Survival and Neurologic Outcomes From Pharmacologic Peptide Administration During Cardiopulmonary Resuscitation of Pulseless Electrical Activity.

BACKGROUND: Outcomes from cardiopulmonary resuscitation (CPR) following sudden cardiac arrest are suboptimal. Postresuscitation targeted temperature management has been shown to have benefit in subjects with sudden cardiac arrest due to ventricular fibrillation, but there are few data for outcomes from sudden cardiac arrest due to pulseless electrical activity. In addition, intra-CPR cooling is more effective than postresuscitation cooling. Physical cooling is associated with increased protein kinase B activity. Therefore, our group developed a novel peptide, TAT-PHLPP9c, which regulates protein kinase B. We hypothesized that when given during CPR, TAT-PHLPP9c would improve survival and neurologic outcomes following pulseless electrical activity arrest. METHODS AND RESULTS: In 24 female pigs, pulseless electrical activity was induced by inflating balloon catheters in the right coronary and left anterior descending arteries for ≈7 minutes. Advanced life support was initiated. In 12 control animals, epinephrine was given after 1 and 3 minutes. In 12 peptide-treated animals, 7.5 mg/kg TAT-PHLPP9c was also administered at 1 and 3 minutes of CPR. The balloons were removed after 2 minutes of support. Animals were recovered and neurologically scored 24 hours after return of spontaneous circulation. Return of spontaneous circulation was more common in the peptide group, but this difference was not significant (8/12 control versus 12/12 peptide; P=0.093), while fully intact neurologic survival was significantly more common in the peptide group (0/12 control versus 11/12 peptide; P<0.00001). TAT-PHLPP9c significantly increased myocardial nicotinamide adenine dinucleotide levels. CONCLUSIONS: TAT-PHLPP9c resulted in improved survival with full neurologic function after sudden cardiac arrest in a swine model of pulseless electrical activity, and the peptide shows potential as an intra-CPR pharmacologic agent.

Years of Potential Life Lost and Mean Age of Adults Experiencing Nontraumatic, Out-of-Hospital Cardiac Arrests - Chicago, 2014-2021.

Approximately 1,000 out-of-hospital cardiac arrests (OHCAs) are assessed by emergency medical services in the United States every day, and approximately 90% of patients do not survive, leading to substantial years of potential life lost (YPLL). Chicago emergency medical services data were used to assess changes in mean age and YPLL from nontraumatic OHCA in adults in biennial cycles during 2014-2021. Among 21,070 reported nontraumatic OHCAs during 2014-2021, approximately 60% occurred among men and 57% among non-Hispanic Black or African American (Black) persons. YPLL increased from 52,044 during 2014-2015 to 88,788 during 2020-2021 (p = 0.002) and mean age decreased from 64.7 years during 2014-2015, to 62.7 years during 2020-2021. Decrease in mean age occurred among both men (p<0.001) and women (p = 0.002) and was largest among Black men. Mean age decreased among patients without presumed cardiac etiology from 56.3 to 52.5 years (p<0.001) and among patients with nonshockable rhythm from 65.5 to 62.7 years (p<0.001). Further study is needed to assess whether similar trends are occurring elsewhere, and to understand the mechanisms that underlie these trends in Chicago because these mechanisms could help guide prevention efforts. Increased public awareness of the risk of cardiac arrest and knowledge of how to intervene as a bystander could help decrease associated mortality.

Nicotinamide restores tissue NAD+ and improves survival in rodent models of cardiac arrest.

