis factor alpha) to anti-inflammatory (M2) ones releasing immune modulatory cytokines (such as IL4 or IL10). The neurotoxic consequences are usually considered secondary to proinflammatory phenotypes whereas anti-inflammatory phenotypes could be neuroprotective [39]. The neuronal activation and dysfunction is in part secondary to microglia activation; thus, the neuroinflammatory process contributes to longterm consequences of SAE. Cytokines, nitric oxide, excitatory gliotransmitters, and neurotoxic metabolites (such as reactive oxygen species) mediate the microglia-mediated neurotoxicity through an increase in neuronal excitability leading to hy-peractivation and excitotoxicity [39, 40]. 当小胶质细胞通过循环内毒素或Toll样受体途径受到刺激时，会激活并呈现形态学、免疫学和新陈代谢的变化。形态学变化的主要特征是突起缩短，称为脱氨化，达到极端的阿米巴形式。小胶质细胞激活的免疫表型多种多样，既有促炎症(M1)释放的促炎细胞因子(如γ干扰素或肿瘤坏死因子α)，也有抗炎(M2)释放免疫调节细胞因子(如IL4或IL10)。通常认为，神经毒性继发于促炎表型，而抗炎表型可能具有神经保护作用。神经元的激活和功能障碍在一定程度上继发于小胶质细胞的活化，因此，神经炎症过程导致SAE的长期后果。细胞因子、一氧化氮、兴奋性胶质递质和神经毒性代谢物（如活性氧）通过增加神经元的兴奋性而激活小胶质细胞介导的神经毒性，从而导致过度激活和兴奋性毒性。 Animal [41, 42] and human [43, 44] studies during sepsis consistently show microglia activation without any known cerebral infection. This concept has recently been challenged as bacterial genomic material and living bacteria have been found in animals and humans without them leading to infectious encephalitis [45]. Whereas brain microbiota is considered absent in healthy subjects, this might be challenged in the critically ill [46]. Thus, targeting microbiota in the ICU could be a relevant therapy in the future [47, 48]. 对动物和人体在脓毒症期间的研究一致显示在没有任何已知的脑部感染下，小胶质细胞被激活。这一概念最近受到了挑战，因为在动物和人体中发现了细菌基因组材料和活细菌，但它们不会导致传染性脑炎。虽然大脑微生物区系在健康受试者中被认为是缺失的，但在危重病人中这一观点可能会受到挑战。因此，针对ICU中的微生物群可能是未来的一种相关疗法。 As microglia activation induces most probably brain damage during sepsis, its modulation seems a relevant approach for treating SAE [49, 50]. Promising experimental results have been published using various interventions including minocycline [51], cholinergic inhibition [52, 53], and vagal nerve stimulation [54]. Rivastigmine administration has been an original and convincing lead in the sepsis setting. It has been shown to reduce microglia activation by restoring the cholinergic inhibition. However, a randomized clinical trial evaluating rivastigmine has been prematurely interrupted for increasing mortality showing that manipulating the microglia may be hazardous [55]. The absence of a microglial phenotype biomarker limits clinical and experimental research allowing to classify easily such a dynamic phenomenon as microglial activation. Microglial activation has been characterized in Alzheimer disease using PET-CT, but its feasibility limits its transposition to septic patients until further improvements are made [56]. 由于小胶质细胞激活最有可能在脓毒症期间引起脑损伤，因此对小胶质细胞的调节似乎是治疗SAE的一种相关方法。已经有实验使用各种干预措施表现出阳性结果，包括米诺环素、胆碱能抑制和迷走神经刺激。卡巴拉汀治疗脓毒症是一种新颖而令人信服的治疗方法。研究表明，它可以通过恢复胆碱能抑制来减少小胶质细胞的活化。然而，一项评估卡巴拉汀的随机临床试验因增加了死亡率而过早中断，表明干预小胶质细胞可能是危险的。小胶质细胞表型生物标记物的缺乏限制了临床和实验研究，使得对小胶质细胞激活这样的动态现象进行分类变得很容易。利用PET-CT可以研究阿尔茨海默病患者的小胶质细胞激活情况，除非得到进一步改善，否则其可行性仅限于阿尔兹海默病患者，而不能应用于脓毒症患者。 One dementia pathophysiology hypothesis is a neuroinflammatory cascade as microglial activation is consistently activated in such diseases. In these pathologies, microglial cells are considered as “primed” and overactivate after being submitted to a second hit. Sepsis can be considered the primer or the second hit [57]. This hypothesis can therefore account for the relationship between the rate of sepsis occurrence and intensity of the cognitive decline but also to its deleterious impact on patients with pre-existing neurodegenerative disease. 有关痴呆症病理生理学假说之一是神经炎性级联反应，因为小胶质细胞的激活在此类疾病中持续存在。在这一理论中，小胶质细胞被认为是“启动的”，并在受到第二次打击后过度激活。脓毒症可以被认为是引爆剂或第二针。因此，这一假说可以解释脓毒症的发生率和认知功能下降的强度之间的关系，也可以解释它对既往神经退行性疾病患者的有害影响。 