Background PGD limits success of lung transplants (LT). RIC lowered reported PGD and rejection (R) in LT. Repetitive RIC (RRIC) regulated ischemic-reperfusion injury (IRI) biology, a mediator of PGD. This study aimed to estimate the ES and sources of RRIC variation on composite indices of IRI relevant to PGD in human studies.

Methods Prospero registered (CRD42022377023) systematic review assessed the ES and sources of variation of RRIC on standardised mean differences (SMD) of IRI indices that influence PGD.

Results 48 studies compared RRIC (n=4682) and controls (n=4793) on composite IRI measures, including brain, heart, endothelial and lung function, fibrinolysis, inflammation and cell death. SMD ES of RRIC was 0.367 (95%CI 0.276-0.458), p<0.0001, PI -0.05-0.78. Mixed effects revealed differences in ES between target organs (Q=39.4, p<0.001) and composite measures of IRI (Q=26, p<0.001); however, all target organs and composite measures of IRI achieved a significant benefit from RRIC. Increased Days of RRIC and diabetes mellitus (DM) were associated with higher RRIC ES, coefficient (CE) 8.1x10-4, p<0.04 and CE 8.3x10-3, p=0.003. Patient age, sex, BMI, hypertension (HT) or dyslipidemia (DL) did not influence ES (p>0.05). Smoking reduced the benefit of RRIC CE -6.0x10-3, p=0.018.

Conclusion RRIC regulated IRI effects with a nontrivial ES across various biologic processes and target organs, including lung, consistent with the construct validity of the composite measure of IRI. RRIC was not inhibited by patient age, sex, BMI, HT, DL, or DM; highlighting that the biological benefits of RIC may be translated to prevent PGD in LT and other conditions IRI mediates.