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Surgical site infections (SSI) account for a major proportion of hospital-acquired infections. They are associated with longer hospital stay, readmissions, increased costs, mortality, and morbidity. Reducing SSI is a goal of the Surgical Care Improvement Project and identifying interventions that reduce SSI effectively is of interest. In a single-blinded randomized controlled trial (RCT) we evaluated the effect of localized warming applied to surgical incisions on SSI development and selected cellular (immune, endothelial) and tissue responses (oxygenation, collagen).After Institutional Review Board approval and consent, patients having open bariatric, colon, or gynecologic-oncologic related operations were enrolled and randomly assigned to local incision warming (6 post-operative treatments) or non-warming. A prototype surgical bandage was used for all patients. The study protocol included intra-operative warming to maintain core temperature ≥36°C and administration of 0.80 FIO2. Patients were followed for 6 wks for the primary outcome of SSI determined by U.S. Centers for Disease Control (CDC) criteria and ASEPSIS scores (additional treatment; presence of serous discharge, erythema, purulent exudate, and separation of the deep tissues; isolation of bacteria; and duration of inpatient stay). Tissue oxygen (PscO2) and samples for cellular analyses were obtained using subcutaneous polytetrafluoroethylene (ePTFE) tubes and oxygen micro-electrodes implanted adjacent to the incision. Cellular and tissue ePTFE samples were evaluated using flow cytometry, immunohistochemistry, and Sircol™ collagen assay (Biocolor Ltd., Carrickfergus, United Kingdom).One hundred forty-six patients participated (n=73 per group). Study groups were similar on demographic parameters and for intra-operative management factors. The CDC defined rate of SSI was 18%; occurrence of SSI between groups did not differ (p=0.27). At 2 wks, warmed patients had better ASEPSIS scores (p=0.04) but this difference was not observed at 6 wks. There were no significant differences in immune, endothelial cell, or collagen responses between groups. On post-operative days one to two, warmed patients had greater PscO2 change scores with an average PscO2 increase of 9-10 mm Hg above baseline (p0.04).Post-operative local warming compared with non-warming followed in this study, which included intra-operative warming to maintain normothermia and FIO2 level of 0.80, did not reduce SSI and had no effect on immune, endothelial cell presence, or collagen synthesis. PscO2 increased significantly with warming, however, the increase was modest and less than expected or what has been observed in studies testing other interventions.