Resuscitating the Globally Ischemic Brain: TTM and Beyond

Abstract

Cardiac arrest (CA) afflicts~550,000 people each year in the USA. A small fraction of CA sufferers survive with a majority of these survivors emerging in a comatose state. Many CA survivors suffer devastating global brain injury with some remaining indefinitely in a comatose state. The pathogenesis of global brain injury secondary to CA is complex. Mechanisms of CAinduced brain injury include ischemia, hypoxia, cytotoxicity, inflammation, and ultimately, irreversible neuronal damage. Due to this complexity, it is critical for clinicians to have access as early as possible to quantitative metrics for diagnosing injury severity, accurately predicting outcome, and informing patient care. Current recommendations involve using multiple modalities including clinical exam, electrophysiology, brain imaging, and molecular biomarkers. This multi-faceted approach is designed to improve prognostication to avoid "self-fulfilling" prophecy and early withdrawal of life-sustaining treatments. Incorporation of emerging dynamic monitoring tools such as diffuse optical technologies may provide improved diagnosis and early prognostication to better inform treatment. Currently, targeted temperature management (TTM) is the leading treatment, with the number of patients needed to treat being~6 in order to improve outcome for one patient. Future avenues of treatment, which may potentially be combined with TTM, include pharmacotherapy, perfusion/oxygenation targets, and pre/postconditioning. In this review, we provide a bench to bedside approach to delineate the pathophysiology, prognostication methods, current targeted therapies, and future directions of research surrounding hypoxic-ischemic brain injury (HIBI) secondary to CA.

Methane-Rich Saline Alleviates CA/CPR Brain Injury by Inhibiting Oxidative Stress, Microglial Activation-Induced Inflammatory Responses, and ER Stress-Mediated Apoptosis

“…While numerous studies have been conducted on brain injury after CPR, these studies mainly focus on the underlying mechanisms. The availability of treatments for brain injury after CA/CPR remains limited [ 27 ]. Therefore, it is essential to develop a new therapeutic method to alleviate brain injury in the early period and promote the survival rate of patients with ROSC.…”

Global Impairment of Cerebral Perfusion Measured using Dynamic Susceptibility Contrast Perfusion-Weighted Imaging in Out-of-Hospital Cardiac Arrest Survivors: A Prospectively Preliminary Study

“…We enrolled OHCA survivors who had undergone DSC-PWI within 6 h after restoration of spontaneous circulation (ROSC). Patients were subsequently excluded if they had (1) younger age than 18 y, (2) CA due to trauma, (3) ineligibility for targeted temperature management (e.g., brain haemorrhage, active bleeding, known terminal illness, poor pre-arrest neurological status), (4) no responsible relative able to approve magnetic resonance imaging (MRI), contraindication for MRI (e.g., indwelling metal device), or (5) opposition to further patient treatment by the next of kin.…”

“…The current high rates of mortality and poor neurological outcome after CA are mainly due to hypoxicischemic brain injury (HIBI), which is a complex pathophysiological mechanism accompanying the impairment of cerebral perfusion [5]. The current gold standard for the assessment of cerebral perfusion is dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI), which is a proven diagnostic tool for BD and has 100% sensitivity and speci city [6,7].…”

Overnight Caloric Restriction Prior to Cardiac Arrest and Resuscitation Leads to Improved Survival and Neurological Outcome in a Rodent Model

“…To our knowledge, there are no studies involving short-term caloric restriction of a single day or less. Pre-clinical analysis of such phenomena may provide simple and translatable approaches to potentially ameliorate recovery following focal ischemia, which affects over 795,000 people per year in the United States ( Provencio et al, 2020 ), and global ischemia, which affects over 550,000 people annually in the United States ( Hosseini et al, 2020 ). In this experiment, we induced global ischemia by cardiac arrest (CA) in rats that were calorically restricted (75%) overnight for 14 h and assessed for changes in outcome.…”