J Clin Investigat Dermatol

Open Access Review Article

December 2015 Volume 3, Issue 2
© All rights are reserved by Wysong et al. Journal of

The Use of Hyaluronidase Clinical & Investigative

Dermatology
in Cosmetic Dermatology: A
Review of the Literature
Brandon E. Cohen1, Sameer Bashey2 and Ashley
Wysong2*
1
New York University School of Medicine, 550 First Avenue, New York,
NY 10001, USA
Abstract 2
Department of Dermatology, Keck School of Medicine, University of
Southern California, 1441 Eastlake Avenue, Los Angeles, California,
Background: Hyaluronidase can be employed to manage a variety 90033, USA
of complications associated with cosmetic hyaluronic acid (HA)
filler injection. However, the indications and treatment protocol for *Address for Correspondence
hyaluronidase use have not been well established. Ashley Wysong, Department of Dermatology, Keck School of Medicine, University
of Southern California, 1441 Eastlake Avenue, Los Angeles, California, 90033,
Objective: Review of the available literature to describe the use of USA, Tel: (323)-442-0084; E-mail: [email protected]
hyaluronidase in the reversal of HA filler injection.
Submission: 21 November 2015
Methods: PubMed/MEDLINE databases were utilized to identify case Accepted: 08 December 2015
reports and studies pertaining to the use of hyaluronidase after HA Published: 12 December 2015
filler injection.
Copyright: © 2015 Cohen BE, et al. This is an open access article
Results: Hyaluronidase can be successfully employed in the distributed under the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
management of uncomplicated nodules and overcorrection,
original work is properly cited.
inflamed nodules, or tissue ischemia associated with HA filler injection.
Hyaluronidase use is dependent on the clinical indication, anatomical Reviewed & Approved by: Dr. Kyoung-Chan Park, Professor,
location, and original injected HA quantity. Department of Dermatology, Seoul National University, Korea.

Conclusion: Hyaluronidase is an important tool for clinicians utilizing

cosmetic HA filler injection. Further reports and studies are warranted
to firmly establish the ideal treatment protocol. For example, the doses of hyaluronidase reported in the literature to
reverse HA filler injection vary greatly from 5 to 300 units [5,7,11].

Introduction Therefore we sought to review the available literature in order to

better elucidate a standardized approach to the use of hyaluronidase
Hyaluronic acid (HA) filler injection is an increasingly popular after HA filler injection. PubMed/MEDLINE databases were utilized
technique utilized for volume replacement, noninvasive skin to identify studies pertaining to the use of hyaluronidase in the
rejuvenation, and soft tissue augmentation. Endogenous HA is a management of complications associated with HA filler injection. All
major structural component of the extracellular matrix of the skin available reports and studies from 1966 to present were considered in
and acts to maintain hydration in the dermis [1]. HA has an absorbent order to provide a comprehensive overview of the literature regarding
capacity one thousand times its volume. Filler injection with the efficacy, safety, recommended use of hyaluronidase.
exogenous HA gel offers a number of advantages that contributes to
its widespread use. HA is resorbable or biodegradable, typically over Hyaluronidase Indications and Approach to Use
6 to18 months duration, and is associated with a less than one percent The efficacy of hyaluronidase for the reversal of HA injections was
risk of hypersensitivity [1-4]. While HA injection is considered formally demonstrated by a randomized, controlled trial conducted by
safe, several types of adverse events are recognized. If injections are Vartanian et al. [12]. In the study, twelve participants received two 0.2
placed too superficially or if excessive quantities are injected, there mL injections of non-animal stabilized HA in the proximal forearm.
is a potential to develop the Tyndall effect, subcutaneous nodules, or One to three days after injection, skin scores were determined on a 0-5
asymmetrical outcomes. Other less common complications include: scale based on the size of augmentation. Participants then randomly
persistent edema, foreign body reactions, bacterial infection, tissue received 0.5 mL of 75 units of hyaluronidase or normal saline
necrosis secondary to vascular occlusion or compression, and visual vehicle. After one week, participants who received hyaluronidase
impairment from embolized filler material [1,4-6]. demonstrated an 80% decline in skin scores, compared to a 10%
decline among saline controls (p<0.001). Ninety days after treatment,
An additional benefit of HA is that it can be degraded through the
there was no palpable remnant of the HA injection in 92% of subjects
use of hyaluronidase [3,7-9]. This is especially important in preventing
in the treatment group, while all control patients injected with saline
some of the adverse outcomes aforementioned. Hyaluronidase is a
continued to have detectable HA [12].
naturally occurring enzyme and has been long used in medicine to
facilitate the diffusion of anesthesia prior to ophthalmic procedures In practice, one primary consideration in the use of hyaluronidase
[7,10]. While the successful use of hyaluronidase to reverse the is in the clinical context in which the removal of HA is desired. In
effects of exogenously injected HA has been described in a number general, complications of HA fillers can be categorized as emergent
of reports, there are currently no accepted standardized guidelines complications, notably vascular obstruction and skin necrosis, and
for its use. The dose, timing, injection technique, and reconstitution non-emergent complications, such as over-correction, non-inflamed
procedure are not currently well established or widely accepted [4]. nodules, edema, and inflammatory nodules [4]. Accordingly the

