ORIGINAL ARTICLES

Transarterial Degradation of Hyaluronic Acid Filler

by Hyaluronidase
Claudio DeLorenzi, BA, MD, FRCS

BACKGROUND Hyaluronidase (HYAL) has been recommended in the emergency treatment of ischemia
caused by accidental intra-arterial injection of hyaluronic acid (HA) dermal fillers. To date, there have been no
published studies showing that HYAL can pass through intact arterial wall to hydrolyze HA emboli.

OBJECTIVE The goal of this study was to study whether or not HYAL could cross intact human facial arterial
wall to hydrolyze HA filler.

MATERIALS AND METHODS Short tied-off segments of fresh human cadaver–sourced facial artery speci-
mens, overfilled with a monophasic dermal filler (dermal filler “sausages”), were immersed in either HYAL or
normal saline as controls. At 4 and 24 hours, the vessels were removed from the preparations, and one end of
each vessel was cut open.

RESULTS Only the HYAL-immersed specimens showed degradation of filler gel.

CONCLUSION In conclusion, cross-linked HA is susceptible to hydrolysis by HYAL when contained within

the intact facial artery in a cadaver model, indicating that direct intra-arterial injection of HYAL is likely not
necessary to help restore the circulation of ischemic tissues. This bench study provides support for the current
recommended treatment of accidental intra-arterial injection with HYAL injection diffusely into ischemic tissues.

The product used in this study was supplied by Allergan Inc. C. DeLorenzi is a paid medical consultant for
Allergan Inc., and Merz Pharmaceuticals GmbH, Canada.

yaluronic acid (HA) fillers are an extremely

H important part of the modern clinician’s clinical
practice, as evidenced by the rapid growth of
nonsurgical procedures recorded in the annual
cosmetic surgery statistics released by the American
Society for Aesthetic Plastic Surgery (see the
American Society for Aesthetic Plastic Surgery’s
cosmetic surgery statistics at http://www.surgery.org/
media/statistics). Accidental intra-arterial injection of
fillers causing ischemia and dermal necrosis is a rare but
serious complication of aesthetic filler treatments.1–6
Several authors have recommended hyaluronidase
(HYAL) injections for treatment of these events.2,3,7–14
This phenomenon is variously described in the
literature occurring with particular injected
medications such as the Nicolau syndrome,15–64
Private Practice, DeLorenzi Clinic, Kitchener-Waterloo, Ontario, Canada
Freudenthal–Nicolau syndrome,43,65 or Embolia Cutis
Medicamentosa.16,17,29–31,36,41,48,50,66–83 The common
medications causing this syndrome include various
antibiotics, nonsteroidal anti-inflammatory
medications, corticosteroids, antihistamines, vaccines,
and many others as noted in the above-mentioned
references. It is clinically characterized by the sudden
onset of pain after injection, concurrent with livedo
reticularis, blistering, dermal necrosis, demarcation,
and subsequently developing into a necrotic ulcer and
subsequent late scarring. The original description
regarding then current treatments of syphilis with
bismuth preparations was given by Freudenthal65 in
1924. The pathophysiology of the syndrome is
contingent on several variables regarding the ability of
the injected material to cause arterial occlusion. This

· · ·
© 2014 by the American Society for Dermatologic Surgery, Inc. Published by Lippincott Williams & Wilkins
ISSN: 1076-0512 Dermatol Surg 2014;40:832–841 DOI: 10.1097/DSS.0000000000000062
·
832

Copyright © American Society for Dermatologic Surgery. Unauthorized reproduction of this article is prohibited.

