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：脓毒症已被世界卫生组织列为“全球卫生优先事项”。已经 据估计，约50%的革兰氏阴性菌导致的脓毒症患者会发生脓毒性休克，其中一半 可能会死目前没有治疗方案来减轻升高的炎症反应和血流动力学 这些患者中存在的不稳定性。治疗主要是支持性的，仅限于血管加压药， 静脉输液和抗生素细菌内毒素在调节宿主炎症反应中的作用 介质，包括细胞因子、趋化因子和补体因子，它们对脓毒性休克的作用广泛存在 文献中有报道。当过量时，这些介质可诱导器官功能障碍、多器官衰竭，甚至死亡。 创新：使用CytoSorb，一种CE认证的体外细胞因子过滤器，以及一种新型的内毒素吸附器， LPSorb，用于减少脓毒性休克中细胞因子风暴和血流动力学不稳定的触发剂和致病剂。 假设：CytoSorb联合LPSorb可减弱炎症介质的过度水平，并降低 败血症血浆中的内毒素 具体目的：1）表征脓毒症猪血浆中的内毒素和炎性细胞因子表达谱 在感染性休克和急性呼吸窘迫的发展过程中2a_c）评估细胞因子和内毒素去除 能力和对血浆pH值、电解质、内源性和外源性凝血途径以及白蛋白水平的影响 台式再循环系统中脓毒症猪血浆中的CytoSorb治疗、LPSorb治疗和CytoSorb+LPSorb。 研究设计：目标1的重点是描述关键脓毒症相关炎性细胞因子水平的变化 在这个高度临床相关的猪败血症模型中， 为了得出炎症状态和血流动力学稳定性丧失之间的相关性， 器官衰竭和死亡。猪（35 kg）将接受“2次打击”外科手术，包括粪便凝块植入， 腹膜腔，随后短暂夹闭上级肠系膜动脉以诱导感染性休克和急性 呼吸窘迫综合征（ARDS）。将在术前和术后每6小时采集一次血样，直至 36小时时出现终末出血。监测将包括生命体征（BT、BP、HR、RR）、全血细胞计数、血生化和 细胞因子和内毒素浓度。在目标2a-c中，将评价CytoSorb、LPSorb和CytoSorb+LPSorb器械 在用于细胞因子和内毒素去除能力的按比例缩小的台式再循环系统中， 治疗可能对血浆凝固和脓毒症猪血浆中的白蛋白含量有影响， procedure.监测将包括细胞因子和内毒素浓度、PT、aPTT、uPTT和白蛋白水平。 影响和转化：如果成功，本研究将证实CytoSorb + LPSorb作为 感染性休克和血流动力学不稳定的确定性治疗。在未来的临床前和 临床研究，这种创新的脓毒症治疗将提供一种高度有效的手段，控制危及生命的 在感染性休克的早期阶段的过度炎症，具有显着提高生存的潜力。