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BACKGROUND: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. METHODS: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. DISCUSSION: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. TRIAL REGISTRATION: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Abstract Background Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. Discussion In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Background: Airway management is a core component of the treatment of cardiac arrest. Where a rescuer cannot establish a patent airway to provide oxygenation and ventilation using standard basic and advanced airway techniques, there may be a need to consider emergency front-of-neck airway access (eFONA, e.g., cricothyroidotomy), but there is limited evidence to inform this approach. Objectives: This scoping review aims to identify the evidence for the use of eFONA techniques in patients with cardiac arrest. Methods: In November 2023, we searched Medline, Embase, and Cochrane Central to identify studies on eFONA in adults. We included randomised controlled trials, non-randomised studies, and case series with at least five cases that described any use of eFONA. We extracted data, including study setting, population characteristics, intervention characteristics, and outcomes. Our analysis focused on four key areas: incidence of eFONA, eFONA success rates, clinical outcomes, and complications. Results: The search identified 21,565 papers, of which 18,934 remained after de-duplication. After screening, we included 69 studies (53 reported incidence, 40 reported success rate, 38 reported clinical outcomes; 36 studies reported complications). We identified only one randomised controlled trial. Across studies, there was a total of 4,457 eFONA attempts, with a median of 31 attempts (interquartile range 16–56.5) per study. There was marked heterogeneity across studies that precluded any pooling of data. There were no studies that included only patients in cardiac arrest. Conclusion: The available evidence for eFONA is extremely heterogeneous, with no studies specifically focusing on its use in adults with cardiac arrest.

Background Sex‐specific risk management may improve outcomes in congenital long QT syndrome (LQTS). We recently developed a prediction score for cardiac events (CEs) and life‐threatening events (LTEs) in postadolescent women with LQTS. In the present study, we aimed to develop personalized risk estimates for the burden of CEs and LTEs in male adolescents with potassium channel‐mediated LQTS. Methods and Results The prognostic model was derived from the LQTS Registry headquartered in Rochester, NY, comprising 611 LQT1 or LQT2 male adolescents from age 10 through 20 years, using the following variables: genotype/mutation location, QTc‐specific thresholds, history of syncope, and β‐blocker therapy. Anderson‐Gill modeling was performed for the end point of CE burden (total number of syncope, aborted cardiac arrest, and appropriate defibrillator shocks). The applicability of the CE prediction model was tested for the end point of the first LTE (excluding syncope and adding sudden cardiac death) using Cox modeling. A total of 270 CEs occurred during follow‐up. The genotype–phenotype risk prediction model identified low‐, intermediate‐, and high‐risk groups, comprising 74%, 14%, and 12% of the study population, respectively. Compared with the low‐risk group, high‐risk male subjects experienced a pronounced 5.2‐fold increased risk of recurrent CEs (P

Background Telecommunicator CPR (T‐CPR), whereby emergency dispatch facilitates cardiac arrest recognition and coaches CPR over the telephone, is an important strategy to increase early recognition and bystander CPR in adult out‐of‐hospital cardiac arrest (OHCA). Little is known about this treatment strategy in the pediatric population. We investigated the role of T‐CPR and related performance among pediatric OHCA. Methods and Results This study was a retrospective cohort investigation of OHCA among individuals 8), the older age group was less likely to receive CPR before emergency medical services arrival (88% versus 69%, P=0.002). For those receiving T‐CPR, bystanders spent a median of 207 seconds (133–270) performing CPR. The median compression rate was 93 per minute (82–107) among those receiving T‐CPR. Conclusions T‐CPR is an important strategy to increase early recognition and early CPR among pediatric OHCA.

