J Reconstr Microsurg 2021; 37(08): 694-703
DOI: 10.1055/s-0041-1726028
Original Article

The Influence of Topically Administered Heparin on Peripheral Microcirculation of the Skin: A Double-Blind, Randomized, Controlled Preliminary Study on 50 Healthy Subjects

1   Department of Pediatric Surgery and Orthopedics, St. Hedwig, University Medical Center Regensburg, Regensburg, Germany
,
Manuel Held
2   Clinic for Plastic, Reconstructive, Hand and Burn Surgery, BG Trauma Center, Tuebingen, Germany
,
Amro Amr
3   Department of Plastic Surgery, Microsurgery and Reconstructive Breast Surgery, Marien Hospital, Stuttgart, Germany
,
Sabrina Krauß
2   Clinic for Plastic, Reconstructive, Hand and Burn Surgery, BG Trauma Center, Tuebingen, Germany
,
Dominik Bender
2   Clinic for Plastic, Reconstructive, Hand and Burn Surgery, BG Trauma Center, Tuebingen, Germany
,
Adrien Daigeler
2   Clinic for Plastic, Reconstructive, Hand and Burn Surgery, BG Trauma Center, Tuebingen, Germany
,
Andrea Wenger
4   Clinic for Plastic, Reconstructive and Aesthetic Surgery, Hand Surgery, Klinikum Traunstein, Traunstein, Germany
› Author Affiliations

Abstract

Background Venous thrombosis is the most common cause of flap failure in the first days after surgery. Although heparin is one of the most important antithrombotic substances and is implemented in the therapy of various diseases, there are only a few studies addressing its topical administration in the field of flap surgery. Especially, very little is known about the effects of topical heparin and its impact on microcirculation. In this study we evaluated to what extent topically administered heparin influences skin microcirculation (capillary venous oxygen saturation SO2, blood filling of microvessels, blood flow, and velocity) in healthy subjects.

Methods Skin perfusion parameters on the forearm were measured with the O2C device in a double-blinded, controlled, and randomized study with 50 healthy subjects after administration of heparin ointment in three different concentrations and a control ointment (dexpanthenol).

Results Topically administrated heparin slightly increased SO2 (max. 187 ± 285 SD or standard deviation % vs. 145 ± 129 SD %), flow (max. 264 ± 427 SD % vs. 151.74 ± 111 SD %), and velocity (max. 153 ± 149 SD % vs. 122 ± 56 SD %) after an incubation time of 60 minutes in comparison to control. No statistically significant difference could be detected regarding heparin concentration.

Conclusion As a first important step in possible future implementing of heparin as a topical administration in flap surgery, our data—although not statistically significant—indicate that heparin can improve microcirculation (SO2, flow) in healthy subjects. Nevertheless, further research in subjects with impaired microcirculation is necessary.



