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The 2 Roles of Hyalurodinase in Filler Complications

Hyaluronic acid (HA) fillers have revolutionized aesthetic medicine, offering a non-surgical approach to facial rejuvenation. However, despite meticulous injection techniques, iatrogenic complications like granulomas, nodules, or vascular compromise can occur. Hyaluronidase emerges as a scientifically validated tool in the dermatologist's armamentarium, enabling the targeted enzymatic reversal of these unwanted effects. The enzyme cleaves the glycosidic bond between N-acetylglucosamine and glucuronic acid residues within the HA molecule, effectively breaking it down into smaller fragments and reducing its viscosity.

Rapid systemic degradation by the liver and kidneys necessitates localized or regional administration of hyaluronidase to maximize its effect at the target site. The relatively short half-life (approximately 30-60 minutes) demands careful timing for optimal efficacy, particularly when dissolving HA fillers. Clinicians must consider the specific hyaluronidase used, including its diffusivity, its ability to target hyaluronan, and potential interactions with surrounding tissues, to achieve the desired outcome. In this blog, we will discuss  the use of hyaluronidase, an enzyme that can be used to reverse or dissolve HA fillers, as a valuable tool for managing these complications.

Complications of HA Injections

Skin Necrosis

Hyaluronic acid (HA) fillers are widely used for facial rejuvenation, but vascular obstruction and subsequent skin necrosis remain a rare but potentially devastating complication. This review explores the mechanisms, risk factors, and management strategies for these ischemic events.

Two primary mechanisms are implicated in HA filler-induced ischemia:

  1. Compression of Blood Vessels: After injection, HA absorbs water and expands, potentially compressing adjacent blood vessels, particularly in areas with limited collateral flow (e.g., glabella, nasal alar). This compression restricts blood supply and leads to tissue ischemia.

  2. Inadvertent Intra-arterial Injection: Accidental injection of HA directly into an artery can cause immediate obstruction, compromising blood flow to downstream tissues and leading to rapid necrosis. Embolization of filler material further increases the risk of necrosis in distant locations.

Skin necrosis typically manifests as blanching, dusky discoloration, and pain in the affected area. Venous occlusion can also occur, presenting with delayed onset of ecchymosis and vague discomfort. The glabella and nasal regions are particularly vulnerable due to their limited collateral blood supply. Prompt intervention is crucial to minimize tissue damage. Here's an overview of potential management strategies:

  1. Vasodilation: Measures like warm compresses, topical 2% nitroglycerine paste, or oral sildenafil may promote blood flow to the ischemic area.

  2. Systemic Corticosteroids: Corticosteroids can help reduce inflammation and edema associated with ischemia.

  3. Anticoagulation: Aspirin or low molecular weight heparin may be considered to prevent further clot formation.

  4. Hyaluronidase Injection: Hyaluronidase, an enzyme that degrades HA, plays a pivotal role in managing ischemic complications. Doses of 30-75 units in saline or lidocaine are typically used.

The optimal timing for hyaluronidase injection remains under investigation. However, earlier administration is generally considered more beneficial. Animal studies suggest significantly reduced necrosis when hyaluronidase is administered within 4 hours compared to 24 hours after HA injection.

Studies suggest direct intravascular injection of hyaluronidase is usually unnecessary, as the enzyme readily diffuses into the vascular lumen. Hyaluronidase can be injected into the region of suspected obstruction to achieve effective diffusion and HA degradation. However, a single case report describes successful management with intra-arterial hyaluronidase injection, highlighting the need for further research on this approach.

Non-inflamed Lessions

Hyaluronic acid (HA) fillers are a popular tool in aesthetic medicine, but sometimes unwanted outcomes like nodules, discoloration, or edema can arise. While these complications are typically non-inflamed, hyaluronidase emerges as a valuable option for managing them.

Non-inflamed HA Complications:

  • Subcutaneous Nodules:  Excessive filler or misplacement can lead to nodules. Uncomplicated nodules may resolve on their own due to HA's natural resorption. However, hyaluronidase offers a solution for bothersome or painful nodules. Literature reports successful resolution of nodules with hyaluronidase injections (75 units). Lower initial doses (30 units) followed by a second session might be preferable to minimize potential side effects.

  • Tyndall Effect:  Superficial HA injection can cause nodules with a bluish hue due to light scattering within the gel (Tyndall effect).

  • Persistent Edema:  Malar edema lasting more than a month may require massage, cold compresses, and potentially hyaluronidase injection. A case report describes successful treatment of recurrent edema with 25 units of hyaluronidase at multiple sessions. However, natural HA resorption might have also played a role over time.

  • Filler Migration:  Hyaluronidase can address complications arising from filler migration. One case describes successful resolution of intraorbital edema after injecting 30 units of hyaluronidase for suspected migrated filler.

Reported doses of hyaluronidase vary across studies. A prospective trial suggests an initial dose of 5-10 units of hyaluronidase in 0.1-0.2 mL saline might be appropriate for non-emergent situations. This approach potentially minimizes the risk of local hypersensitivity reactions.

Hyaluronidase represents a scientifically validated tool for managing HA filler complications. By understanding its mechanism of action, clinical applications, and advanced considerations, doctors can leverage hyaluronidase for safe and effective reversal of unwanted filler effects. As research delves deeper into its potential applications and targeted delivery systems, hyaluronidase is poised to play an even more prominent role in ensuring optimal patient outcomes in aesthetic medicine.

