What is "Hyaluronidase" that Dissolves Hyaluronic Acid? Effects, Risks, and Costs

1. What is Hyaluronidase

In cosmetic medicine and reconstructive medicine,Hyaluronic acid(HA) Non-surgical injection therapy (filler injection) using hyaluronic acid has gained tremendous popularity due to its short downtime and minimally invasive nature. One of the greatest reasons why hyaluronic acid fillers are chosen as the first-line filler worldwide is the existence of hyaluronidase, a "reversal agent (antagonist/dissolving agent)." Hyaluronidase is an enzyme with the ability to break down hyaluronic acid, and it functions as an essential safety measure to dissolve injected hyaluronic acid and return it to its original state in the event of problems after filler injection.

Hyaluronic acid itself is a glycosaminoglycan that naturally exists in the human body, and hypersensitivity reactions caused by modern hyaluronic acid fillers are said to be extremely rare. However, no matter how safe a substance may be, as a medical procedure, there is a non-zero risk of complications or unsatisfactory results. In such cases, the characteristic that hyaluronidase can rapidly dissolve fillers is a decisive advantage that other fillers do not have. In fact, other semi-permanent fillers such as calcium hydroxyapatite (CaHA) do not have dedicated dissolving agents like hyaluronidase. A group of experts including Kurkjian cite the absence of a hyaluronidase-equivalent drug to correct failures or incomplete results as the reason for injectionNose augmentation surgeryWe do not recommend the use of calcium hydroxyapatite in this context. In this way, hyaluronidase is not merely a corrective agent, but is positioned as one of the most important elements ensuring overall safety in procedures using hyaluronic acid fillers.

2. Cases where dissolution is necessary

Cases requiring dissolution of injected filler using hyaluronidase range from minor aesthetic concerns to serious complications requiring urgent intervention. The main indications are as follows.

Overfilling (overcorrection) and misplacement injection

If too much filler is injected or filler is accidentally injected into unintended layers or areas, hyaluronidase can be used to break down excess hyaluronic acid. It is also used to correct contour irregularities that occur after treatment and to smooth out minor irregularities (imperfections).

Formation of nodules or granulomas

Following hyaluronic acid filler injection, nodules or granulomas may form in a delayed manner. As treatment options for these complications, hyaluronic acid dissolution through hyaluronidase injection is recommended alongside local steroid injection and surgical excision.

Dispersal and dissolution of special filler materials

Hyaluronidase may be used for fillers other than pure hyaluronic acid fillers. For example, Algeness (Argenase) a 100% natural biodegradable filler, under exceptional circumstances, hyaluronidase can be injected together with warm saline or a 250–500 mg/mL vitamin C solution to promote gel dispersion, as reported (Karapantzou 2020). Furthermore, in treatment procedures for certain micro-particle fillers (such as preparations containing non-cross-linked hyaluronic acid), hyaluronidase can be administered additionally if complications occur.

Vascular occlusion (most severe case)

"Vascular occlusion," in which filler is inadvertently injected into an artery or blood flow is obstructed by compression from surrounding tissues, is the case that most urgently requires hyaluronidase. Because vascular occlusion can lead to irreversible consequences such as skin necrosis and blindness, immediate dissolution by hyaluronidase is essential. (This will be detailed in the section "5. Emergency Use").

3. Effects and duration

The greatest characteristic of hyaluronidase is the rapid onset of its effects.

Dissolution speed and time limit

Once injected, hyaluronidase rapidly breaks down hyaluronic acid. Particularly with regard to preventing skin necrosis from vascular occlusion, the passage of time determines the outcome. According to animal experimental data, if hyaluronidase is injected subcutaneously within 4 hours of vascular occlusion occurring, potential skin necrosis can be reversibly prevented (DeVictor 2021). Thus, to maximize the effectiveness of hyaluronidase, early detection of signs of complications and immediate administration are required.

Standards regarding dosage and frequency of administration

Currently, there is no medically complete consensus (unified view) established regarding the "optimal dosage" or "frequency of administration" of hyaluronidase as a reversal agent for hyaluronic acid. However, certain effective guidelines have been indicated through multiple clinical studies and expert guidelines.

• Hyaluronidase can be used at any time during the duration of the filler and can be injected multiple times as necessary.
• In a retrospective study of 5000 non-surgical rhinoplasty procedures by Harb and Brewster, when 1500 IU of hyaluronidase dissolved in 1 ml of saline was immediately administered to the injection site and areas showing skin changes in patients showing signs of ischemia, complete recovery was achieved without any sequelae such as necrosis. In this study, no patients required re-administration of hyaluronidase (multiple treatments) (Harb 2020).
• In severe cases such as vascular occlusion, administration of "high-dose" hyaluronidase without hesitation is recommended as a management protocol.

4. Risks and side effects

The provided sources do not include detailed descriptions of direct side effects (such as allergic reactions) caused by hyaluronidase itself, but strict warnings are issued regarding the risks surrounding hyaluronidase use and the risks when its use is delayed.

Lack of consensus on optimal dosage

As mentioned previously, the lack of clear consensus on the optimal dosage and frequency of hyaluronidase becomes a risk for healthcare providers. If the dosage is insufficient, hyaluronic acid may not be completely dissolved and vascular occlusion may progress; conversely, unnecessary overdosing may cause unexpected tissue reactions. Therefore, healthcare providers must first confirm the guidelines and approved indications in their respective countries and use the drug carefully based on their own clinical judgment.

