脓毒症诊断的生物学标志物的研究进展

脓毒症是由致病微生物感染引发的全身炎症反应综合征(SIRS),合并血压降低且经快速液体复苏后血压仍不能恢复正常者称为脓毒性休克(Septic shock),其中一部分患者发展为多器官功能障碍综合症(MODS)。由于目前临床上仍缺乏早期敏感性诊断手段,脓毒症病死率居高不下。每10万人口中约50-300人会发生严重脓毒症,其短期死亡率达20%-25%,当发展为脓毒性休克时其死亡率达50%。随着分子生物学和现代生物技术的不断发展,人们发现多种生物标志物在脓毒症的早期诊断、病情及预后判断,疗效评估中发挥重要作用。因此深入了解脓毒症病理生理机制中不同生物标志物的意义及价值,对于脓毒症及其并发症的早期识别及干预,降低患者病死率及改善患者生活质量有积极意义。本文综述了近几年来对脓毒症的诊断和预后有一定价值的主要标志物及其应用。     

脓毒性心肌功能障碍

脓毒症是由感染引起的全身炎症反应综合征,证实有感染灶存在或有高度可疑的感染灶。脓毒症是ICU内重症患者的主要死亡原因,且发病率随着年龄的增长而逐渐增加。近十年来,虽然政府在救治脓毒症患者中投入了巨大的资金和技术支持,但源于脓毒症或脓毒性休克患者的病死率仍高达30%~60%。心血管系统在脓毒症与脓毒性休克的病理生理学中扮演着重要着色。过去的四五十年,开展了很多脓毒性心肌功能障碍方面的研究,也积累了不少循证医学证据。然而,心脏只是心血管系统的一部分。诸如脓毒症患者机体血流动力学的变化系脓毒症对心脏的直接效应,还是脓毒症引起心脏前、后负荷及神经体液因素的变化,继而引起心脏继发改变的研究,至今仍在继续。本文概述了近年来脓毒性心肌功能障碍的研究进展,使读者更全面地了解脓毒性心肌功能障碍的病理生理学改变,合理有效地指导脓毒症和脓毒性休克患者的临床救治。     

抗内毒素治疗的新策略

脂多糖(Lipopolysaccharide,LPS)是G-菌造成的败血症或脓毒性休克病理中最重要的致病因素,若在整个病理过程的上游,即在细菌内毒素水平阻断脓毒性休克的发生,就可能限制或阻止病理性的次级炎症级联反应。本文综述了各种不同来源的LPS结合蛋白在结合LPS从而中和并阻断内毒素的过程中的功效及应用现状,探讨了最终用于人类败血症或脓毒性休克临床治疗的有效方案。     

microRNA-129-5p在脓毒症患者血清中的表达及对肺内皮细胞的影响

该研究旨在探讨miR-129-5p(microRNA-129-5p)在脓毒症患者血清中的表达及对肺内皮细胞的影响。收集临床脓毒症患者的血液样本,通过荧光实时定量PCR(RT-qPCR)检测miR-129-5p的水平并分析其表达水平与患者临床特征的关系。在肺微血管内皮细胞(HPMEC)中过表达miR-129-5p后,用Transwell和ELISA实验检测其对细胞迁移以及炎症因子释放的影响。RT-qPCR结果显示,与对照组相比,脓毒症组miR-129-5p的表达水平降低(P0.05);与脓毒症组相比,脓毒性休克组miR-129-5p的表达水平更低(P0.05)。miR-129-5p的表达与氧合指数呈正相关,与降钙素原、IL-1β、IL-6、TNF-α水平呈负相关(P0.001),且脓毒性休克组的28天死亡率较脓毒症组高(P0.05)。过表达miR-129-5p可以明显促进细胞的迁移,减少炎症因子IL-1β、IL-6、TNF-α的释放。综上所述,miR-129-5p在脓毒症模型中低表达,病情越重其水平越低,且与氧合指数、降钙素原水平相关。过表达miR-129-5p可以明显促进细胞的迁移并减少炎症因子的释放。     

