Opinion
EDITORIAL
Update on Emergency and Nonemergency
Use of Hyaluronidase in Aesthetic Dermatology
Derek H. Jones, MD
Hyaluronidase has become an essential tool in cosmetic der-
matology as an eraser of unwanted hyaluronic acid (HA) filler.
The purpose of this Editorial is to update the reader on the evi-
dence supporting the use of hyaluronidase in (1) the emer-
gency treatment of vascular occlusion from accidental injec-
tion of HA into a blood vessel and (2) the more common case
of removing small amounts of HA that are simply unwanted,
which is the purpose of the study published by Alam and
colleagues1 in this issue of JAMA Dermatology.
Emergency Use
The most feared complication of HA fillers is accidental injec-
tion into a blood vessel, which can create vascular occlusion
and embolization of HA with tissue ischemia leading to pos-
sible necrosis of skin. In rare cases, immediate blindness may
occur by retrograde flow from
the supratrochlear or angu-
Related article lar artery through anastomo-
ses to the ophthalmic and
retinal arteries. To avoid these problems, it is essential to have
a thorough understanding of vascular anatomy, including the
location and depth of major arteries in the face, and to use in-
jection techniques that minimize intravascular occlusion, in-
cluding (1) avoiding injection sites in the areas where high-
risk vessels are located, (2) injecting slowly, using retrograde
technique, (3) aspirating before injecting, and (4) using a can-
nula when possible.2,3
Treatment of Blindness
At least 98 cases of blindness due to injected filler have been
reported in the literature, with the most common symptom
being immediate loss of vision and pain.3 The highest-risk in-
jection sites are the glabella (38.8%), nasal region (25.5%), na-
solabial fold (13.3%), and forehead (12.2%).3 Once vision loss
occurs, it has, until recently, been considered irreversible.
DeLorenzi4 has proven that hyaluronidase may easily cross ar-
terial walls, and that intra-arterial injection may not be nec-
essary to reverse HA vessel occlusion. Carruthers and
colleagues5 recently described a potential rescue treatment
using a retrobulbar or peribulbar injection technique to inject
high doses of hyaluronidase, which may then cross into the
retinal vasculature and rescue vision. Using this technique,
Chesnut6 has recently reported successful restoration of com-
plete subjective immediate vision loss related to HA filler in-
jection in a patient who was treated with retrobulbar injec-
tions of hyaluronidase (450 U total) within 20 minutes of the
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vision loss. Clinicians who inject HA filler should become fa-
miliar with published emergency protocols.5,6
Treatment of Impending Necrosis
Accidental intravascular injection of filler usually, but not al-
ways, manifests as blanching of the skin in the distribution of
the affected vessel followed by a mottled or reticulated purple
discoloration, which may be delayed. It is essential to take ac-
tion at the first sign of vascular occlusion to restore blood flow
because ischemic tissue death becomes progressive and irre-
versible after a few hours. If a patient reports discoloration with
unusual or severe pain following HA injection, they should be
evaluated as soon as possible. Hirsch et al7 first reported the
injection of hyaluronidase to successfully treat impending ne-
crosis due to intravascular HA injection, and hyaluronidase is
arguably now considered the standard of care in such cases.
Recent consensus recommendations published by Cohen and
colleagues8 regarding impending necrosis recommend injec-
tion of at least 200 U of hyaluronidase at 3- to 4-cm intervals
throughout the area of vascular compromise manifested by is-
chemic, mottled skin discoloration and/or tenderness. This may
be repeated at 60-minute intervals until reperfusion be-
comes evident and daily if needed. Additionally, they recom-
mend instituting an aspirin regimen and warm compresses ap-
plied to the affected areas.
Nonemergency Use
In 2005, Brody9 first reported the successful use of hyaluroni-
dase in the treatment of rare granulomatous HA reactions or the
more common unwanted HA misplacement. Jones et al10 re-
ported in 2010 in vitro studies that proved that higher cross-
linked and more cohesive HAs (eg, Juvéderm; Allergan) are more
resistant to hyaluronidase and take higher doses to break mo-
lecular cross-linking compared with less cross-linked particu-
late HAs (eg, Restylane; Galderma Laboratories LP). A more re-
cent in vivo study in a rat model suggests that the 2 forms of
hyaluronidase approved by the US Food and Drug Administra-
tion (Vitrase, Bausch & Lomb Inc; and Hylenex, Halozyme Thera-
peutics) are roughly equivalent in unit potency and that both
work equally well.11 The much needed human in vivo study pub-
lished in this issue by Alam et al1 is excellent in design and ex-
ecution, and proves that smaller, less concentrated does of hy-
aluronidase are capable of removing small amounts of HA
without removing the entire implant. In my clinical experi-
ence, I start with 10 U of Vitrase for each 0.1 cc of Juvederm that
I estimate must be erased, 5 U for each 0.1 cc of Restylane, and
(Reprinted) JAMA Dermatology Published online April 25, 2018 E1
 Opinion Editorial