星形胶质细胞与血脑屏障功能障碍 Astrocytes and Blood–Brain Barrier Dysfunction Astrocytes represent the brain’s most numerous cells. They play a major role in brain homeostasis, and astrocyte dysfunction has been identified as a potential mechanism of SAE. BBB permeability, brain water balance, and microcirculatory cerebral brain flow (via the release of NO, prostaglandins, and arachidonic) are controlled by astrocytes [58]. They also participate in synaptic plasticity in the “tri-partite” synapse, releasing and reuptaking glutamate, GABA, and glycine. Astrocytes form extensive networks through gap junctions of connexins (Cx), channels permitting the bidirectional exchange of “gliotransmitters,” ions, or small molecules between astrocytes and neurons or in the extracellular milieu (hemichannels). In a neuroinflammatory context induced by LPS, microglial cell activation inhibits gap junction channels and open hemichannels [59]. Whether this occurs in SAE has to be evidenced. 星形胶质细胞是大脑数量最多的细胞，对维持脑内稳态起重要作用，星形胶质细胞功能障碍被认为是SAE的一个潜在机制。血脑屏障通透性、脑水平衡和微循环脑血流(通过释放NO、前列腺素和花生四烯酸)由星形胶质细胞控制，同时它还参与“三部分”突触的可塑性，释放和重吸收谷氨酸、γ-氨基丁酸和甘氨酸。星形胶质细胞通过连接蛋白(Cx)的缝隙连接形成广泛的网络，Cx是允许星形胶质细胞和神经元之间或在细胞外环境(半通道)中双向交换“胶质递质”、离子或小分子的通道。在LPS诱导的神经炎症环境中，小胶质细胞的激活抑制缝隙连接通道和开放半通道。尚未有证据表明这个过程是否发生下SAE中。 In animal models of SAE, astrogliosis has been consistently evidenced [50]; however, these findings have never been reported in humans. Human studies rely solely on neuropathological findings and morphological analysis of glial fibrillary acid protein (GFAP) staining, which are insufficient to analyze the functionality of neuron–glia interaction and astrocytic network. 在SAE的动物模型中，已证实存在星形胶质细胞的增生；然而，这些发现从未在人体中被报道过。对人体的研究仅仅依靠神经病理学结果和胶质纤维酸性蛋白(GFAP)染色的形态学分析，不足以分析神经元-胶质细胞相互作用和星形细胞网络的功能。 缺血过程 Ischemic Processes Ischemic processes are separated in macrocirculatory dysfunction including hypotension, decreased cerebral flow, and impaired autoregulation-and microcirculatory impairment,characterized by neurovascular uncoupling impairment, disruption of the blood–brain barrier, and coagulation cascade activation. Septic shock induces ischemic damages observed in all cases of patients dead of septic shock which are associated in ~ 20% of cases with microhemorrhages associated to disseminated intravascular coagulopathy [60]. 大循环功能障碍包括低血压、脑流量减少、自我调节功能受损和微循环功能障碍，以神经血管解偶联损伤、血脑屏障破坏和凝血级联激活为特征。脓毒症性休克引起缺血性损伤，在所有脓毒症性休克死亡的患者中观察到，大约20%患者与弥散性血管内凝血相关的微量出血相关。 The cerebral blood flow (CBF) is maintained constant by autoregulation as mean systemic arterial pressure ranges between 60 and 150 mmHg. Below 60 mmHg, CBF decreases and induces olighemia whereas when MAP is above 150 mmHg, hyperhemia is observed. A decrease in the CBF has been consistently evidenced in septic shock, and an impairment of its autoregulation has been evidenced to be associated with delirium [29, 61]. 当平均体动脉压（MAP）在60至150 mmHg之间时，脑血流量(CBF)通过自动调节保持恒定。当MAP低于60 mmHg时，脑血流量下降，而当MAP高于150 mmHg时，则出现充血。事实证明，脓毒症性休克时脑血流量减少，其自身调节功能受损与谵妄有关。 Brain microcirculation is finely regulated through complex mechanisms. These depend on the gliovascular unit composed of endothelial cells, astrocytes, and pericytes [62]. When neuronal activity increases and consumes oxygen, the gliovascular unit couples the cerebral flow by vasodilation increasing locally the energy supply [62]. In experimental models of sepsis, the microcirculatory dysfunction has been evidenced by neurovascular uncoupling impairing cerebral vascular supply and leading to a deleterious metabolic crisis [26, 63]. 大脑微循环是通过复杂的机制进行精细调节的,这依赖于由内皮细胞、星形胶质细胞和周围细胞组成的胶质血管单位。当神经元活动增加并消耗氧气时，胶质血管单位通过局部血管扩张增加能量供应来耦合脑血流。在脓毒症的实验模型中，已证实微循环功能障碍为神经血管解偶联，损害脑血管供应，并导致有害的代谢危机。 In specific areas during sepsis, the metabolism is increased. For a normal mean blood pressure between 65 and 70 mmHg, the autoregulating mechanisms of the CBF allow the blood flow to match the energy demand. Sepsis can also impair cerebral autoregulation, compromising a major protection of the brain from ischemia. Thus, a decrease in mean arterial blood pressure below 70 mmHg can result in ischemic damage. Such disturbance could induce a mismatch between cerebral blood flow and metabolic demand [32]. 脓毒症发生时脑特定区域的新陈代谢增强。对于65至70 mmHg之间的正常平均血压，CBF的自动调节机制允许血流与能量需求相匹配。脓毒症会损害大脑的自我调节功能，影响大脑免受缺血的主要保护。因此，平均动脉压降至70 mmHg以下可导致缺血性损伤，这种紊乱导致脑血流和代谢需求不匹配。 Finally, such ischemic process could be involved in longterm cognitive decline as a similar mechanism to vascular dementia. 最后，长期认知能力下降可能与这种缺血过程有关，这与血管性痴呆的机制类似。 