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Every 10 years, the American Heart Association (AHA) Emergency Cardiovascular Care Committee establishes goals to improve survival from cardiac arrest. These goals align with broader AHA Impact Goals and support the AHA’s advocacy efforts and strategic investments in research, education, clinical care, and quality improvement programs. This scientific statement focuses on 2030 AHA emergency cardiovascular care priorities, with a specific focus on bystander cardiopulmonary resuscitation, early defibrillation, and neurologically intact survival. This scientific statement also includes aspirational goals, such as establishing cardiac arrest as a reportable disease and mandating reporting of standardized outcomes from different sources; advancing recognition of and knowledge about cardiac arrest; improving dispatch system response, availability, and access to resuscitation training in multiple settings and at multiple time points; improving availability, access, and affordability of defibrillators; providing a focus on early defibrillation, in-hospital programs, and establishing champions for debriefing and review of cardiac arrest events; and expanding measures to track outcomes beyond survival. The ability to track and report data from these broader aspirational targets will potentially require expansion of existing data sets, development of new data sets, and enhanced integration of technology to collect process and outcome data, as well as partnerships of the AHA with national, state, and local organizations. The COVID-19 (coronavirus disease 2019) pandemic, disparities in COVID-19 outcomes for historically excluded racial and ethnic groups, and the longstanding disparities in cardiac arrest treatment and outcomes for Black and Hispanic or Latino populations also contributed to an explicit focus and target on equity for the AHA Emergency Cardiovascular Care 2030 Impact Goals.

The International Liaison Committee on Resuscitation engages in a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation and first aid science. Draft Consensus on Science With Treatment Recommendations are posted online throughout the year, and this annual summary provides more concise versions of the final Consensus on Science With Treatment Recommendations from all task forces for the year. Topics addressed by systematic reviews this year include resuscitation of cardiac arrest from drowning, extracorporeal cardiopulmonary resuscitation for adults and children, calcium during cardiac arrest, double sequential defibrillation, neuroprognostication after cardiac arrest for adults and children, maintaining normal temperature after preterm birth, heart rate monitoring methods for diagnostics in neonates, detection of exhaled carbon dioxide in neonates, family presence during resuscitation of adults, and a stepwise approach to resuscitation skills training. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the quality of the evidence, using Grading of Recommendations Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence-to-Decision Framework Highlights sections. In addition, the task forces list priority knowledge gaps for further research. Additional topics are addressed with scoping reviews and evidence updates.

Bystander cardiopulmonary resuscitation increases the likelihood of out-of-hospital cardiac arrest survival by more than two-fold. A common barrier to the prompt initiation of compressions is moving victims to the floor, but compression quality on a “floor” versus a “mattress” has not been tested among lay bystanders.

This is the sixth annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. This summary addresses the most recently published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. Topics covered by systematic reviews include cardiopulmonary resuscitation during transport; approach to resuscitation after drowning; passive ventilation; minimizing pauses during cardiopulmonary resuscitation; temperature management after cardiac arrest; use of diagnostic point-of-care ultrasound during cardiac arrest; use of vasopressin and corticosteroids during cardiac arrest; coronary angiography after cardiac arrest; public-access defibrillation devices for children; pediatric early warning systems; maintaining normal temperature immediately after birth; suctioning of amniotic fluid at birth; tactile stimulation for resuscitation immediately after birth; use of continuous positive airway pressure for respiratory distress at term birth; respiratory and heart rate monitoring in the delivery room; supraglottic airway use in neonates; prearrest prediction of in-hospital cardiac arrest mortality; basic life support training for likely rescuers of high-risk populations; effect of resuscitation team training; blended learning for life support training; training and recertification for resuscitation instructors; and recovery position for maintenance of breathing and prevention of cardiac arrest. Members from 6 task forces have assessed, discussed, and debated the quality of the evidence using Grading of Recommendations Assessment, Development, and Evaluation criteria and generated consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence-to-Decision Framework Highlights sections, and priority knowledge gaps for future research are listed.

The International Liaison Committee on Resuscitation initiated a continuous review of new, peer-reviewed published cardiopulmonary resuscitation science. This is the fifth annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations; a more comprehensive review was done in 2020. This latest summary addresses the most recently published resuscitation evidence reviewed by International Liaison Committee on Resuscitation task force science experts. Topics covered by systematic reviews in this summary include resuscitation topics of video-based dispatch systems; head-up cardiopulmonary resuscitation; early coronary angiography after return of spontaneous circulation; cardiopulmonary resuscitation in the prone patient; cord management at birth for preterm and term infants; devices for administering positive-pressure ventilation at birth; family presence during neonatal resuscitation; self-directed, digitally based basic life support education and training in adults and children; coronavirus disease 2019 infection risk to rescuers from patients in cardiac arrest; and first aid topics, including cooling with water for thermal burns, oral rehydration for exertional dehydration, pediatric tourniquet use, and methods of tick removal. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the quality of the evidence, according to the Grading of Recommendations Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations or good practice statements. Insights into the deliberations of the task forces are provided in Justification and Evidence-to-Decision Framework Highlights sections. In addition, the task forces listed priority knowledge gaps for further research.

