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Background: Observation of the electrocardiogram (ECG) immediately following return of spontaneous circulation (ROSC) in resuscitated swine has revealed the interesting phenomenon of sudden ECG rhythm changes (SERC) that occur in the absence of pharmacological, surgical, or other medical interventions., Objective: We sought to identify, quantify, and characterize post-ROSC SERC in successfully resuscitated swine., Methods: We reviewed all LabChart data from resuscitated approximately 4- to 6-month-old swine used for various experimental protocols from 2006 to 2019. We identified those that achieved sustained ROSC and analyzed their entire post-ROSC periods for evidence of SERC in the ECG, and arterial and venous pressure tracings. Presence or absence of SERC was confirmed independently by two reviewers (ACK, DDS). We measured the interval from ROSC to first SERC, analyzed the following metrics, and calculated the change from 60 sec pre-SERC (or from ROSC if less than 60 sec) to 60 sec post-SERC: heart rate, central arterial pressure (CAP), and central venous pressure (CVP)., Results: A total of 52 pigs achieved and sustained ROSC. Of these, we confirmed at least one SERC in 25 (48.1%). Two pigs (8%) each had two unique SERC events. Median interval from ROSC to first SERC was 3.8 min (inter-quartile range 1.0-6.9 min; range 16 sec to 67.5 min). We observed two distinct types of SERC: type 1) the post-SERC heart rate and arterial pressure increased (72% of cases); and type 2) the post-SERC heart rate and arterial pressure decreased (28% of cases). For type 1 cases, the mean (standard deviation [SD]) heart rate increased by 33.6 (45.7) beats per minute (bpm). The mean (SD) CAP increased by 20.6 (19.2) mmHg. For type 2 cases, the mean (SD) heart rate decreased by 39.7 (62.3) bpm. The mean (SD) CAP decreased by 21.9 (15.6) mmHg., Conclusions: SERC occurred in nearly half of all cases with sustained ROSC and can occur multiple times per case. First SERC most often occurred within the first 4 minutes following ROSC. Heart rate, CAP, and CVP changed at the moment of SERC. We are proceeding to examine whether this phenomenon occurs in humans post-cardiac arrest and ROSC.

Background: Large animal studies are an important step in the translation pathway, but single laboratory experiments do not replicate the variability in patient populations. Our objective was to demonstrate the feasibility of performing a multicenter, preclinical, randomized, double-blinded, placebo-controlled cardiac arrest trial. We evaluated the effect of epinephrine on coronary perfusion pressure (CPP) as previous single laboratory studies have reported mixed results., Methods: Forty-five swine from 5 different laboratories (Ann Arbor, MI; Baltimore, MD; Los Angeles, CA; Pittsburgh, PA; Toronto, ON) using a standard treatment protocol. Ventricular fibrillation was induced and left untreated for 6 min before starting continuous cardiopulmonary resuscitation (CPR). After 2 min of CPR, 9 animals from each lab were randomized to 1 of 3 interventions given over 12 minutes: (1) Continuous IV epinephrine infusion (0.00375 mg/kg/min) with placebo IV normal saline (NS) boluses every 4 min, (2) Continuous placebo IV NS infusion with IV epinephrine boluses (0.015 mg/kg) every 4 min or (3) Placebo IV NS for both infusion and boluses. The primary outcome was mean CPP during the 12 mins of drug therapy., Results: There were no significant differences in mean CPP between the three groups: 14.4 ± 6.8 mmHg (epinephrine Infusion), 16.9 ± 5.9 mmHg (epinephrine bolus), and 14.4 ± 5.5 mmHg (placebo) (p = NS). Sensitivity analysis demonstrated inter-laboratory variability in the magnitude of the treatment effect (p = 0.004)., Conclusion: This study demonstrated the feasibility of performing a multicenter, preclinical, randomized, double-blinded cardiac arrest trials. Standard dose epinephrine by bolus or continuous infusion did not increase coronary perfusion pressure during CPR when compared to placebo., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Guidelines for depth of chest compressions in pediatric cardiopulmonary resuscitation (CPR) are based on sparse evidence., Objective: We sought to evaluate the performance of the two most widely recommended chest compression depth levels for pediatric CPR (1.5 in. and 1/3 the anterior-posterior diameter- APd) in a controlled swine model of asphyxial cardiac arrest., Methods: We executed a 2-group, randomized laboratory study with an adaptive design allowing early termination for overwhelming injury or benefit. Forty mixed-breed domestic swine (mean weight = 26 kg) were sedated, anesthetized and paralyzed along with endotracheal intubation and mechanical ventilation. Asphyxial cardiac arrest was induced with fentanyl overdose. Animals were untreated for 9 min followed by mechanical CPR with a target depth of 1.5 in. or 1/3 the APd. Advanced life support drugs were administered IV after 4 min of basic resuscitation followed by defibrillation at 14 min. The primary outcomes were return of spontaneous circulation (ROSC), hemodynamics and CPR-related injury severity., Results: Enrollment in the 1/3 APd group was stopped early due to overwhelming differences in injury. Twenty-three animals were assigned to the 1.5 in. group and 15 assigned to the 1/3 APd group, per an adaptive group design. The 1/3 APd group had increased frequency of rib fracture (6.7 vs 1.7, p < 0.001) and higher proportions of several anatomic injury markers than the 1.5 in. group, including sternal fracture, hemothorax and blood in the endotracheal tube (p < 0.001). ROSC and hemodynamic measures were similar between groups., Conclusion: In this pediatric model of cardiac arrest, chest compressions to 1/3APd were more harmful