J Clin Aesthet Dermatol. 2019;12(12):25–27
by Melissa McCann, BPharm, MBBS, FRACGP
Dr. McCann is with Whitsunday Family Practice and Cosmetic Skin Clinic in Cannonvale, Australia.
FUNDING: No funding was provided for this study.
DISCLOSURES: The author has no conflicts of interest relevant to the content of this article.
ABSTRACT: Despite the establishment of international expert consensus groups, peer-reviewed guidelines, and evidence-based protocols for both reducing the risk of arterial embolization of hyaluronic acid filler from aesthetic injection and promptly treating complications, perhaps the most devastating complication of visual loss remains largely irreversible. This article examines the novel therapeutic approach of using high-dose intravenous hyaluronidase when other attempts to restore vision have failed. Evidence for the safety of the proposed dosing in an emergency setting has been demonstrated in previous papers investigating the use of hyaluronidase for myocardial infarction in the 1970s. This approach has the advantage of reducing the time delay and risks associated with retrobulbar injection. Though rare, the risk of anaphylaxis must be able to be managed.
KEYWORDS: Complications of filler, hyaluronic acid, hyaluronidase, facial filler injection, iatrogenic vision loss, retinal artery occlusion
While rare, increasing case reports of visual loss following aesthetic facial injections have prompted reviews of the world literature and the establishment of expert consensus groups who have subsequently created peer-reviewed guidelines to assist in the emergency management of this catastrophic complication.1–7
Prior to a recent report by Chestnut detailing successful restoration of vision following retrobulbar injection of hyaluronidase, previous published attempts at the reversal of embolisation were unsuccessful.8,9 In addition, a number of approaches alternative to established consenses have been published, including arterial thrombolysis and direct intra-arterial injection of hyaluronidase under radiological guidance, which resulted in partial arterial recanalization; however, this treatment remains out of reach of most injectors.10,11,12
This review discusses the therapeutic alternative of high-dose intravenous hyaluronidase as a relatively safe and previously unexamined approach to follow if visual loss has not been restored and for consideration as an alternative to retrobulbar injection in the event that an experienced ophthalmologist is not able to perform this procedure within 60 to 90 minutes, following which time, blindness is irreversible.6
The pathophysiological and anatomical mechanism for visual loss following facial filler has been well described.3,5,7,13,14 Emboli of filler material injected into an artery of the face, being branches of the facial artery and the external carotid, travel via retrograde then anterograde flow via anastomoses with branches of the internal carotid artery to the ophthalmic or retinal artery. Angiographic findings demonstrate the resultant occlusion might be either of a localized or diffuse nature.13 As retrograde pressure must first exceed systolic pressure and requires a sufficient volume of material to obstruct to the level of the bifurcation of the branch for subsequent antegrade passage of material, is it unsurprising the highest risk areas are adjacent regions of the glabella and nasal regions.1,14 However, case reports and literature reviews confirm diverse facial artery anatomy and the potential for visual loss by following embolization of filler material postinjection into virtually every area on the face.1–7,15–17
Current Hyaluronidase Use approach
Current guidelines recommend lying the patient down in supine position, administering timolol drops into the affected eye only, having the patient rebreathe into a paper bag, and giving the patient 300mg of aspirin to prevent blood clotting.6,8,9,16 Prolonged ocular massage is also performed, and emergency services are called in preparation to transfer the patient to a hospital setting.4
Hyaluronidase is used in the treated area and, if vision is not restored, retrobulbar injection and injection into the supraorbital or supratrochlear foramina are completed by practitioners competent in this procedure in a specialist eye unit.6–8, 26–28 These techniques are utilized based on the evidence that hyaluronidase readily diffuses into the vascular lumen.18–20
Despite the best approach with regard to prevention strategies and adherence to current treatment guidelines, “vision loss caused by [hyaluronic acid] filler embolism [remains] a medical emergency for which there is no proven rescue treatment.”10
Proposed Novel Hyaluronidase use approach
In the 1970s, hyaluronidase was investigated as a potential treatment for myocardial infarction.21–23,29 Unsurprising in the context of our current understanding of thrombus formation, the benefit in this condition was moderate; however, a number of published studies demonstrate the safe use of hyaluronidase in this emergency setting.21–23,29 Doses of 500IU/kg were used and administered as an intravenous bolus in some studies repeated after six hours. The half-life in the circulation is approximately 2 to 5 minutes. Adverse events related to the hyaluronidase were reported as mild. There were no cases of anaphylaxis.