As more people are surviving cardiac arrest, focus needs to shift towards improving neurological outcomes and quality of life in survivors. Brain injury after resuscitation, a common sequela following cardiac arrest, ranges in severity from mild impairment to devastating brain injury and brainstem death. Effective strategies to minimise brain injury after resuscitation include early intervention with cardiopulmonary resuscitation and defibrillation, restoration of normal physiology, and targeted temperature management. It is important to identify people who might have a poor outcome, to enable informed choices about continuation or withdrawal of life-sustaining treatments. Multimodal prediction guidelines seek to avoid premature withdrawal in those who might survive with a good neurological outcome, or prolonging treatment that might result in survival with severe disability. Approximately one in three admitted to intensive care will survive, many of whom will need intensive, tailored rehabilitation after discharge to have the best outcomes.

Outcomes of extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest depend on time to therapy initiation. We hypothesize that it would be feasible to select refractory out-of-hospital cardiac arrest patients for expedited transport based on real-time estimates of the 911 call to the emergency department (ED) arrival interval, and for emergency physicians to rapidly initiate ECPR in eligible patients.

The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the third annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. It addresses the most recent published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. This summary addresses the role of cardiac arrest centers and dispatcher-assisted cardiopulmonary resuscitation, the role of extracorporeal cardiopulmonary resuscitation in adults and children, vasopressors in adults, advanced airway interventions in adults and children, targeted temperature management in children after cardiac arrest, initial oxygen concentration during resuscitation of newborns, and interventions for presyncope by first aid providers. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the certainty of the evidence on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence to Decision Framework Highlights sections. The task forces also listed priority knowledge gaps for further research.

The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the second annual summary of International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations that includes the most recent cardiopulmonary resuscitation science reviewed by the International Liaison Committee on Resuscitation. This summary addresses the role of antiarrhythmic drugs in adults and children and includes the Advanced Life Support Task Force and Pediatric Task Force consensus statements, which summarize the most recent published evidence and an assessment of the quality of the evidence based on Grading of Recommendations, Assessment, Development, and Evaluation criteria. The statements include consensus treatment recommendations approved by members of the relevant task forces. Insights into the deliberations of each task force are provided in the Values and Preferences and Task Force Insights sections. Finally, the task force members have listed the top knowledge gaps for further research.

Despite significant advances in the field of resuscitation science, important knowledge gaps persist. Current guidelines for resuscitation are based on the International Liaison Committee on Resuscitation 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations, which includes treatment recommendations supported by the available evidence. The writing group developed this consensus statement with the goal of focusing future research by addressing the knowledge gaps identified during and after the 2015 International Liaison Committee on Resuscitation evidence evaluation process. Key publications since the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations are referenced, along with known ongoing clinical trials that are likely to affect future guidelines.

The American Heart Association previously recommended implementation of cardiac resuscitation systems of care that consist of interconnected community, emergency medical services, and hospital efforts to measure and improve the process of care and outcome for patients with cardiac arrest. In addition, the American Heart Association proposed a national process to develop and implement evidence-based guidelines for cardiac resuscitation systems of care. Significant experience has been gained with implementing these systems, and new evidence has accumulated. This update describes recent advances in the science of cardiac resuscitation systems and evidence of their effectiveness, as well as recent progress in dissemination and implementation throughout the United States. Emphasis is placed on evidence published since the original recommendations (ie, including and since 2010).

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Introduction:We previously demonstrated that defibrillation followed by chest compression generates more aerosols than chest compression or no-flow state alone. However, the best strategies to prevent aerosol spread during cardiac arrest (CA) resuscitation remain unknown. We hypothesized that mask applications could reduce aerosol spread during chest compressions and defibrillation in a swine CA model.Methods:To simulate witnessed CA with bystander-initiated CPR, 24 female non-intubated swine (43.8 [2.7] kg) underwent 4 minutes of untreated ventricular fibrillation CA followed by 10 two-minute cycles of mechanical chest compression and defibrillation without ventilation. The animals were randomized to receive no mask, cloth mask, surgical mask, N95 mask, or a sealed nose cone over their snouts during resuscitation (n=5/group except nose cone n=4). The diameter (0.3 - 10 μm) and quantity of particles generated during 45-second intervals of no-flow, chest compression, and after each defibrillation were measured 2 inches anterior to the snout.Results:There were no significant differences between total particles generated during chest compression after defibrillation in unmasked versus masked animals regardless of the mask type, while the nose cone significantly reduced total particles. These findings were consistent across all 10 defibrillations (Fig. 1a) and all particle sizes (Fig. 1b). Furthermore, the minimal pre- and post-defibrillation particles detected outside of the nose cone indicated that the ineffectiveness of masks in preventing aerosol spread during CA resuscitation was likely due to their inadequate fit (Fig. 1c).Conclusion:Mask application did not reduce aerosol spread during defibrillation followed by chest compression in a swine CA model. Our data indicate that mask fit is a critical parameter for reducing aerosol transport and do not support mask application on CA victims during bystander-initiated CPR.

