Experimental study of the effects of nitroglycerin, botulinum toxin A, and clopidogrel on bipedicled superficial inferior epigastric artery flap survival.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
03 12 2022
03 12 2022
Historique:
received:
23
07
2022
accepted:
22
11
2022
entrez:
3
12
2022
pubmed:
4
12
2022
medline:
7
12
2022
Statut:
epublish
Résumé
Beneficial effects could be achieved by various agents such as nitroglycerin, botulinum toxin A (BoTA), and clopidogrel to improve skin flap ischaemia and venous congestion injuries. Eighty rats were subjected to either arterial ischaemia or venous congestion and applied to a bipedicled U-shaped superficial inferior epigastric artery (SIEA) flap with the administration of nitroglycerin, BoTA, or clopidogrel treatments. After 7 days, all rats were sacrificed for flap evaluation. Necrotic area percentage was significantly minimized in flaps treated with clopidogrel (24.49%) versus the ischemic flaps (34.78%); while nitroglycerin (19.22%) versus flaps with venous congestion (43.26%). With ischemia, light and electron microscopic assessments revealed that nitroglycerin produced degeneration of keratinocytes and disorganization of collagen fibers. At the same time, with clopidogrel administration, there was an improvement in the integrity of these structures. With venous congestion, nitroglycerin and BoTA treatments mitigated the epidermal and dermal injury; and clopidogrel caused coagulative necrosis. There was a significant increase in tissue gene expression and serum levels of vascular endothelial growth factor (VEGF) in ischemic flaps with BoTA and clopidogrel, nitroglycerin, and BoTA clopidogrel in flaps with venous congestion. With the 3 treatment agents, gene expression levels of tumor necrosis factor-α (TNF-α) were up-regulated in the flaps with ischemia and venous congestion. With all treatment modalities, its serum levels were significantly increased in flaps with venous congestion and significantly decreased in ischemic flaps. Our analyses suggest that the best treatment option for ischemic flaps is clopidogrel, while for flaps with venous congestion are nitroglycerin and BoTA.
Identifiants
pubmed: 36463303
doi: 10.1038/s41598-022-24898-9
pii: 10.1038/s41598-022-24898-9
pmc: PMC9719547
doi:
Substances chimiques
Nitroglycerin
G59M7S0WS3
Botulinum Toxins, Type A
EC 3.4.24.69
Clopidogrel
A74586SNO7
Vascular Endothelial Growth Factor A
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
20891Informations de copyright
© 2022. The Author(s).
Références
Cheng, L. et al. Naringin improves random skin flap survival in rats. Oncotarget 8, 94142 (2017).
pubmed: 29212216
pmcid: 5706862
doi: 10.18632/oncotarget.21589
Gündüz, M., Sekmenli, T., Uğurluoğlu, C. & Çiftçi, İ. The effects of nitroglycerin in the zone of stasis in a rat burn model. Ulus Travma Acil. Cerrahi. Derg. 26, 171–177 (2020).
pubmed: 32185753
Matsumoto, N. M. et al. Experimental rat skin flap model that distinguishes between venous congestion and arterial ischemia: The reverse U-shaped bipedicled superficial inferior epigastric artery and venous system flap. Plast. Reconstr. Surg. 139, 79e–84e (2017).
pubmed: 28027237
doi: 10.1097/PRS.0000000000002900
Lv, Q. B. et al. Effects of diammonium glycyrrhizinate on random skin flap survival in rats: An experimental study. Biomed. Rep. 5, 383–389 (2016).
pubmed: 27588181
pmcid: 4998118
doi: 10.3892/br.2016.733
Moore, M. G. & Deschler, D. G. Clopidogrel (Plavix) reduces the rate of thrombosis in the rat tuck model for microvenous anastomosis. Otolaryngol. Head Neck Surg. 136, 573–576 (2007).
pubmed: 17418254
doi: 10.1016/j.otohns.2006.06.1276
Wang, P., Gu, L., Qin, Z., Wang, Q. & Ma, J. Efficacy and safety of topical nitroglycerin in the prevention of mastectomy flap necrosis: A systematic review and meta-analysis. Sci. Rep. 10, 6753 (2020).
pubmed: 32317705
pmcid: 7174291
doi: 10.1038/s41598-020-63721-1
Hwang, C. J. et al. Rethinking the role of nitroglycerin ointment in ischemic vascular filler complications: An animal model with ICG imaging. Ophthalmic Plast. Reconstr. Surg. 32, 118–122 (2016).
pubmed: 25794030
doi: 10.1097/IOP.0000000000000446
Gdalevitch, P. et al. Effects of nitroglycerin ointment on mastectomy flap necrosis in immediate breast reconstruction: A randomized controlled trial. Plast. Reconstr. Surg. 135, 1530–1539 (2015).
