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The Role of Hyaluronidase for the Skin Necrosis Caused by Hyaluronic Acid Injection-Induced Embolism: A Rabbit Auricular Model Study

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  • Basic Science/Experimental
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Abstract

Background

Skin necrosis is considered the most serious complication of hyaluronic acid dermal filler injection procedures. To effectively treat skin necrosis, hyaluronidase injection is one of the essential preventative treatments, and yet optimal complication management remains an unmet need. Therefore, this paper investigates the effects of hyaluronidase injection timing on the treatment of skin necrosis.

Methods

In an in vitro experiment, the carbazole method was used to determine the degradation time of hyaluronic acid gels in a large volume of hyaluronidase. In vivo experimental rabbit ear models were developed to simulate the skin necrosis caused by hyaluronic acid and the test animals distributed into five groups. Except one control group, the other four groups were injected with a large volume of hyaluronidase as treatment at 2 h, 4 h, 8 h and 16 h, respectively, after models were built. The necrosis degree of models was analyzed with necrotic area and histologic examination on the postoperative 7th day. Besides, temperatures of rabbit ears were observed to demonstrate the healing process of flap models.

Results

The average necrotic area of flaps in the 2-h and 4-h injection groups showed a significant difference compared with that of the control group (p < 0.05; p < 0.05). The histologic examination showed that there were HA embolisms, vascular thrombolytic recanalization and arteriovenous thromboses in the survival area. In addition, the mean temperatures of the rabbit ear flaps fluctuated over time and showed clear differences between distal and proximal parts.

Conclusions

The area of flap necrosis positively correlates with injection timing of the large volume of hyaluronidase. More importantly, when injection timing is within 4 h, treatment effectiveness will be significantly improved.

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References

  1. Wilson MV, Fabi SG, Greene R (2017) Correction of age-related midface volume loss with low-volume hyaluronic acid filler. JAMA Fac Plast Surg 19:88–93

    Article  Google Scholar 

  2. Urdiales-Galvez F, Delgado NE, Figueiredo V, Lajo-Plaza JV, Mira M, Ortiz-Marti F, Del Rio-Reyes R, Romero-Alvarez N, Del Cueto SR, Segurado MA, Rebenaque CV (2017) Preventing the complications associated with the use of dermal fillers in facial aesthetic procedures: an expert group consensus report. Aesthet Plast Surg 41:667–677

    Article  Google Scholar 

  3. Urdiales-Galvez F, Delgado NE, Figueiredo V, Lajo-Plaza JV, Mira M, Moreno A, Ortiz-Marti F, Del Rio-Reyes R, Romero-Alvarez N, Del Cueto SR, Segurado MA, Rebenaque CV (2018) Treatment of soft tissue filler complications: expert consensus recommendations. Aesthet Plast Surg 42:498–510

    Article  Google Scholar 

  4. Edsman K, Nord LI, Ohrlund A, Larkner H, Kenne AH (2012) Gel properties of hyaluronic acid dermal fillers. Dermatol Surg 38:1170–1179

    Article  CAS  PubMed  Google Scholar 

  5. Zhang J, Ma X, Fan D, Zhu C, Deng J, Hui J, Ma P (2014) Synthesis and characterization of hyaluronic acid/human-like collagen hydrogels. Mater Sci Eng C Mater Biol Appl 43:547–554

    Article  CAS  PubMed  Google Scholar 

  6. Tezel A, Fredrickson GH (2008) The science of hyaluronic acid dermal fillers. J Cosmet Laser Ther 10:35–42

    Article  PubMed  Google Scholar 

  7. Harrison J, Rhodes O (2017) Hyaluronidase: understanding its properties and clinical application for cosmetic injection adverse events. Plast Surg Nurs 37:109–111

    Article  PubMed  Google Scholar 

  8. DeLorenzi C (2013) Complications of injectable fillers, part I. Aesthet Surg J 33:561–575

    Article  PubMed  Google Scholar 

  9. Kim EG, Eom TK, Kang SJ (2014) Severe visual loss and cerebral infarction after injection of hyaluronic acid gel. J Craniofac Surg 25:684–686

    Article  PubMed  Google Scholar 

  10. Carruthers JD, Fagien S, Rohrich RJ, Weinkle S, Carruthers A (2014) Blindness caused by cosmetic filler injection: a review of cause and therapy. Plast Reconstr Surg 134:1197–1201

