Hyaluronidase Protocol: Usage, Treatment and Side Effects

The medical aesthetics industry is growing rapidly. Hyaluronic acid dermal fillers are so popular that many training conferences are held across the country (where practitioners learn how to administer fillers). However, the administration technique is only one of the many aspects of filler treatments. When using an injectable filler, it is important to have a good understanding of both physiology and anatomy. At the same time, it is important to consider other issues such as aftercare and the management of complications. It is not uncommon for doctors to seek advice on complication management from networking groups or support forums. It is worrying to see how many doctors do not have the expertise and confidence to manage side effects related to fillers. Inappropriate management of complications can potentially harm the patients. In this article, we will discuss about the protocols of hyaluronidase administration, and the importance of using appropriate protocols in hyaluronidase treatments. Plus, this article will provide insight into the mechanism of action and method of use of hyaluronidase.

About hyaluronidase

Hyaluronidase is a group of injectable enzymes commonly used in managing complications associated with fillers. Chemically, hyaluronidase has a molecular formula of C2455 H3775 N617 O704 S21 and a weight of 53870.9 Da. As implied by its name, hyaluronidase has catalytic activities on hyaluronic acid degradation. Found naturally in the body, hyaluronic acid is a main tissue component that provides resistance liquid diffusion across tissues. Functioning as dispersion agents, hyaluronidase promotes the hydrolysis of hyaluronic acid to accelerate the natural decomposition process. Hyaluronidase is often used medically to increase the permeability of tissues, thereby increasing the uptake of subcutaneous fluids and enhancing drug delivery. In other words, it increases dispersion and distribution to stimulate the absorption of an extravasated or a locally injected substance. Notably, hyaluronidase can be used as an antidote for vinca alkaloid overdose. On a cellular level, hyaluronidase is able to split the glucosaminidic bond between C4 of glucuronic acid and C1 of the glucosamine moiety.

In aesthetic medicine, hyaluronidase is used off label to manage the side effects of filler treatments. The term “off label” refers to the use of a drug or product for indications other than the ones officially approved. Approval for use is usually granted by health authorities such as Food and Drug Administration (FDA) or Medicines and Healthcare products Regulatory Agency (MHRA). Upon approval, these agencies will issue detailed guidelines that encompass indications, dosage, contraindications, precautions, and other important aspects of the treatment. In general, the off-label use of hyaluronidase is justified as long as doctors act in the best interest of patients.

It can be challenging to determine the correct dosage (or to prepare and reconstitute the injection), especially for novice doctors who lack experience. As a result, a lot of doctors resort to online forums or support groups to seek advice from their peers.

There are many factors that should be considered when deciding the dosage and administration method. This includes the amount of hyaluronic acid deposit, the degree of cross-linking and the concentration of hyaluronic acid filler.

Recognizing the complications of hyaluronic acid dermal fillers

Mild side effects such as injection-related swelling, tenderness, and bruising can be managed easily without medical intervention. In most cases, the symptoms are self-limiting and will eventually resolve themselves. When it comes to severe complications (such as inadvertent administration into the artery or vein), it is crucial to use an effective treatment such as hyaluronidase. Injecting hyaluronic acid into the artery could result in the formation of a clot or blockage. Necrosis may also occur if the affected vessel supplies a significant amount of blood to the skin. Apart from that, irreversible skin tissue damage may happen due to insufficient oxygen and blood. Inadvertent filler injection into the vein may also result in blockage. This can potentially lead to the backflow of blood into tissues, thereby elevating pressure. As a result, patient may experience low-grade ischemia.

Among all injection sites, the nose (especially the tip) is most susceptible to necrosis after using a hyaluronic acid filler. Vascular complications are usually severe and require urgent medical care. Inappropriate injection of filler into the angular vessels of the nose could result in skin necrosis and blockage. Injecting fillers into facial artery may result in proximal migration to the internal carotid system. Upon release of pressure, the filler migrates into the central retinal pressure, potentially leading to blindness.

Early detection of symptoms (and prompt treatment) may help to minimize harm. Therefore, practitioners should be equipped with the right skills and knowledge to identify the symptoms of an impending necrosis. There should also be a clear guideline for dealing with complications. More importantly, practitioners should have the confidence and expertise to remedy the situation.

When should hyaluronidase be used?

One of the possible risks of hyaluronic acid fillers is over injection. In the case of an over injection, patients may look pillow-faced or experience unsightly lumpiness. Large volumes of injected filler may be visible in the mid-face. Apart from that, nodules may also occur. Particularly, inflammatory nodules may be observed within 2 days after injection. As for other types of nodules, infection is usually involved. Nodules that occur sub-acutely may occur within 2 weeks after treatment while late nodules usually develop 2 weeks post treatment. Hyaluronidases effectively treat large hematomas, improving absorption through a process called hypodermoclysis (subcutaneous infusion or interstitial infusion of fluids into the body).