pubmed: 26017589
doi: 10.1097/PRS.0000000000001237
Reddy, K. S. H. et al. Role of topical nitroglycerin in preventing keystone flap necrosis. JOP 2(1), 1–4 (2022).
doi: 10.54289/JOP2200101
Yun, M. H., Yoon, E. S., Lee, B.-I. & Park, S.-H. The effect of low-dose nitroglycerin ointment on skin flap necrosis in breast reconstruction after skin-sparing or nipple-sparing mastectomy. Arch. Plast. Surg. 44, 509 (2017).
pubmed: 29069878
pmcid: 5801789
doi: 10.5999/aps.2017.00934
Kim, S. Y. et al. The protective effects of botulinum toxin a against flap necrosis after perforator twisting and its underlying molecular mechanism in a rat model. Ann. Plast. Surg. 77, 242–248 (2016).
pubmed: 26101980
doi: 10.1097/SAP.0000000000000563
Zereyak, U., Özkaya, N. K. & Hasbek, Z. Effect of botulinum toxin-A injected to muscle tissue on perfusion and survival of fasciocutaneous single perforator-pedicled propeller flap in rats. Balkan Med. J. 37, 84 (2020).
pubmed: 31818730
pmcid: 7094189
doi: 10.4274/balkanmedj.galenos.2019.2019.9.44
Uchiyama, A. et al. Protective effect of botulinum toxin A after cutaneous ischemia-reperfusion injury. Sci. Rep. 5, 9072 (2015).
pubmed: 25766279
pmcid: 5390917
doi: 10.1038/srep09072
Park, T. H. et al. Presurgical botulinum toxin a treatment increases angiogenesis by hypoxia-inducible factor-1α/vascular endothelial growth factor and subsequent superiorly based transverse rectus abdominis myocutaneous flap survival in a rat model. Ann. Plast. Surg. 76, 723–728 (2016).
pubmed: 25695458
doi: 10.1097/SAP.0000000000000435
Segreto, F. et al. The use of botulinum toxin in flap surgery: A review of the literature. Surg. Innov. 26, 478–484 (2019).
pubmed: 30734634
doi: 10.1177/1553350619828902
Camargo, C. P. et al. Botulinum toxin type A on cutaneous flap viability in diabetic and tobacco-exposed rats. Acta Cir. Bras. 30, 639–645 (2015).
pubmed: 26465109
doi: 10.1590/S0102-865020150090000009
Vieira, F. A. et al. Effects of clopidogrel and low-molecular-weight heparin on viability of random skin flaps in rats. J. Reconstr. Microsurg. Open. 1, 106–110 (2016).
doi: 10.1055/s-0036-1593403
Irmak, F. et al. Amlodipine improves skin flap viability in rats exposed to nicotine. Turk. J. Plast. Surg. 27, 93 (2019).
Smith, D. K. & Dolan, R. W. Effects of vasoactive topical agents on the survival of dorsal skin flaps in rats. Otolaryngol. Head Neck Surg. 121, 220–223 (1999).
pubmed: 10471861
doi: 10.1016/S0194-5998(99)70175-0
Arnold, P. B., Fang, T., Songcharoen, S. J., Ziakas, G. & Zhang, F. Inflammatory response and survival of pedicled abdominal flaps in a rat model after perivascular application of botulinum toxin type A. Plast. Reconstr. Surg. 133, 491e-e498 (2014).
pubmed: 24352212
doi: 10.1097/PRS.0000000000000030
Moznebi, F. et al. Comparison of effect of botulinum toxin with clopidogrel and concomitant prescription of them in the survival of random skin flap in rats. HMJ. 19(6), 415–23 (2016).
Ballestín, A. et al. Ischemia-reperfusion injury in a rat microvascular skin free flap model: A histological, genetic, and blood flow study. PLoS ONE 13, e0209624 (2018).
pubmed: 30589864
pmcid: 6307726
doi: 10.1371/journal.pone.0209624
Öksüz, M. et al. Effects of ozone pretreatment on viability of random pattern skin flaps in rats. J. Plast. Surg. Hand Surg. 49, 300–305 (2015).
pubmed: 25998721
doi: 10.3109/2000656X.2015.1047452
Oktari, A., Handriani, R. & Musbihah, S. S. Optimization concentration control cell coombs (CCC) for validity tests on crossmatching examination. J. Phys.: Conf. Ser. 1764, 012016 (2021).
