Hyaluronic acid (HA)–based fillers became a gold standard of dermal fillers due to their efficacy and safety. Unlike other products, HA fillers have an antidote substance.1,21,2 Hyaluronidase is a HA-degrading enzyme, being traditionally used in ophthalmology and anesthesia.3–53–53–5 In the past years, hyaluronidase was used to treat HA filler–induced complications.6–96–96–96–9
Despite universal use of hyaluronidase for this indication, multiple aspects remain obscure. Based on published literature and personal experience, the author elucidates questions regarding the appropriate dosage, timing, and technique of hyaluronidase delivery, differences in interaction patterns between the enzyme and different HA gels, and hyaluronidase safety issues.
What is Hyaluronidase? Which Hyaluronidases are Available for Use?
Degradation of native HA in the human tissues is carried out by thermal pathway, free radicals, and specific hyaluronidases. The same mechanisms are probably responsible for elimination of injectable HA gels.
Animal origin hyaluronidases have been used clinically for more than 70 years.10,1110,11 They are FDA-approved agents to facilitate subcutaneous hydration and drug dispersion, especially local anesthetics. By splitting the N-acetylglucosamine moiety and glucoronic moiety of native HA, hyaluronidase induces temporary decrease in viscosity of extracellular matrix and promotes dispersion of injected substances or absorption of localized transudates or exudates.
In dermatology, hyaluronidase was experimentally used in treating diabetic scleredema, scleroderma, lymphedema, and keloid scars.12–1612–1612–1612–1612–16 In the past years, hyaluronidase was used off label for correction of HA filler–induced adverse reactions.
Hyaluronidases currently available for medical use are of either animal origin or human recombinant type (Table 1). Products approved by the FDA include bovine testicular hyaluronidase (Amphadase), ovine testicular hyaluronidase (Vitrase), and recombinant human hyaluronidase (Hylenex).17–1917–1917–19 All the products are considered to be pregnancy category C.
In other countries, only a single variant of the enzyme is commercially available or a compounded agent dominates the market. In Germany, for example, bovine origin hyaluronidase—Hylase “Dessau” is patented and manufactured for many decades.20 In the United Kingdom, Hyalase is distributed by Wockhardt UK Ltd as vials containing 1,500 units of hyaluronidase powder, with no specification of the origin.21 After reconstituting the enzyme, the product should be used within 6 hours.22
To note, patients receiving large doses of salicylates, cortisone, ACTH, estrogens, or antihistamines may require larger amounts of hyaluronidase for equivalent effect, because these drugs apparently render tissues partly resistant to the action of hyaluronidase.17–2017–2017–2017–20
It is generally assumed that enzymes derived from animal tissues, whether commercially distributed or compounded, are more immunogenic than recombinant products and may contain several contaminating substances, such as proteases, immunoglobulins, and vasoactive factors.23 In addition, with compounded products, both safety and potency issues may arise.3 In the United States, quality problems with compounded hyaluronidase resulted in product recalls.24 Thimerosal, used in the past as a preservative in compounded hyaluronidase, has been eliminated from most products due to the sensitization risk.25
Which Complications Can be Treated by Hyaluronidase?
Three main groups of adverse effects induced by HA-based fillers are treated by hyaluronidase: overcorrection or superficial HA implantation, inflammatory or noninflammatory nodules, and local or remote vascular occlusions. These groups differ in the pathogenesis, clinical presentation, intensity, and possible sequela and thus require different therapeutic approach.7,9,267,9,267,9,26
Is Skin Pretesting Needed?
Allergic reactions to hyaluronidase are well documented, but uncommon (0.05%), with most cases documented in the ophthalmology literature.2,27–402,27–402,27–402,27–402,27–402,27–402,27–402,27–402,27–402,27–402,27–402,27–402,27–402,27–402,27–40 A review of the dermatologic literature did not reveal any cases of anaphylaxis or severe allergy to hyaluronidase.2
To preselect patients allergic to hyaluronidase, skin test can be performed. Three units of hyaluronidase are injected intradermally. Local wheal and flare occurring within 5 minutes and persisting 20 to 30 minutes is considered as a positive reaction. Erythema alone does not constitute a positive reaction.
When treating nonemergency complications of HA gels, such as overcorrection, superficial implantation or inflammatory reactions, skin pretesting is considered optional. If the need for enzyme injection is urgent, such as in vascular occlusions, no pretest is performed. In such circumstances, bedside availability of epinephrine is advisable.