Risks when hyaluronidase is not used (or use is delayed)

The risks of failing to take appropriate measures when hyaluronidase should be used are extremely severe. Hyaluronic acid filler injection can cause early complications such as erythema, edema, hematoma, nodule formation, and infection, as well as late complications such as granuloma formation, filler migration, and delayed-type hypersensitivity. However, the most feared is vascular occlusion, and if this is overlooked and hyaluronidase is not administered, it can cause skin necrosis or irreversible blindness due to central retinal artery occlusion/embolism (DeVictor 2021) (Williams 2020).

Some physicians attempt to prevent accidental intravascular injection through a "syringe aspiration test" before injection, but in animal model experiments, the reliability of the aspiration test is only about 53%, and the absence of blood backflow in the syringe does not completely rule out the possibility of intravascular injection (Trevidic 2022). Therefore, injecting hyaluronic acid filler without having hyaluronidase prepared on hand is itself an act that exposes patients to serious risk.

5. Emergency use (Vascular occlusion)

The most critical situation requiring emergency use of hyaluronidase is "Vascular Compromise." Vascular occlusion is caused by embolism from filler being injected directly into an artery, or by external vascular compression due to excessive injection volume or edema.

Incidence of vascular occlusion

In a systematic review by DeVictor et al. of 8,604 patients, transient vascular occlusion was reported in 30 cases (0.35%), skin necrosis in 7 cases (0.08%), and vision loss in 8 cases (0.09%) (DeVictor 2021). Additionally, in Williams et al.'s review, 65 cases of vascular complications following filler injection to the nose were identified, of which 30 were related to nasal skin necrosis, and 33 were related to visual and ophthalmological symptoms including retinal artery occlusion and blindness (Williams 2020). While these are extremely rare events, the consequences when they occur are devastating, necessitating immediate intervention with hyaluronidase.

Symptoms and early detection of vascular occlusion

Suspected symptoms of vascular occlusion include skin blanching (blanching), mottled discoloration (mottling), severe localized pain, eye pain or tooth pain, visual abnormalities, and headaches (Harb 2020). If any of these symptoms appear, injection must be stopped immediately and management to prevent ischemia must be prioritized.

Specific management protocol for vascular occlusion

When vascular occlusion suspected to be caused by hyaluronic acid is suspected, the following protocol is recommended:

• Administration of high-dose hyaluronidase: High-dose hyaluronidase is immediately infiltrated into the affected area and surrounding regions.
• Warm compresses and massage: To promote blood flow, the local area is warmed and massaged vigorously (Harb 2020).
• Use of vasodilators: Vasodilators such as nitroglycerin paste are applied to improve blood flow.
• Hyperbaric oxygen therapy: If ischemic symptoms are progressing, application of hyperbaric oxygen therapy is also considered.

Clinical success cases from emergency administration

Literature reports numerous success cases where rapid emergency administration of hyaluronidase was able to prevent serious sequelae.

• In Harb et al.'s report, among 5,000 treatments, 24 patients (0.48%) showed immediate signs of vascular disorder. When hyaluronidase was immediately infiltrated into 10 of these patients, all achieved complete recovery with no cases progressing to necrosis. Additionally, in another case, gray discoloration of the nasal tip and epidermal loss occurred 2 days after the procedure, but rapid treatment with hyaluronidase and oral antibiotics led to swift recovery (Harb 2020).
• In Sun et al.'s research, 15 cases at risk of skin necrosis followinghyaluronic acid injectionto the nose were reported. Hyaluronidase was used in 13 of these cases, and in 11 of them, progression of nasal skin necrosis was effectively halted (Williams 2020).
• Regarding visual complications, there are reports that in 2 cases where hyaluronidase was used, both achieved complete recovery of visual symptoms (Williams 2020).

These clinical data strongly suggest that early local administration of hyaluronidase against vascular complications caused by hyaluronic acid is an extremely effective therapeutic approach. In particular, injection to the nasal bridge (nasal dorsum) is a high-risk area with a relatively high incidence of embolic events, so hyaluronidase must always be prepared within reach during the procedure and kept in a state of immediate access (Trevidic 2022).

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6. Summary

Hyaluronidase is an extremely important medication that fundamentally supports safety in non-surgical aesthetic medicine using hyaluronic acid fillers. Hyaluronic acid filler itself is an excellent filling material with easily predictable effects and high safety, but it always carries the risk of a rare and devastating complication: vascular occlusion. The fact that hyaluronidase exists and can rapidly dissolve filler in case of emergency is the primary reason why hyaluronic acid is widely supported as a safe option (the safest filler) compared to other filler preparations such as calcium hydroxyapatite.

When symptoms of vascular occlusion occur (skin blanching, severe pain, visual abnormalities, etc.), there is no room for delay. Many clinical cases have demonstrated that rapid and appropriate administration of high-dose hyaluronidase can prevent irreversible outcomes such as skin necrosis or blindness and achieve complete patient recovery (Harb 2020) (Williams 2020).

However, hyaluronidase is ultimately a "safety net of last resort" and should not be relied upon too heavily. To prevent complications from occurring in the first place, it is essential that the physician has deep knowledge of the complex vascular anatomy of the face and nose. Furthermore, during injection, it is necessary to strictly adhere to safe injection techniques such as targeting deep layers such as the periosteum or perichondrium, maintaining the midline, and slowly injecting small amounts of filler (0.1 ml or less per injection) at low pressure (Trevidic 2022). Only when both the constant availability of hyaluronidase and advanced anatomical knowledge and injection techniques are in place can safe and reproducible aesthetic medical treatment be provided to patients.

About the author of this article

Hiromitsu NakamuraPhysician

Zetith Beauty Clinic Ginza, Osaka, Fukuoka

Has research presentation experience at both domestic and international academic conferences, and is involved in technical guidance and education throughout Zetith Beauty Clinic. Specializes in precision aesthetic medicine based on anatomical evidence, pursuing natural results tailored to each individual's skeletal structure and tissues.