Improving Outcomes After Post-Cardiac Arrest Brain Injury: A Scientific Statement From the International Liaison Committee on Resuscitation.

This scientific statement presents a conceptual framework for the pathophysiology of post-cardiac arrest brain injury, explores reasons for previous failure to translate preclinical data to clinical practice, and outlines potential paths forward. Post-cardiac arrest brain injury is characterized by 4 distinct but overlapping phases: ischemic depolarization, reperfusion repolarization, dysregulation, and recovery and repair. Previous research has been challenging because of the limitations of laboratory models; heterogeneity in the patient populations enrolled; overoptimistic estimation of treatment effects leading to suboptimal sample sizes; timing and route of intervention delivery; limited or absent evidence that the intervention has engaged the mechanistic target; and heterogeneity in postresuscitation care, prognostication, and withdrawal of life-sustaining treatments. Future trials must tailor their interventions to the subset of patients most likely to benefit and deliver this intervention at the appropriate time, through the appropriate route, and at the appropriate dose. The complexity of post-cardiac arrest brain injury suggests that monotherapies are unlikely to be as successful as multimodal neuroprotective therapies. Biomarkers should be developed to identify patients with the targeted mechanism of injury, to quantify its severity, and to measure the response to therapy. Studies need to be adequately powered to detect effect sizes that are realistic and meaningful to patients, their families, and clinicians. Study designs should be optimized to accelerate the evaluation of the most promising interventions. Multidisciplinary and international collaboration will be essential to realize the goal of developing effective therapies for post-cardiac arrest brain injury.

Brain computed tomography after resuscitation from in-hospital cardiac arrest.

BACKGROUND: Few data characterize the role of brain computed tomography (CT) after resuscitation from in-hospital cardiac arrest (IHCA). We hypothesized that identifying a neurological etiology of arrest or cerebral edema on brain CT are less common after IHCA than after resuscitation from out-of-hospital cardiac arrest (OHCA). METHODS: We included all patients comatose after resuscitation from IHCA or OHCA in this retrospective cohort analysis. We abstracted patient and arrest clinical characteristics, as well as pH and lactate, to estimate systemic illness severity. Brain CT characteristics included quantitative measurement of the grey-to-white ratio (GWR) at the level of the basal ganglia and qualitative assessment of sulcal and cisternal effacement. We compared GWR distribution by stratum (no edema ≥1.30, mild-to-moderate <1.30 and >1.20, severe ≤1.20) and newly identified neurological arrest etiology between IHCA and OHCA groups. RESULTS: We included 2,306 subjects, of whom 420 (18.2%) suffered IHCA. Fewer IHCA subjects underwent post-arrest brain CT versus OHCA subjects (149 (35.5%) vs 1,555 (82.4%), p < 0.001). Cerebral edema for IHCA versus OHCA was more often absent (60.1% vs. 47.5%) or mild-to-moderate (34.3% vs. 27.9%) and less often severe (5.6% vs. 24.6%). A neurological etiology of arrest was identified on brain CT in 0.5% of IHCA versus 3.2% of OHCA. CONCLUSIONS: Although severe edema was less frequent in IHCA relative to OHCA, mild-to-moderate or severe edema occurred in one in three patients after IHCA. Unsuspected neurological etiologies of arrest were rarely discovered by CT scan in IHCA patients.

Sex-specific disparities in COVID-19 outcomes.

