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.

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.

Almanac - Retrieval-Augmented Language Models for Clinical Medicine.

BACKGROUND: Large language models (LLMs) have recently shown impressive zero-shot capabilities, whereby they can use auxiliary data, without the availability of task-specific training examples, to complete a variety of natural language tasks, such as summarization, dialogue generation, and question answering. However, despite many promising applications of LLMs in clinical medicine, adoption of these models has been limited by their tendency to generate incorrect and sometimes even harmful statements. METHODS: We tasked a panel of eight board-certified clinicians and two health care practitioners with evaluating Almanac, an LLM framework augmented with retrieval capabilities from curated medical resources for medical guideline and treatment recommendations. The panel compared responses from Almanac and standard LLMs (ChatGPT-4, Bing, and Bard) versus a novel data set of 314 clinical questions spanning nine medical specialties. RESULTS: Almanac showed a significant improvement in performance compared with the standard LLMs across axes of factuality, completeness, user preference, and adversarial safety. CONCLUSIONS: Our results show the potential for LLMs with access to domain-specific corpora to be effective in clinical decision-making. The findings also underscore the importance of carefully testing LLMs before deployment to mitigate their shortcomings. (Funded by the National Institutes of Health, National Heart, Lung, and Blood Institute.).

Wolf Creek XVII Part 8: Neuroprotection.

Introduction: Post-cardiac arrest brain injury (PCABI) is the primary determinant of clinical outcomes for patients who achieve return of spontaneous circulation after cardiac arrest (CA). There are limited neuroprotective therapies available to mitigate the acute pathophysiology of PCABI. Methods: Neuroprotection was one of six focus topics for the Wolf Creek XVII Conference held on June 14-17, 2023 in Ann Arbor, Michigan, USA. Conference invitees included international thought leaders and scientists in the field of CA resuscitation from academia and industry. Participants submitted via online survey knowledge gaps, barriers to translation, and research priorities for each focus topic. Expert panels used the survey results and their own perspectives and insights to create and present a preliminary unranked list for each category that was debated, revised and ranked by all attendees to identify the top 5 for each category. Results: Top 5 knowledge gaps included developing therapies for neuroprotection; improving understanding of the pathophysiology, mechanisms, and natural history of PCABI; deploying precision medicine approaches; optimizing resuscitation and CPR quality; and determining optimal timing for and duration of interventions. Top 5 barriers to translation included patient heterogeneity; nihilism & lack of knowledge about cardiac arrest; challenges with the translational pipeline; absence of mechanistic biomarkers; and inaccurate neuro-triage and neuroprognostication. Top 5 research priorities focused on translational research and trial optimization; addressing patient heterogeneity and individualized interventions; improving understanding of pathophysiology and mechanisms; developing mechanistic and outcome biomarkers across post-CA time course; and improving implementation of science and technology. Conclusion: This overview can serve as a guide to transform the care and outcome of patients with PCABI. Addressing these topics has the potential to improve both research and clinical care in the field of neuroprotection for PCABI.

Critical Care Management of Patients After Cardiac Arrest: A Scientific Statement From the American Heart Association and Neurocritical Care Society.

The critical care management of patients after cardiac arrest is burdened by a lack of high-quality clinical studies and the resultant lack of high-certainty evidence. This results in limited practice guideline recommendations, which may lead to uncertainty and variability in management. Critical care management is crucial in patients after cardiac arrest and affects outcome. Although guidelines address some relevant topics (including temperature control and neurological prognostication of comatose survivors, 2 topics for which there are more robust clinical studies), many important subject areas have limited or nonexistent clinical studies, leading to the absence of guidelines or low-certainty evidence. The American Heart Association Emergency Cardiovascular Care Committee and the Neurocritical Care Society collaborated to address this gap by organizing an expert consensus panel and conference. Twenty-four experienced practitioners (including physicians, nurses, pharmacists, and a respiratory therapist) from multiple medical specialties, levels, institutions, and countries made up the panel. Topics were identified and prioritized by the panel and arranged by organ system to facilitate discussion, debate, and consensus building. Statements related to postarrest management were generated, and 80% agreement was required to approve a statement. Voting was anonymous and web based. Topics addressed include neurological, cardiac, pulmonary, hematological, infectious, gastrointestinal, endocrine, and general critical care management. Areas of uncertainty, areas for which no consensus was reached, and future research directions are also included. Until high-quality studies that inform practice guidelines in these areas are available, the expert panel consensus statements that are provided can advise clinicians on the critical care management of patients after cardiac arrest.