线粒体功能障碍 Mitochondrial Dysfunction The metabolic and bioenergetics demands may result in oxidative stress and mitochondrial dysfunction during sepsis [26]. Indeed, early mitochondrial dysfunction has been shown in various brain regions of septic animals, resulting in reduced ATP generation and the production of oxygen/nitrogen reactive species [64]. This metabolic process is proapoptotic and involves the glial cells and neurons. 脓毒症时代谢和生物能需求可能导致氧化应激和线粒体功能障碍。事实上，脓毒症动物的不同脑区已显示出早期线粒体功能障碍，导致ATP生成减少和氧/氮反应物的产生。这一代谢过程是促凋亡的，涉及胶质细胞和神经元。 神经递质功能障碍 Neurotransmitter Dysfunction Aside from mitochondrial dysfunction and oxidative stress, neurons are liable to excitotoxicity [65]. Neurotransmitter concentration in the synaptic cleft is the basis for excitotoxic processes occurring when neurotransmitter release is increased whereas its reuptake is diminished or insufficient [66]. The excitotoxic process is a pathological process occur-ring in neuroinflammation and ischemia but is also secondary to systemic perturbations such as hypoxemia, electrolyte disorders, dysglycemia, drug toxicity, and excess circulating neurotoxic amino acids (ammonium, tyrosine, tryptophan, and phenylalanine) [67, 68]. Excitotoxicity through glutamate receptors (N-methyl D aspartate receptor) induces functional impairment but also cell death, which could account for the clinical and electrophysiological features of SAE. Various synapses seem to be involved in the SAE, notably dopaminergic, β-adrenergic [69], the GABA [70], and the cholinergic ones [52, 71]. During delirium, a dopamine/choline imbalance is suspected [72] but its modulation with cholinergic drugs such as rivastigmine [55] or antidopaminergic drugs, like haloperidol [73], has not shown benefits in patients. On the other side, the risk of delirium is increased by benzodiazepines (GABA agonists) [74], but not reduced by noradrenergic drugs (i.e., dexmedetomidine) in septic patients [75]. 除了线粒体功能障碍和氧化应激，神经元还容易出现兴奋性毒性。当神经递质释放增加而其重摄取减少或不足时，突触间隙中的神经递质浓度是发生兴奋性毒性过程的基础。兴奋性毒性过程是神经炎症和缺血的病理过程，但也继发于全身紊乱，如低氧血症、电解质紊乱、血糖紊乱、药物毒性和循环中过量的神经毒性氨基酸(铵、酪氨酸、色氨酸和苯丙氨酸)。谷氨酸受体(N-甲基-D-天冬氨酸受体)介导的兴奋性毒性可导致功能损害和细胞死亡，这可能是SAE的临床和电生理特征之一。蛛网膜下腔出血似乎涉及各种各样的突触，特别是多巴胺能、β-肾上腺素能、γ-氨基丁酸和胆碱能。在谵妄发生时，人们怀疑多巴胺/胆碱失衡，但它与胆碱能药物如利瓦斯汀或抗多巴胺能药物如氟哌啶醇的调节作用并未显示出对患者的益处。另一方面，在脓毒症患者中，苯二氮卓类药物(GABA激动剂)会增加谵妄的风险，但去甲肾上腺素能药物(即右美托咪啶)并不能降低这种风险。 医源性因素 Iatrogenic Factors There are various drugs commonly administered in septic patients that can be neurotoxic, including antibiotics and sedative agents. Thus, antibiotics overdose has been shown to be associated with delirium. It has to be noted that antibiotic neurotoxicity is not always related to an overdose. Benzodiazepines have been clearly established to induce delirium. All pharmacological factors have to be systematically checked. ICU environment and sleep deprivation are also involved in the occurrence of delirium. The use of the ABCDEF bundle can be applied for controlling potential factors of delirium in septic patients [76]. 脓毒症患者通常服用多种药物，包括抗生素和镇静剂，这些药物可能具有神经毒性。抗生素过量已被证明与谵妄有关。但必须指出的是，抗生素的神经毒性并不总是与过量有关。苯二氮卓类药物已被明确证实可导致谵妄。所有的药理因素都必须进行系统的检查。ICU的环境和睡眠剥夺也与谵妄的发生有关。ABCDEF束的使用可以应用于控制脓毒症患者的谵妄的潜在因素。 蛛网膜下腔出血的功能神经解剖学研究 Functional Neuroanatomy of SAE A neuroanatomical approach to SAE helps in understanding not only SAE clinical features but also its associated increased mortality and long-term psychocognitive disorders (Fig. 2). SAE的神经解剖学方法不仅有助于了解SAE的临床特征，而且有助于了解死亡率增加和长期的心理认知障碍。  图2 脓毒症早期体征(上排)，依赖于特定结构(中排)，与最差结局相关(右排)。疾病行为被认为是对全身炎症的生理反应；谵妄和意识障碍是SAE的临床症状。 SAE=脓毒症相关性脑病，PTSD=创伤后应激障碍 应激反应的神经解剖学 Neuroanatomy of Response to Stress During sepsis, the peripheral inflammation is transmitted to structures controlling autonomic and neuroendocrine systems interconnected to each other and to behavior and cognition centers, which in turn regulates the immune response through the “inflammatory reflex” [77–80]. The intensity of such response may be qualified in regard to the severity of sepsis as adapted, maladapted, or pathological (overactivated or blunted) [81, 82]. Such a distinction implies that recovery or not of sepsis might be influenced by the CNS response. However, there is no clinicobiological criteria to establish such a categorization. Through the neural pathway, the vagus nerve activates early the nucleus tractus solitarii and the locus coeruleus [31, 83, 84], which activate compensatory mechanisms in sepsis such as the control of blood pressure, heart rate, and arousal. These neural centers act as entry points to the CNS and stimulate the other autonomic nuclei and the behavioral and neuroendocrine centers. The precocity of the CNS activation by the neural route might explain that sickness behavior is one of the earliest features of sepsis (Fig. 3) [85]. 