Aesthetic Surgery Journal Advance Access published May 10, 2015

Cosmetic Medicine

Special Topic Aesthetic Surgery Journal

2015, 1–6
© 2015 The American Society for

Treatment of Hyaluronic Acid Filler–Induced Aesthetic Plastic Surgery, Inc.

Reprints and permission:
journals.permissions@oup.com
Impending Necrosis With Hyaluronidase: DOI: 10.1093/asj/sjv018
www.aestheticsurgeryjournal.com
Consensus Recommendations

Joel L. Cohen, MD; Brian S. Biesman, MD; Steven H. Dayan, MD;

Claudio DeLorenzi, MD, FRCS; Val S. Lambros, MD;
Mark S. Nestor, MD, PhD, PA; Neil Sadick, MD; and Jonathan Sykes, MD

Abstract
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 ex-
perienced 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.

Accepted for publication December 29, 2014.

Vascular compromise after soft tissue augmentation with
filler substances is a major concern, as either frank intravascu-
lar injection or, less commonly, arterial compression can
prevent blood flow through arteries supplying the skin or even
the eye.1-4 Certain regions of the face, such as the glabella,
are at a higher risk for developing compromised blood flow
and necrosis given their vascular anatomy, although there
have been reports of tissue necrosis at the nasal ala, lip, and
nasolabial fold areas following treatment with hyaluronic acid
(HA) or calcium hydroxlapatite (Figure 1).1,2,5-7 Impending
necrosis has been reported in cases involving all types of
filler materials (including collagen and HA), with incidences
estimated at 0.001% of total procedures performed.5,8
MANAGEMENT OF IMPENDING NECROSIS
Injection-induced necrosis is a rare but dreaded complication
associated with the use of soft tissue augmentation filler

Dr Cohen is an Associate Clinical Professor in the Department of
Dermatology at the University of Colorado, Boulder, and an Assistant
Clinical Professor in the Department of Dermatology at the University
of California Irvine. Dr Biesman is a Clinical Assistant Professor in the
Departments of Ophthalmology and Otolaryngology and the Division
of Dermatology at Vanderbilt University Medical Center, Nashville,
TN. Dr Dayan is a Clinical Assistant Professor in the Department of
Otolaryngology at the University of Illinois, Chicago. Dr DeLorenzi is
a plastic surgeon in private practice in Kitchener, Ontario, Canada.
Dr Lambros is a Clinical Professor of Plastic Surgery at the
University of California Irvine. Dr Nestor is a Voluntary Associate
Professor in the Department of Dermatology and Cutaneous Surgery
at the University of Miami Miller School of Medicine, FL. Dr Sadick
is a Clinical Professor of Dermatology at Weill Cornell Medical
College, New York, NY. Dr Sykes is a Professor and the Director of
Facial Plastic Surgery in the Department of Otolaryngology at the
UC Davis Health System of the University of California Davis,
Sacramento.
Corresponding Author:
Dr Joel L. Cohen, AboutSkin Dermatology and DermSurgery, Swedish
Medical Center Office, 499 E. Hampden Ave. Suite 450, Englewood,
CO 80113, USA.
E-mail: jcohenderm@yahoo.com
2 Aesthetic Surgery Journal

We provide a systematic protocol for its reconstitution below

based on literature review17,18 and personal experience, in-
cluding the,possible need for skin testing and application in
the management of impending necrosis. In addition, a clini-
cal example of impending necrosis is shown in Figure 2 and
an outline of a suggested treatment algorithm in Table 1.

