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

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.