在脓毒症期间，外周炎症被传递到控制自主神经和神经内分泌系统的结构中，这些系统相互连接，并传递到行为和认知中心，而行为和认知中心又通过“炎症反射”调节免疫反应。根据脓毒症的严重程度，这种反应的强度可以被限定为适应性、适应不良或病理性（过度激活或钝化）。这种区别意味着脓毒症的恢复与否可能受到中枢神经系统反应的影响。然而，没有临床生物学标准来建立这样的分类。迷走神经通过神经通路早期激活孤束核和蓝斑，从而激活脓毒症的代偿机制，如控制血压、心率和觉醒。这些神经中枢作为中枢神经系统的入口点，刺激其他自主神经核团以及行为和神经内分泌中心。中枢神经通路的提前激活可能解释了疾病行为是脓毒症最早的特征之一。  图3脓毒症期间应激网动员方案。外周炎症信号通过激活特定结构(浅蓝色箭头)、室周器官(CVO)或迷走神经核团的3条主要通路(深蓝色箭头)传递到中枢神经系统。行为、神经内分泌和自主神经结构相互联系并受到刺激，导致功能性反应(深绿色箭头和矩形)。 CNS=中枢神经系统，CVO=脑室周围器官，BBB=血脑屏障 Sickness behavior is a physiological response to a systemic inflammation that is clinically characterized by social withdrawal, impaired cognition (psychomotor retardation, impaired attention), altered alertness (anxiety, hypersomnia, fatigue, sleepiness), and eating disorders (anorexia, weight loss, thirst). Thus, a severe sickness behavior can mimic a hypoactive delirium [86]. Use of a specific scale for these entities is therefore clinically useful [87]. Interestingly, in brains of patients who died from septic shock, the neuropathological examination of response to stress structures consistently showed an increased number of apoptotic cells. This finding underlines their particular sensitivity to the excitotoxic process [32, 60, 85]. 疾病行为是对全身性炎症的一种生理反应，临床特征是社交退缩、认知受损(精神运动迟缓、注意力受损)、警觉性改变(焦虑、嗜睡、疲劳、嗜睡)和进食障碍(厌食、体重减轻、口渴)。因此，严重的疾病行为可以模拟低活动性谵妄，对这些实体使用特定的量表在临床上是有用的。有趣的是，在脓毒症性休克死亡患者的大脑中，对应激结构反应的神经病理学检查一直显示凋亡细胞数量增加。这一发现强调了他们对兴奋毒性过程的特殊敏感性。 脑干、死亡率和谵妄 Brainstem and Mortality and Delirium Four broad functions are controlled by the brainstem: brainstem reflexes, sleep–wake cycle, control of vital functions, and modulation of the immune response [88]. Brainstem dysfunction might then result in swallowing disorders, impaired arousal, cardiovascular sympathetic activity and respiratory drive dysfunction, and both cholinergic and adrenergic immunomodulation. These changes might account for the increased mortality, development of organ failure, and fluctuating wakefulness. We have found in deeply sedated critically ill patients that a specific pattern of heterogeneous brainstem reflex abolition was associated with higher mortality and delirium to the absence of oculocephalogyre reflex [89]. Also, a dysfunction of the reticular activating ascending substance has been suggested by the absence of EEG reactivity, and is predictive of death in septic patients [90]. In addition, critical illness increases brainstem latencies of auditory evoked potential suggesting common mechanisms of sepsis with other pathologies [91]. 脑干控制着四大功能：脑干反射、睡眠-觉醒周期、生命功能的控制和免疫反应的调节。脑干功能障碍可能会导致吞咽障碍、觉醒功能受损、心血管交感神经活动和呼吸驱动功能障碍，以及胆碱能和肾上腺素能免疫调节。这些变化可能解释了死亡率的增加、器官衰竭的发展和不稳定的觉醒。我们在深度镇静的危重病人中发现，由于缺乏眼脑回反射，异质性脑干反射消失的特定模式与较高的死亡率和谵妄相关。此外，EEG反应性的缺失提示网状上行激活物质的功能障碍，并可预测脓毒症患者的死亡。危重疾病增加了听觉诱发电位的脑干潜伏期，提示脓毒症与其他病理的共同机制。 Finally, in septic patients, the decrease in heart rate variability is associated with bad outcome and reflects the sympathovagal imbalance [81]. Sepsis is also associated with an impairment in the baroreflex, controlled by medullar nuclei. Circulating inflammatory mediators can diffuse at the level of the area postrema, inducing an intense neuroinflammatory process leading to brainstem dysfunction. These mechanisms are supposed to account for the multifocal necrotizing leukoencephalopathy associated with marked apoptosis within the brainstem autonomic nuclei reported in a patient who died from septic shock [92]. 最后，在脓毒症患者中，心率变异性的降低与不良结局相关，并反映了交感迷走神经失衡。脓毒症还与受髓核控制的压力感受器反射受损有关。循环中的炎症介质可以在末梢区域扩散，引起强烈的神经炎症过程，导致脑干功能障碍。这些机制被认为是多灶性坏死性白质脑病的原因，该病与脓毒症性休克死亡患者脑干自主神经核的显著凋亡有关。 