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列为“全球健康优先事项”。一直以来 据估计，大约50%的由革兰氏阴性菌引起的败血症患者会发展为败血症休克，其中一半 可能会死。目前还没有减轻炎症反应和血流动力学升高的治疗方案。 这些患者身上存在的不稳定性。治疗主要是支持性的，并仅限于血管升压剂的组合， 静脉输液和抗生素。细菌内毒素在调节宿主源性炎症水平中的作用 包括细胞因子、趋化因子和补体因子在内的介质及其在感染性休克中的作用是广泛的 在文献中有报道。当过量时，这些介质会导致器官功能障碍、多器官衰竭，甚至死亡。 创新：使用CE Mark批准的体外细胞因子过滤器CytoSorb，以及新型内毒素吸附器， LPSorb，以减少感染性休克中细胞因子风暴和血流动力学不稳定的触发和致病因素。 假设：CytoSorb与LPSorb联合使用可减轻过度的炎症介质水平并降低水平 脓毒症血浆中的内毒素。 目的：1)研究脓毒症猪血浆内毒素和炎性细胞因子的表达 在感染性休克和急性呼吸窘迫发展过程中。2a-c)评估细胞因子和内毒素清除 对血浆pH、电解质、内源性和外源性凝血途径及白蛋白水平的影响 在台式循环系统中，败血症猪血浆中的CytoSorb疗法、LPSorb疗法和CytoSorb+LPSorb疗法。 研究设计：目标1的重点是表征与脓毒症相关的关键炎性细胞因子水平的变化 在这一高度临床相关的猪脓毒症模型中，感染性休克发生时循环中的细菌内毒素 为了得出炎症状态与血流动力学稳定性丧失之间的关联，导致多发性 器官衰竭和死亡。猪(35公斤)将接受两次手术，涉及粪块植入 腹膜后一过性夹闭肠系膜上动脉引起感染性休克和急性 呼吸窘迫综合征(ARDS)。血液样本将在手术前和手术后每6小时采集一次，直到 晚期出血时间为36小时。指标将包括生命体征(BT、BP、HR、RR)、完整血细胞计数、血液化学和 细胞因子和内毒素浓度。在目标2a-c中，将评估CytoSorb、LPSorb和CytoSorb+LPSorb设备 在一个按比例缩小的台式循环系统中，细胞因子和内毒素的去除能力以及任何潜在的影响 治疗可能对败血症猪血浆凝血功能和白蛋白含量有影响 程序。指标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，这项研究将确认将CytoSorb+LPSorb作为 感染性休克和血流动力学不稳定的明确治疗。等待未来临床前和临床前的积极结果 临床研究表明，这种创新的败血症治疗方法将为控制危及生命的疾病提供一种非常有效的手段。 感染性休克早期的过度炎症，有可能显著提高存活率。