Brain injury following cardiac arrest: pathophysiology for neurocritical care

Abstract

Cardiac arrest induces the cessation of cerebral blood flow, which can result in brain damage. The primary intervention to salvage the brain under such a pathological condition is to restore the cerebral blood flow to the ischemic region. Ischemia is defined as a reduction in blood flow to a level that is sufficient to alter normal cellular function. Brain tissue is highly sensitive to ischemia, such that even brief ischemic periods in neurons can initiate a complex sequence of events that may ultimately culminate in cell death. However, paradoxically, restoration of blood flow can cause additional damage and exacerbate the neurocognitive deficits in patients who suffered a brain ischemic event, which is a phenomenon referred to as "reperfusion injury." Transient brain ischemia following cardiac arrest results from the complex interplay of multiple pathways including excitotoxicity, acidotoxicity, ionic imbalance, peri-infarct depolarization, oxidative and nitrative stress, inflammation, and apoptosis. The pathophysiology of post-cardiac arrest brain injury involves a complex cascade of molecular events, most of which remain unknown. Many lines of evidence have shown that mitochondria suffer severe damage in response to ischemic injury. Mitochondrial dysfunction based on the mitochondrial permeability transition after reperfusion, particularly involving the calcineurin/immunophilin signal transduction pathway, appears to play a pivotal role in the induction of neuronal cell death. The aim of this article is to discuss the underlying pathophysiology of brain damage, which is a devastating pathological condition, and highlight the central signal transduction pathway involved in brain damage, which reveals potential targets for therapeutic intervention.

Keywords: Calcineurin/immunophilin; Cardiac arrest; Excitotoxicity; Mitochondrial dysfunction; Mitochondrial permeability transition (MPT); Pathophysiology of ischemic brain damage; Post-cardiac arrest syndrome (PCAS); Reperfusion injury.

Fig. 1

Pathophysiology of post-cardiac arrest syndrome. The four key components of PCAS were identified as (1) post-cardiac arrest brain injury, (2) post-cardiac arrest myocardial dysfunction, (3) systemic ischemia/reperfusion response, and (4) persistent precipitating pathology

Fig. 2

Relationship to the site of post-cardiac arrest care. Patients with ROSC receive >20-min care during transport or in the ED before hospital admission. The first 20 min after ROSC is defined as the immediate post-arrest phase. Between 20 min and 6–12 h after ROSC is defined as the early post-arrest phase. Between 6 and 12 and 72 h is defined as the intermediate phase. A period beyond 3 days is defined as the recovery phase when prognostification becomes more reliable (cited and modified from Noran 2009)

Fig. 3

Calcium overload and the calcineurin/cyclophilin D signal transduction pathway for the cell death induced after cerebral ischemia. Ischemia induces the loss of ATP-dependent ion homeostasis and leads to an increase in intracellular Na⁺ and extracellular K⁺. Eventually, the cells undergo depolarization. As a result, excessive Ca²⁺ influx due to the activation of voltage-sensitive calcium channels, NMDA, and AMPA receptors activates numerous signal transduction cascades, particularly the calcineurin/cyclophilin D signal transduction pathway. This eventually induces the MPT, leading to mitochondrial dysfunction

Fig. 4

Mitochondrial permeability transition and ischemic brain damage. Various forms of stress, such as brain ischemia, hypoxia, traumatic brain injury, status epilepticus, and encephalitis, induce mitochondrial dysfunction and the MPT that lead to apoptosis or necrosis. Calcineurin and immunophilin (CypD) are the key factors that induce the apoptotic pathway, and the immunosuppressants CsA and FK506 exert their neuroprotection by the inhibition of calcineurin and CypD activity