杏仁核和心理障碍 Amygdala and Psychological Disorders Postsepsis psychological disorders, also gathered under the name “postsepsis syndrome,” involve fear and anxiety circuits, notably the amygdala, the bed nucleus stria terminalis, the hypothalamus, or other brainstem nuclei [93]. Amygdala nuclei are involved in fear behavior expression (generalization, freezing) and traumatic memory formation as well as anxiety and depression symptoms. Also, within the response to stress network, amygdala mediates the response to stress network behavioral changes and the sickness behavior features (anorexia, anxiety, avoidance). In a model of LPS injections, the amygdala microcircuitry has been shown to define anorexic behavior [94]. Within the amygdala, microglia seems to be particularly involved [84], maybe explaining the effi-ciency of corticosteroids in the prevention of PTSD in septic patients [95]. The beneficial effects of corticoids might be explained on gene transcription but also through epigenetics pathways involved in aversive memory formation. 脓毒症后心理障碍，也被称为“脓毒症后综合征”，涉及恐惧和焦虑回路，特别是杏仁核、终纹床核、下丘脑或其他脑干核团。杏仁核参与恐惧行为的表达(泛化、冻结)、创伤性记忆的形成以及焦虑和抑郁症状。此外，在应激反应网络中，杏仁核介导了对应激网络行为变化和疾病行为特征(厌食、焦虑、回避)的反应。在LPS注射的模型中，杏仁核微电路已被证明导致了厌食行为。在杏仁核内，小胶质细胞似乎尤其受累，这可能解释了皮质类固醇在预防脓毒症患者创伤后应激障碍方面的有效性。皮质激素对基因转录的有益影响可能是通过与厌恶记忆形成有关的表观遗传学途径来解释的。 海马、额叶皮质、白质与认知功能减退 Hippocampus, Frontal Cortex, White Matter, and Cognitive Decline Memory formation requires an intact hippocampus and frontal cortex. In septic animals, hippocampal dysfunction has been modeled and excitotoxicity secondary to long-term potentiation, gliosis, neuroinflammation, and increased production of reactive oxygen species (ROS) hypoxemia and ischemia lead to late neuronal death [51]. As these processes might be prolonged after sepsis control, it is not surprising that hippocampal dysfunction can progress toward atrophy [21]. Sepsis alters not only memorization but also other frontal cortexspecific cognitive functions such as attention, verbal fluency, and executive functions [14]. Micromacrovascular and neuroinflammation within the frontal cortex can contribute widely to cognitive impairment. 记忆的形成需要完整的海马体和额叶皮质。在脓毒症动物中，已经建立了海马功能障碍的模型，长时程增强、胶质增生、神经炎症以及活性氧(ROS)低氧血症和缺血增加导致的兴奋性毒性会导致迟发性神经元死亡。由于这些过程在脓毒症控制后可能延长，因此海马功能障碍可能进展为萎缩也就不足为奇了。脓毒症不仅会改变记忆，还会改变其他额叶皮质特有的认知功能，如注意力、语言流畅性和执行功能。额叶皮质内的微血管和神经炎症可广泛导致认知障碍。 Finally, MRI studies in patients with septic shock showed white matter damages as expected according to the pathological findings [11]. This sepsis-induced axonopathy is largely unknown but might be similar to those of critical illness polyneuropathy. It is highly conceivable that it contributes to the long-term cognitive impairment. 最后，根据病理结果，脓毒症休克患者的MRI研究显示脑白质损伤与预期一致。这种脓毒症引起的轴索病在很大程度上是未知的，但可能与重症多发性神经病相似，很有可能它会导致长期认知障碍。 诊 断 Diagnosis 临床特征 Clinical Features SAE is defined by the combination of extracranial infection with clinical signs of neurological dysfunction. SAE clinical manifestation encompasses impairment of awareness, which ranges from delirium (50%) to coma (46%) [6]. Sepsis-related delirium is rather hypoactive than hyperactive. SAE be asso-ciated with focal deficits (18%) [11], seizures (10%) [20, 96], nonepileptic myoclonus, tremor, or asterixis [96]. CAM-ICU and ICSDC can be used for diagnosing delirium and GCS and FOUR for monitoring coma. In deeply sedated patients, the BRASS score can be helpful for detecting brainstem dysfunction [18]. SAE的定义是颅外感染和神经功能障碍的临床体征相结合。SAE的临床表现包括意识障碍，范围从谵妄(50%)到昏迷(46%)。脓毒症相关谵妄是低活动性而非过度活动性。SAE可能与局灶性缺陷(18%)、癫痫(10%)、非癫痫性肌阵挛、震颤或扑翼样震颤有关。CAM-ICU和ICSDC可用于诊断谵妄，GCS和FOUR用于监测昏迷。在深度镇静的患者中，BRASS评分有助于检测脑干功能障碍。 It has to be underlined that sickness behavior is the first manifestation of sepsis, which can be distinguished from hypoactive delirium with the help of an appropriate scale.Second, the ICU physician must look for sepsis in any patient who develops change in mood, behavior, or consciousness. The suspicion of a brain infection must prompt the ICU physician to perform brain imaging and lumbar puncture. Finally, changes in the mental status of a septic patient can be related to other causes besides infection (i.e., electrolyte disturbances, drug overdose or withdrawal, vitamin deficiency, etc.). 