Novel Extracorporeal Therapy for the Reversal of Septic Shock and Restoring Hemodynamic Stability

逆转感染性休克并恢复血流动力学稳定性的新型体外疗法

• 批准号: 10374283
• 负责人: Phillip Chan
• 金额: $ 28.18万
• 依托单位: CYTOSORBENTS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374283
• 关键词: Activated Partial Thromboplastin Time measurement; Acute Respiratory Distress Syndrome; Address; Adoption; Albumins; Antibiotics; Attenuated; Blood; Blood Chemical Analysis; Blood Circulation; Blood Coagulation Disorders; Blood Coagulation Factor; Blood specimen; Caring; Cessation of life; Clinical; Clinical Research; Closure by clamp; Coagulation Process; Combined Modality Therapy; Communities; Complement; Complete Blood Count; Development; Devices; Electrolytes; Endotoxemia; Endotoxins; Etiology; Evaluation; Excision; Family suidae; Functional disorder; Future; Gram-Negative Bacteria; Greater sac of peritoneum; Health Priorities; Hour; Hypoalbuminemia; IV Fluid; Immune response; In Vitro; Inflammation Mediators; Inflammatory; Inflammatory Response; Lead; Life; Literature; Mediator of activation protein; Medical; Medical Device; Modality; Modeling; Molecular; Multiple Organ Failure; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Patients; Performance; Phase; Physiological; Plasma; Pre-Clinical Model; Procedures; Public Health; Reporting; Research; Research Design; Risk; Role; Sepsis; Septic Shock; Severity of illness; Source; Superior mesenteric artery structure; System; Testing; Time; Translations; Treatment Efficacy; Vasoconstrictor Agents; World Health Organization; chemokine; clinically relevant; commercial application; complement C2a; cytokine; cytokine release syndrome; dosage; effective therapy; global health; hemodynamics; implantation; improved; in vivo; innovation; mortality; novel; novel therapeutics; porcine model; pre-clinical; preclinical study; product development; respiratory; response; sepsis induced ARDS; septic; technological innovation

Rationale: Sepsis has been classified by the World Health Organization as a “global health priority.” It has been estimated that ~50% of patients with sepsis due to Gram-negative bacteria will develop septic shock and of these, half may die. There are currently no treatment options for attenuating the elevated inflammatory response and hemodynamic instability that is present in these patients. Therapy is mainly supportive and limited to a combination of vasopressors, intravenous fluid, and antibiotics. The role of bacterial endotoxin in modulating the level of host-derived inflammatory mediators, including cytokines, chemokines, and complement factors, and their contribution to septic shock is widely reported in literature. When in excess, these mediators can induce organ dysfunction, multiorgan failure, and even death. Innovation: Use CytoSorb, a CE Mark approved extracorporeal cytokine filter, together with a novel endotoxin adsorber, LPSorb, to reduce both the trigger and causative agents of cytokine storm and hemodynamic instability in septic shock. Hypothesis: CytoSorb combined with LPSorb attenuates excessive levels of inflammatory mediators and reduces levels of endotoxin in septic plasma. Specific Aims: 1) Characterize the endotoxin and inflammatory cytokine expression profile in plasma from septic pigs during the development of septic shock and acute respiratory distress. 2a-c) Evaluate cytokine and endotoxin removal ability and the impact on plasma pH, electrolytes, intrinsic and extrinsic coagulation pathways and albumin levels of CytoSorb therapy, LPSorb therapy, and CytoSorb+LPSorb in plasma from septic pigs in a benchtop recirculation system. Study Design: The focus of Aim 1 is to characterize changes in levels of key sepsis-associated inflammatory cytokines and bacterial endotoxin in circulation during the onset of septic shock in this highly clinically relevant swine sepsis model in order to draw correlations between the inflammatory status and loss of hemodynamic stability leading up to multiple organ failure and death. Pigs (35kg) will be subjected to a ‘2-hit’ surgical procedure involving fecal clot implantation in the peritoneal cavity, followed by transient clamping of the superior mesenteric artery to induce septic shock and acute respiratory distress syndrome (ARDS). Blood samples will be taken before the procedure and every 6 hours after until the terminal bleed at 36 hours. Metrics will include vitals (BT, BP, HR, RR), complete blood counts, blood chemistries, and cytokine and endotoxin concentrations. In Aim 2a-c, CytoSorb, LPSorb, and CytoSorb+LPSorb devices will be evaluated in a scaled-down benchtop recirculation system for cytokine and endotoxin removal capacity and any potential impact the therapy may have on plasma coagulation and albumin content in septic pig plasma taken 36 hours after the ‘2-hit’ procedure. Metrics will include cytokine and endotoxin concentrations, PT, aPTT, uPTT, and albumin level. Impact and Translation: If successful, this study will confirm the feasibility of implementing CytoSorb + LPSorb as a definitive treatment for septic shock and hemodynamic instability. Pending positive outcomes in future preclinical and clinical studies, this innovative sepsis treatment will provide a highly effective means of controlling life-threatening hyperinflammation during the early stages of septic shock, with the potential to dramatically improve survival.