Citation: 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.
Citation: 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.

ISSN: 2373-1044

approach to using hyaluronidase should be adjusted according to the luminal HA within four hours [22]. Therefore hyaluronidase may be
indication, anatomical location, and desired clinical effect [7,13]. injected into the region of a suspected obstruction rather than directly
into the vasculature. Of note, DeLorenzi reports that through personal
Vascular obstruction and skin necrosis
correspondence the author is aware of one unpublished case where
One uncommon but potentially serious complication of HA filler ischemia resolved only after intra-arterial hyaluronidase injection
injection is skin necrosis [13]. It has been proposed that ischemia may [13]. While reports of intravascular hyaluronidase after filler injection
occur secondary to compression of vasculature by extra-vascular filler were not identified, this technique has been historically described in
material after the HA hydrates and expands, or through inadvertent the literature for other indications, such as for the treatment ulcers in
intra-arterial HA injection [3,6,8,14,15]. There are also reports the context of arterial disease [23].
of skin necrosis in areas distant from the injection site, suggesting
Non-inflamed lesions
embolization after introduction of intra-arterial filler material [3,16].
One particularly ominous complication is the potential for visual Excessive quantities or misplacement of HA may result in the
impairment secondary to intra-arterial injection and obstruction of development of subcutaneous nodules [1,2,7,24]. Given that HA is
branches of the retinal or ophthalmic arteries [4,17,18], which has resorbable, uncomplicated nodules will eventually self-resolve over
most commonly been reported after filler injection into the glabella time [24]. However, if a nodule is painful or if the patient is bothered
or nasolabial folds [17,18]. by its appearance, hyaluronidase can be employed to resolve the
nodule. Several cases have been reported in the literature that describe
Similarly, the most commonly reported injected areas associated
successful resolution of nasojugal and cheek nodules associated with
with skin necrosis include the glabella and nasal ala [3,4,19], as these
HA injection after injection of 75 units of hyaluronidase, reconstituted
regions have limited collateral blood supply [6,8]. Skin necrosis
in 0.5% lidocaine with epinephrine [25,26]. However, several authors
generally presents with blanching and dusky discoloration, along
have advocated the use of lower initial doses. In one report, Hirsh
with pain in the affected area [3,13]. Venous occlusion has also been
and colleagues suggest that an initial injection of 30 units diluted in
described, presenting with the delayed onset of vague discomfort
normal saline, along with follow up 3-4 days later is preferable [27].
and ecchymotic appearing lesions [4,20]. Management of ischemic
complications may include the promotion of vasodilation through In instances of overly superficial injection, nodules may form
warm compress, 2% nitroglycerine paste, or sildenafil, as well with a blue discoloration due to the “Tyndall effect”, in which light
as systemic corticosteroids, anticoagulation with aspirin or low scatters through the HA gel producing wavelengths that are perceived
molecular weight heparin, and intralesional hyaluronidase injection as blue [8,17]. Another potential adverse effect is the development of
[3,8,19-21]. prolonged edema, especially in the malar region [21]. Management