限制性补液复合去甲肾上腺素对脓毒性休克患者血流动力学及氧代谢的影响

目的:探讨限制性补液复合去甲肾上腺素对脓毒性休克患者血流动力学及氧代谢的影响。方法:将62例脓毒性休克患者按照液体复苏策略随机分为限制性液体复苏(治疗组)和常规液体复苏(对照组),每组各31例。观察和比较复苏前后血流动力学指标、氧代谢指标的变化,记录两组低血压、弥散性血管内凝血(DIC)、多器官功能障碍综合征(MODS)、急性呼吸窘迫综合症(ARDS)的发生率及2周病死率。结果:治疗后1 h、3 h、6 h,两组患者CVP、MAP明显升高,HR明显下降(P0.05);治疗后3 h、6 h,治疗组MAP明显低于对照组(P0.05),而两组HR、CVP比较差异均无统计学意义(P0.05)。治疗后1 h、3 h、6 h,两组患者PaCO_2、PaO_2、SaO_2、PaO_2/Fi O_2均不同程度改善,治疗组治疗后3 h、6 h PaO_2、PaO_2/Fi O_2明显高于对照组(P0.05)。治疗后3 d,治疗组MODS的发生率较对照组显著降低(P0.05),而两组低血压、ARDS、DIC及2周病死率均无显著性差异(P0.05)。结论:限制性液体复合小剂量去甲肾上腺素对脓毒性休克患者有助于维持血流动力学稳定,改善全身氧代谢,减少并发症的发生,改善预后。     

老年脓毒症和脓毒性休克患者30天死亡率的危险因素分析

目的:探讨就诊于急诊室诊断为脓毒症或者脓毒性休克的患者30天内死亡率与在急诊室初次获得的参数的关系,并探讨死亡率的危险因素。方法:选取2014年6月到2017年6月就诊于我院急诊室且诊断为脓毒血症或者脓毒性休克并有完整随访资料大于65岁的老年患者145例,将30天内存活的患者分为A组,将30天内死亡的患者分为B组,比较两组之间检验指标及生命体征的差异。根据脓毒症序贯器官衰竭评估快速评分(qSOFA)将qSOFA2分的定义为a组,qSOFA≥2分的定义为b组,比较两组的死亡率。并采用二项Logistic回归分析探讨30天死亡率的独立危险因素。结果:145例患者中,44.8%(n=65)的患者在30天内死亡,33.1%(n=48)的患者需要无创或者侵入性机械通气。A组与B组之间舒张压(P=0.003)、收缩压(P=0.002)、格拉斯哥昏迷量表评分(GCS)(P0.001)、血尿素氮(P0.001)及qSOFA(P0.001)比较均具有统计学差异。a组死亡率(35.7%)显著低于b组(53.3%)(P=0.033)。qSOFA是30天内死亡率的独立危险因素(OR=2.871,P=0.004)。结论:qSOFA是老年脓毒症及脓毒性休克患者30天内死亡的的独立危险因素。     

防御素与脓毒症

脓毒症（sepsis,又名全身性感染）是机体感染后所致的全身炎症反应综合征（systemic inflammatory response syndrome,SIRS）,是创（烧）伤、感染、休克及外科大手术后的常见并发症。重症脓毒症（severe sepsis）、脓毒性休克（septic shock）和多器官功能障碍综合征（multiple organ dysfunction syndrome,     

