Hyaluronidase Protocol

By Lee Rowe / 01 Jul 2015

Aesthetic nurse Lee Rowe outlines the protocol for administering hyaluronidase and highlights the importance of understanding its use in aesthetics


The aesthetic community is expanding, with non-surgical treatments now contributing to 75% of the market, making the industry worth an estimated £3.6 billion in 2015, in the UK alone.1 Numerous training days are held across the UK, qualifying delegates to obtain and use hyaluronic acid (HA) dermal fillers for their patients’ anti-ageing concerns. However, as we know, the art of injecting is just one aspect of this treatment; other aspects include knowledge and understanding of anatomy and physiology, consenting issues, aftercare and, more importantly, complication management. I find practitioners are frequently raising the issue of how to treat complications on support forums, networking groups and during study days. It is a worrying sight to see how many practitioners do not feel confident nor hold the experience to deal with the adverse reactions that can be so detrimental to a patient. The aim of this article is to give the reader a valuable insight into the use of hyaluronidase; how it works and, crucially, when to administer it.

What is hyaluronidase?

Hyaluronidases are a family of injectable enzymes that act as dispersion agents. These help speed up the natural breakdown of hyaluronic acid through hydrolysis.2 Licensed for therapeutic indications, such as increasing tissue permeability to enhance the delivery of drugs or to increase the uptake of subcutaneous fluids, in aesthetics, it is widely used ‘off license’.3 Off license does not necessarily mean it is unsafe to use, but that it is being prescribed and administered in a way that is different to its licensed use. The license is obtained from the Medicines and Healthcare products Regulatory Agency4 (MHRA) and will state what the drug can be used for, how much to give and the age of patients suitable to be treated with it. As long as the practitioner is acting in the patient’s best interests, their autonomy is respected and the patient has fully consented, then hyaluronidase can be administered in the event of an adverse reaction.5 Due to this ‘off license’ use of hyaluronidase, practitioners can only seek guidance from other professionals (as well as use their own expertise) in order to judge how much hyaluronidase to use and how to reconstitute it, which can be limiting if one has little experience of using it. Various factors will influence the administration and dosage – for example, the concentration of HA filler, level of cross-linking and amount of HA deposit.

Recognising complications with HA fillers

There are, of course, several complications associated with having a HA dermal filler treatment, such as bruising, mild swelling and tenderness at the injection site6, which can be easily managed through observation and support on the patient’s behalf. It is the more serious complications, such as when filler is injected into a vein or an artery, that will require medical intervention and the administration of hyaluronidase as part of its management. If HA is injected into an artery this can cause a clot formation around the filler, or the filler itself may cause the blockage. If the vessel is significant in supplying blood to the skin, this can lead to necrosis, an irreversible complication that results in the death of the skin tissue.7,8 This occurs when the skin region cannot access enough blood and oxygen.8 When injected into a vein, HA can also cause a blockage, resulting in blood flowing back into the tissues and therefore increasing pressure and causing low grade ischaemia.8
The nose is one of the most feared sites for necrosis following HA procedures, with the tip being the most affected.9 To give an example of how serious a vascular complication can be, injecting dermal filler into the angular vessels around the nose can potentially lead to blockage and skin necrosis or, in extremely rare cases, blindness.10 Fillers injected into an artery in the face can travel proximally to the internal carotid system whereby, on release of pressure, the product travels into the central retinal artery resulting in possible visual loss or blindness.11 It is therefore imperative that practitioners are able recognise the signs of an impending necrosis and have the skills to be able to act quickly, thus lowering the risk of harm to the patient. Not only must a policy be in place which allows the practitioner to deal with the situation, but they must also be fully competent and confident in what to do.

When should it be used?