Bee and wasp venoms contain hyaluronidase and some individuals, allergic to their stings, were found to be sensitive to hyaluronidase.41 There are no clear-cut standards for using hyaluronidase in patients allergic to bee stings. In non-emergency situations, when history of major allergic reaction to bee or wasp stings exists, skin pretesting by allergist is recommended. In situations in which urgent injection of hyaluronidase is required in such a patient, the risks and benefits of not performing a skin test ought to be weighed.
When to Inject Hyaluronidase?
Granulomatous reactions and overcorrection by HA gels can be successfully addressed by hyaluronidase long after product implantation.1,6,42,431,6,42,431,6,42,431,6,42,43
If active infection is suspected, hyaluronidase should be injected after initiating appropriate antibiotic treatment; otherwise, the enzyme can facilitate spreading of the infection to surrounding areas.7,207,20
In case of unintentional intravascular injection or vascular compression by HA, the product has to be dissolved quickly.44–4744–4744–4744–47 In an animal model, Kim and colleagues48 demonstrated that administration of hyaluronidase 4 hours after filler injection into the auricular arteries of rabbit ears can significantly reduce the size of necrotic areas, compared with delayed injection of hyaluronidase (24 hours after filler injection) or untreated controls.
For remote vascular events, emergency treatment is of even higher importance.26,4926,49 Hayreh and colleagues50 found that in case of retinal ischemic event, the circulation needs to be restored within 90 minutes. Although uncertainty exists whether blindness due to intravascular injection of a filler is treatable at all, immediate injection of hyaluronidase seems to be the most promising step in the management of this devastating complication.49,5149,51
Are All HA Gels Equally Sensitive to Hyaluronidase?
Differences in sensitivity of specific products to enzymatic degradation not only affects tissue residence time of the filler, but also the speed in which the product is dissolved in case of an emergency situation, such as in intravascular occlusion.
Few studies attempted to compare the sensitivity of different gels to hyaluronidase. Sall and colleagues tested the sensitivity of 11 different gels (Restylane, Perlane; Juvederm 18, 24, 24HV, 30, and 30HV; Surgiderm 18, 24XP, 30, and 30XP) to bovine hyaluronidase. They used colorimetric determination of the N-acetyl-D-glucosamine released after 2 hours of incubation of 0.3 mL of each product with 15 units of enzyme.52 They found that Restylane family is more sensitive to degradation than Juvederm and Surgiderm families. The authors speculate that particulate nature of Restylane provides a greater surface to be attacked by the enzyme, making this family of gels faster and easily degradable.
Jones and colleagues53 found similar results, when the efficacy of ovine origin hyaluronidase on 3 different commercially available HA-based fillers was compared. To determine dose–response behavior, 0.4 mL aliquots of Juvederm Ultra, Restylane, and Prevelle Silk were incubated with increasing doses of hyaluronidase (5–40 units) for 30 minutes. All 3 fillers demonstrated dose-dependent responses. Restylane and Prevelle displayed greater sensitivity to any of the enzyme concentration analyzed in the study. When aliquots of the fillers were incubated with 20 units of the enzyme up to 120 minutes, complete degradation of Prevelle occurred after 30 minutes and 90% of Restylane were degraded after 45 minutes of incubation. At 120 minutes, only 37% of Juvederm were degraded. It took 24 hours and 40 units of enzyme to completely degrade this product. The authors attribute degradation resistance of Juvederm to higher HA content and higher level of cross-linking.
Flynn and colleagues54 profiled the degradation patterns of Restylane, Juvederm Ultra, and Belotero Balance by measuring high and low molecular weight components after incubating 0.08 mL of each product with 16 units of ovine hyaluronidase. In this study, all 3 gels were more than 90% degraded within 6 hours of exposure. The difference from results of previous studies can be explained by a different methodology used in this study including much higher enzyme–substrate ratio.
In conclusion, because different HA gels differ in their sensitivity to hyaluronidase, one might consider using higher doses of the enzyme for more resistant fillers, especially in emergency situations.
Are All the Available Hyaluronidases Similar?
To assess the interaction of various fillers with commonly available hyaluronidases, Rao and colleagues55 exposed Restylane, Juvederm, and Belotero Balance to 20 units of Vitrase and 15 units of Hylenex in vitro. With both enzymes, the response was time dependent. Belotero retained its form the most, followed by Juvederm and then Restylane. This reaction pattern was persistent for the 2 hyaluronidases tested. Based on the results, the authors conclude that these products can be used almost interchangeably.
No additional studies comparing potency of other hyaluronidases on HA fillers could be found. When using non–FDA approved or compounded products, the assumption that they all are equally potent can be misleading3 (and personal experience).
How to Inject Hyaluronidase?