Metabolic suppression in the ischemic heart is characterized by reduced levels of NAD+ and ATP. Since NAD+ is required for most metabolic processes that generate ATP, we hypothesized that nicotinamide restores ischemic tissue NAD+ and improves cardiac function in cardiomyocytes and isolated hearts, and enhances survival in a mouse model of cardiac arrest. Mouse cardiomyocytes were exposed to 30 min simulated ischemia and 90 min reperfusion. NAD+ content dropped 40% by the end of ischemia compared to pre-ischemia. Treatment with 100 µM nicotinamide (NAM) at the start of reperfusion completely restored the cellular level of NAD+ at 15 min of reperfusion. This rescue of NAD+ depletion was associated with improved contractile recovery as early as 10 min post-reperfusion. In a mouse model of cardiac arrest, 100 mg/kg NAM administered IV immediately after cardiopulmonary resuscitation resulted in 100% survival at 4 h as compared to 50% in the saline group. In an isolated rat heart model, the effect of NAM on cardiac function was measured for 20 min following 18 min global ischemia. Rate pressure product was reduced by 26% in the control group following arrest. Cardiac contractile function was completely recovered with NAM treatment given at the start of reperfusion. NAM restored tissue NAD+ and enhanced production of lactate and ATP, while reducing glucose diversion to sorbitol in the heart. We conclude that NAM can rapidly restore cardiac NAD+ following ischemia and enhance glycolysis and contractile recovery, with improved survival in a mouse model of cardiac arrest.

Interhospital variability in Out-of-Hospital cardiac arrest survival in a large metropolitan area.

Background: Out-of-hospital cardiac arrest (OHCA) survival varies widely across the United States. The impact of hospital OHCA volume and ST-elevation myocardial infarction (STEMI) Receiving Center (SRC) designation on survival is not fully understood. Methods: This was a retrospective analysis of adult OHCA who survived to hospital admission reported to the Chicago Cardiac Arrest Registry to Enhance Survival (CARES) database from May 1, 2013 to December 31, 2019. Hierarchical logistic regression models were generated and adjusted by hospital characteristics. Survival to hospital discharge (SHD) and cerebral performance category (CPC) 1-2 at each hospital were calculated after adjusting for arrest characteristics. Hospitals were assigned quartiles (Q1-Q4) based on total arrest volume to allow for comparison of SHD and CPC 1-2 between quartiles. Results: 4,020 patients met inclusion criteria. 21 of the 33 Chicago hospitals included in this study were designated SRCs. Adjusted SHD and CPC 1-2 rates ranged from 27.3% to 37.0% and from 8.9% to 25.1%, respectively, by hospital. SRC designation did not significantly affect SHD (OR 0.96; 95% CI, 0.71-1.30) nor CPC 1-2 (OR 1.17; 95% CI, 0.74-1.84). OHCA volume quartiles did not significantly affect SHD (Q2: OR 0.94; 95% CI, 0.54-1.60; Q3: OR 1.30; 95% CI, 0.78-2.16; Q4: OR 1.25; 95% CI, 0.74-2.10) nor CPC 1-2 (Q2: OR 0.75; 95% CI, 0.36-1.54; Q3: OR 0.94; 95% CI, 0.48-1.87; Q4: OR 0.97; 95% CI, 0.48-1.97). Conclusion: Interhospital variability in both SHD and CPC 1-2 cannot be explained by hospital arrest volume nor SRC status. Further research is warranted to explore reasons for interhospital variability.

A cell-penetrating PHLPP peptide improves cardiac arrest survival in murine and swine models.

Out-of-hospital cardiac arrest is a leading cause of death in the US, with a mortality rate over 90%. Preclinical studies demonstrate that cooling during cardiopulmonary resuscitation (CPR) is highly beneficial, but can be challenging to implement clinically. No medications exist for improving long-term cardiac arrest survival. We have developed a 20-amino acid peptide, TAT-PHLPP9c, that mimics cooling protection by enhancing AKT activation via PH domain leucine-rich repeat phosphatase 1 (PHLPP1) inhibition. Complementary studies were conducted in mouse and swine. C57BL/6 mice were randomized into blinded saline control and peptide-treatment groups. Following a 12-minute asystolic arrest, TAT-PHLPP9c was administered intravenously during CPR and significantly improved the return of spontaneous circulation, mean arterial blood pressure and cerebral blood flow, cardiac and neurological function, and survival (4 hour and 5 day). It inhibited PHLPP-NHERF1 binding, enhanced AKT but not PKC phosphorylation, decreased pyruvate dehydrogenase phosphorylation and sorbitol production, and increased ATP generation in heart and brain. TAT-PHLPP9c treatment also reduced plasma taurine and glutamate concentrations after resuscitation. The protective benefit of TAT-PHLPP9c was validated in a swine cardiac arrest model of ventricular fibrillation. In conclusion, TAT-PHLPP9c may improve neurologically intact cardiac arrest survival without the need for physical cooling.