In this context, hyaluronidase, given in doses ranging from 30- of persistent, defined as greater than one-month duration, malar
75 units in normal saline or lidocaine, have been described [8,14]. edema consists of massage of the region, cold compress, systemic
While the exact timeframe for hyaluronidase injection has not been corticosteroid taper, as well as hyaluronidase injection [21]. Richards
well established, hyaluronidase should be injected as early as possible. and colleagues reported a case describing the use of hyaluronidase for
Hirsh and colleagues reported a case in which a patient developed persistent, recurrent swelling two months after HA filler injection [9].
signs of ischemia and impending tissue necrosis after injections The patient was treated with 25 units of hyaluronidase prepared by
into the nasolabial folds. The patient was successfully managed dilution of 50 units/mL hyaluronidase in bacteriostatic 0.9% saline.
by the administration of 30 units of hyaluronidase in the region of The patient presented two more times with the same complaint, at
suspected blockage six hours after the initial injection, along with 4 and 18 months after initial injection, and was successfully treated
two 325 mg aspirin tablets, nitroglycerine paste, and warm compress with 25 units of hyaluronidase at each visit [9]. However, over that
[8]. In contrast, Kim et al. reported a case series of four patients who time period, one could conclude that the edema resolved as the
developed skin necrosis after HA filler injection in the nasal area. Two HA product naturally resorbed. Hyaluronidase may also be used to
patients received hyaluronidase injection (dose undocumented) one manage complications associated with migration of filler material. In
day after the procedure, which failed in salvaging the affected skin one case, a patient received 0.8 mL of HA in the cheeks bilaterally
[3]. In order to further elucidate the timing, Kim et al. conducted and developed intraorbital edema after three months. The authors
an experiment using rabbit ears in which HA filler was injected in hypothesized that the filler material may have migrated from the
the auricular arteries of five rabbits. Hyaluronidase was then injected original injection location. Complete resolution was achieved after a
at 4-hour or 24-hour time points. The authors report that there was single injection of 30 units of hyaluronidase into the lesion [9].
significant reduction in the area of necrosis when hyaluronidase was Given the inconsistency of doses in reported cases, Vartanian and
administered at the 4-hour time point, while no benefit was observed colleagues sought to determine the necessary hyaluronidase dose in
when injected at 24 hours [3]. a prospective trial [12]. Eight participants received three injections
When managing a case of intra-arterial HA injection studies with 0.2 mL of HA and after 3-5 days, each site was randomly injected
suggest that direct intravascular administration of hyaluronidase with 10, 20 or 30 units of hyaluronidase. A total volume of 0.4 mL
is not typically required, as hyaluronidase readily diffuses into the was injected in all cases and hyaluronidase was reconstituted in
vascular lumen [3,13,22]. DeLorenzi conducted a study in which normal saline. Upon follow up, there were no statistically significant
fresh, intact human cadaveric facial arteries were filled with HA and differences between treated doses, although there was a non-
placed in hyaluronidase solution. The authors reported elimination of significant trend towards more rapid decline of skin scores in lesions