Gemperli, R. & Munhoz, A. M. The influence of type of vascular pedicle occlusion on the viability of skin island flaps: A postoperative quantitative assessment of flap survival in an experimental model in rats. Acta Cir. Bras. 28(7), 487–493 (2013).
pubmed: 23842928
doi: 10.1590/S0102-86502013000700002
Stone, R. 2nd. & Rathbone, C. R. Microvascular fragment transplantation improves rat dorsal skin flap survival. Plast. Reconstr. Surg. Glob. Open. 4(12), e1140 (2016).
pubmed: 28293502
pmcid: 5222647
doi: 10.1097/GOX.0000000000001140
Schuster, R., Bar-Nathan, O., Tiosano, A., Lewis, E. C. & Silberstein, E. Enhanced survival and accelerated perfusion of skin flap to recipient site following administration of human α1-antitrypsin in murine models. Adv. Wound Care (New Rochelle). 8(7), 281–290 (2019).
pubmed: 31737418
pmcid: 6855287
doi: 10.1089/wound.2018.0889
Polito, F. et al. Polydeoxyribonucleotide restores blood flow in an experimental model of ischemic skin flaps. J. Vasc. Surg. 55(2), 479–488 (2012).
pubmed: 22051873
doi: 10.1016/j.jvs.2011.07.083
Pharaon, M. R. et al. Early detection of complete vascular occlusion in a pedicle flap model using quantitative [corrected] spectral imaging. Plast. Reconstr. Surg. 126(6), 1924–1935 (2010).
pubmed: 21124132
pmcid: 3338201
doi: 10.1097/PRS.0b013e3181f447ac
Hyza, P. et al. Vasospasm of the flap pedicle: Magnesium sulphate relieves vasospasm of axial flap pedicle in porcine model. Acta Chir. Plast. 57(1–2), 4–8 (2015).
pubmed: 26650106
El Ahmar, I. E., Okda, M. A., Essa, E. S. & Salem, G. M. Predictors of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Menoufia Med. J. 35(1), 120–7 (2022).
Glass, G. E. & Nanchahal, J. Why haematomas cause flap failure: An evidence-based paradigm. J. Plast. Reconstr. Aesthet. Surg. 65(7), 903–910 (2012).
pubmed: 22226889
doi: 10.1016/j.bjps.2011.12.014
Oh, S. H. et al. The potential effect of botulinum toxin type A on human dermal fibroblasts: An in vitro study. Dermatol. Surg. 38(10), 1689–1694 (2012).
pubmed: 22742715
doi: 10.1111/j.1524-4725.2012.02504.x
Ellabban, M. A. et al. The effects of sildenafil and/or nitroglycerin on random-pattern skin flaps after nicotine application in rats. Sci. Rep. 10(1), 3212 (2020).
pubmed: 32081888
pmcid: 7035277
doi: 10.1038/s41598-020-60128-w
Ranadive, S. M., Eugene, A. R., Dillon, G., Nicholson, W. T. & Joyner, M. J. Comparison of the vasodilatory effects of sodium nitroprusside vs. nitroglycerin. J. Appl. Physiol. 123, 402–6 (2017).
pubmed: 28572495
pmcid: 5583612
doi: 10.1152/japplphysiol.00167.2017
Wang, P., Gu, L., Qin, Z., Wang, Q. & Ma, J. Efficacy and safety of topical nitroglycerin in the prevention of mastectomy flap necrosis: A systematic review and meta-analysis. Sci Rep. 10(1), 6753 (2020).
pubmed: 32317705
pmcid: 7174291
doi: 10.1038/s41598-020-63721-1
Vania, R., Pranata, R., Irwansyah, D. & Budiman,. Topical nitroglycerin is associated with a reduced mastectomy skin flap necrosis-systematic review and meta-analysis. J. Plast. Reconstr. Aesthet. Surg. 73(6), 1050–9 (2020).
pubmed: 32146114
doi: 10.1016/j.bjps.2020.01.009
Davis, R. E., Wachholz, J. H., Jassir, D., Perlyn, C. A. & Agrama, M. H. Comparison of topical anti-ischemic agents in the salvage of failing random-pattern skin flaps in rats. Arch. Facial Plast. Surg. 1(1), 27–32 (1999).
pubmed: 10937072
doi: 10.1001/archfaci.1.1.27
Ghanbarzadeh, K., Tabatabaie, O. R., Salehifar, E., Amanlou, M. & Khorasani, G. Effect of botulinum toxin A and nitroglycerin on random skin flap survival in rats. Plast. Surg. (Oakv). 24(2), 99–102 (2016).
pubmed: 27441193
pmcid: 4942244
doi: 10.1177/229255031602400208
Aral, M., Tuncer, S., Şencan, A., Elmas, Ç. & Ayhan, S. The effect of thrombolytic, anticoagulant, and vasodilator agents on the survival of random pattern skin flap. J. Reconstr. Microsurg. 31(7), 487–492 (2015).