Mechanism of Action of Hyaluronidase

Hyaluronidase represents a family of glycosidase enzymes exhibiting varying substrate specificities. In the context of HA fillers, hyaluronidase catalyzes the cleavage of the β-1,4-glycosidic bond between N-acetylglucosamine and glucuronic acid residues within the HA polysaccharide backbone. This enzymatic action effectively depolymerizes the HA filler, reducing its viscosity and promoting its resorption through the lymphatic system. The selection of the optimal hyaluronidase is crucial. Bovine-derived hyaluronidase, for instance, demonstrates broader substrate specificity compared to mammalian isoforms. This translates to its ability to degrade a wider range of HA cross-linking densities, potentially offering greater versatility in clinical practice.

I. Dissolution of Unwanted Filler

Hyaluronidase offers a minimally invasive and targeted approach for misplaced or overcorrected HA fillers. The optimal dose and administration technique depend on several factors. The degree of cross-linking within the HA filler significantly impacts its susceptibility to hyaluronidase. In vitro studies employing differential enzymatic digestion assays can be employed to guide hyaluronidase selection for optimal efficacy based on the specific filler used (brand, manufacturer). The extent and severity of the complication (e.g., size and location of the nodule) dictate the amount of hyaluronidase required. Serial dilutions and hyaluronidase activity assays can be used to determine the precise dosage needed for targeted depolymerization of the filler material. The timing and frequency of hyaluronidase injections can be adjusted to achieve a gradual or more rapid resolution. Pharmacokinetic studies investigating the in vivo degradation profile of different hyaluronidase formulations can inform treatment protocols to achieve the desired speed of correction.

II. Management of Vascular Compromise

Prompt administration of hyaluronidase can be crucial in salvaging tissues compromised by inadvertent intravascular HA filler injection. Hyaluronidase helps disperse the occlusive filler material and potentially prevent tissue necrosis by facilitating reperfusion of the affected area.

Results of Hyaluronidase Application in Complications

Hyaluronic acid (HA) filler complications extend beyond non-inflamed issues. Inflammatory nodules, potentially caused by infection or granulomatous reactions, pose a distinct challenge. Hyaluronidase can be a valuable tool in managing these complications, but its use requires a nuanced approach.

Potential Causes of this may include:

  • Infection and Biofilm Formation: Inflammatory nodules can arise due to bacterial infection and biofilm development within the filler material.

  • Granulomatous Reactions: HA gel or contaminating proteins can trigger granulomatous reactions, leading to inflamed nodules.

The initial approach depends on the suspected cause:

  • Oral antibiotics

  • Incision and drainage (for fluctuant lesions)

  • Intralesional corticosteroids (administered after starting antibiotics)

While hyaluronidase is effective for non-inflamed complications, its use in inflammatory nodules requires caution:

  • Antibiotic Concomitance:  Hyaluronidase can break up the infected collection and potentially disseminate bacteria. Therefore, concurrent oral antibiotic therapy is crucial.

  • Biofilm Disruption:  In vitro studies suggest hyaluronidase can effectively disrupt bacterial biofilms, potentially aiding in infection management. A case report describes successful resolution of an infected nodule with hyaluronidase after antibiotics failed.

  • Granulomatous Reactions:  Hyaluronidase may be helpful for nodules arising from granulomatous reactions. A case report details successful resolution of a sterile chronic granulomatous nodule after hyaluronidase injection.

Potential Complications in Usage of Hyaluronidase

Hyaluronidase is associated with a low risk of adverse effects. However, localized reactions like redness and itching can occur. In one study, 25% of patients experienced such reactions on average thirty minutes after injection. More severe reactions like angioedema and anaphylaxis are rare, with an estimated incidence of 0.1%. It's important to note that documented cases of anaphylaxis involved larger doses used in anesthesia, not the smaller doses used for HA filler complications.

The risk of a hypersensitivity reaction is influenced by the source of the hyaluronidase used. Hyaluronidase extracted from animal tissues (bovine or ovine) carries a higher risk of allergic reactions compared to the human recombinant form (Hylenex). Additionally, a larger dose may increase the risk, as seen in a reported case of angioedema following a high dose of ovine-derived hyaluronidase.

Several strategies can help minimize the risk of hypersensitivity reactions. Some research recommend routine skin allergy testing, especially before using bovine or ovine-derived hyaluronidase. However, this may not be practical in emergency situations like skin necrosis. It's also important to inquire about a patient's history of allergies to bee or wasp stings, as there can be cross-reactivity with the hyaluronidase.

In summary, hyaluronidase represents a valuable adjunct in the management of HA filler complications, offering clinicians a safe and effective means to address a spectrum of issues and ensure optimal patient outcomes in aesthetic medicine. As research continues to advance, further insights into its applications and refinements in delivery systems promise to enhance its role in clinical practice.


The Use of Hyaluronidase in Cosmetic Dermatology: A Review of the Literature (2015)

Treatment of Delayed-onset Inflammatory Reactions to Hyaluronic Acid Filler: An Algorithmic Approach (2022)

What to do about filler migration (2021)


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