Modulating metabolism to mitigate reperfusion injury induced by resuscitation from cardiac arrest: a narrative review

Cardiac arrest remains a leading cause of mortality and morbidity. Overall survival rates remain below 10%, with many survivors suffering from persistent neurological and cognitive impairment. A major contributor to these poor outcomes is reperfusion injury resulting from the necessary restoration of a spontaneous circulation. This restoration triggers a further cascade of metabolic disturbances and tissue injury, predominantly driven by an abrupt surge in reactive oxygen species production. Metabolic modulation offers a promising avenue to limit secondary injury by mitigating reperfusion injury. Strategies include suppression of metabolic demand such as hypothermic temperature control and mitochondrial electron chain inhibition, mitochondrial-targeted antioxidant therapies, and administration of specific energy substrates during the critical early post-resuscitation period. While laboratory studies have demonstrated encouraging results, translation into routine clinical practice has been hindered by a lack of positive outcomes from controlled trials. This reflects challenges in prompt delivery of the strategy, identifying effective therapeutic windows and optimising dosing regimens. This review describes strategies employed to mitigate reperfusion injury after cardiac arrest, their mechanisms of action, outcomes in non-clinical models, the limited human data available to date, and challenges in trial design.