may occur by simple mechanical obstruction (e.g., by
nonsoluble particulates in the medication), perhaps by
activation of intravascular blood clotting (as with
collagen), or even by sclerosing reactions to the blood
vessels themselves. In the case of HA fillers, the root
cause of the vascular obstruction is due to simple
mechanical obstruction of the vessel.
Once the HA material has entered an artery, most
commonly the embolic material will be carried distally
in the normal direction of blood flow, progressively
into smaller sized vessels until such time as the material
can no longer pass any further distally, resulting in
complete obstruction. In the absence of sufficient col-
lateral blood supply, tissue ischemia and eventually
tissue necrosis may result. If injected at high pressures
and at a rapid rate, the embolus may also paradoxi-
cally flow retrograde to the normal direction of blood
flow. A large bolus, after pushing backward inside an
artery into progressively larger vessels, may then get
sidetracked into other branches of the vessel. From
there, fillers may then be carried to distal sites through
proximal vascular tributaries, creating a “paradoxi-
cal” ischemic area far from the site of original
injection. For example, there are several clinical
reports of blindness occurring after filler injec-
tion.1,84,85 Clinically, this phenomenon has even
occurred from the contralateral side where filler
injected, for example, into the left nasolabial fold
region has resulted in blindness in the right eye, the
filler crossing the midline through the extensive vas-
cular collaterals in the nasal region connecting the
periorbital internal carotid vascular territory to those
of the perioral external carotid territory.
Hyaluronic Acid and Hyaluronidase
Hyaluronic acid is a high–molecular weight poly-
saccharide that has many biologic functions in the
extracellular matrix of humans and animals86–88 and is
intimately involved in cell migration, wound healing,
embryogenesis, and even plays important roles in the
pathogenesis of malignant cancers,89–92 to mention but
a few.93 It is a rather viscous substance and has many
truly remarkable properties.88 At physiologic concen-
trations, it is rapidly degraded (at approximately the
same rate as serum albumin) in lymph nodes and the
Copyright © American Society for Dermatologic Surgery. Unauthorized reproduction of this article is prohibited.
DELORENZI
liver.94 By altering the structure of HA slightly by cross-
linking, reduces its susceptibility to HYAL, allowing its
use as a cosmetic filling agent that is well tolerated95 of
reasonable duration. Most of the commercial products
currently available use nonanimal–derived HA (typi-
cally from Streptococcus equi subspecies) that is cross-
linked with a plasticizing agent, 1,4-butanediol digly-
cidyl ether.96 This process creates intermolecular bonds
that create a molecule that is more stable than non–
cross-linked HA and allows for longer duration in situ.
Different companies use different techniques and pro-
portions of the different forms of available HA in their
manufacturing process and combine the cross-linked
product with varying percentages of non–cross-linked
HA, creating a plethora of formulations that differ in
gel hardness, consistency, and lifting capacity.97
The HYALs are actually a family of enzymes that cata-
lyze the hydrolysis of HA.98–100 Hyaluronidase has been
used for various purposes in clinical medicine, including
dispersion of local anesthetics in retrobulbar block,101
hypodermoclysis,102–104 and treatment of extravasation
injuries.105 Hyaluronidase has also been shown to be
effective in vivo in reducing the amount of HA present
in unaesthetic results.10,106–112 In cases of accidental
intravascular injection, HYAL is generally used to
break down the longer, viscous, cohesive HA chains
into small pieces, resulting in a drastic decrease in
viscosity, so that the HA degradation products can pass
through vessels such that vascular obstruction is
relieved. To date, no one has demonstrated that HYAL
can penetrate through an intact arterial wall to degrade
the HA material contained within. If it did not penetrate
through the arterial wall, then presumably physicians
would have to try to inject HYAL directly into an
occluded vessel, technically challenging as it may be.
Treatment of Vascular Obstruction
The ultimate goal of treatment, once HA filler is
blocking access of fresh arterial blood, is to restore the
circulation to the affected area to prevent ischemic
necrosis (see Table 1 for a list of commonly used
modalities). Current strategies involve the immediate
use of mechanical means (massage) to break up the
embolus and move it so that collateral circulation
might help restore blood flow. Antiplatelet therapy
40:8:AUGUST 2014 833
 DEGRADATION OF HA FILLER BY HYAL
TABLE 1. Emergency Treatment of Accidental Intra-arterial Injection of HA-Based Dermal Fillers
HYAL 300–600 IU injection into ischemic
tissues
Warm massage
Topical nitropaste
ASA 72 mg by mouth once daily
Hyperbaric oxygen
Prostaglandin E1 injection
Low–molecular weight heparin
See text for context and References 1–6,53,77–90.
(e.g., low-dose acetylsalicylic acid [ASA]) is used,
which has been shown to be beneficial in other types
of acute ischemic injury. Typically, low-dose ASA 72
mg by mouth is recommended immediately on
diagnosis (Table 2).7 Systemic anticoagulation has
also been tried on occasion for filler embolic
events,113 using the same rationale used for anti-
coagulation in acute coronary syndromes. Warm
compresses may also be helpful to cause vasodilata-
tion, and topical nitro paste7,8,11,114 has been shown
to be effective to improve flow in small dermal
arterioles.115 Hyperbaric oxygen has also been rec-
ommended to reduce the size of ischemic tissue until
vascular ingrowth can occur. Hyperbaric therapy has
shown promise in similar types of ischemic
TABLE 2. Experimental Results (Contents of
Vessels After Immersion)
4 Hours 24 Hours
HYAL 300 IU No gel No gel
Normal saline Gel Gel
Arterial specimens filled with monophasic HA gel were
separately immersed in either 4 mL of normal saline or 2 mL of
normal saline plus 2 mL of bovine testicular HYAL (150 IU/mL).
Arterial segments immersed in HYAL contained only watery
fluid at both 4 and 24 hours, with no remaining gel, whereas
specimens immersed in saline alone contained apparently
intact HA gel.
834 DERMATOLOGIC SURGERY
Copyright © American Society for Dermatologic Surgery. Unauthorized reproduction of this article is prohibited.
Inject slowly and massage vigorously to maintain HYAL in the region
of ischemia. May help to break up embolus to allow collateral
circulation to affected area. Do not massage HYAL away from site,
but toward site to maximize exposure time within ischemic tissues.
May be repeated at higher doses until desired effect. Important to
start as soon as possible after ischemia is suspected
Warm compresses and vigorous massage to help vasodilate and to
break up embolic material into smaller pieces and to open up
collateral vessels
Use 1–2 cm under occlusion at site of compromise, monitor vital signs,
and be aware of hypotension
Antiplatelet effect to help reduce intravascular clotting in regions of
decreased perfusion
May help to reduce size of necrosis by providing oxygenation to
marginally viable tissues until vessel ingrowth occurs
Usually administered under careful observation. Vasodilation may
lower blood pressure rapidly
Risk of bleeding, requires careful monitoring of coagulation profile
injury.116,117 Prostaglandin E1 injection has also been
recommended as a vasodilator (commonly used in
treatment of erectile dysfunction). Prostaglandin E1
has been shown to be helpful in various types of
ischemic injuries and ischemia-reperfusion scenar-
ios,118 but this treatment is usually provided in hos-
pital under careful supervision. Hylaluronidase has
been recommended2,3,7,9,10 because it is believed to be
clinically effective in reduction of the size of the
ischemic lesion by enzymatically breaking down the
embolus so that effective circulation can be restored.
A recent laboratory study in a rabbit ear model
clearly showed that HYAL was effective in preventing
ischemic necrosis of tissues after intra-arterial HA
embolus when administered within 24 hours.3 The
purpose of this study was to assess whether HYAL
could penetrate through an intact arterial wall and
visibly break down HA contained within a human
facial artery specimen.
Methods
After an anatomic teaching session on fresh human
cadavers, the facial arteries were dissected under direct
visualization using loupe magnification (Figure 1).
After direct cannulation in situ, the arteries were filled
with Juvederm Ultra Plus XC (Allergan Inc.,
Markham, ON, Canada). Then, I tied off any side
branches with fine suture material under loupe