Publication History

Received: 20 September 2020

Accepted: 27 January 2021

Article published online:
31 March 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Askari M, Fisher C, Weniger FG, Bidic S, Lee WP. Anticoagulation therapy in microsurgery: a review. J Hand Surg Am 2006; 31 (05) 836-846
  • 2 Betancourt FM, Mah ET, McCabe SJ. Timing of critical thrombosis after replantation surgery of the digits. J Reconstr Microsurg 1998; 14 (05) 313-316
  • 3 Froemel D, Fitzsimons SJ, Frank J, Sauerbier M, Meurer A, Barker JH. A review of thrombosis and antithrombotic therapy in microvascular surgery. Eur Surg Res 2013; 50 (01) 32-43
  • 4 Cigna E, Lo Torto F, Maruccia M. et al. Postoperative care in finger replantation: our case-load and review of the literature. Eur Rev Med Pharmacol Sci 2015; 19 (14) 2552-2561
  • 5 Venkatesh KP, Ambani SW, Arakelians ARL, Johnson JT, Solari MG. Head and neck microsurgeon practice patterns and perceptions regarding venous thromboembolism prophylaxis. J Reconstr Microsurg 2020; 36 (08) 549-555
  • 6 Liu Z, Ji S, Sheng J, Wang F. Pharmacological effects and clinical applications of ultra low molecular weight heparins. Drug Discov Ther 2014; 8 (01) 1-10
  • 7 Kotamarti VS, Shiah E, Rezak KM, Patel A, Ricci JA. Does anticoagulation improve flap outcomes in hypercoagulable patients? A systematic review. J Reconstr Microsurg 2020; 36 (03) 204-212
  • 8 Zavlin D, Chegireddy V, Jubbal KT, Agrawal NA, Spiegel AJ. Management of microsurgical patients using intraoperative unfractionated heparin and thromboelastography. J Reconstr Microsurg 2019; 35 (03) 198-208
  • 9 Ramelli E, Durry A, Ruffenach L, Bruant-Rodier C, Bodin F. Decrease of thrombosis in microsurgical anastomoses: the use of intraoperative pure intraluminal unfractionated heparin. J Reconstr Microsurg 2020; 36 (01) 16-20
  • 10 Pérez M, Sancho J, Ferrer C, García O, Barret JP. Management of flap venous congestion: the role of heparin local subcutaneous injection. J Plast Reconstr Aesthet Surg 2014; 67 (01) 48-55
  • 11 Vecchio C, Frisinghelli A. Topically applied heparins for the treatment of vascular disorders : a comprehensive review. Clin Drug Investig 2008; 28 (10) 603-614
  • 12 Di Nisio M, Middeldorp S. Treatment of lower extremity superficial thrombophlebitis. JAMA 2014; 311 (07) 729-730
  • 13 Costantino C, Kwarecki J, Samokhin AV, Mautone G, Rovati S. Diclofenac epolamine plus heparin plaster versus diclofenac epolamine plaster in mild to moderate ankle sprain: a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III trial. Clin Drug Investig 2011; 31 (01) 15-26
  • 14 Cesarone MR, Belcaro G, Errichi S. et al. Topical heparin: new observations. Angiology 2007; 58 (Suppl. 01) 16S-20S
  • 15 Parisel C, Saffar L, Gattegno L. et al. Interactions of heparin with human skin cells: binding, location, and transdermal penetration. J Biomed Mater Res A 2003; 67 (02) 517-523
  • 16 Sznitowska M, Janicki S. Percutaneous absorption of heparin: a critical review of experimental results. Pol Merkuriusz Lek 2000; 7 (43) 58-63
  • 17 Wade JW, Brabham RF, Allen RJ. Medicinal leeches: once again at the forefront of medicine. South Med J 1990; 83 (10) 1168-1173
  • 18 Talbot SG, Pribaz JJ. First aid for failing flaps. J Reconstr Microsurg 2010; 26 (08) 513-515
  • 19 Koch CA, Olsen SM, Moore EJ. Use of the medicinal leech for salvage of venous congested microvascular free flaps of the head and neck. Am J Otolaryngol 2012; 33 (01) 26-30
  • 20 Stamenova PK, Marchetti T, Simeonov I. Efficacy and safety of topical hirudin (Hirudex): a double-blind, placebo-controlled study. Eur Rev Med Pharmacol Sci 2001; 5 (02) 37-42
  • 21 Rothenberger J, Petersen W, Schaller HE, Held M. Determining the appropriate number and duration of leech therapy in congested tissues using tissue spectrophotometry and laser Doppler flowmetry. Wound Repair Regen 2016; 24 (06) 1023-1029
  • 22 Sawada Y, Hatayama I, Sone K. The effect of continuous topical application of heparin on flap survival. Br J Plast Surg 1992; 45 (07) 515-518
  • 23 Yang E, Kim SW. The effect of topical application of heparin with microneedling on skin flap survival. Plast Reconstr Surg 2009; 124 (4S): 99
  • 24 Henton JMD, Simmons JM, Hettiaratchy S, Jain A. Perfusion dynamics in lower limb reconstruction: investigating postoperative recovery and training using combined white light photospectroscopy and laser Doppler (O2C(®)). J Plast Reconstr Aesthet Surg 2015; 68 (09) 1286-1292
  • 25 Rothenberger J, Krauss S, Held M. et al. A quantitative analysis of microcirculation in sore-prone pressure areas on conventional and pressure relief hospital mattresses using laser Doppler flowmetry and tissue spectrophotometry. J Tissue Viability 2014; 23 (04) 129-136
  • 26 Rothenberger J, Amr A, Schiefer J, Schaller HE, Rahmanian-Schwarz A. A quantitative analysis of the venous outflow of the deep inferior epigastric flap (DIEP) based on the perforator veins and the efficiency of superficial inferior epigastric vein (SIEV) supercharging. J Plast Reconstr Aesthet Surg 2013; 66 (01) 67-72