The author proposes that a smaller dose of 200 to 250IU/kg be used intravenously if other treatment strategies have failed to restore vision following hyaluronic acid filler injection. For a 70kg adult, this would approximate 10 ampules of Hyalase, a commercially available powder form of hyaluronic acid (Wockhardt Ltd., Mumbai, India), and a total dose of 15,000IU. Into each ampule, 1mL of normal saline for injection is injected, the powder rapidly dissolves, the solution is withdrawn, and this process is repeated until a total bolus of 15,000IU in 10mL of saline has been prepared. An intravenous cannula is inserted and the bolus is given followed by a 10mL flush. The patient remains supine, and adrenaline and oxygen are available in the event of anaphylaxis.
Over the next 5 to 10 minutes during which the hyaluronidase remains in the circulation, at an average blood volume of 5L, we would expect a concentration of 3IU of hyaluronidase in every 1mL of circulating volume. Within the first or second cardiac stroke volume, the hyaluronidase would be expected to have traveled from the venous to arterial circulation, including the internal and external carotids, then have flowed to the facial artery and anastomosis with the retinal artery circulation, beginning the onset of hyaluronic acid embolus degradation. This continuous flow over even a 2- to 3-minute period, combined with continuing measures, such as rebreathing and orbital massage, could be considered extremely likely to result in recanalization of the retinal or ciliary arteries. An injector who has used hyaluronidase to dissolve hyaluronic acid, either for impending tissue necrosis or to dissolve unwanted filler, has seen the near-instantaneous effect of the enzymatic degradation. A sufficient concentration of the product, within the lumen of the surrounding and anastomotic circulation, for more than a few minutes and restoration of sight seems likely. In addition, the hyaluronidase in the circulation would have the potential to dissolve any other arterial emboli, including in the cerebral arterial circulation, which are known to complicate some 24 percent of cases of blindness.1,7,24 Intravenous use of the product is off-label, as is retrobulbar injection and any use in aesthetic medicine, and informed consent for treatment with Hyalase should accompany consent for filler treatment. Note that, in pediatric populations, far higher doses of 200,000IU (representing perhaps 7,000IU/kg or more) have been used in the oncology setting, with high rates (5 of 16 patients) of anaphylaxis reported.25
The serious complication of visual loss following hyaluronic acid use in aesthetic medicine, while rare, has posed a particular challenge for all injectors. Despite meticulous technique, use of a cannula, aspiration, knowledge of anatomy, and assurance of correct injection depth, there exist international case reports of visual loss among the patients of meticulous and experienced injectors. Regardless of extraordinary efforts to inject hyaluronidase in close proximity to the retinal artery and ciliary arteries, including injection of high doses of of hyaluronidase in the retrobulbar area, outcomes for patients have been largely devastating.
The intravenous use of high-dose hyaluronidase overcomes many of the challenges with current protocols, such as reduced time to insert an intravenous cannula compared to completing a retrobulbar injection, access to the venous and within seconds the arterial circulation via a peripheral line with a documented previous safety record of the product used at similar doses in myocardial infarction, and ability to prepare a high-concentration bolus quickly and easily that will ensure adequate circulating concentration before product degradation.
It is the author’s hope that this might, in fact, result in the restoration of vision among more patients with this devastating complication.
- Belezany K, Carruthers JDA, Humphrey S, Jones DJ. Avoiding and treating blindness from fillers: a review of the world literature. Dermatologic Surg. 2015;41(10):1097–1117.
- Requena L, Requena C, Christensen L, et al. Adverse reactions to injectable soft tissue fillers. J Am Acad Dermatol. 2011;64(1):1–34.
- Carle MV, Roe R, Novack R, Boyer DS. Cosmetic facial fillers and severe vision loss. JAMA Ophthalmol. 2014;132(5):637–639.
- Szantyr A, Orski M, Marchewka I, et al. Ocular complications following autologous fat injections into facial area: case report of a recovery from visual loss after ophthalmic artery occclusion and a review of the literature. Aesthetic Plast Surg. 2017;41(3):580–584.
- Park KH, Kim YK, Woo SJ. Iatrogenic occlusion of the ophthalmic artery after cosmetic facial filler injections. JAMA Ophthalmol. 2014;132(6):714–723.
- Loh KTD, Chua JJ. Prevention and management of vision loss relating to facial filler injections. Singapore Med J. 2016;57(8):438–443.