Figure 1. Right fresh cadaver facial artery in situ, filled with
HA filler, before suture of branches of facial artery. Dis-
section performed under loupe magnification, and arterial
branches subsequently tied off with fine suture material.
magnification. Distending the vessel with filler
material helped to fill these side branches and
improved visualization of the entire facial artery,
angular artery, and the collateral vessels in the
mid-face. Once the side branches were all tied off and
cut (Figure 2), the vessel was double tied at regular
intervals with 6-0 silk suture and divided, created
small segments of facial artery, plump and full of
facial filler material (analogous to “sausage links” of
vessel filled with HA material; Figure 3).
Figure 2. Right facial artery, removed, filled with HA filler,
before division into short tied-off segments for immersion into
either normal saline (controls), or a solution of normal saline
and 300 IU of bovine testicular HYAL (experimental group).
Copyright © American Society for Dermatologic Surgery. Unauthorized reproduction of this article is prohibited.
DELORENZI
The segments of vessel were then separated into 2
roughly equivalent sets. A coin was flipped to choose
which pile was to be the control group. The specimens
were then placed into plastic specimen jars and
appropriately labeled, with 1 vessel segment per
container (Figure 3). The experimental group
specimens were placed in HYAL 300 IU (2 mL) plus
2 mL of normal saline, whereas the control speci-
mens were immersed in 4 mL of normal saline
(extracted from the same bag of 0.9% sodium
chloride injection, USP; Baxter, Deerfield, IL). Each
specimen container was then placed into its own
biohazard sealed bag and placed upright in a trans-
port container. At 4 hours and 24 hours after
immersion, specimens from each group were selected
and retrieved from the containers. One end of the
vessel was cut off, and the contents expressed,
examined under loupe magnification, and
photographed.
In addition, while dissecting the facial arteries, I also
decided to perform the same study with facial vein
segments, using the same experimental and control
conditions. There were 2 specimens in each group for
both the experimental and control groups for 4 and
24 hours (8 arterial specimens and 8 venous
specimens).
Figure 3. Tied-off segment of facial artery, filled with HA
filler (HA “sausage”), inside plastic specimen container.
40:8:AUGUST 2014 835
 DEGRADATION OF HA FILLER BY HYAL

Results

In the control groups of arterial and venous vessel

specimens immersed in normal saline, the gel appeared
to be intact (unchanged) on qualitative visual inspec-
tion (Figures 4 and 5). The specimens that were
immersed in 300 IU of HYAL were hydrolyzed (i.e.,
appeared to be completely liquefied) at both 4 hours
and at 24 hours (Table 2). In other words, the con-
tents of the vessels in the experimental condition
(HYAL) were very watery, and there was no evidence
of the thick gel consistency seen in the control
specimens. The results with the facial vein segments
were the same (Figures 6 and 7, right side of image
shows vein before and after cutting open after
immersion in HYAL).

Figure 5. Close-up (macro) photograph of cohesive gel

Discussion
Physicians have been recommending the use of HYAL
injection (among other treatments; Table 1 and Figures
6–8) into the region of dermal ischemia after accidental
intra-arterial injection for many years.2,3,5,8–10,119 Until
now, there has never been any laboratory evidence that
shows that HYAL penetrates the intact arterial wall to
have an effect on the HA embolus contained therein.
The benefit of this study was that it demonstrated that
contained in arterial specimen in normal saline immersion
condition (control group) appears similar to gel in syringe
with no apparent degradation upon visual inspection.
HYAL does indeed have the desired effect on HA
embolic material in a laboratory model that roughly
approximates the clinical situation of an accidental
intravascular injection of HA material.

Figure 6. Arterial and venous specimens retrieved from

Figure 4. At division, arterial specimen in control group
(immersed in 4 mL of normal saline only), containing thick
gel material. Compare contents of vessel with HYAL-
immersed specimens in Figures 7 and 8.
immersion in separate vials of bovine testicular HYAL
300 IU (experimental group), before cutting open to
examine contents. Vessels still appear to be plump and full
of material. Compares favorable to Figure 3, before
immersion in HYAL. Material does not appear to have
leaked from vessels during immersion in HYAL solution.