J Clin Investigat Dermatol 3(2): 7 (2015) Page - 02

Citation: 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.

ISSN: 2373-1044

treated with higher doses. Based on these results, the authors suggest Periorbital lesions
that 5-10 units of hyaluronidase administered in a volume of 0.1-0.2
In areas of thinner skin, such as the inferior eyelids, lower doses of
mL (50 units/mL) is an appropriate initial dose in non-emergent
hyaluronidase have been successfully employed. Menon et al. reported
circumstances. It was additionally suggested that use of lower dose
the case of a patient who received 0.4 mL of HA in the lower lids and
might mitigate the risk of local hypersensitivity [12]. developed blue discoloration and evidence of overcorrection [11]. The

Table 1: Overview of reported cases and studies

Hyaluronidase Volume
Author Year Study Type Indication Location Solvent Outcome Adverse Effects
Dose Injected
Skin Necrosis/Vascular Obstruction
Prevention of permanent
Distribution
Impending skin 1.0 mL of sequelae after injection
Hirsch et al. 2007 Case Report right labial 30 units 0.2 mL None
necrosis normal saline was given within six
artery
hours
Two patients received
Case series Impending skin hyaluronidase one
Kim et al. 2011 Nasal area unreported unreported unreported None
(n=4) necrosis day after symptoms
presented without benefit
Non-inflamed Facial Lesions
Overcorrection 4 mL of Resolution of
Andre et al. 2008 Case Report Upper lip 11.2 units 0.3 mL Angioedema
Nodule normal saline overcorrection
Full resolution after two
Non-inflamed 1.0 mL of
Hirsch et al. 2006 Case Report Nasojugal fold 75 units 0.5 mL 75 unit injections (4 day None
blue nodule normal saline
interval)
Four patients
Randomized
After one week, 80% in treatment
controlled
reduction in nodule size group developed
Vartanian trial (n=12) of Uncomplicated 1.0 mL of
2005 Forearm 75 units 0.5 mL in the hyaluronidase localized
et al. hyaluronidase HA nodule normal saline
group vs. 10% in saline hypersensitivity
vs. normal
controls reactions
saline control

Randomized
controlled No statistically significant
Vartanian Uncomplicated 1.0 mL of 10, 20, or 30
2005 trial (n=8) of Forearm 0.4 mL difference between None
et al. HA nodule normal saline units
hyaluronidase doses.
doses
Non-inflamed Periorbital Lesions
Andre & Overcorrection Infraorbital 4 mL of Full resolution within 12
2007 Case Report 11.2 units 0.3 mL None
Levy Nodule Region normal saline hours
1.5 mL of 1% Resolution after
Non-inflamed Infraorbital Transient, mild
Brody 2005 Case Report lidocaine with 75 units 1.0 mL additional injection of 7.5
blue nodule Region ecchymosis
epinephrine units one week later
79% of patients had
Nodule after 0.2 - 0.5 Loss of original
full resolution with one
Hilton Retrospective HA injection Infraorbital 1.0 mL of mL HA treatment
2014 20-75 units injection. Three patients
et al. study (n=14) for tear trough Region normal saline effect in two
(21%) required an
augmentation cases (14.3%)
additional injection
Excess HA Resolution of “lumpy”
0.5%
Lambros resulting in Infraorbital majority within one day,
2004 Case report lidocaine with 75 units 1.5 mL None
et al. uncomplicated Region full resolution within
epinephrine
nodule several days
Left side fully resolved
Bilateral
Menon Uncomplicated 1.0 mL of with one injection, right
2010 Case report Infraorbital 3 units 0.2 mL None
et al. bluish nodules normal saline side required additional
Region
1.5 units
Permanent resolution In one patient
Delayed onset 1.0 mL of within 24 hours in one recurrence on
Richards Case Series Periorbital
2014 perioribtal bacteriostatic 25-30 units 0.5-0.6 mL patient, relapse in two occasions
et al. (n=2) region
swelling saline one patient requiring over 18 month
repeated treatment follow up
Inflamed Nodules
Inflamed Nodule
1.5 mL of 1%
consistent with Full resolution within 24
Brody 2005 Case report Chin lidocaine with 15 units 0.2 mL None
granulomatous hours
epinephrine
reaction

J Clin Investigat Dermatol 3(2): 7 (2015) Page - 03

Citation: 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.

