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Highlights • COVID-19 pandemic has changed the risk-benefit balance for cardiopulmonary resuscitation [CPR]. • Amongst many aerosol producing procedures performed on patients, CPR is a highly aerosol-generating procedure. • Available literature is inadequate to direct clinicians towards keeping low or high threshold for performing CPR in COVID-19 patient.

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: Mitochondrial dysfunction from global ischemic-reperfusion (I/R) injury is a major contributor to post-resuscitation myocardial dysfunction. Polyethylene Glycol-20k (PEG-20k) shortens the no-flow phenomenon and improves microcirculation while MCC950 selectively inhibits activation of the NLRP3-inflammasome ensuing pyroptosis. We evaluated the effect of combined therapy with PEG-20k and MCC950 on myocardial mitochondrial function as measured by electron transport chain complex respiration in a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Methods: 30 Sprague-Dawley rats weighing between 450-550 g were randomized into five groups (n=6): (1) sham (S); (2) control (C); (3) PEG-20k (P); (4) MCC950 (M); (5) combined (P&M). Ventricular fibrillation (VF) was electrically induced and untreated for 6min, followed by 8min CPR. Resuscitation was attempted with a 4J defibrillation. 2mL P was infused over 2 min at the beginning of CPR, while M (10mg/kg) was administered intraperitoneal (IP) immediately after return of spontaneous circulation (ROSC). At ROSC 6hr, 100mg of heart was harvested, transferred directly into ice-cold K medium (1mL), and homogenized to obtain a 10% homogenate. Homogenates (50μL) were transferred to calibrated Oxygraph-2 chambers. Mitochondrial function was measured using high resolution respirometry. Oxygen flux was corrected and expressed by tissue wet weight, pmol/(min*mg). Data were analyzed by one-way analysis of variance (one-way ANOVA) followed by Tukey’s post hoc test for comparisons between multiple groups. Results: Complex I respiration in C was compromised at ROSC 6hr compared to S (564.0±160.0 vs 2729.5±339.5, p Conclusion: Combined Therapy with PEG-20k and MCC950 preserves post-resuscitation myocardial mitochondrial function in a rat model of CA and CPR.

Introduction: Artesunate (ART) possesses anti-inflammatory activity, which can mitigate the systemic inflammatory response in poor outcomes of cardiac arrest (CA). We investigated the effects of ART on myocardial and cerebral function, duration of survival, and inflammation in a rat model of CA and cardiopulmonary resuscitation (CPR). Hypothesis: ART reduces the severity of post resuscitation myocardial and cerebral dysfunction by alleviating inflammation in a rat model of CA and CPR. Methods: 30 male Sprague-Dawley rats weighing between 450g-550g were randomized into 3 groups: Sham (S), Control (C), and Artesunate (A). C and A were divided into subgroups: survival and non-survival (n=6). Ventricular fibrillation (VF) was induced and untreated for 6 min. A 4J defibrillation was attempted after 8 min of CPR. Phosphate buffer (1ml/kg, pH 7.9-8.1) or ART (2.4mg/kg), was administered at return of spontaneous circulation (ROSC). Myocardial function was measured at baseline and every hour for 4h post ROSC. Plasma levels of IL-6, TNF-α and cTnI were detected at baseline and 4h after ROSC. Survival animals were observed for an additional 72h. Neurologic deficit scores were recorded daily. Results: ART reduced the severity of post-resuscitation myocardial dysfunction compared to C. It attenuated IL-6, TNF-α and cTnI plasma levels 4h after ROSC (p Conclusion: ART reduces the severity of post-resuscitation myocardial and cerebral dysfunction, improves survival rate and attenuates inflammation in a rat of model of CA and CPR.

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: 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.

Introduction Spontaneous changes in body temperature after return of circulation (ROSC) from cardiac arrest are common, but the association of these changes with outcomes in hospitalized patients who survive to 24h post-ROSC is not known. We tested the hypothesis that adults who experience temperature lability in the first 24h have worse outcomes compared with those who maintain normothermia. Materials and methods A prospective observational study from a multicenter registry of cardiac arrests (National Registry of Cardiopulmonary Resuscitation) from 355 US and Canadian hospitals. 14,729 adults with return of circulation from a pulseless cardiac arrest. We excluded those who died or were discharged before 24h post-event, those made Do-Not-Resuscitate (DNR) within 24h of event, those that had a preceding trauma, and those with multiple cardiac arrests. Finally, we included only subjects that had both a lowest ( T min ) and highest ( T max ) body temperature value recorded during the first 24-h after ROSC, resulting in a study sample of 3426 patients. Results After adjustment for potential covariates, there was a lower odds of survival in those having an episode of hypothermia (adjusted odds ratio [OR], 0.62; 95% confidence interval [CI], 0.48–0.80), those having an episode of hyperthermia (OR, 0.67; 95% CI, 0.48–0.80), and those having an episode of both (OR, 0.59; 95% CI, 0.39–0.91). Among those who survived to discharge, there was also a lower odds of favorable neurologic performance in those who had an episode of hyperthermia (OR, 0.71; 95% CI, 0.51–0.98). Conclusions Episodes of temperature lability following in-hospital resuscitation from cardiac arrest are associated with lower odds of surviving to discharge. Hyperthermia is also associated with fewer patients leaving the hospital with favorable neurologic performance. Further studies should identify whether therapeutic control over changes in body temperature after in-hospital cardiac arrest improves outcomes.