Introduction:Invasive mechanical support by percutaneous left ventricular assist device (pL-VAD) and percutaneous balloon occlusion of the aorta (pAO) during CPR have recently emerged as feasible resuscitation strategies for refractory cardiac arrest. It is unknown if combining pL-VAD and pAO has additive or synergist benefits during CPR.Hypothesis:Combined pAO and pL-VAD during CPR will significantly enhance coronary and cerebral perfusion pressure (CoPP, CePP), return of spontaneous heartbeat (ROSHB) rate, and post-ROSHB cardiac function compared to either therapy alone after prolonged cardiac arrest in a swine model.Methods:Nineteen swine 52 (3.9) kg; (9 male) were utilized. A pL-VAD (Impella CP®) and a balloon catheter were inserted through the femoral arteries under general anesthesia. Ventricular fibrillation was induced and left untreated for 8 minutes followed by 16 minutes of mechanical CPR (mCPR). Animals were randomized to 3 treatment groups A) pL-VAD (n=6), B) pL-VAD+pAO (n=6), and C) pAO (n=7). Treatment was initiated 24 minutes after arrest. mCPR was continued during treatment. Defibrillation was attempted 3 times starting at minute 28 and then every 4 minutes. Hemodynamics, cardiac function, and blood gases were monitored for 4 hours after ROSHB.Results:Following the intervention, CoPP for Group B increased by a mean (SD) of 26 (15) mmHg which is significantly different from both groups A and C, 3.6 (12) and 7.5 (6.3) mmHg (p=0.007). CePP increased by 2 (11.5), 18.5 (18.6), and 8.3 (6.8) mmHg for groups A, B, and C with no significant differences (p=0.06). The rate of ROSHB was 67% (4 of 6), 83% (5 of 6), and 100% (7 of 7) for groups A, B, and C (p>0.05). All groups exhibited similar levels of post-ROSHB recovery including blood pressure, venous oxygen saturation, cardiac output, ejection fraction, and lactate clearance. Total ionotropic and vasopressor support (epinephrine and norepinephrine) was 56 (25), 50 (5), and 81 (90) mcg/Kg in groups A, B, and C (p=0.66).Conclusion:Combined pAO and pL-VAD resulted in greater improvement of CPR hemodynamics compared to either intervention alone in this model of prolonged cardiac arrest. However, it remains unclear if this translates into better recovery of cardiovascular and neurological function.

Introduction:Intranasal insulin is a putative neuroprotective therapy that could be easily delivered very early after cardiac arrest, but safety at doses extrapolated from animal models have not been studied in humans. We hypothesized that high-dose intranasal insulin can be safely delivered to healthy human subjects.Methods:This was a phase 1, open label dose-finding study of intranasal insulin in healthy participants.The primary objective was to determine the maximum tolerated dose of intranasal insulin in healthy subjects. Placebo and insulin were given intranasally to supine healthy volunteers intranasally at escalating doses from 0 to 1000 units on repeated weekly visits. Serum glucose, insulin, and C-peptide levels were measured serially at 0, 15, 30, 60, 120, 180 and 240 minutes after administration.Results:Twenty four participants (12 female, median age 53.5, IQR 35.75-61) were enrolled. There was no change in average serum glucose after administration of intranasal insulin. Average serum insulin increased slightly in a dose-dependent manner, peaking at 15 minutes. C-peptide went down over time from administration in all groups. One participant had severe hypoglycemia (minimum 24 mg/dL 45 min after receiving 600U intranasal insulin) that was corrected with oral intake and intravenous dextrose. Another participant had transient hypoglycemia (minimum 51 mg/dL at 30 min) also after 600U intranasal insulin with mild symptoms that was corrected with oral intake. Hypoglycemic episodes were associated with increases in serum insulin. Both participants continued in the study without hypoglycemia after additional doses. One participant dropped out for reasons unrelated to the intervention.Discussion:High-dose intranasal insulin up to 1000U was well tolerated, without changes in mean glucose, but with small measurable systemic absorption. Idiosyncratic hypoglycemia requires further study. Delivery of intranasal insulin to the brain at these doses, and efficacy of high-dose intranasal insulin as a neuroprotective therapy after cardiac arrest require further study.