Abstract Aims Implantable defibrillators are considered life-saving therapy in heart failure (CHF) patients. Surprisingly, the recent Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) reached an opposing conclusion from that of numerous other trials about their survival benefit in patients with advanced CHF. A critical analysis of common control trial design may explain this paradoxical finding, with important implications for future studies. Methods and Results Common control trials compare several intervention groups to a single rather than separate control groups. Though potentially requiring fewer patients than trials using separate controls, variation in the common control group will influence all comparisons and creates correlations between findings. During subgroup analyses, this dependency of outcomes may increase belief in the presence of a real subgroup effect when, in fact, it should increase skepticism. For example, a high (r = 0.92), statistically unlikely (p = 0.052) correlation between comparisons was observed across the subgroups reported in SCD-HeFT. Such concordance between amiodarone and a defibrillator across subgroups was unexpected, given how much the effects of these treatments significantly differed from one another in the main study. This suggests the study's subgroup findings (specifically the absence of benefit from defibrillators in advanced CHF) were not necessarily a consequence of treatment; more likely, they resulted from variation in what the treatments were compared against, the common control. Conclusion Common control trials can be more efficient than other designs, but induce dependence between treatment comparisons and require cautious interpretation.

Abstract Background Congenital Long QT Syndrome (LQTS) is a hereditary arrhythmic disorder. We aimed to assess the performance of current genetic variant annotation scores among LQTS patients and their predictive impact. Methods We evaluated 2025 patients with unique mutations for LQT1–LQT3. A patient‐specific score was calculated for each of four established genetic variant annotation algorithms: CADD, SIFT, REVEL, and PolyPhen‐2. The scores were tested for the identification of LQTS and their predictive performance for cardiac events (CE) and life‐threatening events (LTE) and then compared with the predictive performance of LQTS categorization based on mutation location/function. Score performance was tested using Harrell's C‐index. Results A total of 917 subjects were classified as LQT1, 838 as LQT2, and 270 as LQT3. The identification of a pathogenic variant occurred in 99% with CADD, 92% with SIFT, 100% with REVEL, and 86% with PolyPhen‐2. However, none of the genetic scores correlated with the risk of CE (Harrell's C‐index: CADD = 0.50, SIFT = 0.51, REVEL = 0.50, and PolyPhen‐2 = 0.52) or LTE (Harrell's C‐index: CADD = 0.50, SIFT = 0.53, REVEL = 0.54, and PolyPhen‐2 = 0.52). In contrast, high‐risk mutation categorization based on location/function was a powerful independent predictor of CE (HR = 1.88; p

We investigated the risk of coronavirus disease (COVID-19)­ patients transmitting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to emergency medical service (EMS) providers, stratified by aerosol-generating procedures (AGP), in King County, Washington, USA, during February 16–July 31, 2020. We conducted a retrospective cohort investigation using a statewide COVID-19 registry and identified 1,115 encounters, 182 with ≥1 AGP. Overall, COVID-19 incidence among EMS personnel was 0.57 infections/10,000 person-days. Incidence per 10,000 person-days did not differ whether or not infection was attributed to a COVID-19 patient encounter (0.28 vs. 0.59; p>0.05). The 1 case attributed to a COVID-19 patient encounter occurred within an at-risk period and involved an AGP. We observed a very low risk for COVID-19 infection attributable to patient encounters among EMS first responders, supporting clinical strategies that maintain established practices for treating patients in emergency conditions.

Background Patients resuscitated from out‐of‐hospital circulatory arrest (OHCA) frequently have cardiopulmonary resuscitation injuries identifiable by computed tomography, although the prevalence, types of injury, and effects on clinical outcomes are poorly characterized. Methods and Results We assessed the prevalence of resuscitation‐associated injuries in a prospective, observational study of a head‐to‐pelvis sudden‐death computed tomography scan within 6 hours of successful OHCA resuscitation. Primary outcomes included total injuries and time‐critical injuries (such as organ laceration). Exploratory outcomes were injury associations with mechanical cardiopulmonary resuscitation and survival to discharge. Among 104 patients with OHCA (age 56±15 years, 30% women), 58% had bystander cardiopulmonary resuscitation, and total cardiopulmonary resuscitation time was 15±11 minutes. The prevalence of resuscitation‐associated injury was high (81%), including 15 patients (14%) with time‐critical findings. Patients with resuscitation injury were older (58±15 versus 46±13 years; P

