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This month's guideline: The Use of Hyaluronidase in Aesthetic Practice (v2.4)

Authors:
  • Aesthetic Complications Expert Group
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JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY June 2018 • Volume 11 • Number 6
THE USE OF HYALURONIDASE IN AESTHETIC PRACTICE
An Aesthetic Complications Expert (ACE) Group Consensus Paper
Welcome to the JCAD Aesthetic Complications Guidelines by The Aesthetic
Complications Expert (ACE) Group. The ACE Group developed a series of evidence-
based, peer-reviewed guidelines that cover complications that can occur in
nonsurgical aesthetic practices. The objective of this series is to help dermatologists and
other physicians performing aesthetic procedures identify and manage these potential
complications. Each guideline was produced after a vast literature review by leading experts
in the United Kingdom. We hope these guidelines help raise treatment standards within
the medical community and ensure early diagnosis and appropriate management of
complications, ultimately improving outcomes for our patients.
This months guideline:
The Use of Hyaluronidase in Aesthetic
Practice (v2.4)
by Martyn King, MD; Cormac Convery, MD; and Emma Davies, RN, NIP
JCAD AESTHETIC COMPLICATIONS GUIDELINES
J Clin Aesthet Dermatol 2018;11(6):E61–E68
BACKGROUND
Hyaluronic acid (HA)-based dermal llers
are the most commonly used llers in the
aesthetics market.1 A glycosaminoglycan and a
chief component of the extracellular matrix, HA
is mainly responsible for maintaining hydration
in the dermis. HA is a linear polysaccharide
chain with the alternating monosaccharides
d-glucuronic acid and N-acetyl-d-glucosamine.2
Hyaluronidases are enzymes
(endoglycosidases) that can depolymerise HA,
leading to its degradation3 by hydrolyzing the
disaccharides at hexosaminidic b-1through b-4
linkages.4 Hyaluronidase is licensed in the
United Kingdom for enhancing permeation
of subcutaneous or intramuscular injections,
local anaesthetics, and subcutaneous infusions,
and to promote resorption of excess uids and
blood.5 There is considerable evidence for the
o-label use of hyaluronidase for managing
vascular compromise due to inadvertent
intravascular injection or external compression,6
over-correction, asymmetry, and lumps and
nodules7 caused by the injection of HA ller.
There are several sources of hyaluronidase,
and they are generally divided into three
subgroups: mammalian (obtained from the
testes); hookworm or leech; and microbes.8
Recombinant human hyaluronidase (Hylenex®,
Halozyme Therapeutics, San Diego, California)
has a purity 100 times higher than some of
the bovine preparations.9 There is no long-
term data for this product yet, but it has been
speculated to have a lower incidence of allergic
reactions.
Hyaluronidase has immediate eect and a
half-life of two minutes with duration of action
of 24 to 48 hours.10,11 Though it has a short half-
life, its eectiveness lasts longer. This might be
due to the low number units required to have
a clinically signicant eect; thus, even when
the hyaluronidase has mostly degraded, its
action continues. Additionally, the initial action
of hyaluronidase might break cross-links in the
HA dermal ller so that it behaves like native
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JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY June 2018 • Volume 11 • Number 6
THE USE OF HYALURONIDASE IN AESTHETIC PRACTICE
An Aesthetic Complications Expert (ACE) Group Consensus Paper
HA in the skin, which has a half-life of 24 to 48
hours.12
OFF-LABEL USE OF HYALURONIDASE
Although hyaluronidase is not licensed for
the use in correcting problems with dermal
ller injections and o-label promotion is not
allowed by Article 87 of Directive 2001/83/EC,
the use of hyaluronidase is allowed provided
the patient’s best interest and autonomy
are a respected part of informed consent (as
indicated by the 2009 guidelines from the
United Kingdom’s Medicines and Healthcare
Products Regulatory Agency [MHRA]).
INDICATIONS FOR THE USE OF
HYALURONIDASE IN AESTHETIC
PRACTICE
Vascular occlusion. The incidence of
impending necrosis following dermal ller
treatment has been estimated at 0.001 percent
(1 in 100,000 cases).7 Vascular compromise
due to HA ller injection should be treated
immediately (refer to the ACE Group guidance
on impending necrosis13). Normal skin
should be non-discolored and warm, with a
capillary rell time of 1 to 2 seconds, whereas
arterial compromise will have a slow capillary
rell time and dusky or blue-grey-black
appearance, and venous insuciency will have
a fast capillary time and bluish discoloration.14
Signs of impending necrosis also include
pain and coolness of the skin. Hyaluronidase
should be administered as soon as this
complication occurs (within 4 hours).4,15 There
is strong evidence that tissue necrosis can be
prevented or reduced in severity if treatment
is administered within 48 hours.6,16 However,
a small animal-based study tested this theory
and found that injecting hyaluronidase at 24
hours failed to aord any benet.17
Blindness. Blindness due to periocular
embolism of HA is instant and associated
with excruciating ocular pain. The retinal
circulation needs to be restored within 60 to
90 minutes if the retina is to survive. Blindness
is a medical emergency and the patient should
be transferred immediately to the nearest
hospital eye department (Refer to the ACE
Group guidance on blindness18). Retrobulbar
injection of hyaluronidase (150–200 units in
2–4mL of diluent) into the inferolateral orbit19
should be considered by practitioners who
have appropriate experience and competence
while waiting for an ambulance. Treatment of
blindness is rarely successful.19
Tyndall eect. The Tyndall eect refers
to the scattering of light that may be seen in
some patients after injection of HA resulting
in a bluish hue of the skin and most commonly
seen in the sub ocular region. The problem can
be resolved using hyaluronidase (Refer to ACE
Group guidance on the Tyndall eect20).
Unacceptable cosmetic outcome.
Overcorrection or misplacement of HA ller
can be successfully treated with hyaluronidase,
although this is often caused by poor injection
technique or poor choice of product for a
particular indication. If HA is present, then
hyaluronidase is eective, and HA gel has
been successfully removed 63 months post-
treatment.21
Delayed onset
nodules. Lumps or
nodules that appear
several months after
the initial treatment
might be amenable with
hyaluronidase (Refer
to ACE Group guidance on delayed onset
nodules 22). It is important to remember that
hyaluronidase is used to help diuse uids
intradermally and for hypodermoclysis. To
prevent potential dissemination of infection in
inammed nodules, it is important to prescribe
antibiotics for one week before administering
hyaluronidase.