Background:Post-arrest myocardial dysfunction is one of the major causes of rearrest within early period after return of spontaneous circulation (ROSC). Multiple interacting processes including leukocyte-mediated injury is suspected to contribute to deterioration of cardiac function after cardiac arrest. Unlike the standard leukocyte filter (LF), the leukocyte modulation (L-MOD) device is expected to alter the natural inflammatory process by preferentially binding and inactivating the activated leukocytes. We tested the hypothesis that either a standard LF system or a L-MOD device will decrease myocardial injury during extracorporeal cardiopulmonary resuscitation (ECPR).Methods:Total 34 swine (45.5±2.5 kg, male=18, female=16) underwent 8 minutes of untreated ventricular fibrillation cardiac arrest followed by mechanical CPR for 30 minutes. Immediately followed by 8 hours of ECPR with randomly assigned leukocyte treatment protocol; ECPR with standard care (n=10), LF (n=12), and L-MOD (n=12). Left ventricular ejection fraction (LVEF) was evaluated hourly by transthoracic echocardiography. At the end of the study, the heart was removed, fixed and embedded in paraffin. 5- μm sections off the left and right ventricular (RV) free wall were H & E stained for analysis. Five views each of LV and RV under 20хobjective lens were randomly selected with Leica LAS X software. Myofiber degeneration and hemorrhage were graded as 0 (absence) to 3 (severe). Grade was average of 5 views.Results:The mean LVEF at baseline was 65±6%. There were no significantly difference in rate of achieving ROSC (70% vs. 75% vs. 58.3%, p=0.671) and LVEF at 8 hours after initiating ECPR (35±27% vs. 36±31% vs. 28±30%, p=0.776) between the group with control, LF, and LMOD respectively. There were no significant difference in myofiber degeneration grade (LV, 1.5±0.5 vs. 1.1±0.6 vs. 1.4±0.4, p=0.334; and RV, 1.6±0.6 vs. 1.8±0.7 vs. 1.5±0.6, p=0.525) and hemorrhage grade (LV, 0.0±0.1 vs. 0.0±0.1 vs. 0.0±0.1, p=0.841; and RV, 0.0±0.0 vs. 0.0±0.0 vs. 0.0±0.0) between control, LF, and L-MOD groups.Discussion:In swine model with prolonged cardiac arrest treated with ECPR, a standard LF system and a L-MOD device did not decrease early myocardial injury.

Background:Promptly initiated bystander cardiopulmonary resuscitation (CPR) improves survival from out-of-hospital cardiac arrest (OHCA). Many OHCA patients require repositioning (e.g., moved to hard surface) to improve chest compression (CC) quality, which can delay CC. We examined the association between repositioning, CC delay, and patient outcomes.Methods:We used quality improvement data from review of 911 dispatch audio recordings of OHCA in adults eligible for telephone CPR (T-CPR) in King County, WA between 2013 and 2021. OHCA was categorized into 3 groups: CC not delayed, CC delayed due to bystander-reported physical limitations to reposition the patient, or CC delayed for other reasons. The primary outcome was delay in CC defined as the interval between start of T-CPR instructions and CC onset. We performed Kruskal-Wallis and Chi Square tests to evaluate global differences and post-hoc analyses with Bonferroni correction for pairwise differences.Results:Of the 3,483 OHCA patients eligible for T-CPR, median age was 64, 35% were women, 45% were witnessed, 23% had an initial shockable rhythm, and 15% survived to discharge. T-CPR was not delayed between instructions and compressions in 1,618 patients (46%), was delayed due to bystander physical limitations in repositioning the patient in 1,218 (35%), and was delayed for other reasons in 647 (19%). The interval from T-CPR instruction to CC onset was longest for the physical limitations delay group (121 secs, IQR: 69) compared to the other delay group (88 secs, IQR: 65) and the no delay group (54 secs, IQR: 36) (all comparisons p<.05). Bystander CPR was less frequent in the physical limitations delay group (74%) versus no delay (100%) or the other delays group (81%, all comparisons p<.05). In the physical limitation delays group, 154 (13%) of patients ultimately received bystander CPR on a soft surface (e.g., bed). This group also had the lowest hospital discharge survival (11%, p<.05) versus the no delays (17%) and other delays group (17%).Conclusion:Bystander physical limitations are a common barrier to repositioning patients to begin CPR. Repositioning delays were associated with lower likelihood of receiving CPR, longer times to begin CC, and lower survival rates.

The American Heart Association (AHA) commends the recently released Institute of Medicine (IOM) report, Strategies to Improve Cardiac Arrest Survival: A Time to Act(2015). The AHA recognizes the unique opportunity created by the report to meaningfully advance the objectives of improving outcomes for sudden cardiac arrest. For decades, the AHA has focused on the goal of reducing morbidity and mortality from cardiovascular disease though robust support of basic, translational, clinical, and population research. The AHA also has developed a rigorous process using the best available evidence to develop scientific, advisory, and guideline documents. These core activities of development and dissemination of scientific evidence have served as the foundation for a broad range of advocacy initiatives and programs that serve as a foundation for advancing the AHA and IOM goal of improving cardiac arrest outcomes. In response to the call to action in the IOM report, the AHA is announcing 4 new commitments to increase cardiac arrest survival: (1) The AHA will provide up to $5 million in funding over 5 years to incentivize resuscitation data interoperability; (2) the AHA will actively pursue philanthropic support for local and regional implementation opportunities to increase cardiac arrest survival by improving out-of-hospital and in-hospital systems of care; (3) the AHA will actively pursue philanthropic support to launch an AHA resuscitation research network; and (4) the AHA will cosponsor a National Cardiac Arrest Summit to facilitate the creation of a national cardiac arrest collaborative that will unify the field and identify common goals to improve survival. In addition to the AHA’s historic and ongoing commitment to improving cardiac arrest care and outcomes, these new initiatives are responsive to each of the IOM recommendations and demonstrate the AHA’s leadership in the field. However, successful implementation of the IOM recommendations will require a timely response by all stakeholders identified in the report and a coordinated approach to achieve our common goal of improved cardiac arrest outcomes.