- Walker L, King M. This month’s guideline: visual loss secondary to cosmetic filler injection. J Clin Aesthet Dermatol. 2018;11(5):E53–E55.
- Urdiales-Gálvez F, Delgado NE, Figueiredo V, et al. Treatment of soft tissue filler complications: expert consensus recommendations. Aesthetic Plast Surg. 2018;42(2):498–510.
- Chestnut C. Restoration of visual loss with retrobulbar hyaluronidase injection after hyaluronic acid filler. Dermatol Surg. 2018;44(3):435–437.
- Zhu GZ, Sun ZS, Liao WX, et al. Efficacy of retrobulbar hyaluronidase injection for vision loss resulting from hyaluronic acid filler embolization. Aesthetic Surg J. 2017;38(1):12–22.
- Chen YC, Wu HM, Chen SJ, et al. Intra-arterial thrombolytic therapy is not a therapeutic option for filler-related central retinal artery occlusion. Facial Plast Surg. 2018;34(3):
- Oha BL, Jungb CK, Parka KH, et al. Therapeutic intra-arterial hyaluronidase infusion for ophthalmic artery occlusion following cosmetic facial filler (hyaluronic acid) injection. Neuro Ophthalmol. 2014;38(1):39-43.
- Tansatit T, Moon HJ, Apinuntrum P, Phetudom T. Verification of embolic channel causing blindness following filler injection. Aesthetic Plast Surg. 2015;39(1):154–161.
- Khan TT, Colon-Acevedo B, Mettu P, et al. An anatomical analysis of the supratrochlear artery: considerations in facial filler injections and preventing vision loss. Aesthetic Surg J. 2017;37(2):203–208.
- Lohn JW, Penn JW, Norton J, Butler PE. The course and variation of the facial artery and vein: implications for facial transplantation and facial surgery. Ann Plast Surg. 2011;67(2):184–188.
- Hu XZ, Hu JY. Posterior ciliary artery occlusion caused by hyaluronic acid injections into the forehead. Medicine (Baltimore). 2016;95(11):e3124.
- Hwang CJ. Periorbital injectables: understanding and avoiding complications. J Cutan Aesthet Surg. 2016;9(2):73–79.
- Cohen BE, Bashey S, Wysong A. The use of hyaluronidase in cosmetic dermatology: a review of the literature. J Clin Investigat Dermatol. 2015;3(2):7.
- Kim DW, Yoon ES, Ji YH, et al. Vascular complications of hyaluronic acid fillers and the role of hyaluronidase in management. J Plast Reconstr Aesthet Surg. 2011;64(12):1590–1595.
- DeLorenzi C. Transarterial degradation of hyaluronic acid filler by hyaluronidase. Dermatol Surg. 2014;40(8):832–841.
- Cairns JA, Holder DA, Tanser P, Missirlis E. Intravenous hyaluronidase therapy for myocardial infarction in man: double-blind trial to assess infarct size limitation. Circulation. 1982;65(4):764–771.
- Maroko P, Davidson D, Libby P, et al. Effects of hyaluronidase administration on myocardial ischemic injury in acute infarction: a preliminary study in 24 patients. Ann Intern Med. 1975;82(4):516–520.
- Maroko P, Braunwald E. Modification of myocardial infarction size after coronary occlusion. Ann Intern Med. 1973;79(5):
- He M, Sheu M, Huang Z, et al. Sudden bilateral vision loss and brain infarction following cosmetic hyaluronic acid injection. JAMA Ophthalmol. 2013;131(9):1234–1235.
- Szepfalusi Z, Nentwich I, Dobner M, et al. IgE-mediated allergic reaction to hyaluronidase in paediatric oncological patients. Eur J Pediatr. 1997;156(3):
- Cavallini M, Gazzola R, Metalla M, Vaienti L. The role of hyaluronidase in the treatment of complications from hyaluronic acid dermal fillers. Aesthet Surg J. 2013;33(8):
- Tansatit T, Apinuntrum P, Phetudom T. An anatomic basis for treatment of retinal artery occlusions caused by hyaluronic acid injections: a cadaveric study. Aesthetic Plast Surg. 2014;38(6):1131–1137.
- Fraser SG, Adams W. Interventions for acute non-arteritic central retinal artery occlusion. Cochrane Database Syst Rev. 2009;(1):CD001989.
- MILIS Study Group. Hyaluronidase therapy for acute myocardial infarction: results of a randomized, blinded, multicenter trial. Am J Cardiol. 1986;57(15):1236–1243.