without a concurrent benefit for resuscitation outcomes compared to the 1.5 in. compression group., Competing Interests: Declaration of Competing Interest Dr. Salcido performs fee-for-service work for ZOLL Medical. Drs. Salcido and Menegazzi hold a patent on a system for cardiopulmonary resuscitation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Physical and cognitive impairments are common after cardiac arrest, and recovery varies. This study assessed recovery of individual domains of the Cerebral Performance Category- Extended (CPC-E) 1-year after cardiac arrest. We hypothesized patients would have recovery in all CPC-E domains 1-year after the index cardiac arrest., Methods: Prospective cohort study of cardiac arrest survivors evaluating outcome measures mRS, CPC, and CPC-E. Outcomes were assessed at discharge, 3-months, 6-months, and 1-year. We defined recovery of a CPC-E domain when >90% of patients had scores of 1-2 in that domain., Results: Of 156 patients discharged, 57 completed the CPC-E at discharge, and were included in the analysis. 37 patients had follow-up at 3-months, and 23 patients had follow-up at 6 and 12 months. Only 16 patients had assessments at all four timepoints. Domains of alertness (N = 56, 98%) logical thinking (N = 56; 98%), and attention (N = 55; 96%) recovered by hospital discharge. BADL (N = 34; 92%) and motor skills (N = 36; 97%) recovered by 3-months. Most patients (N = 20; 87%) experienced slight-to-no disability or symptoms (mRS 0-2/CPC 1-2) at 1-year follow up. CPC-E domains of short term memory (78%), mood (87%), fatigue (22%), complex ADL (78%), and return to work (65%) did not recover by 1-year., Conclusions: CPC-E domains of alertness, logical thinking, and attention recover rapidly, while domains of short term memory, mood, fatigue, complex ADL and return to work remain chronically impaired 1-year after cardiac arrest. These deficits are not detected by mRS and CPC. Interventions to improve recovery in these domains are needed., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Introduction: Out-of-hospital cardiac arrest (OHCA) is a major cause of morbidity and mortality in the US. Of major concern is a lack of therapies to mitigate associated brain injury. Immune cell infiltration (ICI) into the brain, which may exacerbate injury post-resuscitation, is one possible therapeutic target, although the post-OHCA immune response has not been fully characterized., Objective: In this pilot study, we aimed to detect early post-resuscitation cytotoxic lymphocyte ICI in porcine brain using a model of opioid-mediated asphyxial OHCA., Methods: Ten young, healthy swine (26.7+/-3.4 kg) were sedated, anaesthetized and paralyzed. In eight of the animals, this was followed by induction of asphyxial OHCA via fentanyl bolus and concurrent airway occlusion. The remaining two 'sham' animals were instrumented but did not undergo asphyxia. After nine minutes of asphyxia, mechanical CPR and manual ventilations were started, in an initial BLS followed by ALS configuration. At termination of resuscitation or euthanasia, the whole brain was removed. Immune cells were extracted and analyzed via flow cytometry., Results: 304 +/- 62.2 cells/g were discovered to be CD8 single positive cells in animals that achieved ROSC, 481 +/- 274.4 cells/g in animals that did not achieve ROSC, and 40 +/- 11.31 cells/g in sham animals. CD8 single positive cells made up 0.473 +/- 0.24% of detected cells in animals that achieved ROSC, 0.395 +/- 0.062% in animals that did not achieve ROSC, and 0.19 +/- 0.014% in sham animals (No ROSC vs Sham, p = 0.012)., Conclusions: These data suggest that cytotoxic lymphocytes may be localizing to the brain during cardiac arrest resuscitation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Objective: The two objectives of this report are: first, to describe a comparison of chest compressions unsynchronized or synchronized to native cardiac activity in a porcine model of hypotension, and second, to develop an algorithm to provide synchronized chest compressions throughout a range of native heart rates likely to be encountered when treating PEA cardiac arrest. Methods: We adapted our previously developed signal-guided CPR system to provide compressions synchronized to native electrical activity in a porcine model of hypotension as a surrogate of PEA arrest. We describe the first comparison of unsynchronized to synchronized compressions in a single animal as a proof-of-concept. We developed an algorithm to provide optimal synchronized chest compressions regardless of intrinsic PEA heart rate while simultaneously maintaining the chest compression rate within a desired range. We tested the algorithm with computer simulations measuring the proportion of intrinsic and compression beats that were synchronized, and the compression rate and its standard deviation, as a function of intrinsic heart rate and heart rate jitter. Results: We demonstrate and compare unsynchronized versus synchronized chest compressions in a single porcine model with an intrinsic rhythm and hypotension. Synchronized, but not unsynchronized, chest compressions were associated with increased blood pressure and coronary perfusion pressure. Our synchronized chest compression algorithm is able to provide synchronized chest compressions to over 90% of intrinsic beats for most heart rates while maintaining an average compression rate between 90 and 140 compressions per minute with relatively low variability. Conclusions: Synchronized chest compression therapy for pulseless electrical rhythms is feasible. A high degree of synchronization can be maintained over a broad range of intrinsic heart rates while maintaining the compression rate within a satisfactory range. Further investigation to assess benefit for treatment of PEA is warranted.

