Project Grant R43GM144973

NOVEL EXTRACORPOREAL THERAPY FOR THE REVERSAL OF SEPTIC SHOCK AND RESTORING HEMODYNAMIC STABILITY - 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.