Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

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 United States. 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 hours of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours 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, 2019-12-30).

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

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.

Real-time performance improvement optimizes damage control resuscitation best practice adherence: Results of a pilot prospective observational study.

BACKGROUND: Maintaining balanced blood product ratios during damage control resuscitation (DCR) is independently associated with improved survival. We hypothesized that real-time performance improvement (RT-PI) would increase adherence to DCR best practice. STUDY DESIGN AND METHODS: From December 2020-August 2021, we prospectively used a bedside RT-PI tool to guide DCR in severely injured patients surviving at least 30 min. RT-PI study patients were compared to contemporary control patients at our institution and historic PROMMTT study patients. A subset of patients transfused ≥6 U red blood cells (RBC) in 6 h (MT+) was also identified. The primary endpoint was percentage time in a high ratio range (≥3:4) of plasma (PLAS):RBC and platelet (PLT):RBC over 6 h. Secondary endpoints included time to massive transfusion protocol activation, time to calcium and tranexamic acid (TXA) dosing, and cumulative 6-h ratios. RESULTS: Included patients (n = 772) were 35 (24-51) years old with an Injury Severity Score of 27 (17-38) and 42% had penetrating injuries. RT-PI (n = 10) patients spent 96% of the 6-h resuscitation in a high PLAS:RBC range, no different versus CONTROL (n = 87) (96%) but more than PROMMTT (n = 675) (25%, p < .001). In the MT+ subgroup, optimal PLAS:RBC and PLT:RBC were maintained for the entire 6 h in RT-PI (n = 4) versus PROMMTT (n = 391) patients for both PLAS (p < .001) and PLT ratios (p < .001). Time to TXA also improved significantly in RT-PI versus CONTROL patients (27 min [22-31] vs. 51 min [29-98], p = .035). CONCLUSION: In this prospective study, RT-PI was associated with optimized DCR. Multicenter validation of this novel approach to optimizing DCR implementation is warranted.

The Association of Racial Residential Segregation and Survival After Out-of-Hospital Cardiac Arrest in the United States.

Background: Residential segregation has been identified as drivers of disparities in health outcomes, but further work is needed to understand this association with clinical outcomes for out-of-hospital cardiac arrest (OHCA). We utilized Cardiac Arrest Registry to Enhance Survival (CARES) dataset to examine if there are differences in survival to discharge and survival with good neurological outcome, as well as likelihood of bystander CPR, using validated measures of racial, ethnic, and economic segregation. Methods: We conducted a retrospective observational study using data from the Cardiac Arrest Registry to Enhance Survival (CARES) dataset to examine associations among adult OHCA patients. The primary predictor was the Index of Concentration at the Extremes (ICE), a validated measure that includes race, ethnicity, and income across three measures at the census tract level. The primary outcomes were survival to discharge and survival with good neurological status. A multivariable modified Poisson regression modeling approach with random effects at the EMS agency and hospital level was utilized. Results: We identified 626,264 OHCA patients during the study period. The mean age was 62 years old (SD 17.2 years), and 35.7% (n =223,839) of the patients were female. In multivariable models, we observed an increased likelihood of survival to discharge and survival with good neurological outcome for those patients residing in predominately White population census tracts and higher income census tracts as compared to lower income Black and Hispanic/Latinx population census tracts (RR 1.24, CI 1.20-1.28) and a 32% increased likelihood of receiving bystander CPR in higher income census tracts as compared to reference (RR 1.32, CI 1.30-1.34). Conclusions: In this study examining the association of measures of residential segregation and OHCA outcomes, there was an increased likelihood of survival to discharge, survival with good neurological status, and likelihood of receiving B-CPR for those patients residing in predominately White population and higher income census tracts when compared to predominately Black and/or Hispanic Latinx populations and lower income census tracts. This research suggests that areas impacted by residential and economic segregation are important targets for both public policy interventions as well as addressing disparities in care across the chain of survival for OHCA.

Carbon monoxide as a cellular protective agent in a swine model of cardiac arrest protocol.

