Clinical heterogeneity and phenotyping of post cardiac arrest brain injury: one size may not fit all

Abstract

Post-cardiac arrest brain injury (PCABI) emanates from the injurious pathophysiologic sequelae that take place during and after resuscitation from cardiac arrest. Regrettably, identification of efficacious management strategies to mitigate PCABI has been disappointing with numerous well-conducted randomized control trials yielding neutral results. The reasons for this observation are likely multifactorial, however, increasingly patient and disease-specific heterogeneity is recognized as a crucial factor in clinical decision-making. Traditionally, PCABI has been stratified based upon simple historical characteristics (e.g. location of cardiac arrest, initial rhythm, witnessed vs. unwitnessed) that inadequately reflect in vivo PCABI severity or responses to clinical interventions within individual patients. It is therefore increasingly clear that this approach to PCABI is insufficient. In other syndromes, such as sepsis or acute respiratory distress syndrome, attempts to identify early "phenotypes" of patients reflect growing recognition of considerable between-patient heterogeneity in the disease mechanisms and response to therapeutic interventions. A similar approach should be taken with PCABI. In this review, we described the clinical heterogeneity and phenotypes of PCABI as related to the underlying pathophysiology, selective anatomical vulnerability and electrographic patterns. The overarching aim of the review is the propose a shift to expeditious phenotyping of PCABI severity that focuses on assessing in vivo severity and patterns of injury that could be used for future targeted therapies. We will also discuss potential causes of heterogeneous clinical responses to interventions and highlight future research areas for PCABI that focus on phenotyping and incorporating these considerations into clinical trials.

Keywords: Cardiac arrest; Heterogeneity; Phenotypes; Post-cardiac arrest brain injury; Return of spontaneous circulation.

Fig. 1

Physiology of shockable versus non-shockable rhythms of circulatory arrest. A demonstrates the degeneration of a normal sinus rhythm to ventricular fibrillation with subsequent abrupt collapse of innate hemodynamics (B) and perfusion (C). Conversely, D demonstrates progressive slowing of the innate hemodynamics and underlying electrical cardiac rhythm. In this instance, perfusion decreases gradually over a protracted period of time, thereby exposing the brain to prolonged warm ischemia during systemic hypotension

Fig. 2

Cellular Pathophysiology of post-cardiac arrest brain injury. A demonstrates reperfusion of a previously ischemic neurovascular unit. Microglial (yellow) activation with release of pro-inflammatory cytokines predominates with potential consequent pyroptosis of vulnerable neurons. Astrocyte (purple) activation also is seen with ischemic-reperfusion injury and may contribute to porous blood–brain barrier mechanisms. Axonal and neuron degeneration ensues from a culmination of pathophysiologic sequelae. B demonstrates intracellular mechanisms encompassing calcium infiltration and reactive oxygen species-induced mitochondrial dysfunction. Apoptosis can ensue from mitochondrial pathways

Fig. 3

Anatomical injury patterns of post-cardiac arrest brain injury. On the left panels, illustrations of the brain in coronal (top) and axial (bottom) planes are exhibited. Anatomical foci of selective vulnerability are shown with the following designations: (A) cerebral cortex—grey matter; (B) sub-cortical white matter; (C) hippocampi; (D) basal ganglia (comprised of the caudate, putamen and globus pallidus); (E) thalamus. On the right side of the figure, axial MRI head images are shown revealing selective injury patterns of PCABI with the corresponding alphabetical letter designations corresponding to their anatomic foci labelled on the illustrations (left)

Fig. 4

The cellular origin of blood-based biomarkers of injury to the neurovascular unit. On the left panel, the cellular structure and components of the neurovascular unit are shown comprising of astrocytes (purple) encasing cerebral arterioles, degenerating neuron cell body and axon (pink) and a reactive microglial cell (yellow). The origins of biomarkers are shown in proximity to the cells from which they are released: NSE neuron specific enolase (neuron cell body), Nf-L neurofilament-light (axonal injury), GFAP glial fibrillary acidic protein (astrocytes), UCHL-1 ubiquitin carboxyl hydrolase L1 (neuron cell body), Tau axonal injury. On the right panel, a magnified depiction of the cerebral microvasculature is shown with a porous blood–brain barrier with disruption of astrocyte end foot processes. Leakage of the aforementioned biomarkers into the bloodstream and circulation is demonstrated

Fig. 5

An approach phenotyping post-cardiac arrest patients to facilitate individualized management decisions. A suggested approach of multimodal assessment of PCABI patients is shown as a model of evaluating PCABI disease pathophysiology to facilitate rapid phenotyping of patients. This approach would utilize expeditious implementation of neuroimaging (CT ± MRI), incorporating electroencephalography, blood-based biomarker measurements and bedside neuromonitoring. Doing so may lead to important clinical phenotyping that could be utilized for future clinical trial enrollment, design and outcome assessments

Fig. 6

Phenotyping pathways for post-cardiac arrest brain injury. A suggested pathway for rapid phenotyping could consist of enabling an immediate unconfounded clinical examination with a focus on brainstem evaluation. Thereafter, expeditious neuroimaging with non-contrast CT ± perfusion sequencing followed by point-of-care biomarker assessment and application of generalizable and non-invasive neuromonitoring to evaluate both brain hemodynamics and function