Introduction: We previously found potassium cardioplegia followed by rapid calcium reversal (Kplegia) can achieve defibrillation in a swine model of electrical phase of ventricular fibrillation (VF) comparable to standard care., Hypothesis: Exploring 3 possible potassium dose and timing protocols, we hypothesize Kplegia may benefit resuscitation of longer duration untreated VF., Methods: Three separate blinded randomized placebo-controlled trials were performed with electrically-induced VF untreated for durations of 6, 9, and 12min in a swine model. Experimental groups received infusion of 1 or 2 boluses of intravenous (IV) potassium followed by a single calcium reversal bolus. Potassium was replaced by saline in the control groups. Outcomes included: amplitude spectrum area (AMSA) during VF, resulting rhythms, number of defibrillations, return of spontaneous circulation (ROSC), and hemodynamics for 1h post ROSC. Binomial and interval data outcomes were compared with exact statistics. Serial interval data were assessed with mixed regression models., Results: Twelve, 12, and 8 animals were included at 6, 9, and 12min VF durations for a total of 32. ROSC was achieved in: 4/6 Kplegia and 3/6 control animals in the 6min protocol, (p=1.00), 4/6 Kplegia and 2/6 control animals in the 9min protocol,(p=0.57), and 0/5 Kplegia and 1/3 control animals in the 12min protocol,(p=0.38). Two of 8 Kplegia animals achieved ROSC with chemical defibrillation alone., Conclusions: The majority of animals achieved ROSC after up to 9min of untreated VF arrest using K plegia protocols. K plegia requires further optimization for both peripheral IV and intraosseous infusion, and to assess for superiority over standard care. Institutional Animal Care and Use Committee protocol #15127224., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The early use of automated external defibrillators (AEDs) can save lives by correcting lethal ventricular arrhythmias with minimal operator intervention. AED shock advisements also play a role in termination of resuscitation strategies. AED function is dependent on the accuracy of their shock advisement algorithms, which may differ between manufacturers. We sought to compare the shock advisement performance characteristics of several AEDs. Methods: We conducted a prospective, laboratory-based simulation study evaluating five commercially available AEDs from Cardiac Science, Defibtech, Medtronic, Philips, and Zoll. Shock advisement performance was evaluated for eight ECG rhythms {ventricular fibrillation (VF), ventricular tachycardia (VT), toursades de pointes (TdP), sinus rhythm (SR), atrial fibrillation (AF), atrial flutter (AFL), idioventricular rhythm (IDV), and asystole} that were generated using the SimMan Classic Manikin and the LLEAP Simulator software (Laerdal Medical Inc., Norway). We recorded shock advisement decisions for each of the ECG rhythms three times per device. Shock advisements were coded as discordant if a shock was advised for a non-shockable rhythm or not advised for a shockable rhythm. Results: We analyzed 330 rhythm trials in total (66 per device), finding 28 (8.5%) discordant shock advisements overall. Discordance ranged from 6% to 11% among the five AED models. VF rhythm variants were the most frequent (43%) source of discordant advisements. No shocks were advised for any of the sinus rhythms, AFL, AF with QRS > 40, IDV, or asystole. Conclusions: Discordant shock advisements were observed for each AED and varied between manufacturers, most often involving VF. There may be implications for termination of resuscitation decision making.

Objective: To determine whether the administration of intra-arrest cyclosporine (CCY) and methylprednisolone (MP) preserves left ventricular ejection fraction (LVEF) and cardiac output (CO) after return of spontaneous circulation (ROSC)., Methods: Eleven, 25-30kg female swine were randomized to receive 10mg/kg CCY + 40mg MP or placebo, anesthetized and given a transthoracic shock to induce ventricular fibrillation. After 8 minutes, standard CPR was started. After two additional minutes, the experimental agent was administered. Animals with ROSC were supported for up to 12h with norepinephrine as needed. Echocardiography was performed at baseline, and 1, 2, 6 and 12h post-ROSC. Analysis was performed using generalized estimating equations (GEE) after downsampling continuously sampled data to 5 minute epochs., Results: Eight animals (64%) achieved ROSC after a median of 7 [IQR 5-13] min of CPR, 2 [ IQR 1-3] doses of epinephrine and 2 [IQR 1-5] defibrillation shocks. Animals receiving CCY+MP had higher post ROSC MAP (GEE coefficient -10.2, P = <0.01), but reduced cardiac output (GEE coefficient 0.8, P = <0.01) compared to placebo. There was no difference in LVEF or vasopressor use between arms., Conclusions: Intra-arrest cyclosporine and methylprednisolone decreased post-arrest cardiac output and increased mean arterial pressure without affecting left ventricular ejection fraction.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10 -4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10 -8 ) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

Bipolar disorder (BD) is a major psychiatric illness affecting around 1% of the global population. BD is characterized by recurrent manic and depressive episodes, and has an estimated heritability of around 70%. Research has identified the first BD susceptibility genes. However, the underlying pathways and regulatory networks remain largely unknown. Research suggests that the cumulative impact of common alleles with small effects explains only around 25-38% of the phenotypic variance for BD. A plausible hypothesis therefore is that rare, high penetrance variants may contribute to BD risk. The present study investigated the role of rare, nonsynonymous, and potentially functional variants via whole exome sequencing in 15 BD cases from two large, multiply affected families from Cuba. The high prevalence of BD in these pedigrees renders them promising in terms of the identification of genetic risk variants with large effect sizes. In addition, SNP array data were used to calculate polygenic risk scores for affected and unaffected family members. After correction for multiple testing, no significant increase in polygenic risk scores for common, BD-associated genetic variants was found in BD cases compared to healthy relatives. Exome sequencing identified a total of 17 rare and potentially damaging variants in 17 genes. The identified variants were shared by all investigated BD cases in the respective pedigree. The most promising variant was located in the gene SERPING1 (p.L349F), which has been reported previously as a genome-wide significant risk gene for schizophrenia. The present data suggest novel candidate genes for BD susceptibility, and may facilitate the discovery of disease-relevant pathways and regulatory networks., Competing Interests: The authors have declared that no competing interests exist.