Intra-ischemic hypothermia cardioprotection involves modulation of PTEN/Akt/ERK signaling and fatty acid oxidation.

Therapeutic hypothermia (TH) provides cardioprotection from ischemia/reperfusion (I/R) injury. However, it remains unknown how TH regulates metabolic recovery. We tested the hypothesis that TH modulates PTEN, Akt, and ERK1/2, and improves metabolic recovery through mitigation of fatty acid oxidation and taurine release. Left ventricular function was monitored continuously in isolated rat hearts subjected to 20 min of global, no-flow ischemia. Moderate cooling (30°C) was applied at the start of ischemia and hearts were rewarmed after 10 min of reperfusion. The effect of TH on protein phosphorylation and expression at 0 and 30 min of reperfusion was investigated by western blot analysis. Post-ischemic cardiac metabolism was investigated by 13 C-NMR. TH enhanced recovery of cardiac function, reduced taurine release, and enhanced PTEN phosphorylation and expression. Phosphorylation of Akt and ERK1/2 was increased at the end of ischemia but decreased at the end of reperfusion. On NMR analysis, TH-treated hearts displayed decreased fatty acid oxidation. Direct cardioprotection by moderate intra-ischemic TH is associated with decreased fatty acid oxidation, reduced taurine release, enhanced PTEN phosphorylation and expression, and enhanced activation of both Akt and ERK1/2 prior to reperfusion.

Extracorporeal cardiopulmonary resuscitation (eCPR) and cerebral perfusion: A narrative review.

Extracorporeal cardiopulmonary resuscitation (eCPR) is emerging as an effective, lifesaving resuscitation strategy for select patients with prolonged or refractory cardiac arrest. Currently, a paucity of evidence-based recommendations is available to guide clinical management of eCPR patients. Despite promising results from initial clinical trials, neurological injury remains a significant cause of morbidity and mortality. Neuropathology associated with utilization of an extracorporeal circuit may interact significantly with the consequences of a prolonged low-flow state that typically precedes eCPR. In this narrative review, we explore current gaps in knowledge about cerebral perfusion over the course of cardiac arrest and resuscitation with a focus on patients treated with eCPR. We found no studies which investigated regional cerebral blood flow or cerebral autoregulation in human cohorts specific to eCPR. Studies which assessed cerebral perfusion in clinical eCPR were small and limited to near-infrared spectroscopy. Furthermore, no studies prospectively or retrospectively evaluated the relationship between epinephrine and neurological outcomes in eCPR patients. In summary, the field currently lacks a comprehensive understanding of how regional cerebral perfusion and cerebral autoregulation are temporally modified by factors such as pre-eCPR low-flow duration, vasopressors, and circuit flow rate. Elucidating these critical relationships may inform future strategies aimed at improving neurological outcomes in patients treated with lifesaving eCPR.

Assessment of intensive care unit-free and ventilator-free days as alternative outcomes in the pragmatic airway resuscitation trial.