  • 27 Jokuszies A, Herold C, Niederbichler AD, Vogt PM. Anticoagulative strategies in reconstructive surgery—clinical significance and applicability. Ger Med Sci 2012; 10: Doc01
  • 28 Pan XL, Chen GX, Shao HW, Han CM, Zhang LP, Zhi LZ. Effect of heparin on prevention of flap loss in microsurgical free flap transfer: a meta-analysis. PLoS One 2014; 9 (04) e95111
  • 29 Shalom A, Friedman T, Westreich M. Effect of aspirin and heparin on random skin flap survival in rats. Dermatol Surg 2008; 34 (06) 785-790 , discussion 790
  • 30 Chung TL, Pumplin DW, Holton III LH, Taylor JA, Rodriguez ED, Silverman RP. Prevention of microsurgical anastomotic thrombosis using aspirin, heparin, and the glycoprotein IIb/IIIa inhibitor tirofiban. Plast Reconstr Surg 2007; 120 (05) 1281-1288
  • 31 Lighthall JG, Cain R, Ghanem TA, Wax MK. Effect of postoperative aspirin on outcomes in microvascular free tissue transfer surgery. Otolaryngol Head Neck Surg 2013; 148 (01) 40-46
  • 32 Cho EH, Ligh C, Hodulik KL, Hollenbeck ST. Role of platelet inhibition in microvascular surgery. J Reconstr Microsurg 2014; 30 (09) 589-598
  • 33 Ashjian P, Chen CM, Pusic A, Disa JJ, Cordeiro PG, Mehrara BJ. The effect of postoperative anticoagulation on microvascular thrombosis. Ann Plast Surg 2007; 59 (01) 36-39 , discussion 39–40
  • 34 Stephan B, Schenk JF, Nemeh A, Pindur G. The use of antithrombotic agents in microvascular surgery. Clin Hemorheol Microcirc 2009; 43 (1-2): 51-56
  • 35 Davis RE, Wachholz JH, Jassir D, Perlyn CA, Agrama MH. Comparison of topical anti-ischemic agents in the salvage of failing random-pattern skin flaps in rats. Arch Facial Plast Surg 1999; 1 (01) 27-32
  • 36 Livaoğlu M, Kerimoğlu S, Sönmez B, Livaoğlu A, Karaçal N. The effect of Hirudoid on random skin-flap survival in rats. J Plast Reconstr Aesthet Surg 2010; 63 (06) 1047-1051
  • 37 Guo-Qian Y, Gang W, Zhi-Yong S. Investigation on the microcirculation effect of local application of natural hirudin on porcine random skin flap venous congestion. Cell Biochem Biophys 2012; 62 (01) 141-146
  • 38 Tang Y, Zhou C, Luan J, Hu J. Improvement of length of survival of expanded flap by application of topical papaverine cream. J Plast Surg Hand Surg 2012; 46 (06) 389-392
  • 39 Vecchio C, Frisinghelli D. Topically applied heparins for the treatment of vascular disorders. Clin Drug Investig 2008; 28: 603-614
  • 40 Cesarone MR, De Sanctis MT, Incandela L, Belcaro G, Griffin M. Microvascular changes in venous hypertension due to varicose veins after standardized application of Essaven gel—a placebo-controlled, randomized study. Angiology 2001; 52 (Suppl. 03) S11-S16
  • 41 Reber K. Cutaneous resorption of heparin and heparinoids investigated by autoradiography. J Invest Dermatol 1968; 51 (02) 113-115
  • 42 Zesch A, Schaefer H. Penetration, permeation and resorption of heparin. In vivo studies on human skin. Arzneimittelforschung 1976; 26 (07) 1365-1368
  • 43 Song Y-K, Kim C-K. Topical delivery of low-molecular-weight heparin with surface-charged flexible liposomes. Biomaterials 2006; 27 (02) 271-280
  • 44 Song YK, Hyun SY, Kim HT, Kim CK, Oh JM. Transdermal delivery of low molecular weight heparin loaded in flexible liposomes with bioavailability enhancement: comparison with ethosomes. J Microencapsul 2011; 28 (03) 151-158
  • 45 Shimada K, Yoshihara T, Yamamoto M. et al. Transepidermal water loss (TEWL) reflects skin barrier function of dog. J Vet Med Sci 2008; 70 (08) 841-843
  • 46 Schaefer H, Zesch Z. Penetration of heparin into the human skin. Pharmazie 1976; 31 (04) 251-254
  • 47 Bashir SJ, Chew AL, Anigbogu A, Dreher F, Maibach HI. Physical and physiological effects of stratum corneum tape stripping. Skin Res Technol 2001; 7 (01) 40-48
  • 48 Incandela L, Belcaro G, Nicolaides AN, Geroulakos G, Cesarone MR, De Sanctis MT. Microcirculation after standardized application of Essaven gel on normal skin—a placebo-controlled, randomized study. Angiology 2001; 52 (Suppl. 03) S5-S10
  • 49 Incandela L, Belcaro G, Cesarone MR, De Sanctis MT, Griffin M. Changes in microcirculation in venous ulcers with Essaven gel—a pilot, cross-over, placebo-controlled, randomized study. Angiology 2001; 52 (Suppl. 03) S23-S27
  • 50 Incandela L, Belcaro G, Cesarone MR, De Sanctis MT, Griffin M. Microangiopathy and venous ulceration: topical treatment with Essaven gel—a placebo-controlled, randomized study. Angiology 2001; 52 (Suppl. 03) S17-S21
  • 51 De Sanctis MT, Incandela L, Belcaro G, Cesarone MR. Topical treatment of venous microangiopathy in patients with venous ulceration with Essaven gel—a placebo-controlled, randomized study. Angiology 2001; 52 (suppl 3): S29-S34
  • 52 De Sanctis MT, Cesarone MR, Incandela L, Belcaro G, Ricci A, Griffin M. Four-week treatment with Essaven gel in diabetic microangiopathy—a placebo-controlled, randomized study. Angiology 2001; 52 (suppl 3): S49-S55
  • 53 Cesarone MR, Incandela L, Belcaro G, De Sanctis MT, Ricci A, Griffin M. Two-week topical treatment with Essaven gel in patients with diabetic microangiopathy—a placebo-controlled, randomized study. Angiology 2001; 52 (suppl 3): S43-S48