836 DERMATOLOGIC SURGERY

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Figure 7. Arterial and venous specimens in the experi-
mental condition contain only thin watery material when
cut open to release contents. No gel is found on visual
inspection of vessel contents. Gel appears to have been
completely hydrolyzed to a thin watery consistency by
HYAL effects through the intact arterial and venous walls.
The amount of HYAL used (300 IU) approximates
what I recommended as a preliminary dose of HYAL in
the clinical setting, although I have used well over 1,000
IU in some cases when lower doses did not deliver
clinical improvement (reperfusion). It would also be of
practical significance to do a dose ranging study with
commonly available HYALs with different HA filler
materials to find the optimal doses of HYAL to use for
different HA fillers. It is known that HYAL rapidly
degrades in situ, but how fast? This is yet another
practical problem: we do not know the duration of the
in vivo enzymatic effectiveness of the various HYALs
available in different locations. Canada, for example,
no longer has a commercial, standardized, pharma-
ceutical grade HYAL on the market, so clinicians are
forced to source it from private compounding phar-
macies (introducing various issues of quality control).
Some formulations may last significantly longer than
others, and this has practical implications because it
would determine the appropriate retreatment interval.
A validated laboratory model is needed to determine
dose response and retreatment intervals.
This would give us a valid dose of HYAL to use for
specific forms of HA fillers and clear up the confusion
Copyright © American Society for Dermatologic Surgery. Unauthorized reproduction of this article is prohibited.
DELORENZI
Figure 8. Close-up photograph of thick-walled arterial
specimen after cutting open 1 end. This vessel was
immersed in 300 IU of HYAL with 2 mL of normal saline for
24 hours. As seen in the photograph, only watery contents
drip out from the vessel, with no evidence of HA gel
material. Compare contents with control group specimens
in Figures 4 and 5. This seems to support the hypothesis
that HYAL can effectively hydrolyze HA through the intact
arterial wall and supports the current clinical practice of
flooding ischemic tissues with HYAL after accidental intra-
arterial HA filler embolization.
that the clinicians have to deal with in determining the
appropriate HYAL dosage, routes of administration,
frequency of repetition of HYAL, and ancillary mas-
sage. I stressed that it has not been shown that HYAL
has this same effect in vivo within 4 hours, and the
reader is cautioned that HYAL degrades rapidly
in vivo so that the effects seen in vitro do not neces-
sarily correlate directly with clinical practice. More
work has to be performed to prove the effectiveness of
this dosage in the clinical sphere. It may be that the
dosage has to be repeated more often because of the
degradation of HYAL enzymatic function in vivo.
The weaknesses of this study include the following
issues:
1. In vivo, HYAL undergoes enzymatic degradation,
whereas in this static bench model, the total
amount of HYAL was presumably unaffected
during the exposure time. Therefore, it may be
presumed that the concentration of HYAL in the
40:8:AUGUST 2014 837
 DEGRADATION OF HA FILLER BY HYAL
experimental container was higher than which
would be normally achieved in vivo with the same
dosage parameters.
2. A possible source of experimental error concerns
the possibility that some of the smaller side
branches of the facial arteries and veins dissected
from the cadaver specimens were missed, despite
the use of a surgical telescope during the dissec-
tion. Therefore, it is possible that the HYAL could
have entered the lumen of the vessels through
undetected small openings causing spurious
results. I was conscious of this possibility, and to
reduce the risk of this error, I put the HA material
inside the vessels under some considerable pres-
sure, so that the segments could be examined for
leaks (see the distended facial artery filled with HA
in Figures 1–3). If leaks were present, but the HA
material was too thick to pass through them, then I
would have expected that the thin watery hydro-
lyzed material inside the “HA sausages” would
have leaked out through these openings during the
hydrolysis phase. As shown in Figure 6, the small
segments were still turgid after exposure to HYAL,
indicating that the contents were still under some
pressure. This suggests that no material had leaked
out in the experimental condition (or passively
leaked in).
3. Ideally, the vessels could have been left in situ, and
the HYAL injected around the vessels to more
closely approximate the clinical scenario. How-
ever, this would have required a large number of
fresh cadaver specimens (which were simply not
available to me). Removing the vessels and
separating them into short tied-off specimens
allowed for control of the length exposure time
to saline or HYAL (of known concentration).
4. Laboratory analysis of the filler material before
and after exposure to HYAL was not performed,
and only qualitative results were obtained in this
study. Numerical results of molecular weight,
viscosity, and other basic properties would clearly
be of greater value in future studies because these
could then be plotted on to a graph to determine
optimal treatment parameters.120 Other detection
methods of HA degradation products include
capillary viscometry, mass spectrometry, gel per-
meation chromatography, and other sophisticated
838 DERMATOLOGIC SURGERY
Copyright © American Society for Dermatologic Surgery. Unauthorized reproduction of this article is prohibited.
techniques used to assess small quantities of
material. Ideally, the material contained within
the vessels would have been measured for viscosity
and molecular weight before and after the exper-
imental condition and compared with the control
groups. Qualitatively, the HYAL-exposed speci-
mens showed that the viscosity was drastically
reduced, as is seen in direct in vitro experiments
when the HA is directly in contact with HYAL in
my unpublished work. Gel permeation chroma-
tography and capillary viscometry would be useful
measurements to evaluate the degradation of the
HA material in this situation because this would
give numerical values rather than simple qualita-
tive results of “liquid or gel” as was performed in
this study. Similarly, measurement of the molec-
ular weight of the product before and after
degradation would be useful to get a numerical,
quantitative result rather than a much weaker
qualitative result.
In this study, a popular monophasic filler was used
(Juvederm Ultra Plus XC; Allergan Inc.). It has been
demonstrated in my unpublished work that polyphasic
compounds (such as Restylane; QMED, Uppsala,
Sweden) respond much more quickly to HYAL than
monophasic products in vitro. It is hypothesized that
this observation is because of the fact that enzymatic
degradation is likely to be orders of magnitude faster in
polyphasic compounds because the exposed surface
area of cross-linked HA is orders of magnitude greater
in polyphasic compounds.121,122 The greater surface
area exposed allows for rapid degradation. The
analogy would be melting an ice cube in comparison
to melting ice chips in water. It would be of significant
clinical importance to replicate this study comparing
monophasic to polyphasic products to see whether the
behavior of the HA products in this model is similar to
what is observed in vitro. This might indicate, for
example, that lower doses of HYAL might be indi-
cated for cases of embolic obstruction with polyphasic
products such as Restylane (Medicis Aesthetics Can-
ada Ltd., Toronto, ON, Canada).
In this study, common bovine testicular HYAL was
used, prepared by a local formulating chemist because
standard pharmaceutical grade HYAL (such as the