OBJECTIVE: We sought to evaluate the utility and validity of ICU-free days and ventilator-free days as candidate outcomes for OHCA trials. METHODS: We conducted a secondary analysis of the Pragmatic Airway Resuscitation Trial. We determined ICU-free (days alive and out of ICU during the first 30 days) and ventilator-free days (days alive and without mechanical ventilation). We determined ICU-free and ventilator-free day distributions and correlations with Modified Rankin Scale (MRS). We tested associations with trial interventions (laryngeal tube (LT), endotracheal intubation (ETI)) using continuous (t-test), non-parametric (Wilcoxon Rank-Sum test - WRS), count (negative binomial - NB) and survival models (Cox proportional hazards (CPH) and competing risks regression (CRR)). We conducted bootstrapped simulations to estimate statistical power. MAIN RESULTS: ICU-free days was skewed; median 0 days (IQR 0, 0), survivors only 24 (18, 27). Ventilator-free days was skewed; median 0 (IQR 0, 0) days, survivors only 27 (IQR 23, 28). ICU-free and ventilator-free days correlated with MRS (Spearman's ρ = -0.95 and -0.97). LT was associated with higher ICU-free days using t-test (p = 0.001), WRS (p = 0.003), CPH (p = 0.02) and CRR (p = 0.04), but not NB (p = 0.13). LT was associated with higher ventilator-free days using t-test (p = 0.001), WRS (p = 0.001) and CRR (p = 0.03), but not NB (p = 0.13) or CPH (p = 0.13). Simulations suggested that t-test and WRS would have had the greatest power to detect the observed ICU- and ventilator-free days differences. CONCLUSION: ICU-free and ventilator-free days correlated with MRS and differentiated trial interventions. ICU-free and ventilator-free days may have utility in the design of OHCA trials.

Utilizing community level factors to improve prediction of out of hospital cardiac arrest outcome using machine learning.

OBJECTIVES: To evaluate the impact of community level information on the predictability of out-of-hospital cardiac arrest (OHCA) survival. METHODS: We used the Cardiac Arrest Registry to Enhance Survival (CARES) to geocode 9,595 Chicago incidents from 2014 to 2019 into community areas. Community variables including crime, healthcare, and economic factors from public data were merged with CARES. The merged data were used to develop ML models for OHCA survival. Models were evaluated using Area Under the Receiver Operating Characteristic curve (AUROC) and features were analyzed using SHapley Additive exPansion (SHAP) values. RESULTS: Baseline results using CARES data achieved an AUROC of 84%. The final model utilizing community variables increased the AUROC to 88%. A SHAP analysis between high and low performing community area clusters showed the high performing cluster is positively impacted by good health related features and good community safety features positively impact the low performing cluster. CONCLUSION: Utilizing community variables helps predict neurologic outcomes with better performance than only CARES data. Future studies will use this model to perform simulations to identify interventions to improve OHCA survival.

Baicalein Preconditioning Cardioprotection Involves Pro-Oxidant Signaling and Activation of Pyruvate Dehydrogenase.

Preconditioning has a powerful protective potential against myocardial ischemia-reperfusion injury (I/R). Our prior work demonstrated that baicalein, a flavonoid derived from the root of Scatellaria baicalensis Georgi (also known as Huangqin), confers this preconditioning protection. This study further explored the mechanisms of baicalein preconditioning (BC-PC) in mouse cardiomyocytes. Cells were treated with baicalein (10 µM) for a brief period of time (10 min) prior to simulated ischemia 90 min/reperfusion for 180 min. Baicalein triggered an induction of a small amount of mitochondrial reactive oxygen species (ROS) prior to the initiation of ischemia, assessed by 6-carboxy-2', 7'-dichlorodihydrofluorescein diacetate (6-carboxy-H2DCFDA). It also significantly increased cell viability measured by propidium iodide (PI) and lactate dehydrogenase and preserved mitochondrial membrane potential assessed by TMRM fluorescence intensity. Myxothiazol, a mitochondrial electron transport chain complex III inhibitor, partially blocked ROS generation induced by BC-PC and reduced cell viability. BC-PC increased phosphorylation of Akt (Thr308 and Ser473) and eNOS Ser1177, and nitric oxide (NO) production measured using 4,5-diaminofluorescein diacetate (DAF-2 DA, 1 µM). Akt inhibitor API-2 abolished Akt phosphorylation and reduced DAF-2 production and cell viability. In addition, BC-PC decreased phosphorylation of pyruvate dehydrogenase (PDH) reflecting upregulated PDH activity, and increased ATP production at 30 min during reperfusion. Taken together, baicalein preconditioning-induced cardioprotection involves pro-oxidant generation, activates survival signaling Akt/eNOS/NO, and improves metabolic recovery after I/R injury. Our work provides new perspectives on the effect of baicalein on cardiac preconditioning against I/R injury.

A machine learning approach for modeling decisions in the out of hospital cardiac arrest care workflow.