Background: Intra-resuscitation antiarrhythmic drugs may improve resuscitation outcomes, in part by avoiding rearrest, a condition associated with poor out-of-hospital cardiac arrest (OHCA) outcomes. However, antiarrhythmics may also alter defibrillation threshold. The objective of this study was to investigate the relationship between rearrest and intra-resuscitation antiarrhythmic drugs in the context of the Resuscitation Outcomes Consortium (ROC) amiodarone, lidocaine, and placebo (ALPS) trial., Hypothesis: Rearrest rates would be lower in cases treated with amiodarone or lidocaine, versus saline placebo, prior to first return of spontaneous circulation (ROSC). We also hypothesized antiarrhythmic effects would be quantifiable through analysis of the prehospital electrocardiogram., Methods: We conducted a secondary analysis of the ROC ALPS trial. Cases that first achieved prehospital ROSC after randomized administration of study drug were included in the analysis. Rearrest, defined as loss of pulses following ROSC, was ascertained from emergency medical services records. Rearrest rate was calculated overall, as well as by ALPS treatment group. Multivariable logistic regression models were constructed to assess the association between treatment group and rearrest, as well as rearrest and both survival to hospital discharge and survival with neurologic function. Amplitude spectrum area, median slope, and centroid frequency of the ventricular fibrillation (VF) ECG were calculated and compared across treatment groups., Results: A total of 1144 (40.4%) cases with study drug prior to first ROSC were included. Rearrest rate was 44.0% overall; 42.9% for placebo, 45.7% for lidocaine, and 43.0% for amiodarone. In multivariable logistic regression models, ALPS treatment group was not associated with rearrest, though rearrest was associated with poor survival and neurologic outcomes. AMSA and median slope measures of the first available VF were associated with rearrest case status, while median slope and centroid frequency were associated with ALPS treatment group., Conclusion: Rearrest rates did not differ between antiarrhythmic and placebo treatment groups. ECG waveform characteristics were correlated with treatment group and rearrest. Rearrest was inversely associated with survival and neurologic outcomes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Brain tissue hypoxia may contribute to preventable secondary brain injury after cardiac arrest. We developed a porcine model of opioid overdose cardiac arrest and post-arrest care including invasive, multimodal neurological monitoring of regional brain physiology. We hypothesized brain tissue hypoxia is common with usual post-arrest care and can be prevented by modifying mean arterial pressure (MAP) and arterial oxygen concentration (PaO 2 )., Methods: We induced opioid overdose and cardiac arrest in sixteen swine, attempted resuscitation after 9 min of apnea, and randomized resuscitated animals to three alternating 6-h blocks of standard or titrated care. We invasively monitored physiological parameters including brain tissue oxygen (PbtO 2 ). During standard care blocks, we maintained MAP > 65 mmHg and oxygen saturation 94-98%. During titrated care, we targeted PbtO2 > 20 mmHg., Results: Overall, 10 animals (63%) achieved ROSC after a median of 12.4 min (range 10.8-21.5 min). PbtO 2 was higher during titrated care than standard care blocks (unadjusted β = 0.60, 95% confidence interval (CI) 0.42-0.78, P < 0.001). In an adjusted model controlling for MAP, vasopressors, sedation, and block sequence, PbtO 2 remained higher during titrated care (adjusted β = 0.75, 95%CI 0.43-1.06, P < 0.001). At three predetermined thresholds, brain tissue hypoxia was significantly less common during titrated care blocks (44 vs 2% of the block duration spent below 20 mmHg, P < 0.001; 21 vs 0% below 15 mmHg, P < 0.001; and, 7 vs 0% below 10 mmHg, P = .01)., Conclusions: In this model of opioid overdose cardiac arrest, brain tissue hypoxia is common and treatable. Further work will elucidate best strategies and impact of titrated care on functional outcomes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Measures of chest compression fraction (CCF), compression rate, compression depth and pre-shock pause have all been independently associated with improved outcomes from out-of-hospital (OHCA) cardiac arrest. However, it is unknown whether compliance with American Heart Association (AHA) guidelines incorporating all the aforementioned metrics, is associated with improved survival from OHCA., Methods: We performed a secondary analysis of prospectively collected data from the Resuscitation Outcomes Consortium Epistry-Cardiac Arrest database. As per the 2015 American Heart Association (AHA) guidelines, guideline compliant cardiopulmonary resuscitation (CPR) was defined as CCF >0.8, chest compression rate 100-120/minute, chest compression depth 50-60mm, and pre-shock pause <10s. Multivariable logistic regression models controlling for Utstein variables were used to assess the relationship between global guideline compliance and survival to hospital discharge and neurologically intact survival with MRS ≤3. Due to potential confounding between CPR quality metrics and cases that achieved early ROSC, we performed an a priori subgroup analysis restricted to patients who obtained ROSC after ≥10min of EMS resuscitation., Results: After allowing for study exclusions, 19,568 defibrillator records were collected over a 4-year period ending in June 2015. For all reported models, the reference standard included all cases who did not meet all CPR quality benchmarks. For the primary model (CCF, rate, depth), there was no significant difference in survival for resuscitations that met all CPR quality benchmarks (guideline compliant) compared to the reference standard (OR 1.26; 95% CI: 0.80, 1.97). When the dataset was restricted to patients obtaining ROSC after ≥10min of EMS resuscitation (n=4,158), survival was significantly higher for those resuscitations that were guideline compliant (OR 2.17; 95% CI: 1.11, 4.27) compared to the reference standard. Similar findings were obtained for neurologically intact survival with MRS ≤3 (OR 3.03; 95% CI: 1.12, 8.20)., Conclusions: In this observational study, compliance with AHA guidelines for CPR quality was not associated with improved outcomes from OHCA. Conversely, when restricting the cohort to those with late ROSC, compliance with guidelines was associated with improved clinical outcomes. Strategies to improve overall guideline compliance may have a significant impact on outcomes from