ISSN: 2373-1044

patient was initially treated with 3 units (0.2 mL injected volume) of and one week later presented with an inflamed nodule [10]. Initial
hyaluronidase reconstituted in normal saline into the affect regions. management with intralesional triamcinolone acetonide, an oral
After one treatment, there was resolution of the left side, although the prednisone taper, and a course of cephalexin and trimethoprim-
right side required an additional 1.5 units of hyaluronidase two days sulfamethoxazole were ineffective. The nodule was then injected with
later [11]. While doses greater than 100 units have been reported for 15 units of hyaluronidase in 1% lidocaine with epinephrine (0.2 mL
the management of uncomplicated overcorrection of the lower lids volume) and within one day the lesion permanently resolved (Table
[28], the authors suggest that initial doses as low as 1.5-3 units are 1) [10].
sufficient in this region and reduce the risk of allergic reactions and
Adverse Effects of Hyaluronidase
loss of initial treatment effect [11].
Although hyaluronidase is associated with a low risk of adverse
In a retrospective review of the management of lower eyelid
effects, there have been reports of complications associated with
edema following HA injection in 14 patients, hyaluronidase doses of
its use, notably a risk of hypersensitivity reactions. In the trial by
20-75 units (injected a volume of 0.2-0.5 mL) were injected per region
Vartanian and colleagues, four (25%) patients developed localized
[29]. All patients responded to therapy without known recurrence.
hypersensitivity reactions characterized by transient erythema and
In two cases, all previously injected HA was degraded, resulting in
pruritus, which developed on average thirty minutes after injection
loss of treatment appearance. Accordingly, the authors advocate for
[12]. More severe hypersensitivity reactions, such as facial angioedema
starting at an initial lower dose than those reported in the study,
and anaphylaxis, have also been rarely described, with an estimated
followed by gradual increase in dose over multiple treatment sessions,
incidence of incidence of 0.1% [7,8,10,33]. However, document cases
if necessary [29].
of anaphylaxis are associated with larger doses of utilized to facilitate
The reconstitution of hyaluronidase in solution prior to injection anesthesia administration [34].
has been suggested to facilitate diffusion and produce more rapid
The risk of hypersensitivity is also related to the source of
results than the injection of concentrated hyaluronidase [10];
hyaluronidase employed. There are several commercially available
however, there is heterogeneity among reported cases regarding the
types of hyaluronidase (Table 2). These include hyaluronidase extracted
reconstitution solvent. Available reports describe the reconstitution
from bovine testicular tissue (AmphadaseTM and HydaseTM), ovine
of hyaluronidase in normal saline, lidocaine, or lidocaine with
testicular tissue (VitraseTM), or human recombinant hyaluronidase
epinephrine, often without comment regarding the basis of the
(HylenexTM). The risk of allergic reaction is significantly reduced
choice. In one case reported by Brody and colleagues, a patient
with the use of recombinant human hyaluronidase, compared to
presented with soft nodules with blue discoloration after HA injection
hyaluronidase from ovine or bovine sources [7,35].
in the bilateral infraorbital area [10]. The patient was treated with 75
units of hyaluronidase, given in a volume of 1 mL reconstituted in Andre et al. reported one case of angioedema occurring after
1% lidocaine with epinephrine. Of note, the authors discuss lidocaine a patient was treated with hyaluronidase for over correction of
with epinephrine was selected with the aim of reducing bruising; previous HA filler injection. The patient deferred allergy testing and
however, this was ineffective, suggesting that dilution in normal
saline or lidocaine is adequate [10]. Table 2: Overview of commercially available hyaluronidase products

Inflammatory nodules Trade name Source Product Details

Pregnancy
Category
The development of inflammatory nodules have also been 150 USP units per mL in 2 mL
described after HA injection and may occur due to infection and vial
AmphadaseTM Bovine Derived Contains edetate disodium, C
development of an active biofilm [5,24]. If infection is suspected, initial
calcium chloride, monosodium
management may include oral antibiotics, incision and drainage if basic buffer, and thimerosal
the lesion is fluctuant, and intralesional corticosteroids [2,7,24]. It is 150 USP units per mL in 2 mL
emphasized that steroids should also be administered after antibiotic vial
Contains sodium chloride,
treatment has been initiated [24]. Hyaluronidase injection has also HydaseTM Bovine Derived C
edetate disodium, calcium
been described in the management of painful, inflammatory nodules. chloride, and monosodium
Hyaluronidase has been demonstrated in vitro to effectively break basic buffer
down bacterial biofilms [30] and has been shown to have a role 150 USP units per mL in 2 mL
Human vial
clinically in the management of infections related to filler injections
Recombinant
[31]. Concurrent management with oral antibiotics is recommended HylenexTM
Source# Contains human albumin,
C

as the administration of hyaluronidase may disseminate the injection edetate disodium, and
by breaking up the collection [32]. polysorbate 80
200 USP units per mL in 2 mL
Inflamed nodules may also occur due to granulomatous reactions vial
associated with HA gel or contaminating proteins [25]. Brody et al. VitraseTM Ovine Derived
Contains lactose, potassium
C
phosphate dibasic buffer,
reported a case in which an inflamed nodule demonstrated to be sterile and potassium phosphate
chronic granulomatous inflammation resolved using hyaluronidase. monobasic buffer
The patient received non-animal stabilized HA for perioral rhytides *Wydase: Bovine derived. No longer commercially available
#
Significantly reduced risk of hypersensitivity

J Clin Investigat Dermatol 3(2): 7 (2015) Page - 04

Citation: 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.

