Hypoxic ischemic brain injury (HIBI) after cardiac arrest (CA) is a leading cause of mortality and long-term neurologic disability in survivors. The pathophysiology of HIBI encompasses a heterogeneous cascade that culminates in secondary brain injury and neuronal cell death. This begins with primary injury to the brain caused by the immediate cessation of cerebral blood flow following CA. Thereafter, the secondary injury of HIBI takes place in the hours and days following the initial CA and reperfusion. Among factors that may be implicated in this secondary injury include reperfusion injury, microcirculatory dysfunction, impaired cerebral autoregulation, hypoxemia, hyperoxia, hyperthermia, fluctuations in arterial carbon dioxide, and concomitant anemia. Clarifying the underlying pathophysiology of HIBI is imperative and has been the focus of considerable research to identify therapeutic targets. Most notably, targeted temperature management has been studied rigorously in preventing secondary injury after HIBI and is associated with improved outcome compared with hyperthermia. Recent advances point to important roles of anemia, carbon dioxide perturbations, hypoxemia, hyperoxia, and cerebral edema as contributing to secondary injury after HIBI and adverse outcomes. Furthermore, breakthroughs in the individualization of perfusion targets for patients with HIBI using cerebral autoregulation monitoring represent an attractive area of future work with therapeutic implications. We provide an in-depth review of the pathophysiology of HIBI to critically evaluate current approaches for the early treatment of HIBI secondary to CA. Potential therapeutic targets and future research directions are summarized.

Hypercytokinemic immune dysregulation in COVID-19 is known as cytokine storm syndrome. Interleukin-6 levels ≥80 pg×mL⁻¹ predict an increased risk of respiratory failure and death, and immunomodulatory therapy is an area of urgent investigation

Studies on severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) suggest a protective effect of anti-A antibodies against viral cell entry that may hold relevance for SARS-CoV-2 infection. Therefore, we aimed to determine whether ABO blood groups are associated with different severities of COVID-19. We conducted a multicenter retrospective analysis and nested prospective observational substudy of critically ill patients with COVID-19. We collected data pertaining to age, sex, comorbidities, dates of symptom onset, hospital admission, intensive care unit (ICU) admission, mechanical ventilation, continuous renal replacement therapy (CRRT), standard laboratory parameters, and serum inflammatory cytokines. National (N = 398 671; P = .38) and provincial (n = 62 246; P = .60) ABO blood group distributions did not differ from our cohort (n = 95). A higher proportion of COVID-19 patients with blood group A or AB required mechanical ventilation (P = .02) and CRRT (P = .004) and had a longer ICU stay (P = .03) compared with patients with blood group O or B. Blood group A or AB also had an increased probability of requiring mechanical ventilation and CRRT after adjusting for age, sex, and presence of ≥1 comorbidity. Inflammatory cytokines did not differ between patients with blood group A or AB (n = 11) vs O or B (n = 14; P > .10 for all cytokines). Collectively, our data indicate that critically ill COVID-19 patients with blood group A or AB are at increased risk for requiring mechanical ventilation, CRRT, and prolonged ICU admission compared with patients with blood group O or B. Further work is needed to understand the underlying mechanisms.

Hypoxic ischemic brain injury (HIBI) is the primary determinant of outcome following cardiac arrest.^1,2 Survivors of HIBI can experience a wide range of clinical outcomes along a spectrum encompassing full neurologic recovery, persistent vegetative states, or severe or mild disabilities,^3-6 thereby making accurate prognostication imperative to inform health care teams and caregivers. Considerable efforts have been directed toward identifying accurate neurologic prognostication for patients with HIBI.⁷ Guidelines recommend using multiple modalities including clinical examination, electroencephalography, somatosensory-evoked potentials, and neuroimaging.^8-10

Rationale: Secondary brain hypoxia portends significant mortality in ischemic brain diseases; yet, our understanding of hypoxic ischemic brain injury (HIBI) pathophysiology in humans remains rudimentary. Objective: To quantify the impact of secondary brain hypoxia on injury to the neurovascular unit in patients with HIBI. Methods and Results: We conducted a prospective interventional study of invasive neuromonitoring in 18 post–cardiac arrest patients with HIBI. The partial pressures of brain tissue O ₂ (PbtO ₂ ) and intracranial pressure were directly measured via intraparenchymal microcatheters. To isolate the cerebrovascular bed, we conducted paired sampling of arterial and jugular venous bulb blood and calculated the transcerebral release of biomarkers of neurovascular injury and inflammation in the patients with HIBI and 14 healthy volunteers for control comparisons. Ten patients with HIBI exhibited secondary brain hypoxia (PbtO ₂ <20 mmHg), while 8 exhibited brain normoxia (PbtO ₂ ≥20 mmHg). In the patients with secondary brain hypoxia, we observed active cerebral release of glial fibrillary acidic protein (−161 [−3695 to −75] pg/mL; P =0.0078), neurofilament light chain (−231 [−370 to −11] pg/mL; P =0.010), total tau (−32 [−310 to −3] pg/mL; P =0.0039), neuron-specific enolase (−14 890 [−148 813 to −3311] pg/mL; P =0.0039), and ubiquitin carboxy-terminal hydrolase L1 (−14.7 [−37.7 to −4.1] pg/mL; P =0.0059) indicating de novo neuroglial injury. This injury was unrelated to the systemic global ischemic burden or cerebral endothelial injury but rather was associated with cerebral release of IL-6 (interleukin-6; −10.3 [−43.0 to −4.2] pg/mL; P =0.0039). No cerebral release of the aforementioned biomarkers was observed in patients with HIBI with brain normoxia or the healthy volunteers. Hyperosmolar therapy in the patients with secondary brain hypoxia reduced the partial pressure of jugular venous O ₂ -to-PbtO ₂ gradient (39.6 [34.1–51.1] versus 32.0 [24.5–39.2] mm Hg; P =0.0078) and increased PbtO ₂ (17.0 [9.1–19.7] versus 20.2 [11.9–22.7] mm Hg; P =0.039) suggesting improved cerebrovascular-to-parenchymal O ₂ transport. Conclusions: Secondary brain hypoxia is associated with de novo neuroglial injury and cerebral release of IL-6. Mitigating cerebrovascular-to-parenchymal limitations to O ₂ transport is a promising therapeutic strategy for patients with HIBI with secondary brain hypoxia. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03609333.