Despite no evidence of added benefits, some physicians added lidocaine to diluted hyaluronidase to facilitate vasodilatation.1,9,20,44,451,9,20,44,451,9,20,44,451,9,20,44,451,9,20,44,45 To treat overcorrection, superficial HA implantation or inflammatory reaction, hyaluronidase is delivered to the skin and subcutaneous tissue by direct infiltration of the visible or palpable mass of HA. Massage is recommended to mechanically mix the enzyme with the HA and promote filler degradation.1,6,7,201,6,7,201,6,7,201,6,7,20
In case of vascular obstruction by HA, whether local or remote, theoretically the enzyme has to be delivered directly into the occluded vessel. Practically, the odds to inject the same artery again are very low. Nevertheless, it has been shown ex vivo that cross-linked HA contained within intact artery is susceptible to hydrolysis by hyaluronidase found outside the vessel in its immediate surroundings.56 This indicates that heavy infiltration of the ischemic tissues can substitute for the direct intraarterial injection of hyaluronidase, which is challenging and probably unrealistic in most cases.49,5749,57
According to the consensus recommendations, in case of local impending necrosis, 1 injection every 3 to 4 cm in the ischemic area (area with blanch, violaceous, or reticulate discoloration) is advised followed by thorough massage.46 If no improvement is observed within 60 minutes, additional 3 to 4 injection cycles are performed.
Are Different Doses of Hyaluronidase Needed to Treat Different Adverse Reactions?
To dissolve a palpable lamp of 0.2 mL of Restylane on the skin of healthy volunteers, Vartanian and colleagues25 found the dosage of 10 to 30 units of hyaluronidase sufficient. It is also the author's and others' experience that overfills, superficial implantation, and inflammatory reactions by Restylane can be rapidly corrected by 1.5 to 150 units of the hyaluronidase (Figure 1A–D).6–9,20,58–606–9,20,58–606–9,20,58–606–9,20,58–606–9,20,58–606–9,20,58–606–9,20,58–606–9,20,58–60 For more resistant gels, higher doses or repetitive injections of the enzyme are required.7,587,58 Jones and colleagues53 suggested a rule of thumb: for each 0.1 mL of HA to be eradicated in vivo, the clinician should begin with 5 units of hyaluronidase for Restylane and 10 units for Juvederm.
When treating vascular obstruction, 150 to 200 units is the initial recommended dose.7,44,46,497,44,46,497,44,46,497,44,46,49 If no improvement occurs, repetitive cycles of injections are carried out; 1,500 units and above can be used if indicated (Figure 2A, B).7
Is There Any Toxicity to Native HA Associated With Hyaluronidase Injection?
Hyaluronidase acts immediately once in contact with its substrate, and the duration of activity is typically 24 to 48 hours in dermal tissues.61 Except for Vartanian and colleagues,25 no others have related hypersensitivity reactions to hyaluronidase to its accumulative doses.
Hyaluronidase can theoretically induce tissue toxicity by breaking out native HA. To the best of the author's knowledge, no such observations have ever been documented, even with hyaluronidase use in such a vulnerable population as neonates.62 It might be due to a higher sensitivity of artificial than resident HA to hyaluronidase activity.13 Should significant native HA degradation occur, it is probably rapidly compensated by natural mechanisms of HA synthesis.
With continuous growth in HA-based fillers use, more complications become evident. Hyaluronidase, if properly used, can successfully resolve significant part of them. Registered hyaluronidases, especially if FDA cleared, can provide predictable results. Most of them can be used interchangeably. Other hyaluronidases are available; some originate from compounding pharmacies worldwide. No studies are published to support their potency, safety, and equivalency. When using one of these products, a physician has to be well recognizant with its specific characteristics.
Different brands of HA fillers have different sensitivity to degradation by hyaluronidase. This might become an issue in case urgent break down of the product is required, such as in the case of vascular obstruction. Higher doses of hyaluronidase are probably capable to compensate for relative resistance of the gel to degradation. No documentation of toxicity of hyaluronidase to native tissue HA is available. When indicated, repetitive doses of the enzyme can be safely delivered. Flushing of the ischemic tissue with hyaluronidase can in most cases substitute for direct intravascular injection of the enzyme. For non-emergency HA-associated complications, such as overcorrection, filler misplacement, or inflammatory reaction, lower doses of the enzyme provide an appropriate, but more sustained result. Serious hypersensitivity reactions to hyaluronidase are possible, but so far it is not reported in dermatologic literature. Skin testing allows to preselect patients sensitive to hyaluronidase. In emergency situations, the risks and benefits of not performing a skin test must be weighed.
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