Over injection can be a potential risk when injecting HA fillers, leaving the patient with unsightly lumpiness or looking ‘pillow-faced’, with large volumes of filler visible in the mid face.11 Nodules can also occur following HA anywhere on the face, and those that start within 48 hours of injection may be inflammatory – however, those occurring sub-acutely (up to two weeks post-treatment) or late (after two weeks) are more likely to involve infection.12 Large haematomas can also be treated with hyaluronidase.6 The use of hyaluronidase can improve absorption via hypodermoclysis, the process of interstitial infusion or subcutaneous infusion of fluids into the body.13 It is important to stress that if the practitioner suspects infection then hyaluronidase shouldn’t be used14 and antibiotics should be prescribed. However, another side effect that can be resolved with hyaluronidase is when the Tyndall effect presents itself. This is when the HA is too superficially placed and creates a bluish discoloration of the skin.8
Throughout the procedure the practitioner must observe for signs of blanching of the skin, a change in appearance that may appear dusky or mottled.6 In this instance, the patient may complain of pain and the area might begin to feel cool to touch. If these signs are ignored then the area may turn blue and tissue necrosis can occur.8 Hyaluronidase should be administered as soon as this complication occurs, and there is good evidence that tissue necrosis can be prevented or be less severe the sooner the hyaluronidase is injected.8 Hyaluronidase must be used early, as its effectiveness in dissolving HA fillers is reduced after approximately four hours.8 Whether the situation is an emergency or not, it is imperative that the patient fully understands the implications of why it is being prescribed, how it will be administered and a consent form should be signed. Patients must also be made aware of the impending risks involved with the use of hyaluronidase and that it is being used off license.


How to use hyaluronidase

 A common preparation of hyaluronidase in the UK is made up of 1500 IU of hyaluronidase in a powder for Solution for Injection / Infusion.14 This comes as a freeze-dried white powder in small glass vials or ampoules. As a prescription only medication (POM), it should only be administered following a face-to-face consultation with the prescriber. Below is my technique for preparing hyaluronidase 1500IU:

  1.  Draw up 10ml of water for injection or 0.9%normalsalinein a syringe 
  2.  Reconstitute the hyaluronidase 1500IU with 1ml of the 10ml of normal saline or water for injection
  3. Rotate the vial to ensure the powder is fully dissolved
  4. Draw up the 1ml of hyaluronidase back into the syringe with the remaining 9ml saline or water for injection thus giving a concentration of 150IU/ml. Each 0.01ml will then be 1.5IU of hyaluronidase

 Once the solution is prepared, using a clean non-touch procedure, inject the hyaluronidase into the affected area in small aliquots using a 30 gauge needle for superficial injections and 27 gauge for deeper deposits. Administration should be extremely accurate and limited to the affected area. In the case of nodules, they should be injected directly, and for product that has been injected into the superficial dermis, injections should be placed immediately into and below the product.10 For vascular compromise, serial puncture should be used to inject hyaluronidase along the course of the vessel. The needle should be perpendicular to the skin and several injections are often necessary. During and after the procedure, I recommend massaging the treated area quite vigorously to optimise the result and aid mechanical breakdown.

What are the risks of administrating hyaluronidase?

One complication following the administration of hyaluronidase is allergic reactions,11 and, according to clinical studies, occur at a frequency of approximately 0.05% to 0.69%.1 There appears to be conflicting evidence as to whether a patch test of hyaluronidase should be carried out to rule out evidence of allergic reaction, with several practitioners suggesting that when it is used for elective treatments a patch test should be carried to minimise the risk.8 The patch test should be done intradermally (within or between the skin) and I would advise the practitioner to look for signs of inflammation, erythma and persistent itching. However, if the patient is showing signs of a vascular compromise then it could be justifiable to use the hyaluronidase as soon as possible to lower the risk of further harm.
Another possible side effect of hyaluronidase is its potential to degrade the body’s natural hyaluronic acid in preference to the foreign hyaluronic acid filler that has been injected.15 I would therefore recommend treating the effect rather than absolute dosage, to go slow and to bring the patient back for additional treatments. Following the use of hyaluronidase, I would suggest observing the patient for 30 minutes in a clinical environment and making sure they have appropriate aftercare information. Results are often seen almost immediately, although I have found for denser, more cross-linked products it may take 48 hours for the effects to be seen. A review appointment at two to three weeks should be booked and further treatment offered at this point if needed.


