Comparing Gas and Inhaled Pharmacologic Interventions During Ex Vivo Lung Perfusion: A Systematic Review

Ex vivo lung perfusion (EVLP) has expanded the use of donor lungs by enabling ex vivo assessment, preservation, and rehabilitation before transplantation. Despite these advances, ischemia-reperfusion injury, inflammatory activation, pulmonary edema, and impaired lung mechanics continue to compromise graft quality and contribute to primary graft dysfunction. Inhaled and gaseous interventions have emerged as potential adjunctive therapies to improve donor lung preservation during EVLP; however, a standardized protocol has not yet been established.

PubMed and Embase were used to search human and animal studies evaluating inhaled and gaseous interventions administered during and after EVLP. Articles published from the database's inception to September 22, 2025, were analyzed.

Among the interventions examined, 10% carbon dioxide, carbon monoxide (CO), 40% oxygen (O₂), hydrogen, 40 ppm nitric oxide (NO) with 60% O₂, 2% sevoflurane with 40%-50% O₂, 2-S-amino-6-boronohexanoic acid, fasudil, and β₂-adrenoreceptor agonists most effectively improved lung function. Interestingly, improvements from hydrogen and CO were observed after transplantation, rather than during EVLP, suggesting more persistent or delayed protective effects. Further optimized parameters were observed when moderate O₂ concentrations (40%-60%) were combined with either CO, NO, or sevoflurane, compared with O₂ alone. In contrast, argon, xenon, N-acetylcysteine, sevoflurane or NO with 6% O₂, and liquid ventilation demonstrated minimal benefit.

Inhaled interventions can attenuate both mechanical damage and inflammatory pathways, particularly when used in tailored combinations with 40%-60% O₂. Future research should prioritize standardizing protocols, optimizing gas composition and timing, and assessing long-term posttransplant outcomes to translate these findings into clinical practice.