Therapeutic strategies for ischemia reperfusion injury in emergency medicine

Abstract

Ischemia reperfusion (IR) injury occurs when blood supply, perfusion, and concomitant reoxygenation is restored to an organ or area following an initial poor blood supply after a critical time period. Ischemia reperfusion injury contributes to mortality and morbidity in many pathological conditions in emergency medicine clinical practice, including trauma, ischemic stroke, myocardial infarction, and post-cardiac arrest syndrome. The process of IR is multifactorial, and its pathogenesis involves several mechanisms. Reactive oxygen species are considered key molecules in reperfusion injury due to their potent oxidizing and reducing effects that directly damage cellular membranes by lipid peroxidation. In general, IR injury to an individual organ causes various pro-inflammatory mediators to be released, which could then induce inflammation in remote organs, thereby possibly advancing the dysfunction of multiple organs. In this review, we summarize IR injury in emergency medicine. Potential therapies include pharmacological treatment, ischemic preconditioning, and the use of medical gases or vitamin therapy, which could significantly help experts develop strategies to inhibit IR injury.

Keywords: Emergency medicine; inflammation; ischemia reperfusion; remote ischemic preconditioning; shock; therapeutic hypothermia.

Fig. 1

Schematic images of sequential changes in cytosolic and mitochondrial function during ischemia and reperfusion injury. During hypoxia, reduced O₂ promotes anaerobic glycolysis that generates increased cytosolic lactate leading to acidification. Increased H⁺ activates Na⁺‐H⁺ exchanger leading to increased cytosolic Na⁺, which activates Na⁺‐Ca²⁺ exchanger, causing an increase in cytosolic Ca²⁺. Cytosolic Ca²⁺ overload in turn increases mitochondrial matrix Ca²⁺. Impaired electron transport leads to increased generation of reactive oxygen species (ROS). Impaired respiration and substrate utilization lead to decreased generation of mitochondrial adenosine triphosphate (ATP). During reperfusion state, an increased mitochondrial permeability transition pore (mPTP) opening elevates ROS generation and disrupts intracellular distribution of Ca²⁺, Na⁺, and pH, resulting in subsequent irreversible cell death. ROS further increase to produce even greater mitochondria damage that induces mPTP opening and release of cytochrome c that in turn triggers apoptosis.