If an infection is suspected, hyaluronidase should not be used (antibiotics should be used instead). Hyaluronidase is known to alleviate the Tyndall effect (when hyaluronic acid is injected too superficially and there is a bluish skin discoloration). When performing the injection, practitioners should beware of any signs of skin blanching. For example, a mottled or dusky appearance. If skin blanching occurs, patients may experience pain and a cooling sensation at the treatment area. If left untreated, the area may become bluish, potentially causing tissue necrosis.

For best results, hyaluronidase should be used as soon as any complication is observed. Early treatment with hyaluronidase can help prevent progression to tissue necrosis. Keep in mind that the efficacy of hyaluronidase in dissolving hyaluronic acid is significantly decreased 4 hours after injection. Regardless of the urgency of the situation, patients should be educated about the use of hyaluronidase and the details of the administration process. As with other interventions, patients are required to sign a written consent prior to the treatment. Doctors have the obligation to tell the patient about all the potential risks of using hyaluronidase. Patients should be made aware of the fact that hyaluronidase is being used “off label.”

Steps for using hyaluronidase

An injection typically consists of 1500 IU of hyaluronidase in the form of powder for solution for infusion or injection. The white, freeze-dried powder is supplied in glass ampoules or vials. Hyaluronidase is a prescription-only drug that should only be injected by a qualified medical professional after consultation. Due to its dosage form, hyaluronidase needs to be reconstituted before use. The preparation steps are as follows.

First, draw up 10 milliliters of 0.9% normal saline or water for injection in a syringe. Then, reconstitute 1500 IU of hyaluronidase with one milliliter of water for injection or normal saline. To make sure that the powder is completely dissolved, rotate the vial. After reconstitution, draw up one milliliter of the hyaluronidase solution back to the syringe (which contains the remainder of water for injection or normal saline). This gives a concentration of 150 IU/ml (meaning every 0.01 millimeter will contain 1.5 IU of hyaluronidase). Under sterile conditions, administer hyaluronidase to the treatment site. Superficial injections should be performed in small aliquots with a 30G needle. A 27G needle should be used for deeper injections. Practitioners should make sure that the injection is accurate. When using hyaluronidase, the injection should be limited to the treatment site. As a rule of thumb, nodules should be injected directly. For fillers that have been deposited into the superficial dermis, place the hyaluronidase injections below (or into) the filler. As for the treatment of vascular compromise, use the serial puncture technique to administer hyaluronidase along the vessel. Make sure that the needle is perpendicular to the skin. In most cases, multiple injection are required. Prior to (and after) the procedure, it is recommended to vigorously massage the treated region. This helps to optimize the treatment outcomes while facilitating mechanical decomposition.

Potential side effects of hyaluronidase

Allergy is one of the main complications after administrating hyaluronidase. Based on several studies, the incidence rate of allergic reactions is between 0.05% and 0.69%. A patch test can be used to detect for any potential allergy. When it comes to patch tests, there seems to be conflicting evidence. Some doctors recommends using a patch test before a hyaluronidase injection to minimize the risk of developing allergies, while others suggest to use hyaluronidase as soon as possible (without a patch test). As a general rule, a patch test should be perform prior to a hyaluronidase injection unless there are symptoms of vascular compromise (in which case hyaluronidase should be used immediately).

It may be possible for hyaluronidase to break down the natural hyaluronic acid in the body instead of the injected hyaluronic acid filler. Therefore, it is recommended to individualize the treatment instead of using an absolute dose. At the same time, practitioners are advised to go slow, and perform further treatments when necessary. After injecting hyaluronidase, the patient should be observed for about half an hour in the clinic. It is essential to educate patients about aftercare. Most patients will experience the effects immediately. However, for fillers that are denser and more cross-linked, it may take up to 2 days to see the results. A follow up appointment should be scheduled 2 to 3 weeks after treatment. Additional treatments will be offered as needed.


While generally safe, the complications of dermal filler injections cannot be fully eliminated. Therefore, doctors who offer aesthetic injections should be properly trained to manage and treat filler-related complications. Due to the lack of reliable guidelines about hyaluronidase, many practitioners resort to support group or forum for advice. It is concerning that a surprising number of doctors do not have the expertise (or confidence) to treat and manage complications. By providing an insight into hyaluronidase treatments, we hope to empower doctors to improve patient care. Hyaluronidase is highly effective in managing complications of hyaluronic acid-based fillers. To ensure optimal treatment outcomes, practitioners are advised to follow the protocols outlined in this article. While not mandatory, it is recommended to perform patch test prior to using hyaluronidase (unless in an emergency).