Magnesium (Mg2+) depletion can have detrimental effects in postcardiac arrest patients through multiple potential mechanisms. Therapeutic hypothermia (TH) produces a Mg2+diuresis, but the effects of postcardiac arrest TH on serum Mg2+levels in patients with postcardiac arrest syndrome (PCAS) are yet to be systematically quantified. We conducted a retrospective chart review of 119 consecutive comatose PCAS patients treated with TH between 2005 and 2010 and compared them to 33 matched historic controls (HCs) seen at the same institution between 2002 and 2005 who were not treated with TH. We abstracted data from the first 96 hours postarrest, including date, time, and value of serum Mg2+levels and date, time, and amount of Mg2+repletion, along with outcomes at discharge. The median Mg2+level of TH patients was 2.0 mg/dL [interquartile range (IQR), 1.9–2.2 mg/dL] (0.82 mmol/L [IQR, 0.78–0.90 mmol/L]) versus 2.2 mg/dL [IQR, 1.9–2.4 mg/dL] (0.90 mmol/L [IQR, 0.82–0.99 mmol/L]) (p=0.2) in HCs. In addition, 42.9% (520/1214) of Mg2+levels in TH patients versus 31.9% (43/135) (p=0.014) in HC patients were below 2.0 mg/dL [0.82 mmol/L]. The average number of times the Mg2+level was checked in TH patients was 10.2 (range 1–18) versus 4.1 (range 1–10) in HCs. The TH patients were more likely to receive supplemental Mg2+than HCs (81.5% [97/119] vs. 27.3% [9/33] [p<0.01]). The mean supplemental Mg2+dose was 1.9 g for TH patients versus 0.5 g for HC patients. Mortality in patients treated with TH was 53.1% (60/113) versus 78.6% (22/28) (p=0.014) in HCs. Low serum Mg2+levels with subsequent Mg2+supplementation were more common in comatose patients with PCAS treated with TH compared to normothermic HC patients. The effect of untreated hypomagnesemia on postcardiac arrest outcomes remains to be determined.

Targeted temperature management (TTM) has been investigated experimentally and used clinically for over 100 years. The initial rationale for the clinical application of TTM, historically referred to as therapeutic hypothermia, was to decrease the metabolic rate, allowing the injured brain time to heal. Subsequent research demonstrated the temperature dependence of diverse cellular mechanisms including endothelial dysfunction, production of reactive oxygen species, and apoptosis. Consequently, modern use of TTM centers on neuroprotection following focal or global neurologic injury. Despite a solid basic science rationale for applying TTM in a variety of disease processes, including cardiac arrest, traumatic brain injury, ischemic stroke, neonatal ischemic encephalopathy, sepsis-induced encephalopathy, and hepatic encephalopathy, human efficacy data are limited and vary greatly from disease to disease. Ten years ago, two landmark investigations yielded high-quality data supporting the application of TTM in comatose survivors of out-of-hospital cardiac arrest. Additionally, TTM has been demonstrated to improve outcomes for neonatal patients with anoxic brain injury secondary to hypoxic ischemic encephalopathy. Trials are currently under way, or have yielded conflicting results in, examining the utility of TTM for the treatment of ischemic stroke, traumatic brain injury, and acute myocardial infarction. In this review, we place TTM in historic context, discuss the pathophysiologic rationale for its use, review the general concept of a TTM protocol for the management of brain injury, address some of the common side effects encountered when lowering human body temperature, and examine the data for its use in diverse disease conditions with in-depth examination of TTM for postarrest care and pediatric applications.

Reversal of tissue hypoxia, particularly in the heart and brain, is a fundamental goal of cardiopulmonary resuscitation. However, a growing body of evidence suggests that hyperoxia, especially after return of spontaneous circulation (ROSC), may worsen outcomes. The purpose of this review is to describe the current evidence supporting the concept of controlled oxygenation during and after cardiac arrest.