30 U for each 0.1 cc of Juvéderm Voluma, which is highly cross- amounts of HA implant, I often dilute Vitrase with normal sa-
linked. These doses are corroborated by all 3 dose-ranging line to go from 20 U/0.1 cc to 10 U/0.1 cc or less, which is in the
studies.1,10,11 When attempting to remove smaller or partial dose range studied by Alam and colleagues.1

ARTICLE INFORMATION 2. Jones D. What lies beneath. Dermatol Surg. 2011; injection embolus and a proposed algorithm for
Author Affiliation: Skin Care and Laser Physicians 37(3):387-388. management with hyaluronidase. Dermatol Surg.
of Beverly Hills, Los Angeles, California. 3. Beleznay K, Carruthers JD, Humphrey S, Jones D. 2007;33(3):357-360.

Corresponding Author: Derek H. Jones, MD,
Skin Care and Laser Physicians of Beverly Hills,
9201 Sunset Blvd, Ste 602, Los Angeles, CA 90069
(derekjonesmd@gmail.com).
Published Online: April 25, 2018.
doi:10.1001/jamadermatol.2018.0516
Conflict of Interest Disclosures: Dr Jones is an
investigator, consultant and/or speaker for Allergan,
Merz, and Galderma. No other disclosures are
reported.
REFERENCES
1. Alam M, Hughart R, Geisler A, et al. Effectiveness
of low doses of hyaluronidase to remove hyaluronic
acid filler nodules: a randomized clinical trial
[published online April 25, 2018]. JAMA Dermatol.
doi:10.1001/jamadermatol.2018.0515.
Avoiding and treating blindness from fillers:
a review of the world literature. Dermatol Surg.
2015;41(10):1097-1117.
4. DeLorenzi C. Transarterial degradation of
hyaluronic acid filler by hyaluronidase. Dermatol Surg.
2014;40(8):832-841.
5. Carruthers J, Fagien S, Dolman P. Retro or
peribulbar injection techniques to reverse visual
loss after filler injections. Dermatol Surg. 2015;41
(suppl 1):S354-S357.
6. Chesnut C. Restoration of visual loss with
retrobulbar hyaluronidase injection after hyaluronic
acid filler [published online September 1, 2017].
Dermatol Surg. doi:10.1097/DSS
.0000000000001237
7. Hirsch RJ, Cohen JL, Carruthers JD. Successful
management of an unusual presentation of
impending necrosis following a hyaluronic acid
8. Cohen JL, Biesman BS, Dayan SH, et al.
Treatment of hyaluronic acid filler-induced
impending necrosis with hyaluronidase: consensus
recommendations. Aesthet Surg J. 2015;35(7):
844-849.
9. Brody HJ. Use of hyaluronidase in the treatment
of granulomatous hyaluronic acid reactions or
unwanted hyaluronic acid misplacement. Dermatol
Surg. 2005;31(8 Pt 1):893-897.
10. Jones D, Tezel A, Borell M. In-vitro resistance to
degradation of hyaluronic acid dermal filter by
ovine testicular hyaluronidase. Dermatol Surg.
2010;36:804-809.
11. Shumate GT, Chopra R, Jones D, Messina DJ,
Hee CK. In vivo degradation of cross-linked
hyaluronic acid fillers by exogenous hyaluronidases.
Dermatol Surg. 2018. In press.

E2 JAMA Dermatology Published online April 25, 2018 (Reprinted) jamadermatology.com

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