BACKGROUND: A growing body of research has shown that machine learning (ML) can be a useful tool to predict how different variable combinations affect out-of-hospital cardiac arrest (OHCA) survival outcomes. However, there remain significant research gaps on the utilization of ML models for decision-making and their impact on survival outcomes. The purpose of this study was to develop ML models that effectively predict hospital's practice to perform coronary angiography (CA) in adult patients after OHCA and subsequent neurologic outcomes. METHODS: We utilized all (N = 2398) patients treated by the Chicago Fire Department Emergency Medical Services included in the Cardiac Arrest Registry to Enhance Survival (CARES) between 2013 and 2018 who survived to hospital admission to develop, test, and analyze ML models for decisions after return of spontaneous circulation (ROSC) and patient survival. ML classification models, including the Embedded Fully Convolutional Network (EFCN) model, were compared based on their ability to predict post-ROSC decisions and survival. RESULTS: The EFCN classification model achieved the best results across tested ML algorithms. The area under the receiver operating characteristic curve (AUROC) for CA and Survival were 0.908 and 0.896 respectively. Through cohort analyses, our model predicts that 18.3% (CI 16.4-20.2) of patients should receive a CA that did not originally, and 30.1% (CI 28.5-31.7) of these would experience improved survival outcomes. CONCLUSION: ML modeling effectively predicted hospital decisions and neurologic outcomes. ML modeling may serve as a quality improvement tool to inform system level OHCA policies and treatment protocols.

Personalized Analytics and a Wearable Biosensor Platform for Early Detection of COVID-19 Decompensation (DeCODe): Protocol for the Development of the COVID-19 Decompensation Index.

BACKGROUND: During the COVID-19 pandemic, novel digital health technologies have the potential to improve our understanding of SARS-CoV-2 and COVID-19, improve care delivery, and produce better health outcomes. The National Institutes of Health called on digital health leaders to contribute to a high-quality data repository that will support researchers to make discoveries that are otherwise not possible with small, limited data sets. OBJECTIVE: To this end, we seek to develop a COVID-19 digital biomarker for early detection of physiological exacerbation or decompensation. We propose the development and validation of a COVID-19 decompensation Index (CDI) in a 2-phase study that builds on existing wearable biosensor-derived analytics generated by physIQ's end-to-end cloud platform for continuous physiological monitoring with wearable biosensors. This effort serves to achieve two primary objectives: (1) to collect adequate data to help develop the CDI and (2) to collect rich deidentified clinical data correlating with outcomes and symptoms related to COVID-19 progression. Our secondary objectives include evaluation of the feasibility and usability of pinpointIQ, a digital platform through which data are gathered, analyzed, and displayed. METHODS: This is a prospective, nonrandomized, open-label, 2-phase study. Phase I will involve data collection for the digital data hub of the National Institutes of Health as well as data to support the preliminary development of the CDI. Phase II will involve data collection for the hub and contribute to continued refinement and validation of the CDI. While this study will focus on the development of a CDI, the digital platform will also be evaluated for feasibility and usability while clinicians deliver care to continuously monitored patients enrolled in the study. RESULTS: Our target CDI will be a binary classifier trained to distinguish participants with and those without decompensation. The primary performance metric for CDI will be the area under the receiver operating characteristic curve with a minimum performance criterion of ≥0.75 (α=.05; power [1-ß]=0.80). Furthermore, we will determine the sex or gender and race or ethnicity of the participants, which would account for differences in the CDI performance, as well as the lead time-time to predict decompensation-and its relationship with the ultimate disease severity based on the World Health Organization COVID-19 ordinal scale. CONCLUSIONS: Using machine learning techniques on a large data set of patients with COVID-19 could provide valuable insights into the pathophysiology of COVID-19 and a digital biomarker for COVID-19 decompensation. Through this study, we intend to develop a tool that can uniquely reflect physiological data of a diverse population and contribute to high-quality data that will help researchers better understand COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04575532; https://www.clinicaltrials.gov/ct2/show/NCT04575532. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/27271.

Sex differences in outcomes for out-of-hospital cardiac arrest in the United States.

