Abstract 21: Effects of the Selective NLRP3-Inflammasome Inhibitor MCC950 on Post-Resuscitation Myocardial and Cerebral Function in a Rat Model of Cardiopulmonary Resuscitation

Abstract

Introduction: NLRP3 inflammasome mediated pyroptosis has been demonstrated to increase myocardial and cerebral ischemia/reperfusion injury. MCC950 is a newly developed highly selective inhibitor of the NLRP3 inflammasome. Hypothesis: MCC950 administered following resuscitation will reduce the severity of post-resuscitation myocardial and cerebral dysfunction and improve duration of survival in a rat model of CPR. Methods: 15 male Sprague-Dawley rats weighting between 450-550 g were randomized into three groups: 1) MCC950 2) Control 3) Sham. Ventricular fibrillation (VF) was induced and untreated for 6 min. CPR was then initiated and continued for 8 min. Resuscitation was attempted with a 4 J defibrillation. Either MCC950 (10mg/kg) or vehicle was administered intraperitoneal (IP) in line with cardiac injury animal studies immediately after return of spontaneous circulation (ROSC). Sham underwent the same surgical procedure without VF and CPR. Sublingual microcirculation was measured at baseline (BL), 3, 6 and 48 hrs after ROSC. Ejection fraction (EF) was measured at BL, 1, 3, 6 and 48 hrs after ROSC. Neurologic Deficit Score (NDS) was recorded at 48 hrs after resuscitation. Results: Post-resuscitation ejection fraction and perfused sublingual vessel density were greater in MCC950 compared to control (p<0.05). NDS was also improved in MCC950 compared to control (110 vs 425, p<0.05). Survival at 48 hrs after ROSC was greater in MCC950 (4/5 vs 1/5, p<0.05). Conclusion: Administration of MCC950 following ROSC mitigates post-resuscitation myocardial and cerebral dysfunction, improves sublingual microcirculation and duration of survival in a rat model of CPR.