ISSN: 2373-1044

was then injected with 112.5 units of ovine-derived hyaluronidase Another consideration is that hyaluronidase is contraindicated
and within ten minutes developed angioedema of the face [36]. The in patients who have previously developed hypersensitivity reactions
patient was successfully managed with betamethasone injection and to bee or wasp stings [8,13,25,36]. Physicians should inquire about
a prednisolone taper [36]. While the large dose administered in this a history of allergy to insect stings, as cross reactivity has been
case may have contributed to the reaction, routine skin allergy testing demonstrated with endogenous hyaluronidase antigens [38]. It is also
prior to treatment with hyaluronidase has been advocated by several notable that certain medications, including aspirin, corticosteroids,
authors [9,10,36,37]. Brody et al. suggested intra-dermal injection of estrogens, furosemide, benzodiazepines, phenytoinand anti-
3 units of hyaluronidase to test for the development of a wheal prior
histamines, may make tissues less sensitive to hyaluronidase and
to hyaluronidase treatment, especially if derived from bovine or ovine
larger doses or repeated treatments may be necessary in patients
sources [10]. However, in emergent cases of skin necrosis skin testing
taking these medications [10,36].
may not be practical [14].
Figure 1: Suggested Treatment Algorithm

Presentation with
Hyaluronic acid Filler
Complication

Non-emergent
Emergent (Nodule, Edema or
(Vascular Asymmetry)
compromise/Tissue
Ischemia)

 Hyaluronidase sub-dermal
allergy testing
Treatment ASAP after  Inquire about history of
presentation insect sting allergy
(max 4-6 hours)

 30-75 units of Hyaluronidase

reconstituted in normal saline*
Non-inflamed Nodule Inflamed or Painful
 2% nitroglycerine paste under or Overcorrection Nodule
occlusion

 If not already on anticoagulation,

aspirin (160-325 mg
sublingually) or LMWH (1
mg/kg BID) + antacid

 Consider systemic corticosteroid

taper

 Consider Sildenafil 100 mg daily  5-15 units of hyaluronidase  5-15 units of hyaluronidase
reconstituted in normal saline# reconstituted in normal saline#
 Valacyclovir (500 mg BID) and  1.5-3 units for eyelid area+  Systemic Antibiotics
doxycycline (100 mg BID) for  +/- Intralesional corticosteroids
prophylaxis

 Prompt ophthalmology consult if

visual changes

Reassess within one

Reassess within HOURS WEEK

Figure 1: Suggested treatment algorithm

#Reconstitute 0.5 mL of a 150 IU hyaluronidase vile in 1 mL of normal saline (75 units total). Inject 0.06-0.2 mL (equivalent to 30-75 units).

*Reconstitute a 150 IU hyaluronidase vile in 1 mL of normal saline. Inject 0.2-0.5 mL (equivalent to 5-15 units).

+Reconstitute 0.1 mL of a 150 IU hyaluronidase vile in 1 mL of normal saline (15 units total). Inject 0.1-0.2 mL volume (equivalent to 1.5-3 units).

J Clin Investigat Dermatol 3(2): 7 (2015) Page - 05

Citation: 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.

ISSN: 2373-1044

Conclusions 9. Richards AR (2014) Hyaluronidase. Aesthetics 1: 1-2.

10. Brody HJ (2005) Use of hyaluronidase in the treatment of granulomatous

Hyaluronidase is an important tool in the management of hyaluronic acid reactions or unwanted hyaluronic acid misplacement.
complications related to HA filler injections. The recommended Dermatol Surg 31(8 Pt 1): 893-897.
use and dosage of hyaluronidase depends on the clinical context 11. Menon H, Thomas M, D’Silva J (2010) Low dose of Hyaluronidase to treat
and original quantity of HA administered. The majority of available over correction by HA filler--a case report. J Plast Reconstr Aesthet Surg 63:
types of hyaluronidase contain 150 units per 1 mL, with the e416-e417.
exception of VitraseTM, which is available as 200 units/mL. In the 12. Vartanian AJ, Frankel AS, Rubin MG (2005) Injected hyaluronidase reduces
case of uncomplicated nodules involving periorbital, perioral, and restylane-mediated cutaneous augmentation. Arch Facial Plast Surg 7: 231-
nasal regions, 5-15 units may be initially attempted. For delicate 237.