必须强调的是，病态行为是脓毒症的首发表现，借助适当的量表可以将其与活动减退型谵妄区分开来。第二，ICU医生必须检查所有脓毒症病人在情绪、行为或意识上产生变化的人。怀疑有脑感染，必须立即通知重症监护室医生进行脑成像和腰椎穿刺。最后,脓毒症患者的精神状态变化可能与感染以外的其他原因(如电解质紊乱、药物过量或停药、维生素缺乏等)有关。 神经生理学特征 Neurophysiological Features There are 2 prospective electrophysiological studies in septic patients applying the ACNS guidelines [20, 96, 97]. A recent systematic review indicates that EEG and evoked potentials are sensitive, but not specific, to SAE [9]. 应用ACNS指南对脓毒症患者进行了2项前瞻性电生理研究。最近的一项系统综述表明，EEG和诱发电位对SAE是敏感的，但不是特异性的。 脑电图 Electroencephalogram The electrophysiological classification developed by Young et al. for the classification of SAE severity takes mainly into account the background activity and includes 4 grades (grade 0, normal EEG; grade 1, predominant theta activity; grade 2, predominant delta activity; grade 3, predominant triphasic waves; and grade 4, suppression) [19]. In a prospective study based on 20-min standard EEG done within the first 3 days after ICU admission, Azabou et al. detected delta and theta predominant rhythms in 33% and 48%, triphasic waves in 6%, and suppression in less than 3% among 110 septic patients [20]. Low voltage and absence of reactivity were seen in 65% and 25% of cases, respectively. The predictors of mortality and occurrence of delirium were absence of EEG reactivity, a delta-predominant background, periodic discharges (PDs), Synek grade ≥ 3, and Young grade > 1 at day 1 to 3 following admission. In a study evaluating continuous EEG in 98 severely septic patients, Gilmore et al. detected nonconvulsive status (NCS), PD, and lack of reactivity in 11%, 25%, and 28% of cases, respectively [96]. Only the lack of reactivity was associated with mortality at 1 year. Young等人为SAE严重程度分类制定的电生理分类主要考虑背景活动，包括4个等级，包括4级(0级，正常脑电图；1级，以θ活动为主；2级，以δ活动为主；3级，以三相波为主；4级，抑制)。在一项基于20分钟标准脑电图的前瞻性研究中，Azabou等人在ICU入院后的前3天内完成了这项研究。在110例脓毒症患者中，分别检测到33%和48%的δ和θ主导节律，6%的三相波，不到3%的抑制率。低电压和无反应性的病例分别占65%和25%。在入院后1～3天，无脑电图反应性、以δ波为主的背景、周期性放电(PD)、Synek分级、≥3级和Young分级>1是预测死亡率和发生谵妄的指标。在一项评估98名严重脓毒症患者持续脑电图的研究中，Gilmore等人研究显示，分别有11%、25%和28%的病例检测到无抽搐状态(NCS)、帕金森病(PD)和反应性缺乏，只有缺乏反应性才与1年后的死亡率有关。 The incidences of pseudoepileptic discharges (PED) and epileptic seizures vary between 19 and 48% and 9 to 50% [98], respectively. The discrepancies between studies in terms of sepsis severity, time, duration and type of EEG recording, and EEG criteria account for these wide ranges. It has to be noted that electrographic seizures are always associated with PED, which are predictive, when generalized and frequent, of subsequent electrographic seizure. Continuous EEG monitoring has evidenced that 75–95% of epileptic events are detected in the first 48 h [10]. 假癫痫放电（PED）发生率在19%和48%之间，而癫痫发作的发生率则在9%到50%之间。脓毒症的严重程度、时间、持续时间和脑电图记录类型以及脑电图标准方面的研究之间的差异解释了这种广泛的范围。必须注意的是，电图癫痫发作总是与PED有关，当全身发作和频繁发作时，PED可预测随后的电性癫痫发作。连续脑电图监测表明，75–95%的癫痫事件在最初48小时内被检测到。 There is no strong correlation between clinical manifestation and EEG findings. Thus, clinical seizures are exceptionally reported in septic patients, indicating that electrographic seizures are mostly nonconvulsive [96]. If electrographic seizures are more frequent in patients with delirium at time of EEG, EEG does not show epileptic activity in most comatose and delirious septic patients. Moreover, EEG can be abnormal even without changes in neurological status [10]. 临床表现与脑电图表现无明显相关性。因此，脓毒症患者的临床癫痫发作是异常的，这表明电图癫痫发作大多是非惊厥性的。如果在脑电图中，谵妄患者的脑电图发作更频繁，那么在大多数昏迷和谵妄的脓毒症患者中，脑电图并不显示癫痫活动。此外，即使在神经状态没有改变的情况下，脑电图也可能是异常的。 These findings suggest that EEG changes are rather markers of severity than pathogenic. Indeed, the prognosis value of EEG patterns has been clearly evidenced. Mortality increased from 0% in the case of normal EEG to 50 to 67% in the case of triphasic waves or suppression. Generalized PED and absence of reactivity are predictive of mortality but also subsequent occurrence of delirium after adjustment to severity of sepsis and sedation [20]. Finally, it has been reported that sepsis slightly increases the risk of long-term epilepsy. There is no evidence for recommending a preventive antiepileptic therapy as well as no clear recommendation on how to treat electrographic seizure in septic patients. However, we think continuous EEG should be used, whenever it is available, in septic patients in order to detect nonconvulsive seizures, especially in case of renal or hepatic insufficiency. All potential epileptogenic factors must be assessed in septic patients, in-cluding antibiotic neurotoxicity, drug overdose or withdrawal, electrolyte disturbances, etc. Finally, we recommend brain imaging in case of electrographic seizure or malignant EEG pattern. 