ovine sourced Vitrase [ISTA Pharmaceuticals, Irvine,
CA]) is not available in Canada. It would be of practical
interest to repeat the study using different commonly
available HYAL types found in other countries. It may
be of great practical importance if it is found that one
particular type of HYAL is more effective than another
for a given HA filler material. Until then, clinicians are
forced to treat to effect, or in other words, to use as
much HYAL as necessary to get reperfusion.
Conclusion
In an in vitro model of human cadaveric–sourced
facial artery, a complete embolic obstruction of
monophasic filler material will liquefy completely
when subjected to 300 IU of bovine-sourced HYAL
over a period of 4 hours with no visible difference to
naked eye observation at 24 hours.
Acknowledgments I acknowledge the support of the
Mount Sinai Hospital Surgical Skills Centre and the
University of Toronto Medical School for the use of
their facilities and equipment and gracious assistance
of the staff of the Surgical Skills Centre. I purchased the
bovine hyaluronidase (150 IU/mL) for this study from
York Downs Pharmacy, Toronto, Ontario, Canada.
References
1. Lazzeri D, Agostini T, Figus M, Nardi M, et al. Blindness following
cosmetic injections of the face. Plast Reconstr Surg 2012;129:995–1012.
2. Park TH, Seo SW, Kim JK, Chang CH. Clinical experience with
hyaluronic acid-filler complications. J Plast Reconstr Aesthet Surg
2011;64:892–6.
3. Kim DW, Yoon ES, Ji YH, Park SH, et al. Vascular complications of
hyaluronic acid fillers and the role of hyaluronidase in management.
J Plast Reconstr Aesthet Surg 2011;64:1590–5.
4. Kassir R, Kolluru A, Kassir M. Extensive necrosis after injection of
hyaluronic acid filler: case report and review of the literature. J Cosmet
Dermatol 2011;10:224–31.
5. Dayan SH, Arkins JP, Mathison CC. Management of impending
necrosis associated with soft tissue filler injections. J Drugs Dermatol
2011;10:1007–12.
6. Cox SE, Adigun CG. Complications of injectable fillers and
neurotoxins. Dermatol Ther 2011;24:524–36.
7. Mio K, Stern R. Inhibitors of the hyaluronidases. Matrix Biol 2002;
21:31–7.
8. Hirsch RJ, Lupo M, Cohen JL, Duffy D. Delayed presentation of
impending necrosis following soft tissue augmentation with hyaluronic
acid and successful management with hyaluronidase. J Drugs Dermatol
2007;6:325–8.
9. Hirsch RJ, Cohen JL, Carruthers JD. Successful management of an
unusual presentation of impending necrosis following a hyaluronic
Copyright © American Society for Dermatologic Surgery. Unauthorized reproduction of this article is prohibited.
DELORENZI
acid injection embolus and a proposed algorithm for management with
hyaluronidase. Dermatol Surg 2007;33:357–60.
10. Hirsch RJ, Brody HJ, Carruthers JD. Hyaluronidase in the office:
a necessity for every dermasurgeon that injects hyaluronic acid.
J Cosmet Laser Ther 2007;9:182–5.
11. Glaich AS, Cohen JL, Goldberg LH. Injection necrosis of the glabella:
protocol for prevention and treatment after use of dermal fillers.
Dermatol Surg 2006;32:276–81.
12. Grunebaum LD, Bogdan Allemann I, Dayan S, Mandy S, et al. The risk
of alar necrosis associated with dermal filler injection. Dermatol Surg
2009;35(suppl 2):1635–40.
13. Sclafani AP, Fagien S. Treatment of injectable soft tissue filler
complications. Dermatol Surg 2009;35(suppl 2):1672–80.
14. Van Dyke S, Hays GP, Caglia AE, Caglia M. Severe acute local
reactions to a hyaluronic acid-derived dermal Filler. J Clin Aesthet
Dermatol 2010;3:32–5.
15. Anitua Solano M, Guijarro de Pablos JE, Ortega Navas A,
Gastaca Bilbao JM, et al. An extreme case of Nicolau syndrome
[in Spanish]. Angiologia 1983;35:73–85.
16. Bajaj DR, Qureshi AA. Embolia cutis medicamentosa. J Coll Physicians
Surg Pak 2005;15:187–8.
17. Beissert S, Presser D, Rutter A, Metze D, et al. Embolia cutis
medicamentosa (Nicolau syndrome) after intra-articular injection [in
German]. Hautarzt 1999;50:214–6.
18. Cernescu C. Romanian HIV-AIDS epidemic after a decade of
evolution. Rom J Virol 1999;50:5–15.
19. Cherasse A. Nicolau’s syndrome after local glucocorticoid injection.
Joint Bone Spine 2003;70:390–2.
20. De Sousa R, Dang A, Rataboli PV. Nicolau syndrome following
intramuscular benzathine penicillin. J Postgrad Med 2008;54:332.