Objectives: Sex-specific disparities in morbidity and mortality of COVID-19 illness are not well understood. Neutralizing antibodies (Ab) may protect against severe COVID-19 illness. We investigated the association of sex with disease progression and SARS-CoV-2 Ab response. Methods: In this exploratory analysis of the phase 3, multicenter, randomized, placebo-controlled Convalescent Plasma in Outpatients (C3PO) trial, we examined whether sex was associated with progression to severe illness, defined as a composite of all-cause hospitalization, emergency/urgent care visit, or death within 15 days from study enrollment. Patients had a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test, symptom onset within 7 days, stable condition for emergency department discharge, and were either ≥50 years old or had at least one high-risk feature for disease progression. Patients received blinded convalescent plasma or placebo in a 1:1 fashion and were evaluated on days 15 and 30 after infusion. Blood samples were collected on day 0 (pre-/post-infusion), 15, and 30 to measure Ab levels with the Broad Institute using the Plaque Reduction Neutralization Test assay. Results: Of 511 patients enrolled (median age 54 [Iinterquartile range 41-62] years, 46% male, 66% white, 20% black, 3.5% Asian), disease progression occurred in 36.7% of males and 25.9% of females (unadjusted risk difference 10.8%, 95% confidence interval [CI], 2.8-18.8%). Sex-disparities did not persist when adjusted for treatment group, age, viremic status, symptom onset, and tobacco use (adjusted risk difference 5.6%, 95% confidence interval [CI], -2.2% to 13.4%), but were present in the subgroup presenting 3 or more days after symptom onset (adjusted risk difference 12.6%, 95% CI, 3.4% to 21.9%). Mean baseline Ab levels (log scale) available for 367 patients were similar between sexes (difference 0.19 log units, 95% CI, -0.08 to 0.46). The log-scale mean increase from baseline to day 15 after adjusting for treatment assignment and baseline levels was larger in males than females (3.26 vs. 2.67). A similar difference was noted when the groups were subdivided by outcome. Conclusions: Progression of COVID-19 was similar in males and females when adjusted for age, tobacco use, and viremia status in this study. However, in the cohort presenting 3 or more days after symptom onset, COVID-19 outcomes were worse in males than females. Neutralizing Ab levels increased more in males but did not correlate with sex differences in outcomes.

Survival After Intra-Arrest Transport vs On-Scene Cardiopulmonary Resuscitation in Children.

Importance: For pediatric out-of-hospital cardiac arrest (OHCA), emergency medical services (EMS) may elect to transport to the hospital during active cardiopulmonary resuscitation (CPR) (ie, intra-arrest transport) or to continue on-scene CPR for the entirety of the resuscitative effort. The comparative effectiveness of these strategies is unclear. Objective: To evaluate the association between intra-arrest transport compared with continued on-scene CPR and survival after pediatric OHCA, and to determine whether this association differs based on the timing of intra-arrest transport. Design, Setting, and Participants: This cohort study included pediatric patients aged younger than 18 years with EMS-treated OHCA between December 1, 2005 and June 30, 2015. Data were collected from the Resuscitation Outcomes Consortium Epidemiologic Registry, a prospective 10-site OHCA registry in the US and Canada. Data analysis was performed from May 2022 to February 2024. Exposures: Intra-arrest transport, defined as an initiation of transport prior to the return of spontaneous circulation, and the interval between EMS arrival and intra-arrest transport. Main Outcomes and Measures: The primary outcome was survival to hospital discharge. Patients who underwent intra-arrest transport at any given minute after EMS arrival were compared with patients who were at risk of undergoing intra-arrest transport within the same minute using time-dependent propensity scores calculated from patient demographics, arrest characteristics, and EMS interventions. We examined subgroups based on age (<1 year vs ≥1 year). Results: Of 2854 eligible pediatric patients (median [IQR] age, 1 [0-9] years); 1691 males [59.3%]) who experienced OHCA between December 2005 and June 2015, 1892 children (66.3%) were treated with intra-arrest transport and 962 children (33.7%) received continued on-scene CPR. The median (IQR) time between EMS arrival and intra-arrest transport was 15 (9-22) minutes. In the propensity score-matched cohort (3680 matched cases), there was no significant difference in survival to hospital discharge between the intra-arrest transport group and the continued on-scene CPR group (87 of 1840 patients [4.7%] vs 95 of 1840 patients [5.2%]; risk ratio [RR], 0.81 [95% CI, 0.59-1.10]). Survival to hospital discharge was not modified by the timing of intra-arrest transport (P value for the interaction between intra-arrest transport and time to matching = .10). Among patients aged younger than 1 year, intra-arrest transport was associated with lower survival to hospital discharge (RR, 0.52; 95% CI, 0.33-0.83) but there was no association for children aged 1 year or older (RR, 1.22; 95% CI, 0.77-1.93). Conclusions and Relevance: In this cohort study of a North American OHCA registry, intra-arrest transport compared with continued on-scene CPR was not associated with survival to hospital discharge among children with OHCA. However, intra-arrest transport was associated with a lower likelihood of survival to hospital discharge among children aged younger than 1 year.