Critical Care Management of Patients After Cardiac Arrest: A Scientific Statement from the American Heart Association and Neurocritical Care Society.

The critical care management of patients after cardiac arrest is burdened by a lack of high-quality clinical studies and the resultant lack of high-certainty evidence. This results in limited practice guideline recommendations, which may lead to uncertainty and variability in management. Critical care management is crucial in patients after cardiac arrest and affects outcome. Although guidelines address some relevant topics (including temperature control and neurological prognostication of comatose survivors, 2 topics for which there are more robust clinical studies), many important subject areas have limited or nonexistent clinical studies, leading to the absence of guidelines or low-certainty evidence. The American Heart Association Emergency Cardiovascular Care Committee and the Neurocritical Care Society collaborated to address this gap by organizing an expert consensus panel and conference. Twenty-four experienced practitioners (including physicians, nurses, pharmacists, and a respiratory therapist) from multiple medical specialties, levels, institutions, and countries made up the panel. Topics were identified and prioritized by the panel and arranged by organ system to facilitate discussion, debate, and consensus building. Statements related to postarrest management were generated, and 80% agreement was required to approve a statement. Voting was anonymous and web based. Topics addressed include neurological, cardiac, pulmonary, hematological, infectious, gastrointestinal, endocrine, and general critical care management. Areas of uncertainty, areas for which no consensus was reached, and future research directions are also included. Until high-quality studies that inform practice guidelines in these areas are available, the expert panel consensus statements that are provided can advise clinicians on the critical care management of patients after cardiac arrest.

Inpatient Neurology Deaths and Factors Associated With Discharge to Hospice.

Background and Purpose: The Neurology Mortality Review Committee at our institution identified variability in location of death for patients on our inpatient neurology services. Hospice may increase the number of patients dying in their preferred locations. This study aimed to characterize patients who die on inpatient neurology services and explore barriers to discharge to hospice. Methods: This retrospective study was completed at a single, quaternary care medical center that is a Level I Trauma Center and Comprehensive Stroke Center. Patients discharged by an inpatient neurology service between 6/2019-1/2021 were identified and electronic medical record review was performed on patients who died in the hospital and who were discharged to hospice. Results: 69 inpatient deaths and 74 discharges to hospice occurred during the study period. Of the 69 deaths, 54 occurred following withdrawal of life sustaining treatment (WLST), of which 14 had a referral to hospice placed. There were 88 "hospice-referred" patients and 40 "hospice-eligible" patients. Hospice-referred patients were less likely to require the intensive care unit than hospice-eligible patients. Hospice-referred patients had their code status changed to Do Not Intubate earlier and were more likely to have advanced directives available. Conclusion: Our data highlight opportunities for further research to improve discharge to hospice including interhospital transfers, advanced directives, earlier goals of care discussions, palliative care consultations, and increased hospice bed availability. Importantly, it highlights the limitations of using in-hospital mortality as a quality indicator in this patient population.

Society of Critical Care Medicine Clinical Practice Guidelines for Rapid Sequence Intubation in the Critically Ill Adult Patient.