BackgroundAntiarrhythmic drugs are used commonly in out-of-hospital cardiac arrest for shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, but without proven survival benefit.MethodsIn this randomized, double-blind trial, we compared parenteral amiodarone, lidocaine, and saline placebo, along with standard care, in adults who had nontraumatic out-of-hospital cardiac arrest, shock-refractory ventricular fibrillation or pulseless ventricular tachycardia after at least one shock, and vascular access. Paramedics enrolled patients at 10 North American sites. The primary outcome was survival to hospital discharge; the secondary outcome was favorable neurologic function at discharge. The per-protocol (primary analysis) population included all randomly assigned participants who met eligibility criteria and received any dose of a trial drug and whose initial cardiac-arrest rhythm of ventricular fibrillation or pulseless ventricular tachycardia was refractory to shock.ResultsIn the per-protocol population, 3026 patients were randomly assigned to amiodarone (974), lidocaine (993), or placebo (1059); of those, 24.4%, 23.7%, and 21.0%, respectively, survived to hospital discharge. The difference in survival rate for amiodarone versus placebo was 3.2 percentage points (95% confidence interval [CI], -0.4 to 7.0; P=0.08); for lidocaine versus placebo, 2.6 percentage points (95% CI, -1.0 to 6.3; P=0.16); and for amiodarone versus lidocaine, 0.7 percentage points (95% CI, -3.2 to 4.7; P=0.70). Neurologic outcome at discharge was similar in the three groups. There was heterogeneity of treatment effect with respect to whether the arrest was witnessed (P=0.05); active drugs were associated with a survival rate that was significantly higher than the rate with placebo among patients with bystander-witnessed arrest but not among those with unwitnessed arrest. More amiodarone recipients required temporary cardiac pacing than did recipients of lidocaine or placebo.ConclusionsOverall, neither amiodarone nor lidocaine resulted in a significantly higher rate of survival or favorable neurologic outcome than the rate with placebo among patients with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT01401647.).

Current resuscitation protocols require pausing chest compressions during cardiopulmonary resuscitation (CPR) to check for a pulse. However, pausing CPR when a patient is pulseless can worsen patient outcomes. Our objective was to design and evaluate an ECG-based algorithm that predicts pulse presence with or without CPR. We evaluated 383 patients being treated for out-of-hospital cardiac arrest with real-time ECG, impedance and audio recordings. Paired ECG segments having an organized rhythm immediately preceding a pulse check (during CPR) and during the pulse check (without CPR) were extracted. Patients were randomly divided into 60% training and 40% test groups. From training data, we developed an algorithm to predict the clinical pulse presence based on the wavelet transform of the bandpass-filtered ECG. Principal component analysis was used to reduce dimensionality, and we then trained a linear discriminant model using three principal component modes as input features. Overall, 38% (351/912) of checks had a spontaneous pulse. AUCs for predicting pulse presence with and without CPR on test data were 0.84 (95% CI (0.80, 0.88)) and 0.89 (95% CI (0.86, 0.92)), respectively. This ECG-based algorithm demonstrates potential to improve resuscitation by predicting the presence of a spontaneous pulse without pausing CPR with moderate accuracy.

Background The mechanism by which bystander cardiopulmonary resuscitation (CPR) improves survival following out‐of‐hospital cardiac arrest is unclear. We hypothesized that ventricular fibrillation (VF) waveform measures, as surrogates of myocardial physiology, mediate the relationship between bystander CPR and survival. Methods and Results We performed a retrospective cohort study of adult, bystander‐witnessed patients with out‐of‐hospital cardiac arrest with an initial rhythm of VF who were treated by a metropolitan emergency medical services system from 2005 to 2018. Patient, resuscitation, and outcome variables were extracted from emergency medical services and hospital records. A total of 3 VF waveform measures (amplitude spectrum area, peak frequency, and median peak amplitude) were computed from a 3‐second ECG segment before the initial shock. Multivariable logistic regression estimated the association between bystander CPR and survival to hospital discharge adjusted for Utstein elements. Causal mediation analysis quantified the proportion of survival benefit that was mediated by each VF waveform measure. Of 1069 patients, survival to hospital discharge was significantly higher among the 814 patients who received bystander CPR than those who did not (0.52 versus 0.43, respectively; P

