Improvement in Outcomes and Prevention of Multiple Organ Dysfunction Syndrome After Cardiac Arrest and Successful Cardiopulmonary Resuscitation by Systemic Administration of Bumetanide in Male Mice

BACKGROUND Cardiac arrest (CA) and successful cardiopulmonary resuscitation (CPR) cause post-CA brain injury (PCABI) and extracerebral multiple organ dysfunction (EMOD), leading to low survival and disability in resuscitated patients. The pathogenesis of PCABI is still poorly understood, and no therapeutic-related factors have been identified to improve survival and neurological outcomes to date. Bumetanide is a promising pharmaceutical intervention for some neurological disorders that have some common pathophysiology with PCABI, and it also exhibit systemic protective effects on vital organs under pathological conditions. This study aims to investigate the protective effects of bumetanide on PCABI and EMOD after CA/CPR, and uncover the pathogenesis and biomarkers of PCABI at protein level. METHODS We generated a hyperkalemia-induced asystole CA/CPR mouse model with bumetanide/vehicle treatment after resuscitation. Survival, neurological outcome, functional outcome, key pathophysiological process underlying PCABI, and injury level of EMOD were evaluated. Proteomics analysis of cerebral cortex was performed for investigating mechanisms of PCABI. RESULTS Bumetanide significantly improved outcomes after CA/CPR and reduced the main pathophysiological processes of PCABI, including seizures, neurodegeneration, neuroinflammation, decreased cerebral blood flow, blood-brain barrier disruption, and oxidative stress. CA/CPR-induced injury in heart, lung, liver, kidney, spleen, adrenal gland, spinal cord, pennis, and urinary bladder were also alleviated by bumetanide. Proteomic study and experimental verification identified LCN2/NGAL is a potential biomarker for early neuroprognostication and has association with PCABI severity. CONCLUSIONS Systemic administration of bumetanide improved outcomes and prevented multiple organ dysfunction after CA/CPR. LCN2/NGAL is a novel biomarker for early neuroprognostication at 24 hours after CA/CPR. Clinical Perspective What Is New? Post-resuscitation bumetanide treatment could improve outcomes and prevent brain injury and extracerebral multiple organ dysfunction after hyperkalemia-induced asystole cardiac arrest in mice. Neuronal subpopulations in cerebral cortex were selectively vulnerable, and all major organs had obvious tissue damage with inflammatory cell infiltration and tissue edema after resuscitation. This the first study to identify the pathogenesis and biomarkers of post-cardiac arrest brain injury with proteomic studies, and LCN2/NGAL had a strong and graded association with pathogenesis of PCABI, which could be a marker for monitoring and neuroprognostication. What Are the Clinical Implications? Bumetanide may be a novel pharmacological therapy to improve survival and neurological outcomes in post-resuscitation care, and cerebral-specific quantification of LCN2/NGAL could be used for early neuroprognostication at 24 hours after cardiac arrest. Extracerebral multiple organ injury is common and severe after resuscitation, which needs to be given more attention in clinical management.