TREATMENT PROTOCOL AND EXPERT

RECOMMENDATIONS
(1) Use a significant amount of a hyaluronidase enzyme in
Figure 1. Cross-section of the central third of the lower lip of a
female cadaver (age unknown), showing the cross-sectional
anatomy of the orbicularis oris muscle and the location of the
labial artery. The labial artery is located posterior to the wet dry
line, deep to the labial mucosa, but superficial to the orbicularis
oris muscle. The arrow points to the labial artery, adjacent to
the orbicularis oris muscle. This region is often injected in tech-
niques designed to increase lip eversion (posterior or deep to
the labial artery region) or techniques designed to increase lip
fullness (anterior and superior to the location of the labial artery
region in the figure). Because of the proximity of the labial
artery to the field of injection, this region may be considered to
be a higher risk area to treat with injections of dermal filler.
agents.9 Necrosis can occur from interruption of the vascular
supply to the area, potentially by compression or injury, but
usually from obstruction of the vessel(s) through injection
directly into an artery, causing an embolism that impedes
blood supply.6,9 In order to avoid serious, potentially irre-
versible complications, all physicians should have a height-
ened awareness of the possibility of vascular compromise
when using fillers, specifically look for a regional blanch,
and have an established treatment algorithm in place if a
blanch is suspected or overtly occurs.1,10-14 In these circum-
stances, patients often report symptoms of necrosis varying
from extreme pain with geographic discoloration (such as a
violaceous hue) to a dull persistent ache.15
Hyaluronidases are soluble protein enzymes that degrade
HA and are used to increase drug diffusion and reverse the
effects of HA fillers. Their role in treating complications from
HA fillers has recently been reviewed.16 Commercial formula-
tions include Vitrase (purified ovine testicular hyaluronidase)
and Hylenex (purified recombinant human hyaluronidase).
Hyaluronidases should be accessible in any office that
routinely performs soft tissue augmentation with HA fillers.
the area of necrosis (ie, Vitrase at 200 U).
It is important to avoid under-treatment when
dealing with necrosis, as this could have very signifi-
cant consequences in the regional cutaneous tissue,
such as scabbing and significant scarring. With some
HA products [such as Restylane and Perlane
(Galderma Laboratories, LP, Fort Worth, TX )] it may
be possible to use smaller volumes of a hyaluronidase
to dissolve the HA compared to that required for prod-
ucts such as JuveDerm (Allergan, Inc. Irvine, CA).19
But necrosis is an urgent situation and it is most impor-
tant to flood the area with a sufficient hyaluronidase
enzyme to try to break up or dissolve some of the
product as quickly as possible. In animal experiments,
early injection of a hyaluronidase (4 hours after HA
filler injection into the auricular arteries of the rabbit)
reduced the size of necrotic areas compared to delayed
injection of a hyaluronidase (24 hours after filler injec-
tions) or untreated controls.20
We recommend the immediate use of a minimum of
200 U of Vitrase in all cases of impending necrosis.
Although a hypersensitivity reaction can occur
rarely with a hyaluronidase ( published incidence of 1
in 1000 patients),1,6,21,22—it is not felt necessary to
conduct a skin test in cases of impending necrosis.
However, the treating physician should be prepared for
the rare possibility of allergy and even the extreme pos-
sibility of anaphylaxis. Skin testing with a hyaluroni-
dase is rarely performed by our expert panel when
dissolving the non-urgent circumstance of undesired
bumps or nodules of HA.
Some experts prefer to dilute a hyaluronidase with
lidocaine in order to facilitate vasodilation and disper-
sion when trying to treat someone who has impending
necrosis. An alternative would be to dilute the hyaluron-
idase with saline to allow for more volume and thus
cover a larger area per 200 units of a hyaluronidase, but
clearly saline would not have the potential vasodilatory
properties of lidocaine on local vessels.
A hyaluronidase should be injected into the area
where the circulation of blood supply appears to be
reduced (ie, the area of blanch or violaceous discolora-
tion). There is no need to inject more than a few sites in
Cohen et al 3

Figure 2. This 55-year-old woman presented 4 hours after a hyaluronic acid injection into the lower lip at an outside clinic. (A) On
the first injection the lips were seen to blanch and then became mottled. Hyaluronidase (400 U) was injected into the lower lip and
a warm compress was applied. No further treatment was undertaken and improvement can be seen (B) after 1 day and (C) a few
days later.