The cellular and molecular pathways initiated by traumatic brain injury (TBI) may compromise the function and structural integrity of mitochondria, thereby contributing to cerebral metabolic dysfunction and cell death. The extent to which TBI affects regional mitochondrial populations with respect to structure, function, and swelling was assessed 3 hours and 24 hours after lateral fluid—percussion brain injury in the rat. Significantly less mitochondrial protein was isolated from the injured compared with uninjured parietotemporal cortex, whereas comparable yields were obtained from the hippocampus. After injury, cortical and hippocampal tissue ATP concentrations declined significantly to 60% and 40% of control, respectively, in the absence of respiratory deficits in isolated mitochondria. Mitochondria with ultrastructural morphologic damage comprised a significantly greater percent of the population isolated from injured than uninjured brain. As determined by photon correlation spectroscopy, the mean mitochondrial radius decreased significantly in injured cortical populations (361 ± 40 nm at 24 hours) and increased significantly in injured hippocampal populations (442 ± 36 at 3 hours) compared with uninjured populations (Ctx: 418 ± 44; Hipp: 393 ± 24). Calcium-induced deenergized swelling rates of isolated mitochondrial populations were significantly slower in injured compared with uninjured samples, suggesting that injury alters the kinetics of mitochondrial permeability transition (MPT) pore activation. Cyclosporin A (CsA)-insensitive swelling was reduced in the cortex, and CsA-sensitive and CsA-insensitive swelling both were reduced in the hippocampus, demonstrating that regulated MPT pores remain in mitochondria isolated from injured brain. A proposed mitochondrial population model synthesizes these data and suggests that cortical mitochondria may be depleted after TBI, with a physically smaller, MPT-regulated population remaining. Hippocampal mitochondria may sustain damage associated with ballooned membranes and reduced MPT pore calcium sensitivity. The heterogeneous mitochondrial response to TBI may underlie posttraumatic metabolic dysfunction and contribute to the pathophysiology of TBI.

Activity of the Ca2+-dependent protease calpain is increased in neurons after global and focal brain ischemia, and may contribute to postischemic injury cascades. Understanding the time course and location of calpain activity in the post-ischemic brain is essential to establishing causality and optimizing therapeutic interventions. This study examined the temporal and spatial characteristics of brain calpain activity after transient forebrain ischemia (TFI) in rats. Male Long Evans rats underwent 10 min of normothermic TFI induced by bilateral carotid occlusion with hypovolemic hypotension (MABP 30 mm Hg). Brain calpain activitywas examined between 1 and 72 h after reperfusion. Western blot analysis of regional brain homogenates demonstrated a bimodal pattern of calpain-mediated α-spectrin degradation in the hippocampus, cortex, and striatum with an initial increase at 1 h followed by a more prominent secondary increase at 36 h after reperfusion. Immunohistochemical analysis revealed that calpain activity was primarily localized to dendritic fields of selectively vulnerable neurons at one hour after reperfusion. Between 24 and 48 h after reperfusion neuronal calpain activity progressed from the dorsal to ventral striatum, medial to lateral CA1 hippocampus, and centripetally expanded from watershed foci in the cerebral cortex. This progression was associated with fragmentation of dendritic processes, calpain activation in the neuronal soma and subsequent neuronal degeneration. These observations demonstrate a clear association between calpain activation and subsequent delayed neuronal death and suggest broad therapeutic window for interventions aimed at preventing delayed intracellular Ca2+ overload and pathologic calpain activation.

Introduction:Extracorporeal cardiopulmonary resuscitation (ECPR) has emerged as a promising resuscitation strategy for select patients suffering out-of-hospital cardiac arrest (OHCA), though limited data exists regarding detailed best practices for the complex process of initiating ECPR following OHCA.Hypothesis:Expert consensus using a modified Delphi process can systematically identify detailed best practices for ECPR initiation following adult non-traumatic OHCA.Methods:We utilized a modified Delphi process consisting of two survey rounds and a virtual consensus meeting to systematically identify best practices for ECPR initiation following adult non-traumatic OHCA. A modified Delphi process builds content validity and is an accepted method to develop consensus by eliciting expert opinions through multiple rounds of questionnaires. Consensus was achieved when items reached a high level of agreement, defined as greater than 80% responses for a particular item rated a 4 or 5 on a 5-point Likert scale.Results:Snowball sampling generated a panel of 14 content experts, composed of physicians from four continents and four primary specialties. Seven existing institutional protocols for ECPR cannulation following OHCA were identified and merged into a single comprehensive list of 216 items. The panel ultimately reached consensus on 95 items: Prior to Patient Arrival (8 items), Inclusion Criteria (8), Exclusion Criteria (7), Patient Arrival (8), ECPR Cannulation (21), Go On Pump (17), and Post-Cannulation (26).Conclusion:We present a list of essential items for initiation of ECPR following adult non-traumatic OHCA, generated using a modified Delphi process from an international panel of content experts. These findings can benefit centers currently performing ECPR for OHCA in quality assurance and performance improvement, and can serve as a template for new ECPR programs to follow.