理由：败血症已被世界卫生组织归类为“全球健康优先事项”。它一直 据估计，由于革兰氏阴性细菌引起的败血症患者中约有50％会产生败血性休克，其中一半 可能会死。目前尚无治疗方案来减轻炎症反应升高和血流动力学 这些患者出现的不稳定。治疗主要受支持，并仅限于升压器的组合， 静脉液和抗生素。细菌内毒素在调节宿主炎症水平的作用 介质，包括细胞因子，趋化因子和补体因子及其对败血性休克的贡献广泛 在文献中报道。当过量时，这些介体可以诱导器官功能障碍，多器官失败甚至死亡。 创新：使用CYTOSORB，CE标记批准的体外细胞因子过滤器，以及一种新型的内毒素吸附剂， LPSORB，减少败血性休克中细胞因子风暴和血液动力学不稳定的触发因素和严重的药物。 假设：Cytosorb结合LPSORB减轻过量炎症介质的水平，并降低了水平 败血症血浆中内毒素的毒素。 具体目的：1）表征化粪池中血浆中血浆中内毒素和炎性细胞因子表达谱 在败血性休克和急性呼吸窘迫的过程中。 2A-C）评估细胞因子和内毒素去除 能力以及对等离子体pH，电解质，内在和外部凝血途径以及专辑水平的影响 在台式再循环系统中，来自化粪池的血浆中的血浆中的Cytosorb疗法，LPSORB疗法和细胞质+LPSORB。 研究设计：目标1的重点是表征关键败血症相关炎症细胞因子的变化 在这种高度临床相关的猪败血症模型中，在败血性休克发作期间循环中的自由基内毒素 为了提取炎症状态和血液动力学稳定性丧失之间的相关性，导致多个 器官故障和死亡。猪（35公斤）将进行涉及粪便凝块植入的“ 2击”手术程序 腹膜腔，然后是上肠系膜动脉的瞬时夹紧，以诱导败血性休克和急性 呼吸窘迫综合征（ARDS）。血液样本将在手术之前，每6小时之前采集 终端在36小时内流血。指标将包括生命值（BT，BP，HR，RR），完整的血液计数，血液化学和 细胞因子和内毒素浓度。将评估AIM 2A-C，CYTOSORB，LPSORB和CYTOSORB+LPSORB设备 在缩小的台式台式再循环系统中，用于细胞因子和内毒素去除能力，任何潜在影响 化粪池血浆中的血浆凝结和白蛋白含量可能需要进行治疗，该疗法在“ 2点命中”之后花费了36小时 程序。指标将包括细胞因子和内毒素浓度，PT，APTT，UPTT和白蛋白水平。 影响和翻译：如果成功，这项研究将确认实施Cytosorb + lpsorb的可行性 败血性休克和血液动力学不稳定性的确切治疗。等待未来的临床前的积极成果和 临床研究，这种创新的败血症治疗将提供一种高效控制威胁生命的方法 在败血性休克的早期阶段过度炎症，有可能显着提高生存率。