the area of impending necrosis unless it is a large area or
region, since the material diffuses readily through fascial
planes and can be massaged through the treatment area.
Our expert panel feels that one injection for every 3-4
cm of skin manifesting signs of necrosis is appropriate.
If no improvement (such as less blanching and a
less dusky, violaceous color) is seen within 60 minutes,
additional quantities of a hyaluronidase should be
injected (repeating 3-4 cycles).
A prompt diagnosis and immediate treatment with
high doses of a hyaluronidase are critical to success.
(2) Upon first recognition of vascular compromise (such
as a regional blanch of the skin in a distribution reflec-
tive of the underlying vasculature), apply a warm com-
press and massage vigorously.
The warm compress promotes vascular dilation9,23
and massaging8 at the site may help to break a focal ob-
struction. Apply a warm compress for 5–10 minutes
every 30–60 minutes (avoid burning the skin). Patients
may or may not report the onset of immediate pain, or
sometimes recount “normal” injection-related discomfort
failing to resolve. In many circumstances, a reticulated
and violaceous dusky pattern may be seen within a few
hours or by the next day. Thus, an immediate blanching
and/or a delayed reticulated pattern of the injected area
are important clinical observations. A hyaluronidase, in
significant quantities (see below), should be used imme-
diately upon suspicion of vascular compromise, regard-
less of whether this is noted straight away or in a delayed
time frame.
(3) Massage topical nitroglycerin (NTG) paste into the area.
Because of its vasodilatory properties, topical NTG
may reduce necrotic spread.4,24 However, the use of
NTG paste when dealing with necrosis is controversial.
The amount of NTG recommended is dependent on the
size and area of impending or full necrosis. We recom-
mend application of NTG paste immediately on suspi-
cion of necrosis and up to 2-3 times daily, provided that
the patient is not debilitated with severe headaches or
light-headedness from the NTG itself. Care should be
4 Aesthetic Surgery Journal