Background Air travel affords an opportunity to evaluate resuscitation performance and outcome in a setting where automated external defibrillators (AEDs) are readily available. Methods and Results The study cohort included people aged ≥18 years with out of hospital cardiac arrest (OHCA) traveling through Seattle‐Tacoma International Airport between January 1, 2004 and December 31, 2019 treated by emergency medical services (EMS). The primary outcomes were pre‐EMS therapies (cardiopulmonary resuscitation, application of AED), return of spontaneous circulation, and survival to hospital discharge. Over the 16‐year study period, there were 143 OHCA occurring before EMS arrival, 34 (24%) on‐plane and 109 (76%) off‐plane. Cardiac etiology (81%) was the most common mechanism of arrest. The majority of arrests were bystander‐witnessed and presented with a shockable rhythm; these characteristics were more common in off‐plane OHCA compared with on‐plane (witnessed: 89% versus 74% and shockable: 72% versus 50%). Pre‐EMS therapies including cardiopulmonary resuscitation and AED application were common regardless of arrest location. Compared with on‐plane OHCA, off‐plane OHCA was associated with greater rates of return of spontaneous circulation (68% versus 44%) and 3‐fold higher rate of survival to hospital discharge (44% versus 15%). All survivors of on‐plane OHCA had AED application with defibrillation before EMS arrival. Conclusions When applied to air travel volumes, we estimate 350 air travel‐associated OHCA occur in the United States and 2000 OHCA worldwide each year, nearly a quarter of which happen on‐plane. These events are survivable when early arrest interventions including rapid arrest recognition, AED application, and CPR are deployed.

Brain and heart injury cause most out-of-hospital cardiac arrest deaths but limited pharmacotherapy exists to protect these tissues. Nitrite is a nitric oxide precursor that is protective in pre-clinical models of ischemic injury and safe in Phase I testing. Protection may occur by cGMP generation via the sGC pathway or through S-nitrosothiol and nitrated conjugated linoleic acid (NO2-CLA) formation. We hypothesized that nitrite provided during CPR signals through multiple pathways and that activation of signals is associated with OHCA outcome. To this end, we performed a secondary analysis of a phase 1 study of intravenous nitrite administration during resuscitation in adult out-of-hospital cardiac arrest. Associations between whole blood nitrite and derived plasma signals (cGMP and NO2-CLA) with patient characteristics and outcomes were defined using Chi-square or t-tests and multiple logistic regression. Whole blood nitrite levels correlated inversely with plasma NO2-CLA (p = 0.039) but not with cGMP. Patients with shockable rhythms had higher cGMP (p = 0.027), NO2-CLA (p

Prompt defibrillation is key to successful resuscitation from ventricular fibrillation out-of-hospital cardiac arrest (VF-OHCA). Preliminary evidence suggests that the timing of shock relative to the amplitude of the VF ECG waveform may affect the likelihood of resuscitation. We investigated whether the VF waveform amplitude at the time of shock (instantaneous amplitude) predicts outcome independent of other validated waveform measures. We conducted a retrospective study of VF-OHCA patients ≥18 old. We evaluated three VF waveform measures for each shock: instantaneous amplitude at the time of shock, and maximum amplitude and amplitude spectrum area (AMSA) over a 3-s window preceding the shock. Linear mixed-effects modeling was used to determine whether instantaneous amplitude was associated with shock-specific return of organized rhythm (ROR) or return of spontaneous circulation (ROSC) independent of maximum amplitude or AMSA. The 566 eligible patients received 1513 shocks, resulting in ROR of 62.0% (938/1513) and ROSC of 22.3% (337/1513). In unadjusted regression, an interquartile increase in instantaneous amplitude was associated with ROR (Odds ratio [OR] [95% confidence interval] = 1.27 [1.11–1.45]) and ROSC (OR = 1.27 [1.14–1.42]). However, instantaneous amplitude was not associated with ROR (OR = 1.13 [0.97–1.30]) after accounting for maximum amplitude, nor with ROR (OR = 1.00 [0.87–1.15]) or ROSC (OR = 1.05 [0.93–1.18]) after accounting for AMSA. By contrast, AMSA and maximum amplitude remained independently associated with ROR and ROSC. We did not observe an independent association between instantaneous amplitude and shock-specific outcomes. Efforts to time shock to the maximal amplitude of the VF waveform are unlikely to affect resuscitation outcome. [ABSTRACT FROM AUTHOR]

