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.
Public Health Relevance Statement: Relevance to Public Health: The field of sepsis care currently lacks an effective treatment modality to counteract the cytokine storm that drives septic shock and hemodynamic destabilization. Results from this Phase I research will lay the groundwork for the development of an innovative combination blood purification therapy capable of combating lethal hyperinflammation during septic shock. Demonstrating the in vitro efficacy of this therapy in removing both endotoxin and sepsis-associated inflammatory mediators from native septic plasma is a crucial first step toward assessing the in vivo physiological benefit of the therapy in reversing septic shock and restoring hemodynamic stability to reduce disease severity and overall mortality.
Project Terms: Adoption; Albumins; Antibiotics; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Blood; Blood Reticuloendothelial System; Blood Chemical Analysis; Blood Chemical Analyses; blood chemistry; Blood Circulation; Bloodstream; Circulation; Blood Coagulation Disorders; Coagulation Disorder; Coagulopathy; bleeding disorder; clotting disorder; Blood Coagulation Factor; Coagulation Factors; clotting factor; Clinical Research; Clinical Study; Combined Modality Therapy; Multimodal Therapy; Multimodal Treatment; combination therapy; combined modality treatment; combined treatment; multi-modal therapy; multi-modal treatment; Communities; Complement; Complement Proteins; Complete Blood Count; Cessation of life; Death; Electrolytes; Endotoxins; Future; Gram-Negative Bacteria; Health Priorities; hemodynamics; In Vitro; Lead; Pb element; heavy metal Pb; heavy metal lead; Literature; Medical Device; mortality; Multiple Organ Failure; MOF syndrome; Multiple Organ Dysfunction Syndrome; multiorgan failure; multiple organ system failure; Activated Partial Thromboplastin Time; Partial Thromboplastin Time; aPTT; Activated Partial Thromboplastin Time measurement; Patients; Peritoneal Cavity; Greater sac of peritoneum; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma; Public Health; Research; Study Type; study design; Research Design; ARDS; Acute Respiratory Distress; Adult ARDS; Adult RDS; Adult Respiratory Distress Syndrome; Da Nang Lung; Shock Lung; Stiff lung; wet lung; Acute Respiratory Distress Syndrome; Risk; social role; Role; Septic Shock; Pigs; Suidae; Swine; porcine; suid; Family suidae; Testing; Time; Translations; Vasoconstrictor Agents; Vasoactive Agonists; Vasoconstrictor Drugs; Vasoconstrictors; Vasopressor Agents; vasopressor; World Health Organization; complement C2a; C 2a; C2a; complement 2a; complement C2a fragment; cytokine; Caring; Superior mesenteric artery structure; Superior Mesenteric Artery; dosage; Organ; Blood specimen; Blood Sample; improved; Procedures; Clinical; Phase; Physiological; Physiologic; Medical; Evaluation; Hypoalbuminemia; inflammatory mediator; Inflammation Mediators; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Chemotactic Cytokines; Homologous Chemotactic Cytokines; Intercrines; SIS cytokines; chemoattractant cytokine; chemokine; Immunological response; host response; immune system response; immunoresponse; Immune response; Attenuated; Inflammatory; septic; Life; Endotoxemia; Hour; Source; System; disease severity; Severity of illness; Clampings; Closure by clamp; respiratory; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; Operative Surgical Procedures; Performance; novel; technological innovation; Modality; Devices; Reporting; Abscission; Extirpation; Removal; Surgical Removal; resection; Excision; Modeling; response; Inflammatory Response; Intravenous Fluid; IV Fluid; Causality; causation; disease causation; Etiology; Clotting; Coagulation; Coagulation Process; Mediator; Mediator of Activation; Mediator of activation protein; Address; global health; Preclinical Models; Pre-Clinical Model; in vivo; Molecular; Development; developmental; Pathway interactions; pathway; pre-clinical; preclinical; preclinical study; pre-clinical study; Sepsis; blood infection; bloodstream infection; Treatment Efficacy; intervention efficacy; therapeutic efficacy; therapy efficacy; Outcome; innovation; innovate; innovative; clinically relevant; clinical relevance; implantation; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; commercial application; effective therapy; effective treatment; product development; cytokine release syndrome; cytokine storm; porcine model; pig model; piglet model; swine model; sepsis induced ARDS; ARDS caused by sepsis; acute respiratory distress syndrome caused by sepsis; sepsis ARDS; sepsis acute respiratory distress syndrome; sepsis associated ARDS; sepsis associated acute respiratory distress syndrome; sepsis induced acute respiratory distress syndrome; sepsis related ARDS; sepsis related acute respiratory distress syndrome
