Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a "two-hit" model

Abstract

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.

Keywords: Anemia; Carbon dioxide; Cardiac arrest; Cerebral edema; Cerebral oxygen delivery; Hypothermia; Hypoxic ischemic brain injury; Normobaric hyperoxia; Targeted temperature management.

Fig. 1

A schematic demonstrating the various microvascular and cellular pathophysiologic consequences which occur during the primary and secondary injury in hypoxic ischemic brain injury (HIBI). Decreased cerebral oxygen delivery manifests as reduced neuronal aerobic metabolism, causing reduced cellular adenosine triphosphate (ATP) production. Intracellular calcium accumulation leads to mitochondrial toxicity and further reduced ATP production. Inability to sustain cellular respiration results in cell death and apoptosis. Additionally, in the microvasculature, endothelial dysfunction leads to a porous blood-brain barrier, formation of cerebral edema, formation of microthrombi and limitation of cerebral blood flow with exacerbation of cellular ischemia. AQP 4 Aquaporin-4, RBC Red blood cells, WBC White blood cells

Fig. 2

Magnetic resonance imaging sequences show focal hypoxic ischemic brain injury (HIBI) within the hippocampi and basal ganglia bilaterally. The images shown represent the acute changes after HIBI within the first week after resuscitation. In the top row, T2-weighted sequences reveal abnormal signaling in the hippocampi and basal ganglia as highlighted by the red arrows. In the bottom row, restricted diffusion-weighted imaging confirms HIBI in the affected regions of the hippocampi and basal ganglia as highlighted by the red arrows

Fig. 3

The zone of preserved autoregulation after hypoxic ischemic brain injury appears to be narrowed and right-shifted after cardiac arrest. Within the zone of autoregulation, regional saturation of oxygen (rSO₂) is stable owing to the innate vasoconstriction and vasodilation of the cerebral vasculature to maintain stable cerebral blood flow. Outside the zone of autoregulation, a linear relationship exists between rSO₂ and mean arterial pressure (MAP). By continually integrating the fluctuations of MAP and rSO₂ with one another, a correlation coefficient (COx) can be generated. The COx approaches negative values or near-zero within the preserved zone of autoregulation, resulting in a U-shaped curve. The nadir of the U-shaped curve represents the optimal MAP (MAP_OPT) for each individual patient