Understanding Hyaluronidase Dosage

By Mr Jordan Faulkner / 15 Nov 2022

Mr Jordan Faulkner discusses the total dose of hyaluronidase required to successfully treat dermal filler-induced vascular occlusions

Hyaluronic acid (HA) dermal fillers are the second most common form of minimally-invasive aesthetic procedure across the globe.1,2 Of all HA dermal filler-related complications, vascular occlusion (VO) is one of the least frequent, yet generally the most feared by aesthetic practitioners and patients alike. The incidence is estimated to be as low as 0.001% of procedures performed.2 

Typically, the symptoms of VO onset within minutes to hours, however there are reports of delayed onset VO up to a few days post-injection.1-4 The symptomatology can be quite variable.2,4 The most common symptoms include sudden, progressive pain (at the injection site, or elsewhere) and skin discolouration.2-5 Discolouration can also be variable, particularly depending upon time of onset to presentation. Acutely, it can present with pallor or cyanosis. Either of these, especially if combined with a reticular pattern, should prompt emergency management.4 

The Complications in Medical Aesthetics Collaborative (CMAC) advises practitioners to attempt to dissolve HA fillers, no matter the point of presentation – even in the case of delayed presentation with established necrosis in the form of an eschar.4 

Hyaluronidase treatment 

There are many proposed treatment protocols for acute HA-related VOs, and the mainstay of treatment is enzymatic breakdown of the product with subdermal hyaluronidase injection.4 Although this suggested protocol is now ten years old, there are still relevant points which can be applied to managing a vascular occlusion in current practice. Emergency management protocols for HA dermal filler-induced VO advise doses of up to 1500 units of hyaluronidase per 1ml, dissolved in bacteriostatic 0.9% saline or 1% lidocaine (without adrenaline).2-4 It is clarified that this is not a one-off dose, and treatment should be repeated multiple times with intervals of 15 minutes to one hour.3,4 

The reversal agent should be used to flood the affected area and does not need to be directed into the vessel lumen as hyaluronidase readily diffuses across the vessel wall into the intravascular space.4 The protocols clarify that these repeated doses should continue until evidence of re-established skin tissue perfusion.4 The primary indicator of this is the capillary refill time, which should be below two seconds.

One key feature that I have found to be persistently absent from treatment guidelines is the potential maximum dose of hyaluronidase required. It would be prudent to extend treatment guidelines to include a minimum amount of available hyaluronidase to safely be equipped to manage a VO, should one occur. This would improve patient safety and reduce the risk of patients being part-managed, in the event of an acute HA-induced VO. In light of this, I performed a literature review to evaluate the total hyaluronidase dose required to successfully manage acute HA-related VO, not related to vision loss or blindness. 

Methodology and results 

To review the literature, a PubMed search was performed. The search criteria were ‘hyaluronic acid AND vascular occlusion’, followed by ‘hyaluronidase AND vascular occlusion’. The search was limited to papers with free access to the full text. These searches yielded 36 and nine articles respectively. Of these articles, the inclusion criteria were any articles including: 

1) A protocol for emergency management of dermal filler induced VO 

2) A case report describing successful management with hyaluronidase 

3) A case series or cohort study describing successful management of the above with hyaluronidase 

Discussion 

In 2012, Beer et al. devised a treatment protocol for emergency management of VO in the context of particulate soft tissue augmentation.4 The author commented on the obvious: the inability to perform high level evidence such as a randomised control trial (RCT) to compare rescue treatments for VO, for simple ethical reasons.4 Therefore, we rely on past experience (case reports or case series, as well as expert opinions). Beer et al. presented two cases as such. Unfortunately, both cases describe patients treated with injectable calcium hydroxylapatite (CaHA) and are therefore not directly relevant to this discussion. 

Nevertheless, it is worth noting that the treatment for case two did include the employment of hyaluronidase – 600 units diluted in 5ml normal saline. Here, the aim was to dissolve the native HA to reduce external compression of the affected vessel, hence this treatment protocol can effectively be discounted from our discussion. However, looking at the bigger picture, this paper remains relevant, particularly given the introduction of Allergan’s HA and CA combination filler, HArmonyCa, to the market. 

Cohen et al. wrote a more relevant consensus report on the treatment of HA-induced impending necrosis with hyaluronidase in 2015.2 Their suggested treatment algorithm advises starting with 200 units of hyaluronidase, and suggests mixing with lidocaine over normal saline, in view of its vasodilatory properties.2 They suggested one injection for every 3-4cm of skin showing signs of impending necrosis. 