21. Deutsch J. Severe local reaction to benzathine penicillin. A contribution
to the Nicolau syndrome (dermatitis livedoides) [in German]. Dtsch
Gesundheitsw 1966;21:2433–7.
22. Dupre A, Carrere S, Bonafe JL, Christol B, et al. Eruptive generalized
syringomas, milium and atrophoderma vermiculata. Nicolau and Balus’
syndrome (author’s transl) [in French]. Dermatologica 1981;162:281–6.
23. Erkek E, Tuncez F, Sanli C, Duman D, et al. Nicolau’s syndrome in
a newborn caused by triple DTP (diphtheria-tetanus-pertussis)
vaccination. J Am Acad Dermatol 2006;54:S241–2.
24. Ezzedine K, Vadoud-Seyedi J, Heenen M. Nicolau syndrome following
diclofenac administration. Br J Dermatol 2004;150:385–7.
25. Faucher L, Marcoux D. What syndrome is this? Nicolau syndrome.
Pediatr Dermatol 1995;12:187–90.
26. Forsbach Sanchez G, Eloy Tamez H. Nicolau syndrome caused by
intramuscular administration of diclofenac. Rev Invest Clin 1999;51:71.
27. Garcia-Vilanova-Comas A, Fuster-Diana C, Cubells-Parrilla M,
Perez-Ferriols MD, et al. Nicolau syndrome after lidocaine injection and
cold application: a rare complication of breast core needle biopsy. Int J
Dermatol 2010;50:78–80.
28. Gebert K. Embolitic lumbar artery occlusion following
benzathinpenicillin (penduran). A case contribution to Nicolau
syndrome in adults [in German]. Psychiatr Neurol Med Psychol (Lepiz)
1980;32:443–6.
29. Guarneri C, Polimeni G. Nicolau syndrome following etanercept
administration. Am J Clin Dermatol 2010;11(suppl 1):51–2.
30. Hamilton B, Fowler P, Galloway H, Popovic N, et al. Nicolau
syndrome in an athlete following intra-muscular diclofenac injection.
Acta Orthop Belg 2008;74:860–4.
40:8:AUGUST 2014 839
 DEGRADATION OF HA FILLER BY HYAL
31. Koklu E, Sarici SU, Altun D, Erdeve O. Nicolau syndrome induced by
intramuscular vitamin K in a premature newborn. Eur J Pediatr 2009;
168:1541–2.
32. Koller S, Kranke B. Nicolau syndrome following subcutaneous
glatiramer-acetate injection. J Am Acad Dermatol 2010;64:e16–7.
33. Lansky H. Nicolau syndrome from the viewpoint of the surgeon [in
German]. Zentralbl Chir 1970;95:1194–7.
34. Lee DP, Bae GY, Lee MW, Choi JH, et al. Nicolau syndrome caused by
piroxicam. Int J Dermatol 2005;44:1069–70.
35. Lie C, Leung F, Chow SP. Nicolau syndrome following intramuscular
diclofenac administration: a case report. J Orthop Surg (Hong Kong)
2006;14:104–7.
36. Luton K, Garcia C, Poletti E, Koester G. Nicolau syndrome: three cases
and review. Int J Dermatol 2006;45:1326–8.
37. Masthan SD, Salome M, Madhav, Reddy KC, et al. Nicolau syndrome.
Indian J Dermatol Venereol Leprol 2002;68:45–6.
38. Modzelewska I, Dawidowicz-Szczepanowska A. Nicolau syndrome
following administration of procaine penicillin. Wiad Lek 1980;33:231–3.
39. Muller-Vahl H. Aseptic tissue necrosis: a severe complication after
intramuscular injections [in German]. Dtsch Med Wochenschr 1984;
109:786–92.
40. Muller-Vahl H, Pabst R. An animal model for aseptic necrosis after
intramuscular injections. Int J Tissue React 1984;6:251–4.
41. Mutalik S, Belgaumkar V. Nicolau syndrome: a report of 2 cases.
J Drugs Dermatol 2006;5:377–8.
42. Nagore E, Torrelo A, Gonzalez-Mediero I, Zambrano A. Livedoid skin
necrosis (Nicolau syndrome) due to triple vaccine (DTP) injection. Br J
Dermatol 1997;137:1030–1.
43. Nicolau S. Dermite livédoide et gangréneuse de la consécutive au
injections intra-musculaires dans la syphilis. A propos d’un cas
d’embolie artérielle bismuthique. Ann Mal Vénér 1925;20:321–29.
44. Niedner A, Tiller R. Nicolau syndrome following retacillin compositum
injection [in German]. Z Arztl Fortbild (Jena) 1970;64:39–42.
45. Nischal K, Basavaraj H, Swaroop M, Agrawal D, et al. Nicolau syndrome:
an iatrogenic cutaneous necrosis. J Cutan Aesthet Surg 2009;2:92–5.
46. Ocak S, Ekici B, Cam H, Tastan Y. Nicolau syndrome after intramuscular
benzathine penicillin treatment. Pediatr Infect Dis J 2006;25:749.
47. Okan G, Canter HI. Nicolau syndrome and perforator vessels: a new
viewpoint for an old problem. Cutan Ocul Toxicol 2010;29:70–2.
48. Ozcan A, Senol M, Aydin EN, Aki T. Embolia cutis medicamentosa
(nicolau syndrome): two cases due to different drugs in distinct age
groups. Clin Drug Investig 2005;25:481–3.
49. Panariello L, Ayala F. Nicolau syndrome following intramuscular