Hyaluronidase plays an important role in the management of treating complications with HA dermal fillers, however, it should not be a substitute for good technique. Practitioners who deem themselves qualified to inject and treat patients with HA fillers must also be capable and confident to treat and manage complications. Having some knowledge into the use hyaluronidase is not enough to keep and patients safe, and so it is imperative that a policy is in place that all injectors can follow, justify and administer hyaluronidase without delay in an emergency situation. The policy must provide a set of guiding principles to help with decision-making. This doesn’t have to be complicated but understood by all injectors and reviewed regularly. The need for patch testing doesn’t appear mandatory yet but is often recommended, especially if the situation is not urgent. 

  1. Dr Maurizio Cavallini, Dr Riccardo Gazzola, Dr Marco Metalla, and Dr Luca Vaienti, ‘The Role of Hyaluronidase in the Treatment of Complications From Hyaluronic Acid Dermal Fillers’, Aesthetic Surgery Journal 33(8) (2013), 1167–1174

  2. Hyaluronidase, (US: Drugs.com, 2015) http://www.drugs.com/cdi/hyaluronidase.html

  3. Hyaluronidase Enzyme (UK: Clinica London, 2013) http://www.clinicalondon.co.uk/hyaluronidase-enzyme/

  4. Medicines and Healthcare Products Regulatory Agency, (UK: Gov.uk, 2015) https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency

  5. Off-label or unlicensed use of medicines: prescribers’ responsibilities, (UK: Gov.uk, 2009) https://www.gov.uk/drug-safety-update/off-label-or-unlicensed-use-of-medicines-prescribers-responsibilities

  6. P Lafaille, A Benedotto, ‘Fillers: Contraindications, Side Effects and Precautions’, Journal of Cutan Aesthetic Surgery 3(1) (2010), 16-19.

  7. Necrosis, (US: National Library of Medicine, 2013) http://www.nlm.nih.gov/medlineplus/ency/article/002266.htm

  8. Inglefield C, Collins F, Duckett M, Goldie K, Huss G, Paun S, Williams S, Expert consensus of Botulinum Toxin and Dermal Filler Treatment second edition (UK: Aesthetic Medical Expert Group, 2014)

  9. Dr Lisa Danielle Grunebaum, Dr Inja Bogdan Allemann, Dr Steven Dayan, Dr Stephen Mandy and Dr Lesley Baumann, The Risk of Alar Necrosis Associated with Dermal Filler Injection, (US: Denova Research, 2009) http://www.denovaresearch.com/sites/default/files/2009-%20The%20risk%20of%20alar%20necrosis%20assocaited%20with%20dermal%20filler%20injections.pdf

  10. BertholdRzany,PetraBecker-Wegerich,FrankBachmann,RicardoErdmannandUweWollina, ‘Hyaluronidase in the correction of hyaluronic acid-based fillers: a review and a recommendation for use’, Journal of Cosmetic Dermatology, 8 (2009), 317–32

  11. David Funt and Tatjana Pavicic, ‘Dermal fillers in aesthetics: an overview of adverse events and treatment approaches’, Journal of Clinical, Cosmetic and investigational Dermatology, 6 (2013), 295-316 

    12. Jessica A. Savas ,Steven Yang ,Katlein Franca, Ivan Camacho, Keyvan Nouri, ‘Inflammatory Nodules Following Soft Tissue Filler Use: A Review of Causative Agents Pathology and Treatment Options’, American Journal of Clinical Dermatology, 14(5) (2013), 401-411.

    13. Dr Menahem Sasson and Dr Pesach Shvartzman, Hypodermoclysis: An Alternative Infusion Technique, (US: American Academy of Family Physicians, 2001) http://www.aafp.org/afp/2001/1101/p1575.html

    14. Package Leaflet: Information for the User,(UK:MHRA.gov.uk,2014) http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1452145858773.pdf

    15. Claudio De Lorenzi,‘ Complications of Injectable Fillers, PartI’, Aesthetic Surgery Journal, 33 (2013), 561. 


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