OHCA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Cognitive deficits may detract from quality of life after cardiac arrest. Their pattern and prevalence are not well documented. We used the Computer Assessment of Mild Cognitive Impairment (CAMCI), the Montreal Cognitive Assessment (MOCA) and the 41 Cent Test (41CT) to assess cognitive impairment in cardiac arrest survivors and examine the exams' diagnostic accuracy. We hypothesized that the scores of these exams would indicate the presence of cognitive impairment in arrest survivors, that the overall scores on the three study assessments would correlate with one another, and that the 41CT, MOCA, and executive function element of the CAMCI would vary independently from other non-executive CAMCI components, reflecting executive function impairment after cardiac arrest., Methods: Four researchers administered the CAMCI, MOCA, and/or the 41CT to cardiac arrest survivors after discharge from the intensive care unit between 2010 and 2015. Physicians screened patients with the Mini-Mental State Exam to determine when this cognitive testing was feasible, generally when the patient was able to score 20-25 points on the MMSE. We performed pairwise correlations between the different subscales' and tests' scores., Results: One hundred and fourteen participants completed the CAMCI, of which 38 (33.3%) participants additionally completed the MOCA and 41CT. The median (IQR) percentile score for CAMCI for all 114 participants was 33.5 (18.3, 49.8), which corresponds to moderately low risk of impairment. The median (IQR) for the MOCA was 22.0 (19, 24.8) out of a possible 30, which is considered indicative of abnormal cognitive function, and for the 41CT was 6 (5, 7) out of a possible 7 points when all 38 participants were included. MOCA correlated strongly with the overall CAMCI score (r=0.71); the CAMCI correlated moderately strongly with the 41CT (r=0.62) and the MOCA and 41CT were moderately strongly correlated with each other (r=0.56). When all 114 CAMCI scores were considered, the Executive Accuracy subscale was strongly correlated with the overall CAMCI score (r=0.81)., Conclusion: The CAMCI detects cognitive impairment after cardiac arrest. The MOCA correlates strongly with the overall CAMCI and the executive function subscale of the CAMCI. The 41CT as appears less effective than the MOCA in detecting cognitive deficits., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Previous work has demonstrated that when out-of-hospital cardiac arrest (OHCA) patients achieve return of spontaneous circulation (ROSC), but subsequently have another cardiac arrest prior to hospital arrival (rearrest), the probability of survival to hospital discharge is significantly decreased. Additionally, few modifiable factors for rearrest are known. We sought to examine the association between rearrest and compression-to-ventilation ratio during cardiopulmonary resuscitation (CPR) and to confirm the association between rearrest and outcomes., Hypothesis: Rearrest incidence would be similar between cases treated with 30:2 or continuous chest compression (CCC) CPR, but inversely related to survival and good neurological outcome., Methods: We conducted a secondary analysis of a large randomized-controlled trial of CCC versus 30:2 CPR for the treatment of OHCA between 2011 and 2015 among 8 sites of the Resuscitation OUTCOMES: Consortium (ROC). Patients were randomized through an emergency medical services (EMS) agency-level cluster randomization design to receive either 30:2 or CCC CPR. Case data were derived from prehospital patient care reports, digital defibrillator files, and hospital records. The primary analysis was an as-treated comparison of the proportion of patients with a rearrest for patients who received 30:2 versus those who received CCC. In addition, we assessed the association between rearrest and both survival to hospital discharge and favorable neurological outcome (Modified Rankin Score≤3) in patients with and without ROSC upon ED arrival using multivariable logistic regression adjusting for age, sex, initial rhythm and measures of CPR quality., Results: There were 14,109 analyzable cases that were determined to have definitively received either CCC or 30:2 CPR. Of these, 4713 had prehospital ROSC and 2040 (43.2%) had at least one rearrest. Incidence of rearrest was not significantly different between patients receiving CCC and 30:2 (44.1% vs 41.8%; adjusted OR: 1.01; 95% CI: 0.88, 1.16). Rearrest was significantly associated with lower survival (23.3% vs 36.9%; adjusted OR: 0.46; 95%CI: 0.36-0.51) and worse neurological outcome (19.4% vs 30.2%; adjusted OR: 0.46; 95%CI: 0.38, 0.55)., Conclusion: Rearrest occurrence was not significantly different between patients receiving CCC and 30:2, and was inversely associated with survival to hospital discharge and MRS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Common variants in the gene GATA binding protein 4 (GATA4) show association with alcohol dependence (AD). The aim of this study was to identify rare variants in GATA4 in order to elucidate the role of this gene in AD susceptibility. Identification of rare variants may provide a more complete picture of the allelic architecture at this risk locus., Methods: Sanger sequencing of all 6 coding exons of GATA4 was performed in 528 patients and 517 controls. Four in silico prediction tools were used to determine the effect of a DNA variant on the amino acid sequence and protein function. Five variants were included in the replication step. Of these, 4 were successfully genotyped in our replication cohort of 655 patients and 1,501 controls. All patients fulfilled DSM-IV criteria for AD, and all individuals were of German descent., Results: In the discovery step, 19 different heterozygous variants were identified. Four patient-specific and potentially functionally relevant variants were followed up. Only the variant S379S (c.1137C>T) remained patient specific (1/1,166 patients vs. 0/1,997 controls). None of the variants showed a statistically significant association with AD., Conclusions: The present study elucidated the role of GATA4 in AD susceptibility by identifying rare variants via Sanger sequencing and subsequent replication. Although novel patient-specific rare variants of GATA4 were identified, none received support in the independent replication step. However, given previous robust findings of association with common variants, GATA4 remains a promising candidate gene for AD., (Copyright © 2016 The Authors. Alcoholism: Clinical and Experimental Research published by Wiley Periodicals, Inc. on behalf of Research Society on Alcoholism.)