Allergic or immunogenic reaction to
the HA dermal ller. When an allergic,
immunogenic, or sensitivity reaction occurs and
does not settle on its own within an acceptable
amount of time following a short course of
antihistamines or systemic corticosteroids,
removal of the ller with hyaluronidase is
appropriate. If the reaction is considered
moderate or severe, oral corticosteroids should
be taken before hyaluronidase use to manage
or prevent the potential initial worsening of
symptoms due to the increase in antigens as the
HA is broken down.
STORAGE AND RECONSTITUTION
It is recommended that hyaluronidase be
stored at cool temperatures (2–8˚C, 35–46˚F) to
maintain the quality of the product over a long
period of time. If stored at room temperature
(25˚C, 77˚F), the stability is only guaranteed
for 12 months. Once the ampoule is opened,
hyaluronidase should be used immediately and
any unused contents discarded (Hyalase® SPC).
Hyaluronidase may be reconstituted with
either saline or water for injection (Hyalase
SPC). Saline is less painful on injection and
is recommended for this reason. Although
unlicensed for this purpose, bacteriostatic saline
is often preferred for its additional anaesthetic
properties. Although local anaesthetics may
be used to reconstitute the product, as the
enzymatic action of hyaluronidase can be
aected by pH7, caution should be applied to
the choice of diluent. There is little evidence
to support the addition of local anaesthetic
agents to hyaluronidase,18 and when combined,
may lead to widespread, increased systemic
absorption of anaesthetic and potential
complications.
The volume of diluent used will depend on
the indication and surface area to be treated
and a range of 1 to 10mL has been evidenced
in clinical practice and published papers.
Larger volumes of dilution are recommended
when smaller amounts of Hyalase are
required to allow more precise dosing.
Smaller volumes should be used in the case
of vascular occlusion or when large volumes
of dissolution are required to allow a higher
concentration of Hyalase in a smaller area.
Once the volume of diluent has been chosen,
add 1mL of diluent to the opened ampoule
of Hyalase and ensure the powder is fully
dissolved by drawing up and expelling the
syringe a couple of times. Aspirate the 1mL
of saline with the reconstituted Hyalase,
adding this to the remaining diluent.
Volume to inject (mLs)=
Number of units required (units) x Volume of diluent (mL)
Total number of units (1500 units)
FIGURE 1. Formula
TABLE 1. Aesthetic Complications Group
Emergency Kit
REGION HYALURONIDASE
UNITS
Nasal and perioral skin 15–3026,27
Periorbital 3–4.528
Infraorbital 10–1529
Lower lid 1.530
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THE USE OF HYALURONIDASE IN AESTHETIC PRACTICE
An Aesthetic Complications Expert (ACE) Group Consensus Paper
Agitate the solution to ensure the Hyalase
is mixed throughout the whole volume. The
reconstituted solution can now be drawn
up in a syringe and injected where needed.
The formula for the number of units to be
injected can be found in Figure 1.
DOSAGES OF HYALURONIDASE
Hyaluronidase may degrade the body’s
natural HA in preference to foreign HA filler
that has been injected and specifically cross-
linked to prevent its natural breakdown.14
The dosage required is dependent on several
factors relating to the HA filler; whether it is
particulate or non-particulate, the amount
of cross-linking, and the concentration of
HA.23 Different HA fillers have differing
physical properties that influence their
degradation by hyaluronidase in a time- and
dose-dependent manner. A study by Rao
et al24 demonstrated Restylane® (Galderma
Laboratories, Lausanne, Switzerland)
dissipated most and Belotero® (Merz
Pharmaceuticals, Raleigh, North Carolina)
least.25 However, a more recent study has
shown that Belotero was the fastest to
dissolve and Juvederm Voluma® (Allergan,
Dublin, Ireland) and Restylane® Lyft were the
slowest, with the authors concluding that a
high concentration of HA, larger particle size,
and increased cross-linking increases the
durability of the filler.17
The literature offers examples of widely
divergent doses; however, it is recommended
to inject as much hyaluronidase as required
to obtain the desired effect rather than
following an absolute dosage.14
Dosages for all indications except
vascular occlusion. Although the amount
injected should be titrated to clinical effect,14
Table 1 offers a guide to actual dosages used
in published articles.
A consensus opinion in the literature states
five units of hyaluronidase is needed to break
down 0.1mL of 20mg/mL HA,10 although
there is quite a range. In one instance,
Woodward et al25 recommend 30 units to
dissolve 0.1mL. A further study showed no
statistical difference between the use of 20 or
40 units of hyaluronidase in degrading 0.2mL
(4 to 6mg of HA) of various fillers.23
Treatment results may be assessed from
48 hours4 and may be repeated at intervals
of 48 hours or longer. The degree of further
treatment will depend upon indication, risks
versus benefits, side effects from treatment,
and patient and practitioner satisfaction.
Dosages for vascular occlusion. In the
event of a suspected vascular obstruction,
a high dose pulsed protocol should be
adopted.31 Large volume of hyaluronidase
(450–1500 units) should be infiltrated over
the entire area including the course of the
vessel.4,14,32 Perivascular hyaluronidase will
permeate vascular walls.4,33 Massage the
area to promote diffusion and mechanical
breakdown. Observe and reassess capillary
refill after 60 minutes; if there is still vascular
compromise, repeat treatment at hourly
intervals for up to four cycles.34 The patient
should be kept under observation in clinic
for any adverse reactions and provided
with written aftercare and advice. When
anaphylaxis occurs, it is usually within
minutes, but there have been cases where
there has been a delayed onset. All patients
should be given appropriate aftercare advice,
warned about the symptoms of an allergic or
anaphylactic response, and instructed to seek
appropriate medical attention. Daily follow
up should occur until there is satisfactory
resolution.