RATIONALE: Controversies and practice variations exist related to the pharmacologic and nonpharmacologic management of the airway during rapid sequence intubation (RSI). OBJECTIVES: To develop evidence-based recommendations on pharmacologic and nonpharmacologic topics related to RSI. DESIGN: A guideline panel of 20 Society of Critical Care Medicine members with experience with RSI and emergency airway management met virtually at least monthly from the panel's inception in 2018 through 2020 and face-to-face at the 2020 Critical Care Congress. The guideline panel included pharmacists, physicians, a nurse practitioner, and a respiratory therapist with experience in emergency medicine, critical care medicine, anesthesiology, and prehospital medicine; consultation with a methodologist and librarian was available. A formal conflict of interest policy was followed and enforced throughout the guidelines-development process. METHODS: Panelists created Population, Intervention, Comparison, and Outcome (PICO) questions and voted to select the most clinically relevant questions for inclusion in the guideline. Each question was assigned to a pair of panelists, who refined the PICO wording and reviewed the best available evidence using predetermined search terms. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework was used throughout and recommendations of "strong" or "conditional" were made for each PICO question based on quality of evidence and panel consensus. Recommendations were provided when evidence was actionable; suggestions, when evidence was equivocal; and best practice statements, when the benefits of the intervention outweighed the risks, but direct evidence to support the intervention did not exist. RESULTS: From the original 35 proposed PICO questions, 10 were selected. The RSI guideline panel issued one recommendation (strong, low-quality evidence), seven suggestions (all conditional recommendations with moderate-, low-, or very low-quality evidence), and two best practice statements. The panel made two suggestions for a single PICO question and did not make any suggestions for one PICO question due to lack of evidence. CONCLUSIONS: Using GRADE principles, the interdisciplinary panel found substantial agreement with respect to the evidence supporting recommendations for RSI. The panel also identified literature gaps that might be addressed by future research.

Temperature Management for Comatose Adult Survivors of Cardiac Arrest: A Science Advisory From the American Heart Association.

Targeted temperature management has been a cornerstone of post-cardiac arrest care for patients remaining unresponsive after return of spontaneous circulation since the initial trials in 2002 found that mild therapeutic hypothermia improves neurological outcome. The suggested temperature range expanded in 2015 in response to a large trial finding that outcomes were not better with treatment at 33° C compared with 36° C. In 2021, another large trial was published in which outcomes with temperature control at 33° C were not better than those of patients treated with a strategy of strict normothermia. On the basis of these new data, the International Liaison Committee on Resuscitation and other organizations have altered their treatment recommendations for temperature management after cardiac arrest. The new American Heart Association guidelines on this topic will be introduced in a 2023 focused update. To provide guidance to clinicians while this focused update is forthcoming, the American Heart Association's Emergency Cardiovascular Care Committee convened a writing group to review the TTM2 trial (Hypothermia Versus Normothermia After Out-of-Hospital Cardiac Arrest) in the context of other recent evidence and to present an opinion on how this trial may influence clinical practice. This science advisory was informed by review of the TTM2 trial, consideration of other recent influential studies, and discussion between cardiac arrest experts in the fields of cardiology, critical care, emergency medicine, and neurology. Conclusions presented in this advisory statement do not replace current guidelines but are intended to provide an expert opinion on novel literature that will be incorporated into future guidelines and suggest the opportunity for reassessment of current clinical practice.

Almanac: Retrieval-Augmented Language Models for Clinical Medicine.

Large-language models have recently demonstrated impressive zero-shot capabilities in a variety of natural language tasks such as summarization, dialogue generation, and question-answering. Despite many promising applications in clinical medicine, adoption of these models in real-world settings has been largely limited by their tendency to generate incorrect and sometimes even toxic statements. In this study, we develop Almanac, a large language model framework augmented with retrieval capabilities for medical guideline and treatment recommendations. Performance on a novel dataset of clinical scenarios (n= 130) evaluated by a panel of 5 board-certified and resident physicians demonstrates significant increases in factuality (mean of 18% at p-value < 0.05) across all specialties, with improvements in completeness and safety. Our results demonstrate the potential for large language models to be effective tools in the clinical decision-making process, while also emphasizing the importance of careful testing and deployment to mitigate their shortcomings.

Brain imaging after cardiac arrest.

PURPOSE OF REVIEW: Many patients who survive a cardiac arrest have a disorder of consciousness in the period after resuscitation, and prediction of long-term neurologic outcome requires multimodal assessments. Brain imaging with computed tomography (CT) and MRI is a key component. We aim to provide an overview of the types of neuroimaging available and their uses and limitations. RECENT FINDINGS: Recent studies have evaluated qualitative and quantitative techniques to analyze and interpret CT and MRI to predict both good and poor outcomes. Qualitative interpretation of CT and MRI is widely available but is limited by low inter-rater reliability and lack of specificity around which findings have the highest correlation with outcome. Quantitative analysis of CT (gray-white ratio) and MRI (amount of brain tissue with an apparent diffusion coefficient below certain thresholds) hold promise, though additional research is needed to standardize the approach. SUMMARY: Brain imaging is important for evaluating the extent of neurologic injury after cardiac arrest. Future work should focus on addressing previous methodological limitations and standardizing approaches to qualitative and quantitative imaging analysis. Novel imaging techniques are being developed and new analytical methods are being applied to advance the field.