Objectives: Potassium cardioplegia-induced transient asystole may conserve myocardial energy, foster chemical defribrillation, and improve VF arrest outcome. A trial of potassium infusion with or without calcium reversal was conducted to test for improvement in intra-arrest VF waveform and post-ROSC hemodynamics., Methods: Eighteen swine were randomized to three treatment arms in two phases. VF was electrically induced and untreated for 4min. The animals then received 6min of mechanical CPR. Blinded investigators infused two study medicines peripherally during this interval. One group received 1.5mEq/kg KCl with CPR initiation followed 3min later by CaCl 10% infusion 0.12cm(3)/kg, the second group received 1.5mEq/kg KCl without CaCl, and the third group received placebo infusions. Ten minutes post VF initiation, defibrillation was performed, as appropriate, followed by ACLS for continued arrest or observation for 30min if ROSC. AMSA change from before to 5min post study drug infusion was compared with nonparametric statistics. MAP post ROSC was compared using mixed linear regression analysis., Results: Average normalized AMSA change was -0.15, -0.63, and +0.27 in the KCl, KCl+CaCl, and placebo groups, respectively (p=0.01). Three KCl+CaCl animals developed on organized rhythm chemically without electrical defibrillation. One, 3, and 4 animals in the KCl, KCl+CaCl, and placebo groups, respectively, survived post ROSC. Post ROSC, MAP decreased 1.8mmHg (95% CI -1.4 to 5.1) min(-1) less in the KCl+CaCl group compared to placebo., Conclusions: Chemical defibrillation and ROSC are possible post potassium-induced asystole. Potassium followed by calcium reversal, but not potassium alone, led to ROSC and post-ROSC hemodynamics comparable to recommended therapy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The frequency of lethal overdose due to prescription and non-prescription drugs is increasing in North America. The aim of this study was to estimate overall and regional variation in incidence and outcomes of out-of-hospital cardiac arrest due to overdose across North America., Methods: We conducted a retrospective cohort study using case data for the period 2006-2010 from the Resuscitation Outcomes Consortium, a clinical research network with 10 regional clinical centers in United States and Canada. Cases of out-of-hospital cardiac arrest due to drug overdose were identified through review of data derived from prehospital clinical records. We calculated incidence of out-of-hospital cardiac arrest due to overdose per 100,000 person-years and proportion of the same among all out-of-hospital cardiac arrests. We analyzed the association between overdose cardiac arrest etiology and resuscitation outcomes., Results: Included were 56,272 cases, of which 1351 were due to overdose. Regional incidence of out-of-hospital cardiac arrest due to overdose varied between 0.5 and 2.7 per 100,000 person years (p<0.001), and proportion of the same among all treated out-of-hospital cardiac arrests ranged from 0.8% to 4.0%. Overdose cases were younger, less likely to be witnessed, and less likely to present with a shockable rhythm. Compared to non-overdose, overdose was directly associated with return of spontaneous circulation (OR: 1.55; 95% CI: 1.35-1.78) and survival (OR: 2.14; 95% CI: 1.72-2.65)., Conclusions: Overdose made up 2.4% of all out-of-hospital cardiac arrest, although incidence varied up to 5-fold across regions. Overdose cases were more likely to survive than non-overdose cases., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: The loss of pulses after successful return of spontaneous circulation (ROSC) in out-of-hospital cardiac arrest (OHCA) is known as rearrest (RA). The causes of RA are not well understood., Objectives: To investigate the association between shock pause intervals and RA., Methods: Data from treated OHCA with ROSC and one or more defibrillation attempts were obtained from one site of the Resuscitation Outcomes Consortium. All analyses were conducted internally. Data available for analysis included cases spanning 2006-2008 and 2010-2011. Defibrillator tracings were used to calculate both components of the perishock pause (PSP) interval: the pre- (preSP) and the postshock pauses (postSP). RA and no-RA shock pauses were compared and independent associations between shock pause intervals, patient characteristics, and RA were assessed with the appropriate statistical tests., Results: Analysis included 241 shocks from 101 cases. Forty-one cases (41%) had RA. RA vs. no-RA median (interquartile range) shock pauses in seconds were: preSP 13.5 (6.0-18.0) vs. 15.0 (10.9-21.5) (p = 0.121); postSP 6.0 (3.5-8.2) vs. 8.7 (4.5-13.9) (p = 0.053); and PSP 18.0 (12.3-24.0) vs. 24.0 (16.7-30.2) (p = 0.022). Considering all possible shock pause durations, shock pause lengths and various patient characteristics were not associated with RA. If 30 s or shorter, the preSP (odds ratio [OR] 0.90, 955 confidence interval [CI] 0.82-0.98) and postSP (OR 0.89, 95% CI 0.79-0.99) were related to RA., Conclusion: Shock pause length was inversely associated with RA when shock pause intervals were limited to 30 s or less. Shock pauses and RA were not associated when all durations of shock pauses were considered., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Cardiac arrest is one of the leading causes of death in the United States and is treated by cardiopulmonary resuscitation (CPR). CPR involves both chest compressions and positive pressure ventilations when given by medical providers. Mechanical chest compression devices automate chest compressions and are beginning to be adopted by emergency medical services with the intent of providing high-quality, consistent chest compressions that are not limited by human providers who can become fatigued. Biosignals acquired from cardiac arrest patients have been characterized in their ability to track the effect of CPR on the patient. The authors investigated the feasibility and appropriate response of a biosignal-guided mechanical chest compression device in a swine model of cardiac arrest., Methods: After a custom signal-guided chest compression device was engineered, its ability to respond to biosignal changes in a swine model of cardiac arrest was tested. In a preliminary series of six swine, two biosignals were used: mean arterial pressure (MAP) and a mathematical derivative of the electrocardiogram waveform, median slope (MS). How these biosignals changed was observed when chest compression rate and depth were adjusted by the signal-guided chest compression device, independent of the user. Chest compression rate and depth were adjusted by the signal-guided chest compression device according to a preset threshold algorithm until either of the biosignals improved to satisfy a set "threshold" or until the chest compression rate and depth achieved maximum values. Defibrillation was attempted at the end of each resuscitation in an effort to achieve return of spontaneous circulation (ROSC)., Results: The signal-guided chest compression device responded appropriately to biosignals by changing its rate and depth. All animals exhibited positive improvements in their biosignals. During the course of the resuscitation, three of the six animals improved their MS biosignal to reach the MS threshold, while two of the six animals improved their MAP biosignal to reach the MAP threshold. In the six experiments conducted, defibrillation was attempted on five animals, and two animals achieved ROSC., Conclusions: In this proof-of-concept study, a signal-guided chest compression device was demonstrated to be capable of responding to biosignal input and delivering chest compressions with a broad range of rates and depths., (© 2015 by the Society for Academic Emergency Medicine.)