血清LXA4联合MMP-9预测脓毒症患者发生多器官功能障碍综合征的临床研究

摘要 目的：探讨血清脂氧素A4（LXA4）联合基质金属蛋白酶-9（MMP-9）对脓毒症患者发生多器官功能障碍综合征（MODS）的预测价值。方法：选择2020年1月-2023年1月期间中国人民解放军空军军医大学第二附属医院接受治疗的140例脓毒症患者作为研究对象。根据患者入院28 d内是否发生MODS将其分为MODS组（n=41）和非MODS组（n=99）。检测并对比两组血清LXA4、MMP-9水平。采用单因素及多因素Logistic回归模型分析脓毒症患者发生MODS的影响因素。采用受试者工作特征（ROC）曲线分析血清LXA4、MMP-9对脓毒症患者发生MODS的预测价值。结果：本次纳入的140例脓毒症患者，入院28 d内共有41例发生MODS，发生率为29.29%（41/140）。MODS组血清LXA4水平低于非MODS组，MMP-9水平高于非MODS组（P<0.05）。单因素分析结果显示：脓毒症患者发生MODS与合并高血压、脓毒症病程、存在休克、年龄、合并糖尿病、存在细菌感染、APACHE II评分、疾病严重程度、SOFA评分、存在低血钙、PCT有关（P<0.05）。多因素Logistic回归分析结果显示：年龄偏大、MMP-9偏高、脓毒症病程偏长、LXA4偏低、APACHE II评分偏高、PCT偏高、SOFA评分偏高、存在休克、合并糖尿病、存在低血钙、合并高血压、疾病严重程度为危重、存在细菌感染均是脓毒症患者发生MODS的危险因素（P<0.05）。血清LXA4、MMP-9单独及联合检测预测脓毒症患者发生MODS的曲线下面积（AUC）分别为0.815、0.821和0.898，联合检测的效能优于单独检测。结论：脓毒症并发MODS患者血清LXA4下降，MMP-9升高，二者联合检测对脓毒症并发MODS中具有较好的预测价值。年龄、休克、脓毒症病程、低血钙、APACHE II评分、疾病严重程度、SOFA评分、细菌感染、合并糖尿病、PCT、LXA4、MMP-9、合并高血压均是脓毒症患者发生MODS的影响因素。     

血必净注射液联合持续血液净化治疗重症脓毒症的效果及对血清IL-6、TNF-alpha的影响

目的：研究血必净注射液联合持续血液净化治疗重症脓毒症的效果及对血清白介素-6（IL-6）、肿瘤坏死因子-alpha（TNF-alpha）的 影响。方法：将2012 年1 月至2013 年12 月我院收治124 例重症脓毒症患者随机分为治疗组和对照组,每组62 例。对照组给予 常规抗感染、对症支持、脏器保护治疗,治疗组在此基础上加用血必净注射液联合持续血液净化治疗。于治疗前及治疗第7 天记 录并比较两组患者多器官功能障碍（MODS）发生率、脓毒症休克率、死亡率、好转率、氧合指数（动脉血氧分压（PaO2）/ 吸入氧浓度 （FiO2））、血清IL-6、TNF-alpha水平以及急性生理和慢性健康评分Ⅱ（APACHE Ⅱ）。结果：经7 天治疗后,两组MODS 发生率、IL-6、 TNF-alpha水平以及APACHE Ⅱ评分较治疗前均显著降低,PaO2 /FiO2水平较治疗前显著提高（均P＜0.05）;治疗组脓毒症休克率较 治疗前显著降低（P＜0.05）;治疗组MODS 发生率、脓毒症休克率、死亡率、IL-6、TNF-琢水平以及APACHE Ⅱ评分均显著低于对 照组,好转率以及PaO2 /FiO2水平显著高于对照组（均P＜0.05）。结论：血必净注射液联合持续血液净化治疗重症脓毒症能维护多 器官功能、降低MODS及脓毒症休克发生率,提高动脉血气氧合指数等疗效。     

脓毒性休克的诊疗进展

<正>脓毒症是由于感染引起的全身性炎症反应综合征,为大手术术后、严重创伤或感染后常见并发症。脓毒症的发病机制复杂,病理过程涉及炎症、组织损害、凝血功能、免疫等一系列问题~([1]),且与机体多系统、多器官病理生理性改变相关~([2]),常见致病菌为革兰阴性细菌~([3])。脓毒性休克是重症监护室常见危重症,是脓毒症引起的循环功能障碍表现,具有发病急、进展快,且常累及多个脏器,严重威胁患者生命健康,降低患者的生活质量~([4])。近年来,器官功能支持技术及     