BACKGROUND: Approximately 1000 out-of-hospital cardiac arrest (OHCA) occur each day in the United States. Although sex differences exist for other cardiovascular conditions such as stroke and acute myocardial infarction, they are less well understood for OHCA. Specifically, the extent to which neurological and survival outcomes after OHCA differ between men and women remains poorly characterized in the U.S. METHODS AND RESULTS: Within the national Cardiac Arrest Registry to Enhance Survival (CARES) registry, we identified 326,138 adults with an OHCA from 2013 to 2019. Using multivariable logistic regression, we evaluated for sex differences in rates of survival to hospital admission, survival to hospital discharge, and favorable neurological survival (i.e., without severe neurological disability), adjusted for demographics, cardiac arrest characteristics and bystander interventions. Overall, 117,281 (36%) patients were women. Median age was 62 and 65 years for men and women, respectively. An initial shockable rhythm (25.1% vs 14.7%, standardized difference of 0.26) and an arrest in a public location (22.2% vs. 11.3%; standardized difference of 0.30) were more common in men, but there were no meaningful sex differences in rates of witnessed arrests, bystander cardiopulmonary resuscitation, intra-venous access, or use of mechanical devices for delivering cardiopulmonary resuscitation. Overall, the unadjusted rates of all survival outcomes were similar between men and women: survival to hospital admission (27.0% for men vs. 27.9% for women, standardized difference of -0.02), survival to hospital discharge (10.5% for men vs. 8.6% for women, standardized difference of 0.07), and favorable neurological survival (9.0% for men vs. 6.6% for women, standardized difference of 0.09). After multivariable adjustment, however, men were less likely to survive to hospital admission (adjusted OR = 0.75, 95% CI: 0.73, 0.77), survive to hospital discharge (adjusted OR = 0.83, 95% CI: 0.80, 0.85), or have favorable neurological survival (adjusted OR = 0.88, 95% CI: 0.85, 0.91). CONCLUSIONS: Compared to women, men with OHCA have more favorable cardiac arrest characteristics but were less likely to survive to hospital admission, survive to discharge, nor have favorable neurological survival.

TAT delivery of a PTEN peptide inhibitor has direct cardioprotective effects and improves outcomes in rodent models of cardiac arrest.

We have recently shown that pharmacologic inhibition of PTEN significantly increases cardiac arrest survival in a mouse model, however, this protection required pretreatment 30 min before the arrest. To improve the onset of PTEN inhibition during cardiac arrest treatment, we have designed a TAT fused cell-permeable peptide (TAT-PTEN9c) based on the C-terminal PDZ binding motif of PTEN for rapid tissue delivery and protection. Western blot analysis demonstrated that TAT-PTEN9c peptide significantly enhanced Akt activation in mouse cardiomyocytes in a concentration- and time-dependent manner. Mice were subjected to 8 min asystolic arrest followed by CPR, and 30 mice with successful CPR were then randomly assigned to receive either saline or TAT-PTEN9c treatment. Survival was significantly increased in TAT-PTEN9c-treated mice compared with that of saline control at 4 h after CPR. The treated mice had increased Akt phosphorylation at 30 min resuscitation with significantly decreased sorbitol content in heart or brain tissues and reduced release of taurine and glutamate in blood, suggesting improved glucose metabolism. In an isolated rat heart Langendorff model, direct effects of TAT-PTEN9c on cardiac function were measured for 20 min following 20 min global ischemia. Rate pressure product was reduced by >20% for both TAT vehicle and nontreatment groups following arrest. Cardiac contractile function was completely recovered with TAT-PTEN9c treatment given at the start of reperfusion. We conclude that TAT-PTEN9c enhances Akt activation and decreases glucose shunting to the polyol pathway in critical organs, thereby preventing osmotic injury and early cardiovascular collapse and death.NEW & NOTEWORTHY We have designed a cell-permeable peptide, TAT-PTEN9c, to improve cardiac arrest survival. It blocked endogenous PTEN binding to its adaptor and enhanced Akt signaling in mouse cardiomyocytes. It improved mouse survival after cardiac arrest, which is related to improved glucose metabolism and reduced glucose shunting to sorbitol in critical organs.