Introduction: Rearrest occurs when a patient experiences cardiac arrest after successful resuscitation. The incidence and outcomes of rearrest following out-of-hospital cardiac arrest have been estimated in limited local studies. We sought provide a large-scale estimate of rearrest incidence and its effect on survival., Methods: We obtained case data from emergency medical services-treated, out-of-hospital cardiac arrest from the Resuscitation Outcomes Consortium, a multi-site clinical research network with clinical centers in 11 regions in the US and Canada. The cohort comprised all cases captured between 2006 and 2008 at 10 of 11 regions with prehospital return of spontaneous circulation. We used three methods to ascertain rearrest via direct signal analysis, indirect signal analysis, and emergency department arrival vital status. Rearrest incidence was estimated as the proportion of cases with return of spontaneous circulation that experience rearrest. Regional rearrest incidence estimates were compared with the χ(2)-squared test. Multivariable logistic regression was used to assess the relationship between rearrest and survival to hospital discharge., Results: Out of 18,937 emergency medical services-assessed cases captured between 2006 and 2008, 11,456 (60.5%) cases were treated by emergency medical services and 4396 (38.4%) had prehospital return of spontaneous circulation. Of these, rearrest ascertainment data was available in 3253 cases, with 568 (17.5%) experiencing rearrest. Rearrest differed by region (10.2% to 21.2%, p < 0.001). Rearrest was inversely associated with survival (OR: 0.19, 95% CI: 0.14-0.26)., Conclusions: Rearrest was found to occur frequently after resuscitation and was inversely related to survival., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Out-of-hospital cardiac arrest (OHCA) is a leading cause of mortality in the United States. We sought to evaluate the accuracy of the patient care report (PCR) for detection of 2 clinically important events: return of spontaneous circulation (ROSC) and rearrest (RA)., Methods: We used defibrillator recordings and PCRs for Emergency Medical Services-treated OHCA collected by the Resuscitation Outcomes Consortium's Pittsburgh site from 2006 to 2008 and 2011 to 2012. Defibrillator data included electrocardiogram rhythm tracing, chest compression measurement, and audio voice recording. Sensitivity analysis was performed by comparing the accuracy of the PCR to detect the presence and number of ROSC and RA events to integrated defibrillator data., Results: In the 158 OHCA cases, there were 163 ROSC events and 53 RA events. The sensitivity of PCRs to identify all ROSC events was 85% (confidence interval [CI], .795-.905); to identify primary ROSC events, it was 85% (CI, .793-.907); and to identify secondary ROSC events, it was 78% (CI, .565-.995). The sensitivity of PCRs to identify the presence of all RA events was .60 (CI, .469-.731); to identify primary RA events, it was 71% (CI, .578-.842); and to identify secondary RA events, it was 0. Of the 32 RA incidents captured by the PCR, only 15 (47%) correctly identified the correct lethal arrhythmia., Conclusions: We found that PCRs are not a reliable source of information for assessing the presence of ROSC and post-RA electrocardiogram rhythm. For quality control and research purposes, medical providers should consider augmenting data collection with continuous defibrillator recordings before making any conclusions about the occurrence of critical resuscitation events., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: In the United States, out-of-hospital cardiac arrest from drug overdose (OD-OHCA) caused over 38,000 deaths in 2010. A study in Pittsburgh found that OD-OHCA patients differed demographically and in the resuscitation treatments they received, despite identical AHA resuscitation guidelines. We hypothesized that health-care provider perceptions affect decision-making in the treatment of OD-OHCA versus non-OD OHCA., Methods: We conducted this survey at the National Association of EMS Physicians 2013 Scientific Assembly. Physicians and non-physician health-care providers were given one of two surveys containing 19 questions pertaining to the respondents' affiliated EMS agencies, the estimated proportion of OD-OHCA as well as the drugs involved, and the respondents' belief about the treatments for OD versus non-OD OHCA., Results: One hundred ninety-three respondents participated in this survey. Of the 193, 144 (75%) were physicians and 49 (25%) were nonphysicians. Seventy-nine percent of physicians identified current status as a medical director and 76% of nonphysicians identified as a paramedic. Participants estimated the average monthly proportion of all OHCA due to OD to be 9.4%. Participants ranked opioids, alcohol, antidepressants, and benzodiazepines as the most commonly utilized agents in OD-OHCA. The majority of physicians (42%) felt that the incidence of OD-OHCA was not changing while the majority of nonphysicians (53%) felt the incidence was increasing. Eighty-four percent of all respondents reported the use of naloxone during OD-OHCA resuscitation, while 13% reported administering naloxone during non-OD OHCA resuscitation. Eighty-nine percent of physicians and 67% of nonphysicians indicated that OD-OHCA patients had different demographics than non-OD OHCA, with primary reported differences being age, comorbidities, and socioeconomic status. Sixty-three percent of physicians and 71% of nonphysicians felt that OD-OHCA patients should be treated differently, with primary differences being the incorporation of etiology-specific treatments, performing different CPR with a focus on airway support, and transporting earlier., Conclusions: When surveyed, physicians and nonphysician providers report perceiving OD-OHCA treatment, outcomes, and patient demographics differently than non-OD OHCA and making different treatment decisions based on these perceptions. This may result in etiology-oriented resuscitation in the out-of-hospital setting, despite the lack of OD-specific resuscitation guidelines.