这些发现表明，脑电图的改变更多地是严重程度的标志，而不是致病性的标志。事实上，脑电图模式的预测价值已经被明确证明。死亡率从正常脑电图的0%增加到三相波或抑制的情况下的50%至67%。泛发性PED和缺乏反应性是死亡率的预测指标，但在调整脓毒症和镇静剂的严重程度后，也会随后出现谵妄。最后，据报道，脓毒症略微增加了长期癫痫的风险。没有证据推荐预防性抗癫痫治疗，也没有明确建议如何治疗脓毒症患者的电图癫痫。然而，我们认为在脓毒症患者中，只要有连续脑电图，就应该使用它来检测非惊厥性发作，尤其是在肾或肝功能不全的情况下。脓毒症患者必须评估所有潜在的致痫因素，包括抗生素神经毒性、药物过量或停药、电解质紊乱等。最后，我们建议在脑电图癫痫发作或恶性脑电图模式的情况下进行脑成像。 诱发电位 Evoked Potentials Subcortical (i.e., N20–N23 interlatency) and cortical (N20–N70 interlatency) pathways of somatosensory evoked potential (SSEP) are impaired early in 34% and 84% of 68 septic patients [99]. Evoked potentials are useful for assessing SAE in sedated critically ill patients, as, in contrast to EEG, their latencies are slightly altered by sedatives. Thus, increased P14–N20 SSEP interlatency was associated with mortality in this population [91]. 皮层下通路(即N20-N23潜伏期)和皮层(N20-N70潜伏期)体感诱发电位（SSEP）通路早期受损比例分别有34%和84%。诱发电位对评估镇静危重患者的SAE很有用，因为与脑电图相比，镇静剂可以轻微改变其潜伏期。因此，在该人群中，P14-N20 SSEP潜伏期延长与死亡率相关。 脑成像 Brain Imaging There is retrospective or prospective imaging studies on a homogeneous and large cohort of septic patients. The only prospective MRI study was performed on 72 septic shock patients who developed an acute brain dysfunction defined by focal neurological sign (18%), seizure (10%), coma (46%), and delirium (49%). The MRI was normal in half of cases in this selected cohort. New white matter hyperdensities (suggestive of vasogenic edema) and ischemic stroke were observed in half of the remaining cases [11]. Sepsis can be complicated by posterior reversible encephalopathy syndrome (PRESS) [37]. Because of the risk of transporting septic patients, brain imaging should be indicated upon relevant clinical deterioration, including focal neurological deficit, seizure, and unexplained impaired consciousness. MRI is more specific and sensitive than brain CT scan, which conversely is easier and may complete a body scan. Transcranial Doppler imaging could also predict the occurrence of SAE with good diagnostic performance; however, these results are not found consistent, because of discrepancy in population, severity of sepsis, time of the test, and TCD criteria. 对一群同质的脓毒症患者进行回顾性或前瞻性的影像研究。唯一的前瞻性MRI研究是在72名脓毒症性休克患者身上进行的，他们出现了急性脑功能障碍，表现为局灶性神经体征(18%)、癫痫(10%)、昏迷(46%)和谵妄(49%)。在所选队列中，半数病例的MRI正常。余下的一半病例中观察到新的白质高密度（提示血管源性水肿）和缺血性卒中。脓毒症可并发后部可逆性脑病综合征(PRESS)。由于转运脓毒症患者有风险，脑成像应在相关临床恶化时显示，包括局部神经功能缺损、癫痫发作和不明原因的意识障碍。MRI比头颅CT扫描更具特异性和敏感性，而头颅CT扫描更容易完成全身扫描，经颅多普勒显像也能预测SAE的发生，具有良好的诊断价值。然而，由于人群、脓毒症严重程度、检测时间和TCD标准的差异，这些结果并不一致。 生物标记 Biomarkers Biomarkers might be helpful for detecting and monitoring SAE by targeting different structures involved in the pathophysiological processes. Some markers of systemic inflammation can be associated with the occurrence of SAE, such as C reactive protein or procalcitonin. There are also various markers of brain damage. N-Terminal propeptide of CNP (NT-proCNP), protein S100b, and neuron-specific enolase (NSE) or neurofilament, are respectively biomarkers of endothelial dysfunction, microglial activation, and brain injury with axonal damage [100–102]. They can be measured in the plasma or in the CSF. Although their increase can correlate with the severity of SAE, their sensibility and specificity re-main low, limiting their clinical relevancy. One may argue that their combined assessment might improve their clinical and prognosis value. 生物标志物通过靶向参与病理生理过程的不同结构，可能有助于检测和监测SAE。一些全身炎症标志物可能与SAE的发生有关，如C反应蛋白或降钙素原，以及各种脑损伤的标志。神经肽N-末端前肽(NT-proCNP)、蛋白S100B和神经元特异性烯醇化酶(NSE)或神经丝分别是内皮功能障碍、小胶质细胞活化和脑损伤伴轴突损伤的生物标志物，可以在血浆或脑脊液中测量。尽管其升高可能与SAE的严重程度相关，但它们的敏感性和特异性仍然很低，限制了它们的临床相关性。