乌司他丁联合阿托莫兰对感染性休克患者血清IL-6, TNF-alpha和PCT 水平 的影响

目的：探究乌司他丁联合阿托莫兰对感染性休克患者血清白细胞介素-6(IL-6)、肿瘤坏死因子-alpha(TNF-alpha)和降钙素原（PCT） 水平的影响。方法：选择2013 年6 月～2015年12 月期间我院收治感染性休克患者79 例为研究对象;采用随机数字法将其分为 观察组（39 例）和对照组（40 例）,观察组患者给予乌司他丁联合阿托莫兰治疗,对照组给予常规抗感染治疗;观察并比较两组患 者治疗前后IL-6、TNF-alpha和PCT 水平,比较两组患者药物不良反应、多器官功能障碍综合征(MODS)发生率及病死率。结果：治疗 前两组患者间IL-6、TNF-alpha及PCT 水平均无差异（P<0.05）;治疗后两组患者IL-6、TNF-alpha及PCT 均显著下降,且观察组IL-6、 TNF-alpha及PCT 水平低于对照组（P<0.05）;治疗过程中两组患者药物不良反应发生率无差异（P>0.05）;治疗后观察组MODS 及死 亡发生率均低于对照组（P<0.05）。结论：乌司他丁联合阿托莫兰能够改善对感染性休克患者炎症反应,降低机体IL-6、TNF-alpha及 PCT 水平,降低MODS 发生率及病死率,在临床治疗感染性休克具有重要价值。     

Reduction in circulating level of HMGB-1 following continuous renal replacement therapy in sepsis

Early recovery from shock improves prognosis in patients with severe sepsis and septic shock. During this period, cytokine imbalances mediate the development of organ damage and mortality. In Japan, we have access to hemoperfusion using an immobilized polymyxin B fiber column for endotoxin removal (PMX-DHP) and continuous hemodiafiltration (CHDF) as artificial support for patients with septic shock, with the aim of improving hemodynamics and organ dysfunction caused by elevated inflammatory cytokines and mediators. In this Short communication, we discuss recent findings showing anti-inflammatory treatment following these continuous renal replacement therapies in sepsis.     

The therapeutic value of protein (de)nitrosylation in experimental septic shock

Cardiovascular dysfunction and organ damage are hallmarks of sepsis and septic shock. Protein S-nitrosylation by nitric oxide has been described as an important modifier of protein function. We studied whether protein nitrosylation/denitrosylation would impact positively in hemodynamic parameters of septic rats. Polymicrobial sepsis was induced by cecal ligation and puncture. Female Wistar rats were treated with increasing doses of DTNB [5,5′-dithio-bis-(2-nitrobenzoic acid)] 30 min before or 4 or 12 h after sepsis induction. Twenty-four hours after surgery the following data was obtained: aorta response to phenylephrine, mean arterial pressure, vascular reactivity to phenylephrine, biochemical markers of organ damage, survival and aorta protein nitrosylation profile. Sepsis substantially decreases blood pressure and the response of aorta rings and of blood pressure to phenylephrine, as well as increased plasma levels of organ damage markers, mortality of 60% and S-nitrosylation of aorta proteins increased during sepsis. Treatment with DTNB 12 h after septic shock induction reversed the loss of response of aorta rings and blood pressure to vasoconstrictors, reduced organ damage and protein nitrosylation and increased survival to 80%. Increases in protein S-nitrosylation are related to cardiovascular dysfunction and multiple organ injury during sepsis. Treatment of rats with DTNB reduced the excessive protein S-nitrosylation, including that in calcium-dependent potassium channels (BK_Ca), reversed the cardiovascular dysfunction, improved markers of organ dysfunction and glycemic profile and substantially reduced mortality. Since all these beneficial consequences were attained even if DTNB was administered after septic shock onset, protein (de)nitrosylation may be a suitable target for sepsis treatment.     

Multiple organ dysfunction syndrome.