Vascular occlusion is often immediate;
however, the Aesthetic Complications Expert
group have found many reported cases when
the symptoms of ischaemia start several
hours or even days later. This may be due
to the dermal filler being intravascular but
trapped at a bifurcation or branch point,
only to dislodge at a later point to cause
an occlusion.33 Alternatively, if the venous
return is compromised by secondary swelling
following injection of hydrophilic dermal
filler, this can cause increased pressure in
the arterial tree and a reduction in tissue
perfusion.
INTRADERMAL PATCH TESTING
A test patch should be performed
except when the indication is for vascular
compromise and a delay could result in
further harm to the patient.35 An intradermal
injection of 4 to 8 units of hyaluronidase in
the forearm and observing the results after
30 minutes has been advocated.36 However,
it is recommended that a higher test dose
of 20 units of hyaluronidase is used, as
a positive reaction at lower doses might
not be recognised.37 A positive reaction is
identified by a weal and itching observed at
the injection site, minor inflammation, and
erythema.
DRUG INTERACTIONS
The most common interactions occur with
furosemide, benzodiazepines, phenytoin,
dopamine, and α-adrenergic agonists, so
it is important to obtain a medical history.
Although interactions are not particularly
significant, it is best to avoid them if
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THE USE OF HYALURONIDASE IN AESTHETIC PRACTICE
An Aesthetic Complications Expert (ACE) Group Consensus Paper
possible. Several drugs act as antagonists to
hyaluronidase, including anti-inflammatory
drugs (such as ibuprofen, aspirin, diclofenac),
anti-histamines, mast cell stabilisers,
Vitamin C, flavonoids, and anti-oxidants.3
Higher doses or repeated treatments may
be required with concomitant use of these
medicines.32 Where possible, patients should
be advised to stop taking non-prescribed
medication in advance of treatment.
ADMINISTRATION
Prior to injection, the area should be
inspected, palpated, and marked out if
needed. The area should be cleansed and
disinfected using an appropriate skin solution
and the procedure should be carried out using
an aseptic technique. A 27G or 30G needle
with an appropriate length to treat the depth
of the area should be used. Administration
should be accurate and limited to the aected
area. Depth may be dicult to assess on
palpation; therefore injections should cover
the upper and lower borders of the product
that has been injected.
Nodules, and product that has been
injected into the supercial dermis should be
injected directly, injections should be placed
immediately into and below the product.38
[[Not sure what the previous sentence is
trying to convey]] For vascular compromise,
serial puncture should be used to inject
hyaluronidase along the course of the vessel
and cover the aected area.4 The needle should
be perpendicular to the skin and several
injections are often necessary.
During and after the procedure, the
treated area should be massaged vigorously
to optimise the result and aid mechanical
breakdown. Due to the spreading eect of
hyaluronidase, treatment should not be
performed in an area where botulinum toxin
treatment has been performed within the last
48 hours or on an area of infected skin, unless
there is a vascular occlusion and the risks
outweigh the benets.
FOLLOW-UP
Results are often seen almost immediately;
although for denser, more cross-linked
products, it may take 48 hours for the eects
to be seen. Consent should be obtained for the
practitioner to inform the patient’s General
Practitioner (See Appendix 1 for an example of
a patient consent form). A review appointment
should be oered at this point, along with
further treatment if needed.
Following administration of hyaluronidase,
the patient should be observed for 60 minutes
to ensure no adverse reactions occur. Aftercare
instructions should be given. In the event
of any delayed reaction to the treatment,
the patient should be seen at the earliest
opportunity.
COMPLICATIONS
Bruising and swelling post-treatment are
common.15,39 The most serious complication
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THE USE OF HYALURONIDASE IN AESTHETIC PRACTICE
An Aesthetic Complications Expert (ACE) Group Consensus Paper
following the administration of hyaluronidase
is an allergic reaction. Depending on the area
treated, dierent allergic responses have
been described. Local reactions are by far
the most common, and according to clinical
studies, occur at a rate of 0.05 to 0.69 percent.3
However, these gures are likely to be a little
lower due to under reporting. Signs include
edema, erythema, pain, and itching. Urticaria
and angioedema have been reported in less
than 0.1 percent of cases.40 Anaphylaxis has
occurred with the use of hyaluronidase when
high doses have been administered and with
intravenous administration (refer to Aesthetic
Complications Expert Group Anaphylaxis
guidance). Type I (IgE mediated) and Type IV
(mediated by T-cells) hypersensitivity reactions
have occurred after hyaluronidase treatment.
Following the use of hyaluronidase, the patient
should be observed for 60 minutes in a clinical
environment and given appropriate aftercare
information (Appendix 2).
A history of allergic reaction to wasp or bee
stings represents an increased risk of allergic
reaction to hyaluronidase and should be
considered as a relative contraindication, as
the venom of stinging insects might contain
hyaluronidase and this mechanism might
be the source of sensitization in aected
individuals.14,41,42 Unless there is a past medical
history of allergic reaction or anaphylaxis
to hyaluronidase or insect bites, previous
history of allergy seems unrelated for the
administration of hyaluronidase and it can be
safely performed.43
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hyaluronidase in plastic surgery. Plast Reconstr
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15. Cavallini M, Gazzola R, Metalla M, Vaienti L.
The role of hyaluronidase in the treatment of
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ES. Vascular complications of HA llers and the
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18. Walker L, King M. Visual loss secondary to
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Carruthers A. Blindness caused by cosmetic ller
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20. King M. Management of Tyndall eect. Aesthetic
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21. United Kingdom Medicines and Healthcare
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con1523594013492.pdf. Accessed 16 May 2018.
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correction of HA-based llers: a review and a
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23. Juhász MLW, Levin MK, Marmur ES. The kinetics
of reversible HA ller injection treated with
hyaluronidase. Dermatol Surg. 2017;43:841–847.
24. Rao V, Chi S, Woodward J. Reversing facial
llers: interactions between hyaluronidase and
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llers. J Drugs Dermatol. 2014;13(9):1053–1056.
25. Woodward J, Khan T, Martin J. Facial ller
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27. Cox SE. Clinical experience with ller
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2):1661–1666.