但也有人提出，这些指标的联合评估可能会改善他们的临床和预后价值。 管 理 Management The treatment of SAE is based both on the management of sepsis and on the correction of potential neurotoxic factors and management of seizure, delirium, and coma. There is no specific treatment of SAE. Recent randomized clinical trials have not evidenced any benefit of statins and dexmedetomidine for preventing delirium in septic patients [103, 104], despite their respective anti-neuroinflammatory and noradrenergic/antiapoptotic properties. If rivastigmine was theoretically interest-ing because of its potential microglial effect, it has been shown to increase mortality without reducing delirium in ICU patients, including septic ones. The SAILS and HARP2 trials failed to further demonstrate such effects in an interventional trial [103, 105]. SAE的治疗既基于脓毒症的处理，也基于潜在的神经毒性因素的纠正，以及癫痫、谵妄和昏迷的处理。目前尚无治疗SAE的特效药。虽然他汀类药物和右旋美托咪啶各自具有抗神经炎和去甲肾上腺素能/抗细胞凋亡的特性，但最近的随机临床试验没有证据表明这对预防脓毒症患者的谵妄有任何益处。如果说利瓦斯汀因其潜在的小胶质细胞效应而在理论上是有用的，它已经被证明可以增加ICU患者（包括败血脓毒症患者）死亡率，而不会减少谵妄。SAILS和HARP2试验在一项干预试验中未能进一步证明这种效应。 There is no specific recommendation on pharmacological management of sepsis-associated delirium and seizure. It has to be reminded that fever can be due to neuroleptic malignant syndrome and choice of the anti-epileptic drug depends on renal and liver organ failure. To date, no specific sedative agent is particularly recommended, except that sedation has to be avoided or discontinued whenever possible [106]. The effect of sevoflurane on mortality and inflammatory parameters is currently assessed (NCT03643367). Ketamine is potentially neuroprotective in SAE but has not yet been tested in interventional trials. Enhanced sensitivity towards benzodiazepines is present in systemic inflammatory processes. Dexmedetomidine, an alpha agonist agent, has been shown to increase delirium-free days and reduce 28-day mortality rate in septic shock [104]. However, a recent large study showed that early goal-directed sedation based on dexmedetomidine did not show any benefit in critically ill patients [75]. 目前尚无关于脓毒症相关谵妄和癫痫的药理学管理的具体建议。需要提醒的是，发热可能是由于抗精神病药物恶性综合征，抗癫痫药物的选择取决于肾、肝器官衰竭。迄今为止，除了尽可能避免或停止镇静外，没有特别推荐使用特定的镇静剂。目前正在评估七氟醚对死亡率和炎症参数的影响(NCT03643367)。氯胺酮在SAE中具有潜在的神经保护作用，但尚未在介入性试验中进行测试。对苯二氮卓类药物的敏感性增强存在于全身炎症过程中。右美托咪定是一种α激动剂，已被证明可以增加脓毒性休克患者的无谵妄天数并降低28天死亡率。然而，最近的一项大型研究表明，基于右美托咪定的早期目标定向镇静对危重病人没有任何益处。 While SAE could result from a mismatch between energy demand and cerebral blood flow, a personalized target of mean arterial pressure defined upon Doppler criteria could be evaluated in further work. However, such an approach has never been evaluated. 虽然SAE可能是能量需求和脑血流之间的不匹配造成的，但根据多普勒标准定义的平均动脉压个性化目标可以在进一步的工作中进行评估。然而，这种方法从未被评估过。 The nonpharmacological interventions recommended for preventing or treating delirium should be applied in septic patients, including early mobilization [107], discontinuation of sedation [106], rehydration, management of physical and psychological discomfort [108], and avoidance of prodelirious drugs. 对于脓毒症患者，应采用预防或治疗谵妄的非药物干预措施，包括早期活动，停用镇静，补液，处理身体和心理不适，避免使用致痫药物。 结 论 Conclusion SAE is a major complication of sepsis. It is characterized by changes in neurological status, ranging from sickness behavior to delirium to coma. It is associated with changes in EEG background activity and less frequently with electrographic seizures. It has a major impact on outcome, as it increases mortality and causes long-term psychocognitive disorders. Neuroinflammation, ischemia, and excitoxicity are its main pathophy-siological mechanisms. Brainstem dysfunction might account for increased mortality while amygdala and hippocampus/frontal cortex dysfunction for psy-chological and cognitive disorders. There is no specific treatment for SAE, which depends on management of sepsis, delirium, seizure, and coma. SAE是脓毒症的主要并发症，它的特点是神经状态的改变，从疾病行为到谵妄再到昏迷。它与脑电图背景活动的变化有关，而与脑电图癫痫发作的关系较弱。SAE对疾病结局有重大影响，增加了死亡率，并导致长期的心理认知障碍。神经炎症、缺血和兴奋性是其主要病理生理机制。脑干功能障碍可能是死亡率增加的原因，而杏仁核和海马/额叶皮质功能障碍是心理和认知障碍的原因。SAE没有特效的治疗方法，主要包括对脓毒症、谵妄、癫痫发作和昏迷的处理。 END 翻 译 李文玉 医学硕士 山东第一医科大学  在线速递 翻译：李文玉 编辑：宋 璇 审校：王春亭 |
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来自： limingxin1969 > 《CRRT》