Background: Women with congenital long QT syndrome (LQTS) experience increased cardiac event risk after the onset of adolescence, perhaps stemming from the known modulating effects of sex hormones on the cardiac potassium channels.Objective: We hypothesized that the effect of sex hormones on cardiac ion channel function may modify electrocardiographic (ECG) parameters associated with the propensity for ventricular tachyarrhythmias during the menstrual cycle in women with LQTS.Methods: We prospectively enrolled 65 women with congenital LQTS (type 1 LQTS [LQT1], n = 24 [36.9%]; type 2 LQTS [LQT2], n = 20 [30.8%]) and unaffected female relatives (n = 21 [32.3%]). Patients underwent three 7-day ECG recordings during their menstrual cycles. Simultaneous saliva testing of sex hormone levels was conducted on the first day of each 7-day ECG recording cycle.Results: The mean age was 35 ± 8 years, without a significant difference among the groups. In women with LQT2, linear mixed effects models showed significant inverse correlations of the corrected QT interval with progesterone levels (P < .001) and with the progesterone to estradiol ratio (P < .001). Inverse relationships of the R-R interval with estradiol levels (P = .003) and of the T-wave duration with testosterone levels (P = .014) were also observed in women with LQT2. In contrast, no significant associations were observed between ECG parameters and sex hormone levels in women with LQT1 or unaffected relatives.Conclusion: This is the first study to prospectively assess correlations between repolarization dynamics and sex hormone levels during the menstrual cycle in women with congenital LQTS. Our findings show genotype-specific unique corrected QT dynamics during the menstrual cycle that may affect the propensity for ventricular tachyarrhythmia in women with LQTS, particularly women with LQT2. [ABSTRACT FROM AUTHOR]

Background: Use of oral contraceptives (OCs) may modulate the clinical course of women with congenital long QT syndrome (LQTS). The safety of OC use by sex hormone content has not been assessed in women with LQTS.Objective: We aimed to evaluate the association of OCs with the risk of cardiac events (CEs) in women with LQTS.Methods: Beginning in 2010, information on menarche onset, OC use, pregnancy, and menopause were obtained from women enrolled in the Rochester LQTS Registry. Type of OC was categorized as progestin-only, estrogen-only, or combined (estrogen/progestin). Andersen-Gill multivariate modeling was used to evaluate the association of time-dependent OC use with the burden of CE (total number of syncope, aborted cardiac arrest, and LQTS-related sudden cardiac death) from menarche onset through 40 years. Findings were adjusted for genotype, corrected QT duration, and time-dependent β-blocker therapy.Results: A total of 1659 women with LQTS followed through March 2021, of whom 370 (22%) were treated with an OC. During a cumulative follow-up of 35,797 years, there were a total of 2027 CE. Multivariate analysis showed that progestin-only OC was associated with a pronounced 2.8-fold (P = .01) increased risk of CEs in women who did not receive β-blocker therapy, while β-blockers were highly protective during progestin-only OC treatment (hazard ratio 0.22; P = .01; P = .006 for β-blocker-by-OC interaction). The risk associated with OC use without concomitant β-blocker treatment was pronounced in women with LQTS type 2.Conclusion: Our findings suggest that progestin-only OC should not be administered in women with LQTS without concomitant β-blocker therapy. OCs should be used with caution in women with LQTS type 2. [ABSTRACT FROM AUTHOR]