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30. Van Dyke S, Hays GP, Caglia AE, Caglia M. Severe
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31. DeLorenzi C. New high dose pulsed
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32. Landau M. Hyaluronidase caveats in
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THE USE OF HYALURONIDASE IN AESTHETIC PRACTICE
An Aesthetic Complications Expert (ACE) Group Consensus Paper
33. DeLorenzi C. Transarterial degradation of
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35. Andre P, Fléchet ML. Angioedema after
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36. Flynn T. Hyaluronidase. Body Language, Issue 44.
37. Vartanian JA, Frankel AS, Rubin MG. Injected
hyaluronidase reduces restylane-mediated
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2005;7:231–237.
38. Rzany B, Becker-Wegerich P, Bachmann F,
Erdmann R, Wollina U. Hyaluronidase in the
correction of HA-based llers: a review and a
recommendation for use. J Cosmet Dermatol.
2009;8(4):317–323.
39. Yocum RC, Kennard D, Heiner LS. Assessment and
implication of the allergic sensitivity to a single
dose of recombinant human hyaluronidase
injection: a double-blind, placebo-controlled
clinical trial. J Infus Nurs;2007;30(5):293–299.
40. Dunn AL, Heavner JE, Racz G, Day M.
Hyaluronidase: A review of approved
formulations, indications and o-label use in
chronic pain management. Expert Opin Biol Ther.
2010;10(1):127–131.
41. Cohen BE, Bashey S, Wysong A. The use of
hyaluronidase in cosmetic dermatology: a review
of the literature. J Clin Investigat Dermatol.
2015;3(2):7.
42. Lee A, Grummer SE, Kriegel D, Marmur E.
Hyaluronidase. Dermatol Surg. 2010;36(7):1071–
1077.
43. Szepfalusi Z, Nentwich I, Dobner M, Pillwein K,
Urbanek R. IgE-mediated allergic reaction to
hyaluronidase in paediatric oncological patients.
Eur J Pediat. 1997;156(3):199–203.
HYALURONIDASE EXPERT GROUP: Martyn King, MD; Emma Davies, RN, NIP; Sharon King, RN, NIP; Cormac Convery, MD; Lee Walker, MD.
HYALURONIDASE CONSENSUS GROUP: Helena Collier, RGN, NIP; Ben Coyle, MD; Sam Robson, MD; Tamie Shoaib, Patrick Treacey, MD.
Access the complete library of guidelines here.
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THE USE OF HYALURONIDASE IN AESTHETIC PRACTICE
An Aesthetic Complications Expert (ACE) Group Consensus Paper
©Aesthetic Complications Expert Group, The Use of Hyaluronidase in Aesthetic Practice v2.4, Page 7 of 12
Appendix 1: Consent for treatment with Hyalase® to dissolve hyaluronic acid dermal fillers
Hyaluronic acid (HA) fillers are sterile gels consisting of non-animal stabilised hyaluronic acid for injection into
the skin to correct facial lines, wrinkles and folds, for lip enhancement and for shaping facial contours.
Occasionally these fillers need to be dissolved when the aesthetic treatment has not produced the desired
outcome or there is a possibility of vascular occlusion or impending necrosis (tissue death) which could lead to
compromise of healthy tissue.
Hyalase® (hyaluronidase 1500 units) has an off-license use in aesthetic medicine and except in the case of
emergency administration requires the patient to undergo a skin patch test at least twenty minutes prior to the
procedure being undertaken. The skin patch test is carried out by injecting Hyalase® into the subcutaneous
tissue of the forearm and observed for signs of reaction (i.e. hives or wheals). If a positive patch test result is
observed, treatment with Hyalase® cannot be carried out. Erythema or redness and slight vasodilation may be
expected.
Hyalase® is an enzyme which breaks down hyaluronic acid fillers, but it can also break down naturally occurring
hyaluronic acid present in the body, the results can be unpredictable and the effect dramatic. I understand that
there will be loss of volume and there can be some skin laxity which in itself may not provide a good aesthetic
result. Although some of the effects can be immediate, I understand that it can take up to 14 days for the final
results to be seen and the treatment may need to be repeated.
Hyalase® administration can result in anaphylaxis (a severe allergic reaction which in itself is life threatening and
requires immediate medical attention) and I understand this and have been given full counselling and the
opportunity to discuss the treatment with Hyalase®, conservative treatment options or leaving the dermal filler
to break down naturally which may take several months dependent on the type of filler used and the area
treated.
The use of and the indications for the administration of Hyalase® have been explained to me by my practitioner
and I have had the opportunity to have all questions answered to my satisfaction. After the treatment some
other common injection-related reactions might occur. These reactions include redness, swelling, pain, itching,
bruising and tenderness at the injection site. They have generally been described as mild to moderate and
typically resolve spontaneously a few days after injection. Bruising may occasionally be more significant.
I acknowledge that I will have to remain at the clinic for ____ minutes after the procedure so that I can be
observed by the medical staff and that I may need to return to the clinic ____ days/weeks after treatment to
assess if further Hyalase® is to be administered.
I have answered the questions regarding my medical history to the best of my knowledge. I have also received
the aftercare information and its contents have been explained to me and I will follow the advice given.
I consent to being treated with Hyalase®
Name Date
Signature Practitioner
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JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY June 2018 • Volume 11 • Number 6
THE USE OF HYALURONIDASE IN AESTHETIC PRACTICE
An Aesthetic Complications Expert (ACE) Group Consensus Paper
©Aesthetic Complications Expert Group, The Use of Hyaluronidase in Aesthetic Practice v2.4, Page 8 of 12
Appendix 2: Hyalase® (Hyaluronidase) Injection Aftercare
Keep this aftercare leaflet safe and present it to the treating physician in the
event of an adverse reaction
Hyalase® is an enzyme which breaks down hyaluronic acid fillers, but it can also break down
naturally occurring hyaluronic acid present in the body. The results can be unpredictable and
the effect dramatic with possible loss of volume and some skin laxity. Although some of the
effects can be immediate, it can take up to 2 weeks for the final results to be seen and the
procedure may need to be repeated.
Hyalase® administration can result in anaphylaxis (a severe allergic reaction) which in itself is
life threatening and requires immediate medical attention. Symptoms of a severe allergic
reaction can include shortness of breath, wheezing, coughing, difficulty swallowing, swelling
of the tongue, eyelids, lips, hoarseness of the voice, stomach pain, nausea or diarrhoea.
