Topical Tacrolimus Outperforms Topical Nitroglycerin for Pedicled Flap Survival in an Ischemic Rodent Model: Gross and Histologic Analysis

PURPOSE: A common postoperative complication associated with mastectomies is skin necrosis (1). Our previous studies have shown that topical tacrolimus (TT) decreases rates of skin necrosis in an ischemic flap rodent model (2)(3). Clinically, we treat our patients who have breast skin necrosis with topical nitroglycerin (TN). This study compares the efficacy of TT versus TN. METHODS: A cranially based dorsal skin flap measuring 3×10cm was raised and reinset on 25 Sprague-Dawley rats. Rats were randomized to receive either TT or TN. 0.2g of selected ointment was administered to each rat both immediately post-operatively and then twice daily. Rats were sacrificed 7 days postoperatively. Fiji software was used to measure surface area of healthy tissue, reversible ischemia and full-thickness necrosis. Biopsies of tissue samples were taken from three randomly chosen animals in each group. Hematoxylin and eosin-stained slides were prepared. A blinded pathologist described the conditions of the dermal layer. RESULTS: The average area of the dorsal flaps in the TT and TN groups was 26.4 and 24.5 cm, respectively. In the TT cohort, the average healthy, ischemic and necrotic areas were 47.9%, 30.0%, and 22.1%, respectively. In the TN cohort, the average healthy, reversible ischemic and necrotic areas were 31.4%, 36.3%, and 32.3%, respectively. Total healthy tissue was significantly greater for rats receiving TT when compared to TN (p=0.035). Under light microscopy, reversibly ischemic tissue of rats treated with TT demonstrated increased granulation tissue compared to rats treated with TN. Similarly, necrotic tissue of TT treated rats demonstrated granulation tissue, fibroblasts, myofibroblasts and inflammatory cells while rats treated with TN demonstrated only inflammatory cells, without associated granulation tissue. CONCLUSIONS: TT treatment was associated with significantly more healthy tissue when compared to TN. The presence of granulation tissue in reversibly ischemic and necrotic flaps treated with TT and the absence of granulation tissue in flaps treated with TN correlates with our gross findings of increased healthy tissue in our TT treated rodent model compared to TN. This study has identified that topical tacrolimus may be a better treatment for postoperative skin ischemia than topical nitroglycerin. Topical tacrolimus warrants clinical investigation for this purpose. REFERENCES: 1. Robertson S, Jeevaratnam J, Agrawal A, Cutress R. Mastectomy skin flap necrosis: challenges and solutions. BCTT. 2017;Volume 9:141-152. doi:10.2147/BCTT.S81712 2. Jung W, Van Y vu R, Huang H, Wald G, Otterburn DM. The Effect of Pre-and Postsurgical Topical Tacrolimus on Pedicled Flap Survival in Rats: A Pilot Study. Plastic and Reconstructive Surgery Global Open. 2021;9(10 Suppl). 3. Wald G, Van YV, Towne W, Otterburn DM. The Effect of Topical Tacrolimus on Pedicled Flap Survival: A Histological Analysis. Ann Plast Surg. 2021;87(1s):S57-S59. doi:10.1097/SAP.0000000000002799