Introduction:Sudden Cardiac Arrest (CA) affects more than 400,000 people per year in the United States. Although a third of these patients survive to hospital admission, another 60-70% go on to die due to failed recovery of vital organ function. Microvascular thrombosis has been suggested as a potential contributor to prolonged organ dysfunction, but no antithrombotic therapies have been shown to be beneficial and coagulofibrinolytic abnormalities in prolonged CA remain poorly understood.Objectives:To establish key biomarkers of porcine coagulation and fibrinolysis in the setting of prolonged CA and cardiopulmonary resuscitation (CPR) and test the ability of ART-123 (recombinant human thrombomodulin alpha) to reverse these abnormalities.Methods:15 pigs (n=5 per group) underwent 8 minutes of no-flow CA followed by 50 minutes of mechanical CPR. Animals were randomized to receive saline or ART-123 (~1mg/kg) pre-arrest (5 minutes prior to ventricular fibrillation) or post-arrest (2 minutes after initiation of CPR).Results:Robust and ongoing activation of coagulation and fibrinolysis were detected throughout the resuscitation. After 50 minutes of CPR, plasma tests suggested consumptive coagulopathy, while whole blood testing (thromboelastography) indicated a persistent hypercoagulable state. ART-123 had a clear anticoagulant effect irrespective of timing (TAT complexes 381±25 vs. 238±18 vs. 226±12, p<0.01, and d-dimer 4.86±0.54 vs. 2.39±0.2 vs. 2.46±0.21 for vehicle, pre-arrest, post-arrest, p = 0.05). A pro-fibrinolytic effect was also observed, but only when the drug was given before no-flow, with a significant increase in levels of free endogenous tPA (1.2±0.12 vs. 3.29±0.29 vs. 1.72±0.3, p < 0.001) and corresponding suppression of free PAI-1 (0.59±0.15 vs. 0.14±0.01 vs. 0.41±0.09, p < 0.001).Conclusion:Our porcine CA model provides an excellent platform for evaluating antithrombotic interventions. Plasma testing after prolonged CA/CPR suggests consumptive coagulopathy, although TEG indicates a persistent hypercoagulable state. ART-123 given before no-flow or just after CPR demonstrates antithrombotic effects, although the specific modes of action depending on the timing of administration.

Background:The efficacy of targeted temperature management remains unclear for patients treated with extracorporeal cardiopulmonary resuscitation (ECPR) due to refractory cardiac arrest.Methods:We analyzed the Extracorporeal Life Support Organization registry between 2010 and 2019. Patients 18-79 years old who received ECPR and had a reported temperature were included. First, we compared outcomes between patients who completed intentional cooling (IC) and those who did not complete intentional cooling (NIC). Among those who completed IC, we compared the outcomes between i) actual observed temperature <34°C, 34 - 36°C, and ≥36°C, and ii) hypothermia duration below 36°C for <12 hours, 12 - 48 hours, and >48 hours. The primary outcome was in-hospital death within 90 days. Cox proportional hazard models were conducted with adjustment for covariates.Results:Among a total of 8,060 patients who received ECPR, 911 patients who had a record of actual temperature were identified. After multivariable adjustment, there was no significant difference in in-hospital mortality between patients treated with IC and NIC (Hazard ratio [HR] 1.13 [95% CI 0.93 - 1.39], p=0.2252). However, among patients treated with IC, recorded temperature at 34 - 36°C had a significantly lower adjusted HR for in-hospital mortality compared with ≥36°C (HR 0.73 [0.56 - 0.97], p=0.0274). Maintaining a temperature <36°C for 12 - 48 hours had a significantly lower adjusted HR for in-hospital mortality compared with <36°C for <12 hours (HR 0.70 [0.53 - 0.91], p=0.0080).Conclusion:In this exploratory analysis, IC was not associated with lower in-hospital mortality in patients treated with ECPR. However, among those treated with IC, achieving a target temperature of 34 - 36°C and maintaining it for 12 - 48 hours were associated with lower in-hospital mortality.

Background:Extracorporeal cardiopulmonary resuscitation (ECPR) improves survival of patients with prolonged cardiac arrest (CA) that is refractory to standard CPR and ACLS. It has been proposed that ECPR accentuates inflammation after CA, potentially limiting its effectiveness. The benefits of leukocyte filters or leukocyte-modulating devices in conjunction with ECPR have not been studied.Hypothesis:When paired with ECPR, inflammation-modulating devices targeting leukocytes may improve recovery of cardiac function after prolonged cardiac arrest.Methods:In a randomized study, 24 swine (40±5kg) underwent 8min of untreated ventricular fibrillation CA followed by CPR with mechanical chest compressions and impedance threshold device for 30 min (total arrest time = 38min), immediately followed by 8h of ECPR with heparin anticoagulation and temperature maintained at 33°C. Group 1 (n=8) had standard ECPR system (control), Group 2 (n=8) had a leukocyte filter device (LF) added to the ECPR circuit, an and Group 3 (n=8) had a leukocyte modulation device (LMOD) added to the ECPR circuit. Recovery of cardiac function was measured using a cardiac resuscitablity score (CRS) and left ventricular ejection fraction (LVEF) via transthoracic echocardiography. Data was collected at baseline (prior CA) and after 8h of ECPR. Data analysis: single-factor ANOVA test (p<0.05 significance).Results:There were no statically significant differences between the groups in CRS (Control = 3.3 ± 2.4, LF = 4.0 ± 2.8, LMOD = 2.1 ± 2.6; p=0.37) or LVEF (Control = 59% ± 27%, LF = 49% ± 29% LMOD = 34% ± 38%: p=0.34) at 8 hours after ECPR initiation (Table 1).Discussion:In this swine model of prolonged cardiac arrest treated with ECPR, addition of a leukocyte filter or leukocyte modulation device to the ECPR circuit did not improve recovery of cardiac function during the first 8 hours after initiating ECPR.