If you have any of the above symptoms please report to your nearest Accident
and Emergency Department or call 999 for an ambulance.
After the procedure some other common injection-related reactions might occur. These
reactions include redness, swelling, pain, itching, bruising and tenderness at the injection site.
They have generally been described as mild to moderate and typically resolve spontaneously
after a few days after injection. Bruising may occasionally be more significant.
If you have any concerns following treatment, do not hesitate to contact us on <telephone
number>. If this is outside of normal hours, please leave an answerphone message and we
will normally get straight back to you.
I have been treated with _____ Units of Hyaluronidase (Hyalase®) reconstituted in ____ mls
of Saline / Water (delete as applicable) to dissolve a hyaluronic acid dermal filler. A skin patch
test was administered to the left/right (delete as applicable) forearm. No sign of an allergic
reaction was noted and the procedure undertaken. Following injection, I was monitored for
60 minutes within the clinic.
Date of procedure: Amount administered:
Area treated:
... 12,14,25 HA fillers were approved by the FDA for the first time only in 2003. 26 HA fillers are used on the face for several purposes; based on their rheology, they can be used to improve fine lines, get volume enhancement, bony projections, etc.; moreover, HA fillers developed for body contouring also exist. 27 At the moment, there is no commercially available filler specifically formulated for nasal filling. ...
... Even if medical literature clearly shows that, once injected, HYAL activity lasts about 24 to 48 hours, an immediate surgical approach is not advisable due to the potentially associated intraoperative and/or postoperative problems related to tissue inflammation. 26,42 By evaluating HYAL range of action and endogenous HA turnover at the level of fibroblasts (5 g/ day), Bektas et al empirically suggested to perform the intervention in a time lapse ranging from 1 week to 6 months following HYAL injection. 10,43 As stated by the ASAPS in 2020, 55,436 rhinoplasty procedures were performed in the United States. ...
Article
Background Nonsurgical nasal reshaping (nSNR) with hyaluronic acid (HA) filler is a well-established procedure performed to ameliorate nasal appearance and considered a valid alternative to surgical rhinoplasty in selected patients. Objective The aim of our study is to evaluate the decision-making process and management of patients undergoing rhinoplasty, with previous HA filler injection, and evaluate if consensus could be achieved to recommend guidelines. Methods Between April and May 2021 an on-line survey was sent to 402 Italian surgeons of different specialties. The survey collected information regarding types of treatment of patients who have previously undergone nSNR, who should undergo surgical rhinoplasty. For those surgeons using hyaluronidase an additional information was collected. Results In a range of time of two months (April-May 2021) a total of 72 surgeons replied and completed the survey: out of the 402 questionnaires sent, the response rate was of approximately 18%. The majority of respondent (61,5%) replied to inject hyaluronidase (HYAL) in patients who had to undergo a rhinoplasty but reported previous nSNR. Of the surgeons who use HYAL, 70% performed rhinophasty after a waiting time of 3 to 4 weeks. Conclusions Either direct surgical approach or hyaluronidase injection first seems to be a viable options. The use of HYAL before surgery is the choice with the broadest consensus in our survey. However a larger case-control study with long follow-ups is necessary to understand if in patient seeking surgical rhinoplasty who already received nSNR, the injection of hyaluronidase prior to surgery is mandatory, recommended or not.
... Hyaluronic acid-based (HA) filler has become the most popular injectable augmentation preparation 1 due to its biocompatibility, moderate length of efficacy (3-12 months), and reversibility of many complications using hyaluronidase. 2 However, its use is not without complications. Complica- Table 1 The patient's LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score at the time of presentation. ...
... The dose of hyaluronidase was calculated using the aesthetic complication guidelines from the Journal of Clinical and Aesthetic Dermatology. 2 After a patch test of 20 units was nonreactive, a total of 130 units of hyaluronidase were administered to the left midface over the zygoma, where the patient reported the initial filler injection was placed. He was readmitted to the hospital service to restart intravenous ceftriaxone and metronidazole. ...
Article
Full-text available
Hyaluronic acid-based filler is the most popular injectable augmentation preparation due to its efficacy and safety compared to other injection fillers. The complication of infected filler is known, but it is unknown exactly how long filler persists prior to reabsorption. A case was presented of filler-exacerbated facial cellulitis that occurred 2.5 years after hyaluronic acid-based filler administration. The presence of residual filler was confirmed with magnetic resonance imaging, suggesting that hyaluronic acid-based fillers may persist longer than previously thought and act as a reservoir for regional bacterial infections refractory to antibiotics.
... Hyaluronidase hydrolyzes hyaluronic acid (HA) and has been utilized to remove HA filler nodules. 1 Local injection of hyaluronidase can cause adverse effects such as local pruritus, burning sensation, swelling, erythema, and ecchymosis that are limited to the injection site, the spread of infection, and allergic reactions. [2][3][4][5] Here, I report three cases of severe hyaluronidase-associated ecchymosis and edema that affected tissues far away from the site of hyaluronidase injection. This adverse effect was observed with the use of human recombinant hyaluronidase (Hylenex™; Halozyme Therapeutics, Inc.; stock solution of 150 USP units/ml). ...
... Hyaluronidase hydrolyzes hyaluronic acid (HA) and has been utilized to remove HA filler nodules. 1 Local injection of hyaluronidase can cause adverse effects such as local pruritus, burning sensation, swelling, erythema, and ecchymosis that are limited to the injection site, the spread of infection, and allergic reactions. [2][3][4][5] Here, I report three cases of severe hyaluronidase-associated ecchymosis and edema that affected tissues far away from the site of hyaluronidase injection. This A 60-year-old male had tear trough correction with a crosslinked HA filler (Juvéderm ® Ultra XC; Allergan Inc.) delivered with a 25G cannula. ...
... This would be difficult to identify on a CT scan. Furthermore, onset of action of HAS is within minutes and effects last up to 48 h (4,11). Therefore, it is expected that patients with painful symptoms due to rectal wall infiltration could experience rapid relief after HAS injection. ...