Introduction: We sought to compare characteristics of emergency medical services-treated out-of-hospital cardiac arrests resulting from suspected drug overdose with non-overdose cases and test the relationship between suspected overdose and survival to hospital discharge., Methods: Data from emergency medical services-treated, non-traumatic out-of-hospital cardiac arrests from 2006 to 2008 and late 2009 to 2011 were obtained from four EMS agencies in the Pittsburgh, Pennsylvania metropolitan area. Case definition for suspected drug overdose was naloxone administration, indication on the patient care report and/or indication by a review of hospital records. Resuscitation parameters included chest compression fraction, rate, and depth and the administration of resuscitation drugs. Demographic and outcome variables compared by suspected overdose status included age, sex, and survival to hospital discharge., Results: From 2342 treated out-of-hospital cardiac arrests, 180 were suspected overdose cases (7.7%) and were compared to 2162 non-overdose cases. Suspected overdose cases were significantly younger (45 vs. 65, p<0.001), less likely to be witnessed by a bystander (29% vs. 41%, p<0.005), and had a higher rate of survival to hospital discharge (19% vs. 12%, p=0.014) than non-overdoses. Suspected overdose cases had a higher overall chest compression fraction (0.69 vs. 0.67, p=0.018) and higher probability of adrenaline, sodium bicarbonate, and atropine administration (p<0.001). Suspected overdose status was predictive of survival to hospital discharge when controlling for other variables (p<0.001)., Conclusion: Patients with suspected overdose-related out-of-hospital cardiac arrest were younger, received different resuscitative care, and survived more often than non-overdose cases., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Monitoring during resuscitation remains relatively crude. Near-infrared spectroscopy (NIRS) measures aggregate oxygen saturation in a volume of tissue. We assessed the utility of continuous StO2 measurement in a porcine model of cardiac arrest, and explored the effects of differential vasoconstriction on StO2. We hypothesized that (1) StO2 trends correspond with the onset of loss of pulses, resuscitation, and return of spontaneous circulation (ROSC); (2) epinephrine has a dose-dependent effect on StO2., Methods: We anesthetized and instrumented 7 female swine, placing a NIRS probe on the left forelimb to recorded StO2. After 8 min of untreated VF and 2 min of CPR, we randomized animals to 0.015 mgkg(-1) (SDE) or 0.1mgkg(-1) (HDE) epinephrine. After 3 min of CPR, animals were defibrillated. Animals with ROSC were given SDE, then HDE for subsequent hemodynamic deteriorations. Data were analyzed with descriptive statistics and generalized linear model (alpha=0.05) to determine overall slope of pooled StO2 across animals for resuscitation segments., Results: Four animals received HDE and three SDE. All achieved ROSC. Significant coefficients (ΔStO2 min(-1)) were noted for resuscitation segments. StO2 decreased after loss of pulses (-29.1; 95%CI -33.4, -24.7; p<0.01) but plateaued during CPR (-0.2; 95%CI -1.2, 0.8; p=0.71). There was a graded decline in StO2 between SDE (-1.3; 95%CI -1.5, -1.2; p<0.01) and HDE (-3.1; 95%CI -5.8, -0.4; p=0.03). The slowest change occurred with ROSC (0.4; 95%CI 0.3, 0.5; p<0.01)., Conclusions: In a porcine model of OHCA, peripheral StO2 rapidly decreased after loss of pulses, but did not improve with CPR or epinephrine. It increased extremely slowly after ROSC., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Implementation barriers for extracorporeal life support in out-of-hospital cardiac arrest (OHCA) include initiation delay and candidate selection. We explored ischemia duration, cardiopulmonary resuscitation (CPR) duration, and physiologic variables that discriminated animals with return of spontaneous circulation (ROSC). We instrumented eight female swine (31.9 +/- 9.8 kg) with femoral artery and external jugular vein cannula. After 8 (n = 4) or 15 (n = 4) minutes ventricular fibrillation (VF), animals received 30, 40, 50, or 60 minutes of CPR and then drugs (.6 U/kg vasopressin, .1 mg/kg epinephrine, .1 mg/kg propranolol, sodium bicarbonate as indicated) after 5 minutes of CPR. Extracorporeal membrane oxygenation (ECMO) flow rate was 3 L/min < or =2 hours and then 1.5 L/min < or =2 hours before weaning. Animals were defibrillated (150 J biphasic) > or =15 minutes ECMO. Primary outcome for successful resuscitation was ROSC (organized rhythm with systolic blood pressure >80 mmHg). We measured arterial blood gas, electrolytes, mean arterial pressure (MAP), coronary perfusion pressure (CPP), and five quantitative VF waveform measures at key intervals. Continuous variables were compared with two-sample t test. All 8-minute VF animals were successfully resuscitated and had ROSC. MAP was higher at the beginning (27.0 +/- 7.1 vs. 15.0 +/- 4.4; p = .03) and end (31.3 +/- 12.8 vs. 11.5 +/- 7.3; p = .03) of CPR in animals successfully resuscitated. CPP was higher at the beginning of CPR (11.9 +/- 4.6 vs. 3.3 +/- 2.2;p = .01) and the end of CPR (18.5 + 12.1 vs..9 +/- 1.4; p = .03) among animals with ROSC. Amplitude spectrum area (AMSA) was superior at the end of CPR (-2.0 +/- 1.8 vs. -5.0 +/- 1.4; p = .04) in animals successfully resuscitated. In a porcine OHCA model, MAP and CPP at the beginning and end of CPR were higher in animals successfully resuscitated. AMSA was superior at the end of CPR in animals successfully resuscitated.