Their suggested interval period was 60 minutes, at which point the dose should be repeated if resolution was not achieved, repeating up to three to four cycles, thus suggesting 800 units of hyaluronidase should be adequate.2 They did include a disclaimer in their discussion, that different formulations of hyaluronidase may vary in efficacy, and therefore this consensus is only applicable to the most widely used formulation in the US at the time, Vitrase.2 The transferability of this information to use of the UK’s current most widely used formulation, Hyalase, is questionable. 

More recently, in 2018, an expert panel of aesthetic practitioners combined to develop consensus recommendations for the treatment of soft tissue filler complications.3 Again, this only provides low level (level V) evidence. Previous evidence referenced in this paper had recommended doses of 200-300 units of hyaluronidase.3 They go on to suggest repeating hourly until clinical resolution is achieved, permitting doses up to 1500 units.3 No specific brand names were given in this paper. 

The most recently published guideline available from this PubMed search was produced by Murray et al. (CMAC), in May 2021.5 This guidance is UK-based and relates to the prescription-only medicine (POM) formulation of hyaluronidase produced by Wockhardt in Wrexham. Their guideline, referenced in the introduction to this article, suggests using 1500 units of hyaluronidase in 1ml of 0.9% bacteriostatic saline or 1-2% lidocaine.5 

Murray et al. further developed their protocol in August 2021, when they updated their advice on the interval between repeated doses of hyaluronidase. Based upon the half-life of hyaluronidase when injected subcutaneously or intramuscularly (5.1 and 7.5 minutes, respectively), they suggest repeating doses every 15 minutes until clinical resolution is achieved.6 This was the first time an author had taken the half-life into consideration when suggesting the appropriate interval, across papers in this review. 

In another single case report of delayed HA-induced VO, a patient presented with pain and discoloration at the injection site and beyond, with onset more than 48 hours post-injection.1 He was treated with three doses of 500 units of hyaluronidase in 10ml of solution hourly, more than three hours. At three hours, a remarkable change in skin colour was noted and after a further hour, the patient was sent home.1 He was followed up 14 hours later and received a further single injection of 500 units in 10ml.2 The diluent was not given in the article. He was reviewed at 15 days and had no residual scarring.1 In their discussion, they commented on the lack of unanimity of the correct dose or interval between doses between suggested protocols.1 

Outcomes 

Each of these papers have their own limitations, many of them shared. All evidence discussed in this article is of low level: case reports and expert opinions only. It is unlikely that we will ever overcome the impossibility of performing a large RCT, as it would be immoral to trial variable doses or concentrations of hyaluronidase in cases of VO, given the risk of undertreating an individual leading to long term facial disfigurement. Not to mention, the logistical nightmare that would be involved in enrolling enough clinicians to gather data prospectively for such an infrequent complication. 

A key limitation of this article itself is the relatively small yield of articles that include information relevant to the question in hand. This is undoubtedly, in part, down to the inclusion of articles with free access to the full text only. However, this approach was taken with good reason. Many aesthetic practitioners in the UK work independently or in a private aesthetic clinic. Many of them no longer engage in clinical work in the NHS. Therefore, they are unlikely to remain affiliated with their university or a large NHS institution. This creates a financial barrier between those needing access to this information, and a large percentage of the information itself. 

For reference, when the search was repeated without limiting it to those with free access only, the total number of articles yielded was 183, compared to only 45 with free full access. In practice, aesthetic clinicians are more likely to rely upon dedicated resources such as the Aesthetic Complications Expert (ACE) Group World or the CMAC than a PubMed search, especially in the event of an emergency. For reference, the ACE Group World guideline for emergency management of a VO does not include a potential total dose required.

Next steps 

In summary, we require a large scale, nationwide survey of medical injectors at all levels. This should be anonymous to reduce under-reporting. This survey should evaluate the understanding of injectors on the signs and symptoms of HA-induced VO. It should evaluate their opinion on the appropriate emergency management. Finally, it should collate information on the number of experiences of VO of each clinician, what dosing regimen of hyaluronidase was used in those cases, and whether the treatment was successful or not. This would provide higher-level evidence, in the form of a retrospective cross-sectional study. 

The information produced would allow us to describe the highest total dose of hyaluronidase required to resolve a VO to date, and from that suggest a minimum storage amount of hyaluronidase for injectors to work comfortably, knowing they will be able to adequately manage a VO, should one occur, with the stock they have immediate access to. Last of all, this protocol should be free and readily available to all medical injectors using hyaluronic acid dermal fillers. 

Upgrade to become a Full Member to read all of this article.