Development of a Mechanically Ventilated and Sedated Model of Canine Septic Shoc

犬败血性休克机械通气和镇静模型的开发

• 批准号: 7593075
• 负责人: Charles Natanson
• 金额: $ 15.99万
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593075
• 关键词: Algorithms; American; Analgesics; Animal Model; Animals; Antibiotics; Bacterial Infections; Biological Assay; Blood; Canis familiaris; Cardiopulmonary; Case Study; Critical Care; Development; Dose; End Point; Ensure; Event; Gene Proteins; Genes; Goals; Heart; Hospitals; Human; Incidence; Journals; Manuscripts; Measures; Mechanical ventilation; Mechanics; Modeling; Oligonucleotide Microarrays; Patients; Pattern; Peripheral Blood Mononuclear Cell; Physiological; Physiology; Plasma; Proteomics; Protocols documentation; Purpose; Rate; Research; Sedation procedure; Sepsis; Septic Shock; Severities; Severity of illness; Survivors; Time; Treatment Protocols; Unconscious State; design; hemodynamics; model development; mortality; novel therapeutics; protein expression; septic

Despite the use of effective antibiotics in combination with intense cardiopulmonary support, the mortality rate from sepsis and septic shock for the last three decades has remained high (29%). During this time, the incidence of reported cases of sepsis in hospitals has more than doubled. Understanding the pathogenic mechanisms and developing new therapeutic approaches to the treatment of sepsis is necessary. One component of the research to achieve this goal is the development of animal models that accurately reproduce events encountered clinically. The primary purpose of this protocol is to develop a 96 h model of canine septic shock. This model will incorporate the conventional hemodynamic and mechanical ventilatory support utilized in human patients with septic shock including continuous sedation and analgesic treatment. This model is designed to ensure that animals will be treated similar to human septic patients that require mechanical ventilation and therefore be maintained in a semiconscious to unconscious state. This will be from the time that sepsis is initiated until the time of sacrifice. Although survival will be a primary endpoint in these studies, physiologic endpoints will provide other important measures. To obtain maximal use of these animals, blood that would be otherwise discarded will be used to perform oligonucleotide microarrays from peripheral blood mononuclear cells and proteomics from plasma. The purpose of these assays is to identify patterns of gene or protein expression which correlate with the severity of illness during sepsis and can differentiate between survivors and non-survivors. The characterization of gene and protein expression during sepsis has been a major focus of our critical care sepsis research group over the last ten years. During the development of this model performed in 33 animals. A standardized treatment regimen and algorithms were define. We found that increasing severity of intrabronchial bacterial infections correlated with an increase in mortality. Proteomic analysis also shown a dose and time dependent correlation between protein expression and survival. A manuscript describing survival, physiologic endpoints and blood analysis results in this sedated and ventilated model of sepsis was recently accepted to the American Journal of Physiology - Heart and Circulatory Physiology.

尽管使用了有效的抗生素和强有力的心肺支持，但在过去的三十年里，败血症和感染性休克的死亡率仍然很高(29%)。在此期间，医院报告的败血症病例增加了一倍多。了解脓毒症的发病机制和开发新的治疗方法是必要的。为了实现这一目标，研究的一个组成部分是开发准确复制临床遇到的事件的动物模型。该方案的主要目的是建立一种96h犬感染性休克模型。这一模式将结合人类感染性休克患者使用的传统血流动力学和机械呼吸支持，包括持续镇静和止痛治疗。该模型旨在确保动物将得到类似于人类败血症患者的治疗，这些患者需要机械通风，因此保持在半昏迷到昏迷状态。这将是从败血症开始到牺牲的时间。虽然存活率将是这些研究的主要终点，但生理学终点将提供其他重要的衡量标准。为了最大限度地利用这些动物，原本会被丢弃的血液将被用来从外周血单核细胞中进行寡核苷酸微阵列，并从血浆中进行蛋白质组学。这些检测的目的是确定在脓毒症期间与疾病严重程度相关的基因或蛋白表达模式，并可以区分幸存者和非幸存者。在过去的十年里，脓毒症期间基因和蛋白表达的特征一直是我们重症监护脓毒症研究小组的主要关注焦点。 在这个模型的发展过程中，对33只动物进行了实验。定义了标准化的治疗方案和算法。我们发现，支气管内细菌感染的严重程度与死亡率的增加有关。蛋白质组学分析还表明，蛋白质表达与存活之间存在剂量和时间依赖关系。最近，美国生理学-心脏和循环生理学杂志接受了一篇手稿，描述了在这种镇静和通风的脓毒症模型中的生存、生理终点和血液分析结果。