Table 1. Management of Impending Necrosis: Treatment Protocol and presentations in which the tissue is not healing
Expert Recommendations well.1 Hyperbaric oxygen has the potential to deliver
Upon first recognition of vascular (1) Use a significant amount of a
oxygen deep into the skin and may help to keep
compromise hyaluronidase enzyme in the area of oxygen-dependent tissues viable. It is frequently
necrosis (ie, Vitrase at minimum 200 U). used for wound healing in compromised vasculari-
(2) Apply a warm compress and massage
vigorously.
ty.25 Intuitively it makes sense, but with so many
(3) Massage topical nitroglycerin (NTG) variables involved and experience limited, it is hard
paste into the area. to assess its true value fully.26
(4) Introduce an oral aspirin regimen.
(b) It has been postulated that topical oxygen “cosme-
ceutical therapy” to the affected area twice daily
Daily follow-up (1) Look for signs of improvement or any
further signs of occlusion or necrosis.
could potentially enhance the rate of epithelializa-
(2) With improvement, stop the NTG paste. tion. However, data to support this practice are
(3) Without improvement, repeat weak and completely anecdotal.
hyaluronidase, NTG paste, and aspirin
regimen.
(c) There have been recommendations for other prod-
ucts, such as low molecular weight heparin use,
Patient aftercare (1) Routine wound care: intravenous prostaglandin E, and also Sildenafil
(a) Ensure adequate hydration. (Viagra) in the armamentarium, to try to treat im-
(b) Wound debridement of necrotic pending necrosis.
skin.
(2) General supportive care. (7) Patient aftercare involves routine wound care, ensur-
(3) Monitor for secondary infection. ing adequate hydration, frequent appropriate wound
debridement of necrotic skin, general supportive care,
and monitoring for secondary infection.
Minimize scarring by providing diligent wound care
taken, as larger amounts may not only lead to some with daily dressings, depending on the location, depth
degree of headache or light-headedness, but can also of wound, and amount of tissue loss. Keep the wound
can also cause systemic effects such as orthostasis. To covered with ointment to prevent crusting and mini-
prevent severe orthostasis and risks of falls, we recom- mize bacterial contamination until healing is complete.9
mend that the patient be lying down during NTG treat- Peroxide can potentially impede wound healing and
ment sessions. is not recommended.27 Patients who are diagnosed
(4) Introduce an oral aspirin regimen. promptly and treated within 24 hours will usually have
Start the patient on an oral aspirin regimen of 2 pills the best outcomes. A delay in diagnosis and treatment
of 325 mg daily to try to prevent further clot formation has been associated with some degree of skin loss,
due to vascular compromise, and an antacid to prevent ulceration, and delayed healing, requiring many weeks
aspirin-associated gastritis. The duration of aspirin of wound care, and can result in different degrees of
treatment would depend on the clinical scenario and scarring.
whether improvement is seen, but in our experience a
1-week’ course would be typical.
(5) Follow patients daily for signs of improvement or any
further signs of occlusion or necrosis.
DISCUSSION
A hyaluronidase and NTG can be continued as
needed over the next few days. It is important that pa- Injection-induced necrosis is a rare but serious conse-
tients are followed daily at this critical stage. quence of soft tissue augmentation with filler agents. The
(a) If improvement is noted the NTG paste massages use of hyaluronidases to prevent serious, potentially irre-
can be stopped, although there is some anecdotal versible complications is “off label” and published data are
evidence that continued use of NTG for 1–2 days, limited. Our collective experience has demonstrated that a
if tolerated, can accelerate resolution of the reticu- prompt diagnosis and immediate treatment with a hyal-
lated vascular congestion. uronidase is both effective and essential. For the first time
(b) If there is no improvement or if progression of ne- we can provide a systematic protocol for the use of hyal-
crosis occurs the above regimen of a hyaluroni- uronidases, along with other measures or adjunctive treat-
dase, NTG paste, and aspirin should be repeated ments that can help, such as aspirin.
daily, typically for 2-3 days. While our priority is to instruct in the prompt diagnosis of
(6) Other considerations: impending necrosis and its immediate treatment with high
(a) It has been suggested that hyperbaric oxygen could doses of a hyaluronidase (at least 200 U), the benefits of dilu-
be used in instances of severe necrosis or delayed tion, use of cannulas, and use of NTG paste are still debated.
Cohen et al
Cannulas, for example, would appear to be safer; however,
their use must be balanced against control of the injection.
It is important to recognize that doses that have been ob-
served to be effective against one product will not necessarily
apply to other formulations. Thus, the recommendations
in this consensus document apply to the most widely-used
hyaluronidase product (Vitrase), where we have the most
experience. Specific knowledge of the hyaluronidase used
can help determine the initial dose required for treatment of
adverse events.
CONCLUSION
A prompt diagnosis and immediate treatment of impending
necrosis with high doses of a hyaluronidase (at least 200 U)
are critically important. It is hoped that the recommenda-
tions we provide are helpful and will encourage further clini-
cal investigation.
Acknowledgements
The authors acknowledge Brian Bulley, MSc, of Inergy Limited,
for medical writing support. Valeant (Bridgewater, NJ)
Pharmaceuticals North America LLC funded Inergy’s activities
pertaining to this manuscript.
Disclosures
Dr Biesman is a consultant for Merz (Greensboro, NC), Allergan
(Irvine, CA), Galderma (Fort Worth, TX), and Valeant. Dr
DeLorenzi is a paid medical director for Merz (Merz, Burlington,
Ontario) and Allergan (Markham, Ontario, Canada), and an
advisor for Kythera (West Lake Village, CA), Valeant, Baxter
(Deerfield, IL), and Johnson & Johnson (Mentor, Santa Barbara,
CA). Dr Dayan participates in clinical research and acts as
a speaker and consultant to Valeant, Allergan, and Merz.
Dr Cohen has participated in clinical research with Allergan,
Merz and Galderma. He also acts as a consultant to Valeant,
Allergan, Merz and Galderma. Dr Sadick is an investigator and
trainer for Valeant. Dr Nestor is a consultant, advisor, and inves-
tigator for Valeant. Drs Lambros and Sykes have no disclosures.
Funding
Medical writing support was funded by Valeant Pharmaceuticals
North America, LLC.
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