Article
Full-text available
Peri-rectal spacers provide protection to the rectum for patients receiving radiation therapy treating prostate cancers. Commonly used hydrogel spacers hold the disadvantage that they cannot be readily reversed should inadvertent injection outside of the target area occurs, potentially leading to ischemia of the rectal mucosa leading to severe pain and ulceration, which can then lead to superinfection and pelvic abscess formation, and subsequently recto-prostatic fistulas. This could require major surgical intervention. New hyaluronic acid spacers are readily reversible with hyaluronidase and provide a valuable means to correct any misinjected spacer. We present a patient with prostate cancer who was planned for radiation therapy and required a rectal spacer. The hyaluronic acid rectal spacer was injected in part into the rectal wall. The patient was asymptomatic, and a sigmoidoscopy confirms healthy bowel mucosa only. The misinjected hyaluronic acid was successfully treated with targeted injection of hyaluronidase into only the rectal wall portion. Serial follow-up imaging demonstrated rapid dissolution of the misinjected hyaluronic acid with the well-positioned hyaluronic acid remaining. The patient did not experience any side effects of the hyaluronidase.
Article
Hyaluronic acid (HA) is the most common dermal filler in use. It improves wrinkles and volume loss not only by filling and volumizing but also by hydrating the injected area with its water affinity. It is a naturally occurring component of skin, and there is a negligible risk of immunologic or allergic reaction with injection. It is rapidly degraded by the injection of hyaluronidase, thus creating an ideal injectable material that is low risk and reversible. Its duration of effect may be longer than expected based on bioavailability of the HA product due to collagen synthesis or fibroblast stimulation.
Article
Introduction: Blindness after periocular cosmetic filler injection is a rare but devastating complication. Complication management protocols recommend injecting retrobulbar hyaluronidase if visual loss related to accidental intravascular injection of hyaluronic acid occurs. Given the dramatic increase in cosmetic filler injections and the variety of professionals that can deliver them, it is reasonable to assume that the incidence of complications will rise significantly. Objective: To evaluate if there is evidence-based efficacy of retrobulbar hyaluronidase injection in visual loss secondary to periocular cosmetic filler injection. Material and methods: The authors performed a search of English and Spanish language articles following the PRISMA statement published on the use of retrobulbar hyaluronidase to reverse vision loss precipitated by hyaluronic acid gel fillers. Articles reviewed included case reports/series and experimental investigations. We identified a total of 13 patients in this review following defined inclusion and exclusion criteria. Finally, we included 15 articles in the study, 12 of them were cases / case series. The 2 remaining articles are experimental studies in animals with a control group, in which after causing selective occlusion of the ophthalmic artery, serial injections of retroocular hyaluronidase are administered with control of visual function. Results: Of the 15 articles included in the study, we studied 17 patients treated with retrobulbar hyaluronidase for hyaluronic acid-induced blindness. Improvement was demonstrated in 3 cases. Animal studies demonstrate variable data are provided regarding the recovery of visual acuity. Conclusions: There is no confirmed evidence of retrobulbar hyaluronidase injection effectiveness in treating visual loss due to accidental intravascular injection of hyaluronic acid. More studies are needed to show the efficacy of hyaluronidase as a treatment for blindness caused by hyaluronic acid.
Article
Background: The use of hyaluronic acid (HA) fillers for medical aesthetic purposes is increasing worldwide. Nonetheless, adverse events do occur because of patient-specific issues, injection technique, or product factors. It would be mandatory to consider cultural and anatomical features of Asians in preventing and managing the complications of HA injections. Methods: Literature search of studies looking at current evidence and guidelines on the management of complications following HA filler injections in Asian patients was conducted. This was followed by an expert group discussion that was convened to reach consensus recommendations on the best clinical practices. Results: The expert panel provided specific recommendations focusing on the safe use of soft tissue fillers in Asian patients, including early identification of adverse events and how to prevent and comprehensively manage these outcomes. Conclusions: Here we provide consensus statements of Asian experts in dermatology, plastic surgery, ophthalmology and aesthetic medicine mainly focusing on AEs with higher risk for Asians, and can be used to guide physicians in treating Asian population.
Resumen Introducción La pérdida visual relacionada con la inyección periocular de rellenos con fines cosméticos es infrecuente pero muy grave. Como recomendaciones protocolizadas ante la pérdida visual por inyección intravascular inadvertida de ácido hialurónico se encuentran, entre otras, la inyección de hialorunidasa en el espacio retroocular. Es de esperar que, dada la creciente demanda de tratamientos de rellenos estéticos y la gran heterogeneidad de profesionales que pueden administrarlos, el número de casos y complicaciones relacionadas con estos procedimientos se incremente de manera sustancial. Objetivo Evaluar si existe evidencia científica para recomendar la inyección retroocular de hialuronidasa en el tratamiento de pérdidas visuales relacionadas con la inyección periocular de ácido hialurónico cosmético. Material y métodos Hemos realizado una búsqueda de artículos publicados en inglés y español siguiendo la declaración PRISMA sobre el uso de hialuronidasa retrobulbar para revertir la pérdida de visión producida por los rellenos de ácido hialurónico. Los artículos revisados incluyeron los casos clínicos y las investigaciones experimentales. Identificamos a un total de 13 pacientes en esta revisión siguiendo unos criterios de inclusión y exclusión definidos. Finalmente, incluimos 15 artículos en el estudio, 13 de ellos fueron casos/series de casos. Los 2 artículos restantes son estudios experimentales en animales con grupo control, en los que, tras provocar una oclusión selectiva de la arteria oftálmica, se administran inyecciones seriadas de hialuronidasa retroocular con control de la función visual. Resultados De los 15 artículos incluidos en el estudio, recogimos los datos de un total de 17 pacientes que, tras inyección de ácido hialurónico facial por motivos estéticos, presentaron una disminución brusca de la visión y en los que se inyectaron dosis variables de hialuronidasa retroocular. De ellos, únicamente en 3 pacientes se ha reportado una mejoría de la visión. En los 2 estudios experimentales se aportan datos variables respecto a la recuperación de la agudeza visual. Conclusiones La evidencia científica disponible hasta la fecha no permite afirmar que el uso de la hialuronidasa retroocular es útil en el tratamiento de la pérdida visual relacionada con la inyección intravascular inadvertida de ácido hialurónico. Son necesarios más estudios que evidencien la eficacia de la hialuronidasa como tratamiento en la ceguera provocada por ácido hialurónico.
