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Introduction: Previous studies have demonstrated that ferroptosis, a newly defined iron-dependent cell death, mediates ischemia/reperfusion induced cardiomyopathy. However, it is unclear whether ferroptosis plays a role in post-resuscitation myocardial dysfunction (PRMD). This study investigated the effects of UAMC-3203, a novel analog of ferroptosis specific inhibitors, on myocardial function after cardiopulmonary resuscitation (CPR). Hypothesis: Administration of UAMC-3203 during CPR alleviates PRMD in a rat model of cardiac arrest (CA) and CPR. Methods: 18 male Sprague-Dawley rats weighing between 450-550g were randomized into 3 groups: 1) Sham, 2) Control, and 3) UAMC-3203 (5mg/kg, IP at start of precordial compression). Ventricular fibrillation (VF) was induced and continued for 6min. CPR was then initiated for 8min, after which defibrillation was attempted. Ejection fraction (EF), cardiac output (CO) and myocardial performance index (MPI) were measured by echocardiography at baseline, 15min, 1h, 3h and 6h respectively after return of spontaneous circulation (ROSC). Results: A significant reduction in cardiac function was observed after resuscitation. At 15 minutes after ROSC, ultrasound showed no difference in cardiac function between UAMC and control. However, at 1, 3, and 6 h after ROSC, UAMC significantly improved myocardial function (p Conclusion: A ferroptosis-specific inhibitor, UAMC-3203, alleviated PRMD significantly in a rat of model of CA and CPR. Further study is needed to determine the benefit of this agent in larger animals and potential safety in humans before it can be tested in clinical resuscitation.

Introduction: Massive systemic inflammation is a primary cause of myocardial dysfunction following cardiac arrest (CA) and resuscitation (CPR). We investigated the effects of ω-3 polyunsaturated fatty acids (ω-3 PUFA) on systemic inflammation and myocardial function after CA and CPR. Hypothesis: Administration of ω-3 PUFA at the start of CPR will alleviate post CPR inflammation and improve cardiac function in a rat model of CA and CPR. Methods: 18 male Sprague-Dawley rats weighing between 450g-550g were randomized into three groups: Sham, Control, and ω-3 PUFA. Ventricular fibrillation (VF) was induced and untreated for 6 min. 4J defibrillation was attempted after 8 min of CPR. Saline placebo or ω-3 PUFA (5mL/kg) was infused at the start of CPR and continued for 4h. Ejection fraction (EF), cardiac output (CO) and myocardial performance index (MPI) were measured by echocardiography at baseline, 1, 3 and 6h after return of spontaneous circulation (ROSC). Inflammatory cytokines (IL-6 and TNF-α) and cardiac biomarker (cTnI) levels in plasma were detected at baseline and 6 hrs after ROSC. Results: A decrease in EF and CO and an increase in MPI occurred after resuscitation. Significant improvement was noted in ω-3 PUFA compared to control animals (p Conclusion: Administration of ω-3 PUFA attenuates post-resuscitation systemic inflammation and improves myocardial function in a rat model of CA and CPR.

Introduction: Neurologic and myocardial dysfunction after successful resuscitation is prominent and mitochondrial dysfunction is predicted to be a key determinant of poor outcomes. Mitochondria contribute a critical role as effectors and targets of reperfusion injury. However, the onset and severity of mitochondrial dysfunction during cardiac arrest (CA) is not fully understood. The present study was done to explore whether changes in cerebral and myocardial mitochondria differ after cardiac arrest and cardiopulmonary resuscitation (CPR). Hypothesis: Mitochondrial injury is more severe in the brain compared to the heart during and following cardiac arrest and CPR. Methods: Sprague-Dawley rats weighing between 450 - 550 g were randomized into 4 groups (n=6): 1) sham (surgery, no ventricular fibrillation (VF) or CPR), 2) VF (VF 8 mins, no CPR); 3) VF and CPR (VF 8 mins and CPR 8 mins, no defibrillation); ROSC 1 h (VF 8 mins, CPR 8 mins, defibrillation, and observe 1 h after ROSC). VF was induced through a guide wire advanced from the right jugular vein into the right ventricle. Brain and heart mitochondria were extracted by differential centrifugation and used to measure oxidative phosphorylation and calcium retention capacity (CRC). Results: Compared with sham, brain mitochondrial CRC in VF, VF+CPR and ROSC 1 h were decreased (110±11 vs. 70±13, 62±24, 50±6 nmol Ca 2+ /mg protein, p2+ /mg protein). Brain mitochondrial oxidative phosphorylation with complex I substrate glutamate in VF, VF+CPR and ROSC 1 h were all decreased compared to sham (127 + 8 vs 92±17, 84±12, and 92±15, p Conclusions: Mitochondria in the brain are more sensitive to injury during CA and CPR compared to heart mitochondria. With markedly decreased CRC, mitochondria are likely to contribute to cerebral reperfusion injury during CPR and ROSC. Preservation of cerebral mitochondrial activity and mitochondrial function during cardiac arrest may improve post-resuscitation neurological function.