Collateral status, hyperglycemia, and functional outcome after acute ischemic stroke.

BACKGROUND: Mixed data exist regarding the association between hyperglycemia and functional outcome after acute ischemic stroke when accounting for the impact of leptomeningeal collateral flow. We sought to determine whether collateral status modifies the association between treatment group and functional outcome in a subset of patients with large vessel occlusion enrolled in the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial. METHODS: In this post-hoc analysis, we analyzed patients enrolled into the SHINE trial with anterior circulation large vessel occlusion who underwent imaging with CT angiography prior to glucose control treatment group assignment. The primary analysis assessed the degree to which collateral status modified the effect between treatment group and functional outcome as defined by the 90-day modified Rankin Scale score. Logistic regression was used to model the data, with adjustments made for thrombectomy status, age, post-perfusion thrombolysis in cerebral infarction (TICI) score, tissue plasminogen activator (tPA) use, and baseline National Institutes of Health Stroke Scale (NIHSS) score. Five SHINE trial centers contributed data for this analysis. Statistical significance was defined as a p-value < 0.05. RESULTS: Among the 1151 patients in the SHINE trial, 57 with angiographic data were included in this sub-analysis, of whom 19 had poor collaterals and 38 had good collaterals. While collateral status had no effect (p = 0.855) on the association between glucose control treatment group and functional outcome, patients with good collaterals were more likely to have a favorable functional outcome (p = 0.001, OR 5.02; 95% CI 1.37-16.0). CONCLUSIONS: In a post-hoc analysis using a subset of patients with angiographic data enrolled in the SHINE trial, collateral status did not modify the association between glucose control treatment group and functional outcome. However, consistent with prior studies, there was a significant association between good collateral status and favorable outcome in patients with large vessel occlusion stroke. TRIAL REGISTRATION: ClinicalTrials.gov Identifier is NCT01369069. Registration date is June 8, 2011.

Absence of antibody responses to SARS-CoV-2 N protein in COVID-19 vaccine breakthrough cases.

Understanding the risk factors for breakthrough coronavirus disease 2019 (COVID-19) (BC19) is critical to inform policy. Herein, we assessed Delta (Lineage B.1.617.2) variant-specific effectiveness of the BNT162b2 (Pfizer) vaccine and characterized Delta-driven BC19 cases (fully vaccinated individuals who get infected) with known-time-since-vaccination. In this longitudinal prospective study (January 21-October 30, 2021), 90 naïve and 15 convalescent individuals were enrolled at the initiation of vaccination. Samples from 27 unvaccinated individuals with previous laboratory-confirmed COVID-19 diagnosis were collected at a single time point. Longitudinal serology profile (antibodies against severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] S and N proteins) and live-virus-based neutralization capacities were assessed while controlling for age. Sex, age, history of reactions to the COVID-19 vaccine, and viral neutralization capacities were identified as significant risk factors for breakthrough COVID-19. At 8 months postvaccination, male sex, individuals ⩾65 years of age, and individuals who experienced noticeable side effects with the COVID-19 vaccine were at 5.47 (p-value = 0.0102), 4.33 (p-value = 0.0236), and 4.95 (p-value = 0.0159) fold greater risk of BC19 as compared to their peers, respectively. Importantly, every five-fold increase in viral neutralization capacities (by live-virus-based assays) was significantly associated with ~4-fold reduction in the risk occurrence of breakthrough COVID-19 (p-value = 0.045). Vaccine boosting remarkably increased these viral neutralization capacities by 16.22-fold (p- value = 0.0005), supporting the importance of the BNT162b2 booster in efforts to control the incursion of future variants into the population at large. Strikingly, BC19 cases exhibited a delayed/absent antibody response to the N protein, suggesting limited exposure to the virus. Since antibodies against N protein are widely used to evaluate the extent of virus spread in communities, our finding has important implications on the utility of existing serological diagnostic and surveillance for COVID-19.