The multiple organ dysfunction syndrome (MODS), though newly described, has manifested itself in intensive care unit (ICU) patients for several decades. As the name implies, it is a syndrome in which more than one organ system fails. Failure of these multiple organ systems may or may not be related to the initial injury or disease process for which the patient was admitted to the ICU. MODS is the leading cause of morbidity and mortality in current ICU practice. While the pathophysiology of MODS is not completely known, much evidence indicates that, during the initial injury which precipitates ICU admission, a chain of events is initiated which results in activation of several endogenous metabolic pathways. These pathways release compounds which, in and of themselves, are usually cytoprotective. However, an over exuberant activation of these endogenous systems results in an inflammatory response which can lead to development of failure in distant organs. As these organs fail, they activate and propagate the systemic inflammatory response. No therapy has proven entirely efficacious at modulating this inflammatory response and the incidence and severity of MODS. In current ICU practice, treatment is focused on prevention and treating individual organ dysfunction as it develops. With increased understanding of the pathophysiology of MODS therapy will come newer modalities which inhibit or interfere with the propagation of the endogenous systemic inflammatory response. These newer therapies hold great promise and already some are undergoing clinical investigation.     

Maternal exercise training attenuates endotoxin-induced sepsis in mice offspring

Regular exercise during pregnancy can prevent offspring from several diseases, such as cardiovascular diseases, obesity, and type II diabetes during adulthood. However, little information is available about whether maternal exercises during pregnancy protect the offspring from infectious diseases, such as sepsis and multiple organ dysfunction syndrome (MODS). This study aimed to investigate whether maternal exercise training protects the offspring from endotoxin-induced septic shock in mice. Female C57BL/6 mice performed voluntary wheel exercises during pregnancy. All dams and offspring were fed normal chow with sedentary activity during lactation and after weaning. At 10-week-old, mice were intraperitoneally injected a lethal (30 mg/kg) or nonlethal (15 mg/kg) dose of lipopolysaccharide (LPS), following which the survival of mice that were administered a lethal dose was monitored for 60 h. Plasma, lung, and liver samples were collected 18 h after the injection to evaluate the cytokine concentration or mRNA expression from those administered a nonlethal dose. Although maternal exercise training could not prevent lethality during an LPS-induced septic shock, it significantly inhibited the LPS-induced loss of body weight in female offspring. Regular maternal exercise significantly inhibited the mRNA expression of the LPS-induced inflammatory cytokines, such as interleukin-1β (IL-1β) and interferon-γ (IFN-γ), in the plasma and liver. Thus, maternal exercise inhibited the LPS-induced inflammatory response in female offspring, suggesting that regular exercise during pregnancy could be a potential candidate of the onset of sepsis and MODS in offspring.     

An overview of cytokines and heat shock response in polytraumatized patients

Early after injury, local tissue damage induces a local and systemic inflammatory response that activates the immune system and leads to the development of systemic inflammatory response syndrome (SIRS). This post-traumatic response often results in uncontrolled release of inflammatory mediators and over-activation of the immune system, which occasionally results in multiple organ dysfunction syndrome (MODS). In parallel, a state of immunosuppression develops. This counter-regulating suppression of different cellular and humoral immune functions has been termed “compensatory anti-inflammatory response syndrome (CARS).” Both SIRS and CARS occur simultaneously even in the initial phase after injury. Pro- and anti-inflammatory cytokines have been suggested to play a major role in development of SIRS, although the degree of involvement of the different cytokines is quite disparate. While TNF-α and IL-1β are quite irrelevant for predicting organ dysfunction, IL-6 is the parameter that best predicts mortality. The hyperinflammatory state seems to be the cause of post-traumatic immunosuppression and heat shock proteins (HSPs), which have been proposed as one of the endogenous stimuli for the deterioration of the immune system acting as danger-associated molecular patterns (DAMPs). Extracellular HSPA1A released from injured tissues increase up to ten times immediately after trauma and even more in patients with MODS. It has powerful immune properties that could contribute to post-traumatic immunosuppression through several mechanisms that have been previously described, so HSPs could represent trauma-associated immunomodulatory mediators. For this reason, HSPA1A has been suggested to be a helpful early prognostic biomarker of trauma after severe injury: serial quantification of serum HSPA1A and anti-Hsp70 concentrations in the first hours after trauma is proposed to be used as a predictive biomarker of MODS and immunosuppression development in polytraumatized patients.