areas such the lower eyelid, doses starting at 1.5-3 units may be 13. DeLorenzi C (2014) Complications of injectable fillers, part 2: vascular
employed. Similar starting doses may be utilized for inflammatory complications. Aesthet Surg J 34: 584-600.
nodules, along with systemic antibiotics, followed by intralesional 14. Grunebaum LD, Bogdan Allemann I, Dayan S, Mandy S, Baumann L (2009)
or systemic corticosteroids. In emergent cases of ischemia and The risk of alar necrosis associated with dermal filler injection. Dermatol Surg
impending skin necrosis, 30-75 units of hyaluronidase may be 35 Suppl 2: 1635-1640.

administered to the suspected region of blockage, along with warm 15. Inoue K, Sato K, Matsumoto D, Gonda K, Yoshimura K (2008) Arterial
compress, nitroglycerine, and, in patients who are not already taking embolization and skin necrosis of the nasal ala following injection of dermal
fillers. Plast Reconstr Surg 121: 127e-128e.
anticoagulants, systemic anti-coagulation or anti-platelet agents.
The direct intravascular injection of hyaluronidase is not generally 16. Schanz S, Schippert W, Ulmer A, Rassner G, Fierlbeck G (2002) Arterial
embolization caused by injection of hyaluronic acid (Restylane). Br J Dermatol
required, as hyaluronidase has been shown to diffuse across vessel 146: 928-929.
walls. After an ischemic event, systemic antibiotic and anti-herpetic
17. Park SW, Woo SJ, Park KH, Huh JW, Jung C, et al. (2012) Iatrogenic retinal
prophylaxis is also recommended.
artery occlusion caused by cosmetic facial filler injections. Am J Ophthalmol
Evidence to support the use of lidocaine with or without 154: 653-662.e1.

epinephrine is lacking [32]. Therefore, normal saline can be considered 18. Peter S, Mennel S (2006) Retinal branch artery occlusion following injection
to reconstitute the hyaluronidase (Figure 1). Given the potential for of hyaluronic acid (Restylane). Clin Experiment Ophthalmol 34: 363-364.

local and systemic allergic reactions associated with hyaluronidase, 19. Glaich AS, Cohen JL, Goldberg LH (2006) Injection necrosis of the glabella:
skin testing may be considered in non-emergent cases. The risk of protocol for prevention and treatment after use of dermal fillers. Dermatol
Surg 32: 276-281.
hypersensitivity may be mitigated by the use of human recombinant
hyaluronidase rather than animal derived sources. 20. Sclafani AP, Fagien S (2009) Treatment of injectable soft tissue filler
complications. Dermatol Surg 35 Suppl 2: 1672-1680.
As the popularity of HA filler injections continued to increase,
21. Funt D, Pavicic T (2013) Dermal fillers in aesthetics: an overview of adverse
hyaluronidaseuse can be expected to rise in parallel. Therefore events and treatment approaches. Clin Cosmet Investig Dermatol 6: 295-316.
continued report of cases and further prospective trials of
22. DeLorenzi C (2014) Transarterial degradation of hyaluronic acid filler by
hyaluronidase are warranted to continue to elucidate the indications hyaluronidase. Dermatol Surg 40: 832-841.
and ideal treatment protocol.
23. Castro CM, Grilli H, Grois J (1963) Intra-arterial hyaluronidase in the treatment
References of certain forms of lower limb ulcerations. Angiology 14: 277-284.

1. Requena L, Requena C, Christensen L, Zimmermann US, Kutzner H, et al. 24. Narins RS, Coleman WP 3rd, Glogau RG (2009) Recommendations and
(2011) Adverse reactions to injectable soft tissue fillers. J Am Acad Dermatol treatment options for nodules and other filler complications. Dermatol Surg
64: 1-34. 35 Suppl 2: 1667-1671.