Out-of-hospital cardiac arrest (OHCA) affects over 360,000 adults in the United States each year with a 50-80% mortality prior to reaching medical care. Despite aggressive supportive care and targeted temperature management (TTM), half of adults do not live to hospital discharge and nearly one-third of survivors have significant neurologic injury. The current treatment approach following cardiac arrest resuscitation consists primarily of supportive care and possible TTM. While these current treatments are commonly used, mortality remains high, and survivors often develop lasting neurologic and cardiac sequela well after resuscitation. Hence, there is a critical need for further therapeutic development of adjunctive therapies. While select therapeutics have been experimentally investigated, one promising agent that has shown benefit is CO. While CO has traditionally been thought of as a cellular poison, there is both experimental and clinical evidence that demonstrate benefit and safety in ischemia with lower doses related to improved cardiac/neurologic outcomes. While CO is well known for its poisonous effects, CO is a generated physiologically in cells through the breakdown of heme oxygenase (HO) enzymes and has potent antioxidant and anti-inflammatory activities. While CO has been studied in myocardial infarction itself, the role of CO in cardiac arrest and post-arrest care as a therapeutic is less defined. Currently, the standard of care for post-arrest patients consists primarily of supportive care and TTM. Despite current standard of care, the neurological prognosis following cardiac arrest and return of spontaneous circulation (ROSC) remains poor with patients often left with severe disability due to brain injury primarily affecting the cortex and hippocampus. Thus, investigations of novel therapies to mitigate post-arrest injury are clearly warranted. The primary objective of this proposed study is to combine our expertise in swine models of CO and cardiac arrest for future investigations on the cellular protective effects of low dose CO. We will combine our innovative multi-modal diagnostic platform to assess cerebral metabolism and changes in mitochondrial function in swine that undergo cardiac arrest with therapeutic application of CO.

Anaerobic Lactate Production Is Associated With Decreased Microcirculatory Blood Flow and Decreased Mitochondrial Respiration Following Cardiovascular Surgery With Cardiopulmonary Bypass.

OBJECTIVES: Quantify the relationship between perioperative anaerobic lactate production, microcirculatory blood flow, and mitochondrial respiration in patients after cardiovascular surgery with cardiopulmonary bypass. DESIGN: Serial measurements of lactate-pyruvate ratio (LPR), microcirculatory blood flow, plasma tricarboxylic acid cycle cycle intermediates, and mitochondrial respiration were compared between patients with a normal peak lactate (≤ 2 mmol/L) and a high peak lactate (≥ 4 mmol/L) in the first 6 hours after surgery. Regression analysis was performed to quantify the relationship between clinically relevant hemodynamic variables, lactate, LPR, and microcirculatory blood flow. SETTING: This was a single-center, prospective observational study conducted in an academic cardiovascular ICU. PATIENTS: One hundred thirty-two patients undergoing elective cardiovascular surgery with cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients with a high postoperative lactate were found to have a higher LPR compared with patients with a normal postoperative lactate (14.4 ± 2.5 vs. 11.7 ± 3.4; p = 0.005). Linear regression analysis found a significant, negative relationship between LPR and microcirculatory flow index ( r = -0.225; ß = -0.037; p = 0.001 and proportion of perfused vessels: r = -0.17; ß = -0.468; p = 0.009). There was not a significant relationship between absolute plasma lactate and microcirculation variables. Last, mitochondrial complex I and complex II oxidative phosphorylation were reduced in patients with high postoperative lactate levels compared with patients with normal lactate (22.6 ± 6.2 vs. 14.5 ± 7.4 pmol O 2 /s/10 6 cells; p = 0.002). CONCLUSIONS: Increased anaerobic lactate production, estimated by LPR, has a negative relationship with microcirculatory blood flow after cardiovascular surgery. This relationship does not persist when measuring lactate alone. In addition, decreased mitochondrial respiration is associated with increased lactate after cardiovascular surgery. These findings suggest that high lactate levels after cardiovascular surgery, even in the setting of normal hemodynamics, are not simply a type B phenomenon as previously suggested.

Machine learning model to predict evolution of pulseless electrical activity during in-hospital cardiac arrest.