Introduction: Epinephrine is the primary drug given during cardiopulmonary resuscitation (CPR), when given early, to reverse cardiac arrest (CA) by stimulation of α-adrenergic receptors in vascular smooth muscle. This increases coronary perfusion pressure (CPP) and increases rate of return of spontaneous circulation (ROSC). However, the use of epinephrine is not associated with a significant difference in long-term survival or favorable neurologic outcome when given late after arrest onset. In the present study, we compared the effects of aortic injection of polyethylene glycol-20k (PEG-20k) vs. epinephrine during CPR on CPP and postresuscitation myocardial and cerebral function in a rat model of CA. Hypothesis: Aortic injection of PEG-20k during CPR will increase CPP to the same extent as epinephrine without adversely affecting post-resuscitation myocardial and cerebral function. Methods: Twenty four male Sprague-Dawley rats weighing between 450-550 g were randomized into four groups: 1) PEG-20k 2) epinephrine 3) saline placebo 4) saline-intra-aorta (IA). Eight minutes of CPR was initiated after 6 minutes of untreated ventricular fibrillation. PEG-20k IA (10% est. total blood volume [1.8ml]), saline IA, saline IV or epinephrine IV (20ug/kg) was given after 4 minutes of CPR by continuous infusion over 3 minutes. CPP was recorded continuously and resuscitation was attempted with 4 Joule defibrillation. Myocardial function was measured at baseline, 2, 4, and 6 hours after ROSC by echocardiography and neurologic deficit scores (NDS) were recorded at 24, 48, and 72 hours after ROSC. Results: In both saline groups, CPP did not change. However, aortic injection of PEG-20k increased CPP significantly to the same extent as epinephrine (Fig 1). Post-resuscitation ejection fraction was significantly greater in PEG-20k compared to epinephrine (64 + 1 vs 45 + 3, p+ 50 vs 450 + 50, p

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 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.

Introduction: Gasdermin D (GSDMD), a previously unknown protein, serves as a key effector in pyroptosis and its inhibition has protective effects during cerebral ischemia and reperfusion. Necrosulfonamide (NSA) specifically blocks the mixed lineage kinase domain-like pseudo kinase (MLKL), which directly binds to GSDMD preventing pyroptotic cell death and interleukin-1 (IL-1) release. In this study, we investigated the effects of NSA on survival and neurological function after cardiac arrest and resuscitation. Hypothesis: Administration of NSA following cardiopulmonary resuscitation (CPR) will improve survival and neurological function in a rat model of cardiac arrest. Methods: Twelve male Sprague-Dawley rats weighting between 450-550g were utilized. Ventricular fibrillation was induced and untreated for 6 min followed by defibrillation after 8 min of CPR. Animals were then randomized into two groups: NSA and control. NSA (10mg/kg) or vehicle was administered 5 minutes after restoration of spontaneous circulation (ROSC) by intraperitoneal injection. Duration of survival and neurological deficit scores were recorded at 24, 48, and 72 hours after ROSC. Results: All animals were resuscitated successfully. Duration of survival was significantly longer in the NSA group compared to control (p Conclusion: Administration of NSA after ROSC improves post-resuscitation survival and neurological function in a rat model of cardiac arrest.

Introduction: Cerebral ischemia-reperfusion injury produces inflammation and cerebral microcirculatory dysfunction after cardiopulmonary resuscitation (CPR). Melatonin (N-acetyl-5-methoxytryptamine) has both anti-inflammatory and anti-oxidative properties. In this study, we investigated the effects of melatonin on inflammation and cerebral microcirculation after cardiopulmonary resuscitation in a rat model of cardiac arrest. Hypothesis: Melatonin decreases the systemic inflammatory response after cardiopulmonary resuscitation and will preserve cerebral microcirculation in a rat model of cardiac arrest. Method: Eighteen male Sprague Dawley rats weighing between 450-550 g were randomized into three groups: 1) sham: no ventricular fibrillation (VF) and CPR; 2) CPR control: untreated VF for 6 min followed by 8 min CPR; 3) CPR+melatonin: untreated VF for 6 min followed by 8 min CPR. Melatonin (10 mg/kg) was administered intraperitoneal (IP) in line with hypoxia-ischemia animal studies after return of spontaneous circulation (ROSC). Serum TNF- α, IL-1 β and cerebral microcirculation were measured at baseline and 6 h following ROSC. Result: Serum TNF-α and IL-1β were significantly lower in the CPR+melatonin group at 6h after ROSC compared to CPR controls ( p p Conclusion: In a rat model of cardiac arrest, melatonin reduced systemic inflammation and preserved cerebral microcirculation following resuscitation.