Clinicians' approach to predicting post-cardiac arrest outcomes for patients enrolled in a United States clinical trial.

PURPOSE: Perceived poor prognosis can lead to withdrawal of life-sustaining therapies (WLST) in patients who might otherwise recover. We characterized clinicians' approach to post-arrest prognostication in a multicenter clinical trial. METHODS: Semi-structured interviews were conducted with clinicians who treated a comatose post-cardiac arrest patient enrolled in the Influence of Cooling Duration on Efficacy in Cardiac Arrest Patients (ICECAP) trial (NCT04217551). Two authors independently analyzed each interview using inductive and deductive coding. The clinician reported how they arrived at a prognosis for the specific patient. We summarized the frequency with which clinicians reported using objective diagnostics to formulate their prognosis, and compared the reported approaches to established guidelines. Each respondent provided demographic information and described local neuroprognostication practices. RESULTS: We interviewed 30 clinicians at 19 US hospitals. Most claimed adherence to local hospital neuroprognostication protocols (n = 19). Prognostication led to WLST for perceived poor neurological prognosis in 15/30 patients, of whom most showed inconsistencies with guidelines or trial recommendations, respectively. In 10/15 WLST cases, clinicians reported relying on multimodal testing. A prevalent theme was the use of "clinical gestalt," defined as prognosticating based on a patient's overall appearance or a subjective impression in the absence of objective data. Many clinicians (21/30) reported using clinical gestalt for initial prognostication, with 9/21 expressing high confidence initially. CONCLUSION: Clinicians in our study state they follow neuroprognostication guidelines in general but often do not do so in actual practice. They reported clinical gestalt frequently informed early, highly confident prognostic judgments, and few objective tests changed initial impressions. Subjective prognostication may undermine well-designed trials.

Duration of cardiopulmonary resuscitation and outcomes for adults with in-hospital cardiac arrest: retrospective cohort study.

OBJECTIVE: To quantify time dependent probabilities of outcomes in patients after in-hospital cardiac arrest as a function of duration of cardiopulmonary resuscitation, defined as the interval between start of chest compression and the first return of spontaneous circulation or termination of resuscitation. DESIGN: Retrospective cohort study. SETTING: Multicenter prospective in-hospital cardiac arrest registry in the United States. PARTICIPANTS: 348 996 adult patients (≥18 years) with an index in-hospital cardiac arrest who received cardiopulmonary resuscitation from 2000 through 2021. MAIN OUTCOME MEASURES: Survival to hospital discharge and favorable functional outcome at hospital discharge, defined as a cerebral performance category score of 1 (good cerebral performance) or 2 (moderate cerebral disability). Time dependent probabilities of subsequently surviving to hospital discharge or having favorable functional outcome if patients pending the first return of spontaneous circulation at each minute received further cardiopulmonary resuscitation beyond the time point were estimated, assuming that all decisions on termination of resuscitation were accurate (that is, all patients with termination of resuscitation would have invariably failed to survive if cardiopulmonary resuscitation had continued for a longer period of time). RESULTS: Among 348 996 included patients, 233 551 (66.9%) achieved return of spontaneous circulation with a median interval of 7 (interquartile range 3-13) minutes between start of chest compressions and first return of spontaneous circulation, whereas 115 445 (33.1%) patients did not achieve return of spontaneous circulation with a median interval of 20 (14-30) minutes between start of chest compressions and termination of resuscitation. 78 799 (22.6%) patients survived to hospital discharge. The time dependent probabilities of survival and favorable functional outcome among patients pending return of spontaneous circulation at one minute's duration of cardiopulmonary resuscitation were 22.0% (75 645/343 866) and 15.1% (49 769/328 771), respectively. The probabilities decreased over time and were <1% for survival at 39 minutes and <1% for favorable functional outcome at 32 minutes' duration of cardiopulmonary resuscitation. CONCLUSIONS: This analysis of a large multicenter registry of in-hospital cardiac arrest quantified the time dependent probabilities of patients' outcomes in each minute of duration of cardiopulmonary resuscitation. The findings provide resuscitation teams, patients, and their surrogates with insights into the likelihood of favorable outcomes if patients pending the first return of spontaneous circulation continue to receive further cardiopulmonary resuscitation.