Effect of rapid EEG on anti-seizure medication usage

Objective: To study how early diagnoses from rapid EEG (rEEG) during the initial evaluation of patients with suspected non-convulsive seizures correlates with changes in anti-seizure medication (ASM) use. Methods: We performed a retrospective chart review of 100 consecutive adult patients at an academic medical center who underwent rEEG monitoring for suspected non-convulsive seizures. We collected information on the timing of ASM administration and categorized EEG diagnoses as seizures (SZ), highly epileptiform patterns (HEP), or normal or slow activity (NL/SL). We used a χ² test to determine whether the use of ASMs was significantly different between SZ/HEP and NL/SL cases. Results: Of 100 patients, SZ were found in 5%, HEP in 14%, and no epileptiform/ictal activity in 81%. Forty-six percent of patients had received ASM(s) before rEEG. While 84% of HEP/SZ cases were started or continued on ASMs, only 51% of NL/SL cases were started or continued on ASMs after rEEG (χ² [1, n=100] = 7.09, p=0.008). Thirty-seven patients had received sedation (i.e., propofol or dexmedetomidine) prior to rEEG. In 15 patients (13/30 NL/SL, 2/7 HEP/SZ), sedation was discontinued following rEEG. Significance: Our study demonstrates that seizures were rapidly ruled out with rEEG in 81% of patients while 19% of patients were rapidly identified as having seizures or being at higher risk for seizures. The rapid evaluation of patients correlated with a significant reduction in ASM treatment in NL/SL cases compared to HEP/SZ cases. Thus, early access to EEG information may lead to more informed and targeted management of patients suspected to have nonconvulsive seizures.

Liraglutide 3 mg on weight, body composition, and hormonal and metabolic parameters in women with obesity and polycystic ovary syndrome: a randomized placebo-controlled-phase 3 study.

OBJECTIVE: To study the efficacy and safety of the GLP-1 analog liraglutide 3 mg (LIRA 3 mg) vs. placebo (PL) for reduction of body weight (BW) and hyperandrogenism in women with obesity and polycystic ovary syndrome (PCOS). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Hospital-based outpatient endocrine and metabolic center. PATIENT(S): Women diagnosed with PCOS (NIH criteria) were randomly assigned to LIRA 3 mg (n = 55) or PL (n = 27) once daily for 32 weeks with lifestyle intervention. INTERVENTION(S): Study visits at baseline and 32 weeks included BW and body composition by dual-energy x-ray absorptiometry. Oral glucose tolerance tests were done with sex steroids, free androgen index (FAI), and lipids measured in the fasting sample. MAIN OUTCOME MEASURE(S): The primary end points were changes in BW and FAI. Safety was assessed in all patients who received at least one dose of the study drug. RESULT(S): Change in BW from baseline to week 32 was -5.7% (±0.75) with LIRA 3 mg vs. -1.4% (±1.09) with PL. At week 32, more participants on LIRA 3 mg than on PL achieved at least 5% weight reductions (25 of 44 vs. 5 of 23). Free androgen index significantly reduced with LIRA 3 mg compared with the PL where the mean FAI slightly increased. Gastrointestinal events, which were mostly mild to moderate, were reported in 58.2% of the LIRA 3 mg-subjects and 18.5% of PL subjects. CONCLUSION(S): LIRA 3 mg once daily appears superior to PL in reducing BW and androgenicity and improving cardiometabolic parameters in women with PCOS and obesity. CLINICAL TRIAL REGISTRATION NUMBER: NCT03480022.

Proceedings of the Second Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness.

This proceedings article presents actionable research targets on the basis of the presentations and discussions at the 2nd Curing Coma National Institutes of Health (NIH) symposium held from May 3 to May 5, 2021. Here, we summarize the background, research priorities, panel discussions, and deliverables discussed during the symposium across six major domains related to disorders of consciousness. The six domains include (1) Biology of Coma, (2) Coma Database, (3) Neuroprognostication, (4) Care of Comatose Patients, (5) Early Clinical Trials, and (6) Long-term Recovery. Following the 1st Curing Coma NIH virtual symposium held on September 9 to September 10, 2020, six workgroups, each consisting of field experts in respective domains, were formed and tasked with identifying gaps and developing key priorities and deliverables to advance the mission of the Curing Coma Campaign. The highly interactive and inspiring presentations and panel discussions during the 3-day virtual NIH symposium identified several action items for the Curing Coma Campaign mission, which we summarize in this article.