Background: During pulseless electrical activity (PEA) the cardiac mechanical and electrical functions are dissociated, a phenomenon occurring in 25-42% of in-hospital cardiac arrest (IHCA) cases. Accurate evaluation of the likelihood of a PEA patient transitioning to return of spontaneous circulation (ROSC) may be vital for the successful resuscitation. The aim: We sought to develop a model to automatically discriminate between PEA rhythms with favorable and unfavorable evolution to ROSC. Methods: A dataset of 190 patients, 120 with ROSC, were acquired with defibrillators from different vendors in three hospitals. The ECG and the transthoracic impedance (TTI) signal were processed to compute 16 waveform features. Logistic regression models where designed integrating both automated features and characteristics annotated in the QRS to identify PEAs with better prognosis leading to ROSC. Cross validation techniques were applied, both patient-specific and stratified, to evaluate the performance of the algorithm. Results: The best model consisted in a three feature algorithm that exhibited median (interquartile range) Area Under the Curve/Balanced accuracy/Sensitivity/Specificity of 80.3(9.9)/75.6(8.0)/ 77.4(15.2)/72.3(16.4) %, respectively. Conclusions: Information hidden in the waveforms of the ECG and TTI signals, along with QRS complex features, can predict the progression of PEA. Automated methods as the one proposed in this study, could contribute to assist in the targeted treatment of PEA in IHCA.

Using generative artificial intelligence in bibliometric analysis: 10 years of research trends from the European Resuscitation Congresses.

Aims: The aim of this study is to use generative artificial intelligence to perform bibliometric analysis on abstracts published at European Resuscitation Council (ERC) annual scientific congress and define trends in ERC guidelines topics over the last decade. Methods: In this bibliometric analysis, the WebHarvy software (SysNucleus, India) was used to download data from the Resuscitation journal's website through the technique of web scraping. Next, the Chat Generative Pre-trained Transformer 4 (ChatGPT-4) application programming interface (Open AI, USA) was used to implement the multinomial classification of abstract titles following the ERC 2021 guidelines topics. Results: From 2012 to 2022 a total of 2491 abstracts have been published at ERC congresses. Published abstracts ranged from 88 (in 2020) to 368 (in 2015). On average, the most common ERC guidelines topics were Adult basic life support (50.1%), followed by Adult advanced life support (41.5%), while Newborn resuscitation and support of transition of infants at birth (2.1%) was the least common topic. The findings also highlight that the Basic Life Support and Adult Advanced Life Support ERC guidelines topics have the strongest co-occurrence to all ERC guidelines topics, where the Newborn resuscitation and support of transition of infants at birth (2.1%; 52/2491) ERC guidelines topic has the weakest co-occurrence. Conclusion: This study demonstrates the capabilities of generative artificial intelligence in the bibliometric analysis of abstract titles using the example of resuscitation medicine research over the last decade at ERC conferences using large language models.

Observing the stages of bystander intervention in virtual reality simulation / 世界急诊医学杂志（英文）

BACKGROUND@#Understanding bystander reactions to an emergency is an important component of effective training. Four stages of bystander intervention (BI) have been previously described: noticing the situation as a problem, interpreting when it is appropriate to intervene, recognizing personal responsibility to intervene, and knowing how to intervene. Using virtual reality (VR) to simulate emergencies such as sudden cardiac arrest (SCA) can be used to study these stages.@*METHODS@#In a secondary analysis of an observational cohort study, we analyzed bystander self-efficacy for stages of BI before and after simulated SCA. Each subject participated in a singleplayer, immersive, VR SCA scenario. Subjects interacted with simulated bystanders through voice commands (“call 911”, “get an AED”). Actions taken in scenario, like performing CPR, were documented. Scenario BI actions were compared based on dichotomized comfort/discomfort.@*RESULTS@#From June 2016 to June 2017, 119 subjects participated. Average age was 37±14 years, 44% were female and 46% reported CPR training within 2 years. During the scenario, 98% “noticed the event” and “interpreted it as a problem”, 78% “took responsibility”, and 54% “possessed the necessary skills”. Self-efficacy increased from pre- to post-scenario: noticing the event increased from 80% to 96%; interpreting as a problem increased from 86% to 97%; taking responsibility increased from 56% to 93%; possessing necessary skills increased from 47% to 63% (P<0.001).@*CONCLUSION@#Self-efficacy to respond to an SCA event increased pre- to post-scenario. Bystanders who reported feeling comfortable “taking responsibility to intervene” during an emergency were more likely to take action during a simulated emergency.