A multicenter, randomized, doubleblind, placebo-controlled trial of amantadine to stimulate awakening in comatose patients resuscitated from cardiac arrest.

OBJECTIVE: We hypothesized that the administration of amantadine would increase awakening of comatose patients resuscitated from cardiac arrest. METHODS: We performed a prospective, randomized, controlled pilot trial, randomizing subjects to amantadine 100 mg twice daily or placebo for up to 7 days. The study drug was administered between 72 and 120 hours after resuscitation and patients with absent N20 cortical responses, early cerebral edema, or ongoing malignant electroencephalography patterns were excluded. Our primary outcome was awakening, defined as following two-step commands, within 28 days of cardiac arrest. Secondary outcomes included length of stay, awakening, time to awakening, and neurologic outcome measured by Cerebral Performance Category at hospital discharge. We compared the proportion of subjects awakening and hospital survival using Fisher exact tests and time to awakening and hospital length of stay using Wilcoxon rank sum tests. RESULTS: After 2 years, we stopped the study due to slow enrollment and lapse of funding. We enrolled 14 subjects (12% of goal enrollment), seven in the amantadine group and seven in the placebo group. The proportion of patients who awakened within 28 days after cardiac arrest did not differ between amantadine (n=2, 28.6%) and placebo groups (n=3, 42.9%; P>0.99). There were no differences in secondary outcomes. Study medication was stopped in three subjects (21.4%). Adverse events included a recurrence of seizures (n=2; 14.3%), both of which occurred in the placebo group. CONCLUSION: We could not determine the effect of amantadine on awakening in comatose survivors of cardiac arrest due to small sample size.

Improving Outcomes After Post-Cardiac Arrest Brain Injury: A Scientific Statement From the International Liaison Committee on Resuscitation.

This scientific statement presents a conceptual framework for the pathophysiology of post-cardiac arrest brain injury, explores reasons for previous failure to translate preclinical data to clinical practice, and outlines potential paths forward. Post-cardiac arrest brain injury is characterized by 4 distinct but overlapping phases: ischemic depolarization, reperfusion repolarization, dysregulation, and recovery and repair. Previous research has been challenging because of the limitations of laboratory models; heterogeneity in the patient populations enrolled; overoptimistic estimation of treatment effects leading to suboptimal sample sizes; timing and route of intervention delivery; limited or absent evidence that the intervention has engaged the mechanistic target; and heterogeneity in postresuscitation care, prognostication, and withdrawal of life-sustaining treatments. Future trials must tailor their interventions to the subset of patients most likely to benefit and deliver this intervention at the appropriate time, through the appropriate route, and at the appropriate dose. The complexity of post-cardiac arrest brain injury suggests that monotherapies are unlikely to be as successful as multimodal neuroprotective therapies. Biomarkers should be developed to identify patients with the targeted mechanism of injury, to quantify its severity, and to measure the response to therapy. Studies need to be adequately powered to detect effect sizes that are realistic and meaningful to patients, their families, and clinicians. Study designs should be optimized to accelerate the evaluation of the most promising interventions. Multidisciplinary and international collaboration will be essential to realize the goal of developing effective therapies for post-cardiac arrest brain injury.