Akt1-mediated CPR cooling protection targets regulators of metabolism, inflammation and contractile function in mouse cardiac arrest.

Therapeutic hypothermia initiated during cardiopulmonary resuscitation (CPR) in pre-clinical studies appears to be highly protective against sudden cardiac arrest injury. Given the challenges to implementing CPR cooling clinically, insights into its critical mechanisms of protection could guide development of new CPR drugs that mimic hypothermia effects without the need for physical cooling. Here, we used Akt1-deficient mice that lose CPR hypothermia protection to identify hypothermia targets. Adult female C57BL/6 mice (Akt1+/+ and Akt1+/-) underwent 8 min of KCl-induced asystolic arrest and were randomized to receive hypothermia (30 ± 0.5°C) or normothermia. Hypothermia was initiated during CPR and extended for 1 h after resuscitation. Neurologically scored survival was measured at 72 h. Other outcomes included mean arterial pressure and target measures in heart and brain related to contractile function, glucose utilization and inflammation. Compared to northothermia, hypothermia improved both 2h mean arterial pressure and 72h neurologically intact survival in Akt1+/+ mice but not in Akt1+/- mice. In Akt1+/+ mice, hypothermia increased Akt and GSK3ß phosphorylation, pyruvate dehydrogenase activation, and NAD+ and ATP production while decreasing IκBα degradation and NF-κB activity in both heart and brain at 30 min after CPR. It also increased phospholamban phosphorylation in heart tissue. Further, hypothermia reduced metabolic and inflammatory blood markers lactate and Pre-B cell Colony Enhancing Factor. Despite hypothermia treatment, all these effects were reversed in Akt1+/- mice. Taken together, drugs that target Akt1 and its effectors may have the potential to mimic hypothermia-like protection to improve sudden cardiac arrest survival when administered during CPR.

Baicalein Cardioprotection via Oxidant Scavenging and Akt-Nitric Oxide Signaling: Identification of Early Reperfusion Phase as the Critical Therapeutic Window.

Baicalein is a natural flavonoid with anti-oxidant activities protecting against ischemia/reperfusion (I/R) injury. Previous studies suggest that oxidative burst early after reperfusion accelerates cell death. We therefore investigated the critical therapeutic window of baicalein by examining the timing of baicalein treatment in relation to its oxidant modulating and cytoprotective effects. Using an established chick cardiomyocyte model of I/R, we administered baicalein at various time points after reperfusion and assessed cell viability and the profiles of reactive oxygen species (ROS), nitric oxide (NO), and Akt phosphorylation. Baicalein administered at the onset of reperfusion resulted in a concentration-dependent reduction of cell death (25 µM 48.2±1.9%, 50µM 43.8±1.5%, 100µM 36.6±2.1%, vs. I/R control 57.3±1.4%, all p<0.05). Baicalein (100µM) timely and effectively scavenged ROS burst and enhanced NO production in the early reperfusion phase. Cotreatment with NO synthase (NOS) inhibitor l-NAME (200µM) partially abrogated the cytoprotective effect. Baicalein (100µM) given after reperfusion lost protective effect in a time-dependent manner with cytoprotection completely lost if >60min. Even with only 15-min delay after reperfusion, the ROS scavenging effect was abolished and the NO enhancing effect markedly reduced. The phosphorylation of Akt, an upstream regulator of eNOS, also diminished as the delay lengthened. In conclusion, baicalein treatment after reperfusion confers cardioprotection in a concentration- and time-dependent manner. The critical therapeutic window lies in the early reperfusion phase, during which ROS scavenging and Akt-eNOS mediated NO signaling are most effective.

Evaluation of an Enhanced Peer Mentoring Program on Scholarly Productivity and Promotion in Academic Emergency Medicine: A Five-Year Review.