Article
Background: Treatment with hyaluronic acid (HA) fillers as a strategy for rejuvenation has experienced a significant growth in recent years, accompanied by a parallel increase in its complications, the treatment of which, such as hyaluronidase, we must be aware of. Patients/methods: 14 patients (28 eyes) had indication for upper blepharoplasty surgery in the Hospital Universitario y Politécnico La Fe. After surgery, periocular skin of one eye of each patient was infiltrated with 300 U of hyaluronidase (14 cases) while the skin of the fellow eye was preserved untreated (14 controls). All samples were studied by the Pathology department and finally 6 variables (skin structure alteration, degeneration of elastic fibers, deposits, collagen fibers destructuring, inflammation, other findings) were analyzed. Results: No differences in skin structure, elastic fibers and collagen dermal fibers were found between hyaluronidase treated skin and controls. A significant association between ex vivo application of hyaluronidase in periocular skin and the presence of amorphous extracellular deposits within the dermis was found. Conclusions: Hyaluronidase applied ex vivo to periocular skin led to presence of deposits within the extracellular matrix compared to control eyelid skin but elastin and collagen dermis structure remained unaltered.
Article
AimDermal fillers have been progressively used for cosmetic procedures. Concurrently, the rates of filler complications have also increased. The aim of this study is to describe the clinical management and treatment we performed in patients with complications occurred after filler injection.Methods From March 2000 to February 2020, 197 patients have been evaluated for complications due to filler injection. For each patient type of material, symptoms and signs were recorded. Ultrasound evaluation was used to obtain information about the type, amount and location of the injected material. Magnetic Resonance Imaging was performed in those patients who were candidate for surgery. Based on the clinical manifestations, we performed a targeted therapy.ResultsThe local and systemic medical therapy allowed us a complete remission of the clinical signs and symptoms in all patients presented with edema and erythema. We obtained optimal results with surgery, where a complete removal of the injected material was possible. In all the cases in which the complete removal of the infiltrated area could have led to functional impairments, we performed partial removal with poor outcomes.Conclusion We observed complex clinical manifestations in the patients subjected to permanent fillers. An accurate knowledge upon the effects of the materials on tissues, a specific instrumental evaluation and a targeted therapy are crucial. We suggest the use of absorbable fillers. Patient should be subjected to filler implant in authorized structures by an expert specialist with experience in filler injection and with a thorough knowledge of the anatomical structures.Level of Evidence IVThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.
Article
Full-text available
Over the past 60 years, hyaluronidase has been successfully utilized in ophthalmic surgery and is now being implemented in dermatosurgery as well as in other surgical disciplines. The enzyme is considered a “spreading factor” as it decomplexes hyaluronic acid (also called hyaluronan, HA), an essential component of the extracellular matrix (ECM). When applied as an adjuvant, hyaluronidase enhances the diffusion capacity and bioavailability of injected drugs. Therefore, the enzyme has been used as a local adjuvant to increase the diffusion capacity of local anesthetics, increasing the analgesic efficacy, and the anesthetized area particularly in the first minutes following injection, resulting in diminished intra- and postoperative pain. In aesthetic medicine, the off-label use of hyaluronidase is considered the gold standard for the management of HA-filler-associated complications. Here, we review the clinical use, underlying biological mechanisms, and future directions for the application of hyaluronidase in surgical and aesthetic medicine.
Article
Full-text available
Injection-induced necrosis is a rare but dreaded consequence of soft tissue augmentation with filler agents. It usually occurs as a result of injection of filler directly into an artery, but can also result from compression or injury. We provide recommendations on the use of hyaluronidase when vascular compromise is suspected. Consensus recommendations were developed by thorough discussion and debate amongst the authors at a roundtable meeting on Wednesday June 18, 2014 in Las Vegas, NV as well as significant ongoing written and verbal communications amongst the authors in the months prior to journal submission. All authors are experienced tertiary care providers. A prompt diagnosis and immediate treatment with high doses of hyaluronidase (at least 200 U) are critically important. It is not felt necessary to do a skin test in cases of impending necrosis. Some experts recommend dilution with saline to increase dispersion or lidocaine to aid vasodilation. Additional hyaluronidase should be injected if improvement is not seen within 60 minutes. A warm compress also aids vasodilation, and massage has been shown to help. Some experts advocate the use of nitroglycerin paste, although this area is controversial. Introducing an oral aspirin regimen should help prevent further clot formation due to vascular compromise. In our experience, patients who are diagnosed promptly and treated within 24 hours will usually have the best outcomes. © 2015 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.
Article
Background: Hyaluronidase is an enzyme capable of dissolution of hyaluronic acid (HA). There is a lack of evidence-based research defining time- and concentration-dependent reversal of HA filler using hyaluronidase. Objective: To explore the efficacy of different concentrations of hyaluronidase in digesting commercially available HA-based reversible fillers-Belotero Balance (BEL), Juvederm Ultra XC (JUVXC), Juvederm Ultra Plus (JUVX+), Juvederm Voluma XC (JUVV), Restylane-L (RESL), Restylane Silk (RESS), and Perlane/Restylane Lyft (RESLYFT). Materials and methods: This was a blinded randomized study involving 15 participants. Participants received HA filler injection into their back, followed by no secondary injection, or injection with normal saline, 20 or 40 units of hyaluronidase. Using a 5-point palpation scale, the degradation of HA filler was monitored over 14 days. Results: In the authors' study, there is a significant decrease in HA filler degradation using 20 and 40 units of hyaluronidase compared with no secondary injection or normal saline. There is no significant difference in HA filler dissolution when comparing 20 to 40 units of hyaluronidase. Conclusion: Lower concentrations of hyaluronidase may be just as effective as higher concentrations to degrade HA filler in situations where the reversal of cutaneous augmentation with HA filler arises.