    Article  CAS  PubMed  Google Scholar 

  11. Basora JF, Fernandez R, Gonzalez M, Adorno J (2014) A case of diffuse alveolar hemorrhage associated with hyaluronic acid dermal fillers. Am J Case Rep 15:199–202

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kwon SG, Hong JW, Roh TS, Kim YS, Rah DK, Kim SS (2013) Ischemic oculomotor nerve palsy and skin necrosis caused by vascular embolization after hyaluronic acid filler injection: a case report. Ann Plast Surg 71:333–334

    Article  CAS  PubMed  Google Scholar 

  13. Hyman DA, Marcus BC (2015) Complications of facial fillers. Curr Otorhinolaryngol Rep 3:42–45

    Article  Google Scholar 

  14. Salval A, Ciancio F, Margara A, Bonomi S (2017) Impending facial skin necrosis and ocular involvement after dermal filler injection: a case report. Aesthet Plast Surg 41:1198–1201

    Article  Google Scholar 

  15. Ferneini EM, Ferneini AM (2016) An overview of vascular adverse events associated with facial soft tissue fillers: recognition, prevention, and treatment. J Oral Maxillofac Surg 74:1630–1636

    Article  PubMed  Google Scholar 

  16. Wang Q, Zhao Y, Li H, Li P, Wang J (2018) Vascular complications after chin augmentation using hyaluronic acid. Aesthet Plast Surg 42:553–559

    Article  Google Scholar 

  17. Robati RM, Moeineddin F, Almasi-Nasrabadi M (2018) The risk of skin necrosis following hyaluronic acid filler injection in patients with a history of cosmetic rhinoplasty. Aesthet Surg J 38:883–888

    Article  PubMed  Google Scholar 

  18. Rzany B, DeLorenzi C (2015) Understanding, avoiding, and managing severe filler complications. Plast Reconstr Surg 136:196S–203S

    Article  CAS  PubMed  Google Scholar 

  19. Funt D, Pavicic T (2013) Dermal fillers in aesthetics: an overview of adverse events and treatment approaches. Clin Cosmet Investig Dermatol 6:295–316

    PubMed  PubMed Central  Google Scholar 

  20. DeLorenzi C (2014) Transarterial degradation of hyaluronic acid filler by hyaluronidase. Dermatol Surg 40:832–841

    Article  CAS  PubMed  Google Scholar 

  21. Ozturk CN, Li Y, Tung R, Parker L, Piliang MP, Zins JE (2013) Complications following injection of soft-tissue fillers. Aesthet Surg J 33:862–877

    Article  PubMed  Google Scholar 

  22. DeLorenzi C (2014) Complications of injectable fillers, part 2: vascular complications. Aesthet Surg J 34:584–600

    Article  PubMed  Google Scholar 

  23. Quezada-Gaon N, Wortsman X (2016) Ultrasound-guided hyaluronidase injection in cosmetic complications. J Eur Acad Dermatol Venereol 30:e39–e40

    Article  CAS  PubMed  Google Scholar 

  24. Bailey SH, Fagien S, Rohrich RJ (2014) Changing role of hyaluronidase in plastic surgery. Plast Reconstr Surg 133:127e–132e

    Article  CAS  PubMed  Google Scholar 

  25. Shumate GT, Chopra R, Jones D, Messina DJ, Hee CK (2018) In vivo degradation of crosslinked hyaluronic acid fillers by exogenous hyaluronidases. Dermatol Surg 44:1075–1083

    Article  CAS  PubMed  Google Scholar 

  26. Jones DH (2018) Update on emergency and nonemergency use of hyaluronidase in aesthetic dermatology. JAMA Dermatol 154:763–764

    Article  PubMed  Google Scholar 

  27. King M, Convery C, Davies E (2018) This month’s guideline: the use of hyaluronidase in aesthetic practice (v2.4). J Clin Aesthet Dermatol 11:E61–e68

    PubMed  PubMed Central  Google Scholar 

  28. Buhren BA, Schrumpf H, Hoff NP, Bolke E, Hilton S, Gerber PA (2016) Hyaluronidase: from clinical applications to molecular and cellular mechanisms. Eur J Med Res 21:5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. DeLorenzi C (2017) New high dose pulsed hyaluronidase protocol for hyaluronic acid filler vascular adverse events. Aesthet Surg J 37:814–825