When ischemic brain is reperfused, there is in vulnerable neurons immediate inhibition of protein synthesis associated with a large increase in phosphorylation of the α-subunit of eukaryotic initiation factor 2 [eIF2α, phosphorylated form eIF2α(P)]. We examined eIF2α kinase and eIF2α(P) phosphatase activity in brain homogenate postmitochondrial supernatants obtained from rats after 3 to 30 min of global brain ischemia (cardiac arrest), after 5 min of ischemia and 5 min of reperfusion (5R), and after 10 min of ischemia and 90 min reperfusion (90R). Because it has been suggested that PKR might be specifically responsible for producing eIF2α(P) during reperfusion, we also examined in brain homogenates from wild-type and PKR0/0C57BL/6J × 129/SV mice the effect of 5 min of ischemia and 5 min of reperfusion on eIF2α(P). Cytosolic brain eIF2α(P) in the 5R and 90R rats was 18- and 23-fold that of nonischemic controls without any change in the rate of eIF2α(P) dephosphorylation. There was no change in eIF2α kinase activity between 3 and 30 min of ischemia but an 85% decrease in the 5R group; the 90R group was similar to controls. In wild-type and PKR0/0mice total eIF2α was identical, and there was an identical 16-fold increase in eIF2α(P) at 5 min of reperfusion. Our observations contradict hypotheses that PKR activation, loss of eIF2α(P) phosphatase activity, or any general increase in eIF2α kinase activity are responsible for reperfusion-induced phosphorylation of eIF2α, and we suggest that the mechanism may involve regulation of the availability of eIF2α to a kinase.

Postischemic brain reperfusion is associated with a substantial and long-lasting reduction of protein synthesis in selectively vulnerable neurons. Because the overall translation initiation rate is typically regulated by altering the phosphorylation of serine 51 on the α-subunit of eukaryotic initiation factor 2 (eIF-2α), we used an antibody specific to phosphorylated eIF-2α [eIF-2(αP)] to study the regional and cellular distribution of eIF-2(αP) in normal, ischemic, and reperfused rat brains. Western blots of brain postmitochondrial supernatants revealed that ~1% of all eIF-2α is phosphorylated in controls, eIF-2(αP) is not reduced by up to 30 minutes of ischemia, and eIF-2(αP) is increased ~20-fold after 10 and 90 minutes of reperfusion. Immunohistochemistry shows localization of eIF-2(αP) to astrocytes in normal brains, a massive increase in eIF-2(αP) in the cytoplasm of neurons within the first 10 minutes of reperfusion, accumulation of eIF-2(αP) in the nuclei of selectively vulnerable neurons after 1 hour of reperfusion, and morphology suggesting pyknosis or apoptosis in neuronal nuclei that continue to display eIF-2(αP) after 4 hours of reperfusion. These observations, together with the fact that eIF-2(αP) inhibits translation initiation, make a compelling case that eIF-2(αP) is responsible for reperfusion-induced inhibition of protein synthesis in vulnerable neurons.

Global brain ischemia and reperfusion result in the degradation of the eukaryotic initiation factor (eIF) 4G, which plays a critical role in the attachment of the mRNA to the ribosome. Because eIF-4G is a substrate of calpain, these studies were undertaken to examine whether calpain I activation during global brain ischemia contributes to the degradation of eIF-4G in vivo.Immunoblots with antibodies against calpain I and eIF-4G were prepared from rat brain postmitochondrial supernatant incubated at 37°C with and without the addition of calcium and the calpain inhibitors calpastatin or MDL-28,170. Addition of calcium alone resulted in calpain I activation (as measured by autolysis of the 80-kDa subunit) and degradation of eIF-4G; this effect was blocked by either 1 μmol/L calpastatin or 10 μmol/L MDL-28,170. In rabbits subjected to 20 minutes of cardiac arrest, immunoblots of brain postmitochondrial supernatants showed that the percentage of autolyzed calpain I increased from 1.9% ± 1.1% to 15.8% ± 5.0% and that this was accompanied by a 68% loss of eIF-4G. MDL-28,170 pretreatment (30 mg/kg) decreased ischemia-induced calpain I autolysis 40% and almost completely blocked eIF-4G degradation. We conclude that calpain I degrades eIF-4G during global brain ischemia.