Neuroinflammation and the immune system in hypoxic ischaemic brain injury pathophysiology after cardiac arrest.

Hypoxic ischaemic brain injury after resuscitation from cardiac arrest is associated with dismal clinical outcomes. To date, most clinical interventions have been geared towards the restoration of cerebral oxygen delivery after resuscitation; however, outcomes in clinical trials are disappointing. Therefore, alternative disease mechanism(s) are likely to be at play, of which the response of the innate immune system to sterile injured tissue in vivo after reperfusion has garnered significant interest. The innate immune system is composed of three pillars: (i) cytokines and signalling molecules; (ii) leucocyte migration and activation; and (iii) the complement cascade. In animal models of hypoxic ischaemic brain injury, pro-inflammatory cytokines are central to propagation of the response of the innate immune system to cerebral ischaemia-reperfusion. In particular, interleukin-1 beta and downstream signalling can result in direct neural injury that culminates in cell death, termed pyroptosis. Leucocyte chemotaxis and activation are central to the in vivo response to cerebral ischaemia-reperfusion. Both parenchymal microglial activation and possible infiltration of peripherally circulating monocytes might account for exacerbation of an immunopathological response in humans. Finally, activation of the complement cascade intersects with multiple aspects of the innate immune response by facilitating leucocyte activation, further cytokine release and endothelial activation. To date, large studies of immunomodulatory therapies have not been conducted; however, lessons learned from historical studies using therapeutic hypothermia in humans suggest that quelling an immunopathological response might be efficacious. Future work should delineate the precise pathways involved in vivo in humans to target specific signalling molecules.

Cerebral hemodynamics after cardiac arrest: implications for clinical management.

Following resuscitation from cardiac arrest, hypoxic ischemic brain injury (HIBI) ensues, which is the primary determinant of adverse outcome. The pathophysiology of HIBI can be compartmentalized into primary and secondary injury, resulting from cerebral ischemia during cardiac arrest and reperfusion following successful resuscitation, respectively. During the secondary injury phase, increased attention has been directed towards the optimization of cerebral oxygen delivery to prevent additive injury to the brain. During this phase, cerebral hemodynamics are characterized by early hyperemia following resuscitation and then a protracted phase of cerebral hypoperfusion termed "no-reflow" during which additional hypoxic-ischemic injury can occur. As such, identification of therapeutic strategies to optimize cerebral delivery of oxygen is at the forefront of HIBI research. Unfortunately, randomized control trials investigating the manipulation of arterial carbon dioxide tension and mean arterial pressure augmentation as methods to potentially improve cerebral oxygen delivery have shown no impact on clinical outcomes. Emerging literature suggests differential patient-specific phenotypes may exist in patients with HIBI. The potential to personalize therapeutic strategies in the critical care setting based upon patient-specific pathophysiology presents an attractive strategy to improve HIBI outcomes. Herein, we review the cerebral hemodynamic pathophysiology of HIBI, discuss patient phenotypes as it pertains to personalizing care, as well as suggest future directions.