OBJECTIVE: To design, implement, and evaluate the effectiveness of an enhanced peer mentoring program (EPMP) for faculty in emergency medicine aimed at overcoming traditional mentoring challenges. METHODS: Full time faculty (Clinical Instructor, Assistant, and Associate levels) were placed into peer groups (based upon their primary academic roles) led by senior faculty advisors at the Professor level. Peer groups met at least quarterly from 2012 to 2017. In lieu of a structured curriculum, session topics were informed by individual faculty surveys and peer group consensus. Areas of focus included work-life balance, prioritizing academic commitments, identification of mentors (both within and external to the department and university), networking opportunities, promotions goals, and career satisfaction. RESULTS: Effectiveness of the EPMP was evaluated by academic productivity and advancement over a 5- year period. A total of 22 faculty members participated in the program. There was an increase in promotions to the next academic level, from 3 promotions in the five years before the program to 7 promotions in the five years of the program. Total grant funding increased 3-fold from $500,000 to $1,706,479 from the first year to the last year of the evaluation period. CONCLUSIONS: This enhanced peer mentoring program was effective in mitigating many of the traditional mentoring challenges faced by faculty in academia and was successful in improving both academic productivity and advancement.

Large urban center improves out-of-hospital cardiac arrest survival.

BACKGROUND: Large cities pose unique challenges that limit the effectiveness of system improvement interventions. Successful implementation of integrated cardiac resuscitation systems of care can serve as a model for other urban centers. METHODS: This was a retrospective analysis of prospectively collected data of adult cases of non-traumatic cardiac arrest who received treatment by Chicago Fire Department EMS from September 1, 2013 through December 31, 2016. We measured temporal OHCA outcomes during implementation of system-wide initiatives including telephone-assisted and community CPR training programs; high performance CPR and team based simulation training; new post resuscitation care and destination protocols; and case review for EMS providers. Outcomes measured included bystander CPR rates, return of spontaneous circulation (ROSC), hospital admission and survival, and favorable neurologic outcomes (CPC 1-2). Relative risk was determined by logistic regression model where observed group-specific outcomes are expressed as odds ratios (OR). RESULTS: We included 6103 adult OHCA cases occurring outside of health care facilities from September 1, 2013 through December 31, 2016. Significantly improved outcomes (p < 0.05) were observed between 2013 and 2016 for bystander CPR (11.6% vs 19.4%), ROSC (28.6% vs 36.9%), hospital admission (22.5% vs 29.4%), survival (7.3% vs 9.9%), and CPC 1-2 (4.3% vs 6.4%). Utstein survival increased from 16.3%-35.4% and CPC 1-2 survival from 11.6%-29.1% (p < 0.05). After adjustment for OHCA characteristics, survival with CPC 1-2 increased over time (OR 1.15, p = 0.0277). CONCLUSIONS: Densely populated cities with low survival rates can overcome systematic challenges and improve OHCA survival.

A machine learning based model for Out of Hospital cardiac arrest outcome classification and sensitivity analysis.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) affects nearly 400,000 people each year in the United States of which only 10% survive. Using data from the Cardiac Arrest Registry to Enhance Survival (CARES), and machine learning (ML) techniques, we developed a model of neurological outcome prediction for OHCA in Chicago, Illinois. METHODS: Rescue workflow data of 2639 patients with witnessed OHCA were retrieved from Chicago's CARES. An Embedded Fully Convolutional Network (EFCN) classification model was selected to predict the patient outcome (survival with good neurological outcomes or not) based on 27 input features with the objective of maximizing the average class sensitivity. Using this model, sensitivity analysis of intervention variables such as bystander cardiopulmonary resuscitation (CPR), targeted temperature management, and coronary angiography was conducted. RESULTS: The EFCN classification model has an average class sensitivity of 0.825. Sensitivity analysis of patient outcome shows that an additional 33 patients would have survived with good neurological outcome if they had received lay person CPR in addition to CPR by emergency medical services and 88 additional patients would have survived if they had received the coronary angiography intervention. CONCLUSIONS: ML modeling of the complex Chicago OHCA rescue system can predict neurologic outcomes with a reasonable level of accuracy and can be used to support intervention decisions such as CPR or coronary angiography. The discriminative ability of this ML model requires validation in external cohorts to establish generalizability.