Volatile Anesthetic-Based Combination Strategies Against Ischemia–Reperfusion Injury: Experimental Evidence, Molecular Mechanisms, and Translational Limitations

Ischemia–reperfusion (I/R) injury is a complex pathological process involving adenosine triphosphate (ATP) depletion, calcium overload, excessive reactive oxygen species generation, mitochondrial dysfunction, inflammatory activation, and regulated cell death. Volatile anesthetics, including sevoflurane, desflurane, and isoflurane, may modulate several of these processes through antioxidant and prosurvival signaling, suppression of inflammatory pathways, and regulation of apoptosis. Because I/R injury involves interconnected mechanisms, combining interventions that act on different targets may offer additional protection. Experimental studies have investigated volatile anesthetics together with fullerenol C60, ischemic conditioning, and selected pharmacological interventions. Other combination strategies involving ozone conditioning and boric acid have also been evaluated in experimental models, although these have not established the effects of combining either intervention with a volatile anesthetic. This narrative review examines the molecular mechanisms and organ-specific evidence underlying these approaches, with particular attention to study design, treatment timing, and the interpretation of combined effects. While some combinations have shown greater protection than individual interventions, the findings remain heterogeneous, and formal analyses distinguishing additivity from synergy are generally lacking. Clinical evidence is limited, and further studies are needed to establish whether these experimental findings can be translated into meaningful patient outcomes.