diclofenac injection: a case report. Dermatol Ther 2008;21(suppl 1):S10–2.
50. Park HJ, Kim MS, Park NH, Jung SW, et al. Sonographic findings in
Nicolau syndrome following intramuscular diclofenac injection: a case
report. J Clin Ultrasound 2010;39:111–3.
51. Rygnestad T, Kvam AM. Streptococcal myositis and tissue necrosis
with intramuscular administration of diclofenac (Voltaren). Acta
Anaesthesiol Scand 1995;39:1128–30.
52. Saputo V, Bruni G. Nicolau syndrome caused by penicillin
preparations: review of the literature in search for potential risk factors
[in Italian]. Pediatr Med Chir 1998;20:105–23.
53. Sarifakioglu E. Nicolau syndrome after diclofenac injection. J Eur Acad
Dermatol Venereol 2007;21:266–7.
54. Schroter K, Lorenz K. Nicolau syndrome, form of drug-induced
embolism. Clinical picture–etiology and pathogenesis–prevention–
840 DERMATOLOGIC SURGERY
Copyright © American Society for Dermatologic Surgery. Unauthorized reproduction of this article is prohibited.
comparison with Hoigne syndrome [in German]. Z Arztl Fortbild
1971;65:725–31.
55. Senel E, Ada S, Gulec AT, Caglar B. Nicolau syndrome aggravated by
cold application after i.m. diclofenac. J Dermatol 2008;35:18–20.
56. Stechly HJ. 2 cases of Nicolau syndrome in children [in Polish]. Pediatr
Pol 1982;57:267–70.
57. Stechly HJ. Nicolau syndrome. Pediatr Pol 1982;57:287–92.
58. Stiehl P, Weissbach G, Schroter K. Nicolau syndrome. Pathogenesis
and clinical aspects of penicillin-induced arterial embolism. Schweiz
Med Wochenschr 1971;101:377–85.
59. Stricker BH, van Kasteren BJ. Diclofenac-induced isolated myonecrosis
and the Nicolau syndrome. Ann Intern Med 1992;117:1058.
60. Taraszkiewicz F, Kiss B, Szorc W, Gruntowicz A, et al. Nicolau
syndrome. Pol Tyg Lek 1979;34:1759–61.
61. Uri O, Behrbalk E. Tissue necrosis following intramuscular administration
of various drugs (Nicolau syndrome): clinical presentation, pathophysiology
and treatment [in Hebrew]. Harefuah 2009;148:186–8, 209.
62. Varga L, Asztalos L. Nicolau syndrome after ketazon injection [in
Hungarian]. Orv Hetil 1990;131:1143–6.
63. Weinmann G, Schaefer L. Nicolau syndrome—a complication of depot-
penicillin therapy [in German]. Acta Paediatr Acad Sci Hung 1977;18:41–5.
64. Wronecki K, Czernik J. The Nicolau syndrome in children (author’s
transl) [in German]. Z Kinderchir 1981;32:367–70.
65. Freudenthal W. Lokales embolisches bismogenol-exanthem. Arch
Dermatol Syph 1924;147:155–60.
66. Albrecht KH, Littmann K, Richter HJ, Eigler FW. Animal experiment
studies of embolia cutis medicamentosa [in German]. Langenbecks
Arch Chir 1984;362:17–23.
67. Bockers M, Bohm G. Embolia cutis medicamentosa. Circumscribed
skin necrosis following intramuscular injections [in German]. Med
Welt 1983;34:1450–3.
68. Brachtel R. Embolia cutis medicamentosa (author’s transl) [in
German]. Med Klin 1976;71:504–6.
69. Brachtel R, Meinertz T. Local skin necroses after intramuscular injection—
experimental animal studies. Arch Dermatol Res 1977;258:281–8.
70. Dill-Muller D. Medical emergencies following dermatological
injections and infusions [in German]. Hautarzt 2006;57:195–201.
71. Geukens J, Rabe E, Bieber T. Embolia cutis medicamentosa of the foot
after sclerotherapy. Eur J Dermatol 1999;9:132–3.
72. Guarneri C, Polimeni G, Guarneri F, Cuzzocrea S. Embolia cutis
medicamentosa following thiocolchicoside injection. J Eur Acad
Dermatol Venereol 2008;22:1005–6.
73. Harde V, Schwarz T. Embolia cutis medicamentosa following subcutaneous
injection of glatiramer acetate. J Dtsch Dermatol Ges 2007;5:1122–3.
74. Kienast AK, Mentze D, Hoeger PH. Nicolau’s syndrome induced
by intramuscular vaccinations in children: report of seven patients and
review of the literature. Clin Exp Dermatol 2008;33:555–8.
75. Kohler LD, Schwedler S, Worret WI. Embolia cutis medicamentosa. Int
J Dermatol 1997;36:197.
76. Kohler LD, Worret WI, Hofmann H. Atypical zosteriform segmental
embolia cutis medicamentosa [in German]. Hautarzt 1997;48:492–5.
77. Koontz D, Alshekhlee A. Embolia cutis medicamentosa following
interferon beta injection. Mult Scler 2007;13:1203–4.
78. Kunzi T, Ramstein C, Pirovino M. Circumscribed skin necrosis
following intramuscular injection (embolia cutis medicamentosa)
[in German]. Praxis (Bern 1994) 1995;84:640–3.

