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.

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.

Shining a light on cerebral autoregulation: Are we anywhere near the truth?

The near-infrared spectroscopy (NIRS)-derived cerebral oximetry index (COx) has become popularized for non-invasive neuromonitoring of cerebrovascular function in post-cardiac arrest patients with hypoxic-ischemic brain injury (HIBI). We provide commentary on the physiologic underpinnings and assumptions of NIRS and the COx, potential confounds in the context of HIBI, and the implications for the assessment of cerebral autoregulation.

Impact of Skin Pigmentation on Cerebral Regional Saturation of Oxygen Using Near-Infrared Spectroscopy: A Systematic Review.

OBJECTIVES: Near-infrared spectroscopy (NIRS) is used in critical care settings to measure regional cerebral tissue oxygenation (rSo2). However, the accuracy of such measurements has been questioned in darker-skinned individuals due to the confounding effects of light absorption by melanin. In this systematic review, we aim to synthesize the available evidence on the effect of skin pigmentation on rSo2 readings. DATA SOURCES: We systematically searched MEDLINE, Cochrane Database of Systematic Reviews, Embase, and Google Scholar from inception to July 1, 2023. STUDY SELECTION: In compliance with our PROSPERO registration (CRD42022347548), we selected articles comparing rSo2 measurements in adults either between racial groups or at different levels of skin pigmentation. Two independent reviewers conducted full-text reviews of all potentially relevant articles. DATA EXTRACTION: We extracted data on self-reported race or level of skin pigmentation and mean rSo2 values. DATA SYNTHESIS: Of the 11,495 unique records screened, two studies (n = 7,549) met our inclusion criteria for systematic review. Sun et al (2015) yielded significantly lower rSo2 values for African Americans compared with Caucasians, whereas Stannard et al (2021) found little difference between self-reported racial groups. This discrepancy is likely because Stannard et al (2021) used a NIRS platform which specifically purports to control for the effects of melanin. Several other studies that did not meet our inclusion criteria corroborated the notion that skin pigmentation results in lower rSo2 readings. CONCLUSIONS: Skin pigmentation likely results in attenuated rSo2 readings. However, the magnitude of this effect may depend on the specific NIRS platform used.

Evidence for direct CO2 -mediated alterations in cerebral oxidative metabolism in humans.

AIM: How the cerebral metabolic rates of oxygen and glucose utilization (CMRO2 and CMRGlc, respectively) are affected by alterations in arterial PCO2 (PaCO2) is equivocal and therefore was the primary question of this study. METHODS: This retrospective analysis involved pooled data from four separate studies, involving 41 healthy adults (35 males/6 females). Participants completed stepwise steady-state alterations in PaCO2 ranging between 30 and 60 mmHg. The CMRO2 and CMRGlc were assessed via the Fick approach (CBF × arterial-internal jugular venous difference of oxygen or glucose content, respectively) utilizing duplex ultrasound of the internal carotid artery and vertebral artery to calculate cerebral blood flow (CBF). RESULTS: The CMRO2 was altered by 0.5 mL × min-1 (95% CI: -0.6 to -0.3) per mmHg change in PaCO2 (p < 0.001) which corresponded to a 9.8% (95% CI: -13.2 to -6.5) change in CMRO2 with a 9 mmHg change in PaCO2 (inclusive of hypo- and hypercapnia). The CMRGlc was reduced by 7.7% (95% CI: -15.4 to -0.08, p = 0.045; i.e., reduction in net glucose uptake) and the oxidative glucose index (ratio of oxygen to glucose uptake) was reduced by 5.6% (95% CI: -11.2 to 0.06, p = 0.049) with a + 9 mmHg increase in PaCO2. CONCLUSION: Collectively, the CMRO2 is altered by approximately 1% per mmHg change in PaCO2. Further, glucose is incompletely oxidized during hypercapnia, indicating reductions in CMRO2 are either met by compensatory increases in nonoxidative glucose metabolism or explained by a reduction in total energy production.

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.