Article
The purpose of this article is to update the changes to the author’s protocols used to manage acute filler related vascular events from those previously published in this journal. For lack of a better term, this new protocol has been called the High Dose Pulsed Hyaluronidase (HDPH) protocol for vascular embolic events with hyaluronic acid (HA) fillers. The initial protocol used involved many different modalities of treatment. The current protocol is exceedingly simple and involves solely the use of hyaluronidase in repeated high doses. Despite the simplicity of the treatment, it has proven itself to be very successful over the past two years of clinical use. There has been no partial or complete skin loss associated with this protocol since its implementation if the protocol was implemented within 2 days of the ischemic event onset. The protocol involves diagnosis and repeated administration of relatively high doses hyaluronidase (HYAL) into the ischemic tissue repeated hourly until resolution (as detected clinically through capillary refill, skin color, and absence of pain). The dosage of HYAL varies as the amount of ischemic tissue, consistent with the new underlying hypothesis that we must flood the occluded vessels with a sufficient concentration of HYAL for a sufficient period of time in order to dissolve the HA obstruction to the point where the products of hydrolysis can pass through the capillary beds. Although vascular embolic events are rare, it is important to note that the face has higher risk and lower risk areas for filler treatment, but there are no “zero risk” areas with respect to filler treatments. Even with good anatomic knowledge and correct technique, there is still some nonzero risk of vascular embolic events (including highly skilled, experienced injectors). However, with careful low pressure, low volume injection technique, and adequate preparation for treatment of acute vascular events, the risk is quite manageable and the vast majority of adverse events are very treatable with an excellent prognosis, with a few exceptions. This new protocol offers excellent results, but requires further research to determine optimal parameters for various HA fillers.
Book
This book offers an excellent and comprehensive overview on the clinical use of fillers in aesthetic medicine that will assist both novice and advanced practitioners. Based on an evidence-based perspective, the book opens by describing the most common fillers, with information on their characteristics, efficacy and safety. The main part of the book then explains how to use fillers for the most frequent facial indications, such as the glabella, nasolabial folds, infraorbital hollow, nose, cheeks, lips and marionette lines. This new edition also includes chapters on extrafacial indications and treatment planning. All specific aesthetic procedures for the facial and extrafacial areas are described step by step, with the emphasis on a hands-on approach that highlights important do's and don'ts. The book concludes with chapters on how to deal with adverse reactions and how to combine fillers with other aesthetic procedures, ranging from botulinum toxin A to plastic surgery. © 2014 Springer-Verlag Berlin Heidelberg. All rights are reserved.
Article
Background: Most of the complications associated with hyaluronic acid (HA) fillers can be addressed by hyaluronidase. Extensive experience with this enzyme was accumulated in ophthalmology and anesthesia. In dermatologic use multiple aspects still remain controversial. Objective: To elucidate questions with regard to hyaluronidase use in HA-induced complications, including appropriate dosage, timing, and technique of delivery, differences in the activity of hyaluronidases of different origins, interaction between the enzymes and different HA gels, and safety issues. Materials and methods: Extensive review of the relevant literature was conducted. The conclusions are based on this review and personal author's experience. Results: FDA-approved hyaluronidases provide predictable results and can be used interchangeably. A physician has to be closely familiar with specific characteristics of other hyaluronidases. Different brands of HA fillers have different sensitivity to degradation by hyaluronidase. For filler overcorrection or misplacement, low dose of the enzyme has to be injected directly into the palpable HA mass. In case of vascular accident, flushing of the ischemic area with high doses of hyaluronidase is required. Hypersensitivity reactions to hyaluronidase are so far not reported in dermatologic literature. Conclusion: With increased popularity of HA fillers, hyaluronidase had become an indispensable tool in dermatology office. It is safe and reliable for treatment of HA-induced complications.
Article
The use of facial fillers has greatly expanded over the past several years. Along with increased use comes a rise in documented complications, ranging from poor cosmetic result to nodules, granulomas, necrosis, and blindness. Awareness of the potential types of complications and options for management, in addition to the underlying facial anatomy, are imperative to delivering the best patient care. This article defines the complications and how to treat them and provides suggestions to avoid serious adverse outcomes.
Article
Background: Although there are several case reports of facial skin ischemia/necrosis caused by hyaluronic acid filler injections, no systematic study of the clinical outcomes of a series of cases with this complication has been reported. Methods: The authors report a study of 20 consecutive patients who developed impending nasal skin necrosis as a primary concern, after nose and/or nasolabial fold augmentation with hyaluronic acid fillers. The authors retrospectively reviewed the clinical outcomes and the risk factors for this complication using case-control analysis. Results: Seven patients (35 percent) developed full skin necrosis, and 13 patients (65 percent) recovered fully after combination treatment with hyaluronidase. Although the two groups had similar age, sex, filler injection sites, and treatment for the complication, 85 percent of the patients in the full skin necrosis group were late presenters who did not receive the combination treatment with hyaluronidase within 2 days after the vascular complication first appeared. In contrast, just 15 percent of the patients in the full recovery group were late presenters (p = 0.004). Conclusions: Nose and nasolabial fold augmentations with hyaluronic acid fillers can lead to impending nasal skin necrosis, possibly caused by intravascular embolism and/or extravascular compression. The key for preventing the skin ischemia from progressing to necrosis is to identify and treat the ischemia as early as possible. Early (<2 days) combination treatment with hyaluronidase is associated with the full resolution of the complication. Clinical question/level of evidence: Therapeutic, IV.
Article
Vascular occlusion causing blindness is a rare yet greatly feared complication of the use of facial aesthetic fillers. The authors performed a review of the aesthetic literature to ascertain the reported cases of blindness and the literature reporting variations in the vascular anatomy of the human face. The authors suggest a small but potentially helpful addition to the accepted management of the acute case. Cases of blindness, mostly irreversible, from aesthetic filler injections have been reported from Asia, Europe, and North America. Autologous fat appears to be the most frequent filler causing blindness. Some cases of partial visual recovery have been reported with hyaluronic acid and calcium hydroxylapatite fillers. The sudden profusion of new medical and nonmedical aesthetic filler injectors raises a new cause for alarm about patient safety. The published reports in the medical literature are made by experienced aesthetic surgeons and thus the actual incidence may be even higher. Also, newer injectors may not be aware of the variations in the pattern of facial vascular arborization. The authors present a summary of the relevant literature to date and a suggested helpful addition to the protocols for urgent management.