pubmed: 26212388
doi: 10.1055/s-0035-1554938
Stoehr, J. R., Kearney, A. M., Massie, J. P., Ko, J. H. & Dumanian, G. A. Botulinum toxin in the treatment of vasopressor-associated symmetric peripheral gangrene. Plast. Reconstr. Surg. Glob. Open 9(5), e3582 (2021).
pubmed: 34036024
pmcid: 8140772
doi: 10.1097/GOX.0000000000003582
Akçal, A., Karşıdağ, S., Sucu, D. Ö., Turgut, G. & Uğurlu, K. Microsurgical reconstruction in pediatric patients: A series of 30 patients. Ulus Travma Acil. Cerrahi. Derg. 19(5), 411–416 (2013).
pubmed: 24214781
doi: 10.5505/tjtes.2013.09515
Wanitphakdeedecha, R. et al. The effect of botulinum toxin type A in different dilution on the contraction of fibroblast—In vitro study. J. Cosmet Dermatol. 18(5), 1215–1223 (2019).
pubmed: 31328889
pmcid: 6851680
doi: 10.1111/jocd.13058
Schweizer, D. F. et al. Botulinum toxin A and B raise blood flow and increase survival of critically ischemic skin flaps. J. Surg. Res. 184(2), 1205–1213 (2013).
pubmed: 23651811
doi: 10.1016/j.jss.2013.04.004
Fatemi, M. J., Forootan, K. S., Jalali, S. Z. S., Mousavi, S. J. & Pedram, M. S. The effect of enoxaparin and clopidogrel on survival of random skin flap in rat animal model. World J. Plast. Surg. 1(2), 64–70 (2012).
pubmed: 25734046
pmcid: 4345431
Akan, M. et al. Effects of clopidogrel and high dose aspirin on survival of skin flaps in rats. Scand. J. Plast. Reconstr. Surg. Hand Surg. 39(1), 7–10 (2005).
pubmed: 15848959
doi: 10.1080/02844310410017951
Fichter, A. M. et al. Impact of different antithrombotics on the microcirculation and viability of perforator-based ischaemic skin flaps in a small animal model. Sci. Rep. 6, 35833 (2016).
pubmed: 27767060
pmcid: 5073281
doi: 10.1038/srep35833
Chappell, J. et al. Extensive proliferation of a subset of differentiated, yet plastic, medial vascular smooth muscle cells contributes to neointimal formation in mouse injury and atherosclerosis models. Circ. Res. 119(12), 1313–1323 (2016).
pubmed: 27682618
pmcid: 5149073
doi: 10.1161/CIRCRESAHA.116.309799
An, X. et al. Inhibition of platelets by clopidogrel suppressed Ang II-induced vascular inflammation, oxidative stress, and remodeling. J. Am. Heart Assoc. 7(21), e009600 (2018).
pubmed: 30608200
pmcid: 6404205
doi: 10.1161/JAHA.118.009600
Keelan, J. & Hague, J. P. The role of vascular complexity on optimal junction exponents. Sci. Rep. 11, 5408 (2021).
pubmed: 33686129
pmcid: 7940437
doi: 10.1038/s41598-021-84432-1
Guo, D., Wang, Q., Li, C., Wang, Y. & Chen, X. VEGF stimulated the angiogenesis by promoting the mitochondrial functions. Oncotarget 8(44), 77020–77027 (2017).
pubmed: 29100366
pmcid: 5652760
doi: 10.18632/oncotarget.20331
Vourtsis, S. A. et al. Improvement of a long random skin flap survival by application of vascular endothelial growth factor in various ways of local administration in a rat model. Indian J. Plast. Surg. 45(1), 102–108 (2012).
pubmed: 22754163
pmcid: 3385372
doi: 10.4103/0970-0358.96596
Yingxin, G., Guoqian, Y., Jiaquan, L. & Han, X. Effects of natural and recombinant hirudin on VEGF expression and random skin flap survival in a venous congested rat model. Int. Surg. 98(1), 82–87 (2013).
pubmed: 23438282
pmcid: 3723165
doi: 10.9738/CC171.1
Ritsu, M. et al. Critical role of tumor necrosis factor-α in the early process of wound healing in skin. J. Dermatol. Dermatol. Surg. 21(1), 14–19 (2017).
doi: 10.1016/j.jdds.2016.09.001
Wang, Y. et al. TNF-α-induced LRG1 promotes angiogenesis and mesenchymal stem cell migration in the subchondral bone during osteoarthritis. Cell Death Dis. 8, e2715 (2017).
pubmed: 28358372
pmcid: 5386532
doi: 10.1038/cddis.2017.129