79. Lee MW, Kim KJ, Choi JH, Sung KJ, et al. A case of embolia cutis
medicamentosa. J Dermatol 2003;30:927–8.
80. Marangi GF, Gigliofiorito P, Toto V, Langella M, et al. Three cases of
embolia cutis medicamentosa (Nicolau’s syndrome). J Dermatol 2010;
37:488–92.
81. Rauch HJ. Embolia cutis medicamentosa [in German]. Wien Med
Wochenschr 1982;132:395–7.
82. Razinskas G, Lechner W. Embolia cutis medicamentosa following
intramuscular injection of pyrazolone-containing preparations [in
German]. Z Hautkr 1985;60:1639–45.
83. Sonntag M, Hodzic-Avdagic N, Bruch-Gerharz D, Neumann NJ.
Embolia cutis medicamentosa after subcutaneous injection of
pegylated interferon-alpha [in German]. Hautarzt 2005;56:968–9.
84. Silva MT, Curi AL. Blindness and total ophthalmoplegia after aesthetic
polymethylmethacrylate injection: case report. Arq Neuropsiquiatr
2004;62:873–4.
85. Toyoda H, Muraki F, Imanari T, Kinoshita-Toyoda A.
Microdetermination of hyaluronan in human plasma by high-
performance liquid chromatography with a graphitized carbon column
and postcolumn fluorometric detection. J Chromatogr B Analyt
Technol Biomed Life Sci 2011;879:950–4.
86. Garg HG, Hales CA. Chemistry and biology of hyaluronan (1st ed).
Elsevier: Amsterdam; Boston, 2004; pp. 1 online resource (xviii, 605 p).
87. Laurent TC. The chemistry, biology, and medical applications of
hyaluronan and its derivatives. Portland Press: London; Miami, 1998.
88. Meyer K. The biological significance of hyaluronic acid and
hyaluronidase. Physiol Rev 1947;27:335–59.
89. Jiang D, Liang J, Noble PW. Hyaluronan as an immune regulator in
human diseases. Physiol Rev 2010;91:221–64.
90. Guo N, Li X, Mann MM, Funderburgh ML, et al. Hyaluronan
synthesis mediates the fibrotic response of keratocytes to transforming
growth factor beta. J Biol Chem 2010;285:32012–9.
91. El Maradny E, Kanayama N, Kobayashi H, Hossain B, et al. The role
of hyaluronic acid as a mediator and regulator of cervical ripening.
Hum Reprod 1997;12:1080–8.
92. Price RD, Berry MG, Navsaria HA. Hyaluronic acid: the scientific and
clinical evidence. J Plast Reconstr Aesthet Surg 2007;60:1110–9.
93. Girish KS, Kemparaju K. The magic glue hyaluronan and its eraser
hyaluronidase: a biological overview. Life Sci 2007;80:1921–43.
94. Reed RK, Laurent UB, Fraser JR, Laurent TC. Removal rate of [3H]
hyaluronan injected subcutaneously in rabbits. Am J Physiol 1990;259:
H532–5.
95. Edsman K, Nord LI, Öhrlund  A, Lärkner H, et al. Gel properties of
hyaluronic acid dermal fillers. Dermatol Surg 2012;38:1170–79.
96. Flynn TC, Sarazin D, Bezzola A, Terrani C, et al. Comparative
histology of intradermal implantation of mono and biphasic
hyaluronic acid fillers. Dermatol Surg 2011;37:637–43.
97. Borrell M, Leslie DB, Tezel A. Lift capabilities of hyaluronic acid fillers.
J Cosmet Laser Ther 2011;13:21–7.
98. Stern R, Jedrzejas MJ. Hyaluronidases: their genomics, structures, and
mechanisms of action. Chem Rev 2006;106:818–39.
99. Menzel EJ, Farr C. Hyaluronidase and its substrate hyaluronan:
biochemistry, biological activities and therapeutic uses. Cancer Lett
1998;131:3–11.
100. Meyer K, Rapport MM. Hyaluronidases. Adv Enzymol Relat Subj
Biochem 1952;13:199–236.
101. Gills JP, Loyd TL. A technique of retrobulbar block with paralysis of
orbicularis oculi. J Am Intraocul Implant Soc 1983;9:339–40.
Copyright © American Society for Dermatologic Surgery. Unauthorized reproduction of this article is prohibited.
DELORENZI
102. Spandorfer PR. Subcutaneous rehydration: updating a traditional
technique. Pediatr Emerg Care 2011;27:230–6.
103. Dunn AL, Heavner JE, Racz G, Day M. Hyaluronidase: a review of
approved formulations, indications and off-label use in chronic pain
management. Expert Opin Biol Ther 2010;10:127–31.
104. Hechter O, Dopkeen SK, Yudell MH. The clinical use of hyaluronidase
in hypodermoclysis. J Pediatr 1947;30:645–56.
105. Goolsby TV, Lombardo FA. Extravasation of chemotherapeutic
agents: prevention and treatment. Semin Oncol 2006;33:139–43.
106. Lambros V. The use of hyaluronidase to reverse the effects of
hyaluronic acid filler. Plast Reconstr Surg 2004;114:277.
107. Soparkar CN, Patrinely JR, Tschen J. Erasing restylane. Ophthal Plast
Reconstr Surg 2004;20:317–8.
108. Brody HJ. Use of hyaluronidase in the treatment of granulomatous
hyaluronic acid reactions or unwanted hyaluronic acid misplacement.
Dermatol Surg 2005;31:893–7.
109. Pierre A, Levy PM. Hyaluronidase offers an efficacious treatment for
inaesthetic hyaluronic acid overcorrection. J Cosmet Dermatol 2007;6:
159–62.
110. Smith KC. Reversible vs. nonreversible fillers in facial aesthetics:
concerns and considerations. Dermatol Online J 2008;14:3.
111. Rzany B, Becker-Wegerich P, Bachmann F, Erdmann R, et al.
Hyaluronidase in the correction of hyaluronic acid-based fillers: a review
and a recommendation for use. J Cosmet Dermatol 2009;8:317–23.
112. Menon H, Thomas M, D’Silva J. Low dose of hyaluronidase to treat
over correction by HA filler—a case report. J Plast Reconstr Aesthet
Surg 2010;63:e416–7.
113. Cohen JL. Understanding, avoiding, and managing dermal filler
complications. Dermatol Surg 2008;34(suppl 1):S92–9.
114. Georgescu D, Jones Y, McCann JD, Anderson RL. Skin necrosis after
calcium hydroxylapatite injection into the glabellar and nasolabial folds.
Ophthal Plast Reconstr Surg 2009;25:498–9.
115. Kleydman K, Cohen JL, Marmur E. Nitroglycerin: a review of its use in
the treatment of vascular occlusion after soft tissue augmentation.
Dermatol Surg 2012;38:1889–97.
116. Zhang Q, Chang Q, Cox RA, Gong X, et al. Hyperbaric oxygen
attenuates apoptosis and decreases inflammation in an ischemic wound
model. J Invest Dermatol 2008;128:2102–12.
117. Thom SR. Hyperbaric oxygen: its mechanisms and efficacy. Plast
Reconstr Surg 2011;127(suppl 1):131S–41S.
118. Steigerwalt RD Jr, Cesarone MR, Pascarella A, De Angelis M, et al.
Ocular and optic nerve ischemia: recognition and treatment
with intravenous prostaglandin E1. Panminerva Med 2011;53:119–24.
119. MacKenzie AR. Adverse effects from intravascular injection of
hyaluronic acid. J Drugs Dermatol 2007;6:581; author reply 81.
120. Tezel A, Fredrickson GH. The science of hyaluronic acid dermal fillers.
J Cosmet Laser Ther 2008;10:35–42.
121. Sall I, Ferard G. Comparison of the sensitivity of 11 crosslinked
hyaluronic acid gels to bovine testis hyaluronidase. Polym Degrad
Stabil 2007;92:915–19.
122. Jones D, Tezel A, Borrell M. In vitro resistance to degradation of
hyaluronic acid dermal fillers by ovine testicular hyaluronidase.
Dermatol Surg 2010;36:804–9.
Address correspondence and reprint requests to: Claudio
DeLorenzi, BA, MD, FRCS, DeLorenzi Clinic, 150 Edna
Street, Kitchener, ON N2H 6S1, Canada, or e-mail:
fillercomplication@gmail.com
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