2. Bailey SH, Cohen JL, Kenkel JM (2011) Etiology, prevention, and treatment 25. Hirsch RJ, Brody HJ, Carruthers JD (2007) Hyaluronidase in the office: a
of dermal filler complications. Aesthet Surg J 31: 110-121. necessity for every dermasurgeon that injects hyaluronic acid. J Cosmet
Laser Ther 9: 182-185.
3. Kim DW, Yoon ES, Ji YH, Park SH, Lee BI, et al. (2011) Vascular complications
of hyaluronic acid fillers and the role of hyaluronidase in management. J Plast 26. Lambros V (2004) The use of hyaluronidase to reverse the effects of
Reconstr Aesthet Surg 64: 1590-1595. hyaluronic acid filler. Plast Reconstr Surg 114: 277.

4. Park TH, Seo SW, Kim JK, Chang CH (2011) Clinical experience with 27. Hirsch RJ, Narurkar V, Carruthers J (2006) Management of injected
hyaluronic acid-filler complications. J Plast Reconstr Aesthet Surg 64: 892- hyaluronic acid induced Tyndall effects. Lasers Surg Med 38: 202-204.
896.
28. Pierre A, Levy PM (2007) Hyaluronidase offers an efficacious treatment for
5. Ozturk CN, Li Y, Tung R, Parker L, Piliang MP, et al. (2013) Complications inaesthetic hyaluronic acid overcorrection. J Cosmet Dermatol 6: 159-162.
following injection of soft-tissue fillers. Aesthet Surg J 33: 862-877.
29. Hilton S, Schrumpf H, Buhren BA, Bolke E, Gerber PA (2014) Hyaluronidase
6. Kang MS, Park ES, Shin HS, Jung SG, Kim YB, et al. (2011) Skin necrosis of injection for the treatment of eyelid edema: a retrospective analysis of 20
the nasal ala after injection of dermal fillers. Dermatol Surg 37: 375-380. patients. Eur J Med Res 19: 30.

7. Cavallini M, Gazzola R, Metalla M, Vaienti L (2013) The role of hyaluronidase 30. Pecharki D, Petersen FC, Scheie AA (2008) Role of hyaluronidase in
in the treatment of complications from hyaluronic acid dermal fillers. Aesthet Streptococcus intermedius biofilm. Microbiology 154(Pt 3): 932-938.
Surg J 33: 1167-1174.
31. Dayan SH, Arkins JP, Brindise R (2011) Soft tissue fillers and biofilms. Facial
8. Hirsch RJ, Cohen JL, Carruthers JD (2007) Successful management of Plast Surg 27: 23-28.
an unusual presentation of impending necrosis following a hyaluronic
32. Rzany B, Becker-Wegerich P, Bachmann F, Erdmann R, Wollina U (2009)
acid injection embolus and a proposed algorithm for management with
Hyaluronidase in the correction of hyaluronic acid-based fillers: a review and
hyaluronidase. Dermatol Surg 33: 357-360.

J Clin Investigat Dermatol 3(2): 7 (2015) Page - 06

Citation: 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.

ISSN: 2373-1044

a recommendation for use. J Cosmet Dermatol 8: 317-323. 36. Andre P, Flechet ML (2008) Angioedema after ovine hyaluronidase injection
for treating hyaluronic acid overcorrection. J Cosmet Dermatol 7: 136-138.
33. Borchard K, Puy R, Nixon R (2010) Hyaluronidase allergy: a rare cause of
periorbital inflammation. Australas J Dermatol 51: 49-51. 37. Cohen JL (2008) Understanding, avoiding, and managing dermal filler
complications. Dermatol Surg 34 Suppl 1: S92-S99.
34. Ebo DG, Goossens S, Opsomer F, Bridts CH, Stevens WJ (2005) Flow-
assisted diagnosis of anaphylaxis to hyaluronidase. Allergy 60: 1333-1334. 38. Hemmer W, Focke M, Kolarich D, Dalik I, Gotz M, et al. (2004) Identification
by immunoblot of venom glycoproteins displaying immunoglobulin E-binding
35. Dunn AL, Heavner JE, Racz G, Day M (2010) Hyaluronidase: a review N-glycans as cross-reactive allergens in honeybee and yellow jacket venom.
of approved formulations, indications and off-label use in chronic pain Clin Exp Allergy 34: 460-469.
management. Expert Opin Biol Ther 10: 127-131.

J Clin Investigat Dermatol 3(2): 7 (2015) Page - 07