    Article  PubMed  Google Scholar 

  30. Rao V, Chi S, Woodward J (2014) Reversing facial fillers: interactions between hyaluronidase and commercially available hyaluronic-acid based fillers. J Drugs Dermatol JDD 13:1053–1056

    CAS  PubMed  Google Scholar 

  31. Juhasz MLW, Levin MK, Marmur ES (2017) The kinetics of reversible hyaluronic acid filler injection treated with hyaluronidase. Dermatol Surg 43:841–847

    Article  CAS  PubMed  Google Scholar 

  32. Jones D, Tezel A, Borrell M (2010) In vitro resistance to degradation of hyaluronic acid dermal fillers by ovine testicular hyaluronidase. Dermatol Surg 36:804–809

    Article  CAS  Google Scholar 

  33. Ferraz RM, Sandkvist U, Lundgren B (2018) Degradation of hylauronic acid fillers using hyaluronidase in an in vivo model. J Drugs Dermatol JDD 17:548–553

    PubMed  Google Scholar 

  34. Loh KTD, Phoon YS, Phua V, Kapoor KM (2018) Successfully managing impending skin necrosis following hyaluronic acid filler injection, using high-dose pulsed hyaluronidase. Plast Reconstr Surg Glob Open 6:e1639

    Article  PubMed  PubMed Central  Google Scholar 

  35. Hong JY, Seok J, Ahn GR, Jang YJ, Li K, Kim BJ (2017) Impending skin necrosis after dermal filler injection: a “golden time” for first-aid intervention. Dermatol Ther. https://doi.org/10.1111/dth.12440

    Article  PubMed  Google Scholar 

  36. Kim HJ, Kwon SB, Whang KU, Lee JS, Park YL, Lee SY (2018) The duration of hyaluronidase and optimal timing of hyaluronic acid (HA) filler reinjection after hyaluronidase injection. J Cosmet Laser Ther 20:52–57

    Article  CAS  PubMed  Google Scholar 

  37. Kim DW, Yoon ES, Ji YH, Park SH, Lee BI, Dhong ES (2011) Vascular complications of hyaluronic acid fillers and the role of hyaluronidase in management. J Plast Reconstr Aesthet Surg JPRAS 64:1590–1595

    Article  PubMed  Google Scholar 

  38. Bitter T, Muir HM (1962) A modified uronic acid carbazole reaction. Anal Biochem 4:330–334

    Article  CAS  PubMed  Google Scholar 

  39. Park KY, Kim HK, Kim BJ (2014) Comparative study of hyaluronic acid fillers by in vitro and in vivo testing. J Eur Acad Dermatol Venereol 28:565–568

    Article  CAS  PubMed  Google Scholar 

  40. Salgarello M, Selvaggi G, Lahoud P, Fadda G, Farallo E (2004) Neurocutaneous island flap: an experimental model using the rabbit ear. Ann Plast Surg 53:146–149

    Article  PubMed  Google Scholar 

  41. Zhuang Y, Yang M, Liu C (2016) An islanded rabbit auricular skin flap model of hyaluronic acid injection-induced embolism. Aesthet Plast Surg 40:421–427

    Article  Google Scholar 

  42. Cohen JL, Biesman BS, Dayan SH, DeLorenzi C, Lambros VS, Nestor MS, Sadick N, Sykes J (2015) Treatment of hyaluronic acid filler-induced impending necrosis with hyaluronidase: consensus recommendations. Aesthet Surg J 35:844–849

    Article  PubMed  Google Scholar 

  43. Wang M, Li W, Zhang Y, Tian W, Wang H (2017) Comparison of intra-arterial and subcutaneous testicular hyaluronidase injection treatments and the vascular complications of hyaluronic acid filler. Dermatol Surg 43:246–254

    Article  CAS  PubMed  Google Scholar 

  44. Zomer HD, Trentin AG (2018) Skin wound healing in humans and mice: challenges in translational research. J Dermatol Sci 90:3–12

    Article  PubMed  Google Scholar 

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Funding

This study was supported by National Natural Science Foundation of China (81470720, 31271032).

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Correspondence to Jihua Li.

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Li, J., Xu, Y., Wang, Y. et al. The Role of Hyaluronidase for the Skin Necrosis Caused by Hyaluronic Acid Injection-Induced Embolism: A Rabbit Auricular Model Study. Aesth Plast Surg 43, 1362–1370 (2019). https://doi.org/10.1007/s00266-019-01398-2

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