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Transarterial Degradation of Hyaluronic Acid Filler Allergan
by Hyaluronidase IT/ADBD0219/18c

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

Private Practice, DeLorenzi Clinic, Kitchener-Waterloo, Ontario, Canada

· · ·
© 2014 by the American Society for Dermatologic Surgery, Inc. Published by Lippincott Williams & Wilkins
ISSN: 1076-0512 Dermatol Surg 2014;0:1–10 DOI: 10.1097/DSS.0000000000000062
·
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Copyright © American Society for Dermatologic Surgery. Unauthorized reproduction of this article is prohibited.
 DEGRADATION OF HA FILLER BY HYAL

activation of intravascular blood clotting (as with susceptibility to HYAL, allowing its use as a cosmetic
collagen), or even by sclerosing reactions to the blood filling agent that is well tolerated95 of reasonable
vessels themselves. In the case of HA fillers, the root duration. Most of the commercial products currently
cause of the vascular obstruction is due to simple available use nonanimal–derived HA (typically from
mechanical obstruction of the vessel. Streptococcus equi subspecies) that is cross-linked
with a plasticizing agent, 1,4-butanediol diglycidyl
Once the HA material has entered an artery, most ether.96 This process creates intermolecular bonds
commonly the embolic material will be carried distally that create a molecule that is more stable than non–
in the normal direction of blood flow, progressively cross-linked HA and allows for longer duration in
into smaller sized vessels until such time as the material situ. Different companies use different techniques and
can no longer pass any further distally, resulting in proportions of the different forms of available HA
complete obstruction. In the absence of sufficient col- in their manufacturing process and combine the
lateral blood supply, tissue ischemia and eventually cross-linked product with varying percentages of
tissue necrosis may result. If injected at high pressures non–cross-linked HA, creating a plethora of for-
and at a rapid rate, the embolus may also paradoxi- mulations that differ in gel hardness, consistency, and
cally flow retrograde to the normal direction of blood lifting capacity.97
flow. A large bolus, after pushing backward inside an
artery into progressively larger vessels, may then get The HYALs are actually a family of enzymes that cat-
sidetracked into other branches of the vessel. From alyze the hydrolysis of HA.98–100 Hyaluronidase has
there, fillers may then be carried to distal sites through been used for various purposes in clinical medicine,
proximal vascular tributaries, creating a “paradoxi- including dispersion of local anesthetics in retrobulbar
cal” ischemic area far from the site of original block,101 hypodermoclysis,102–104 and treatment of
injection. For example, there are several clinical extravasation injuries.105 Hyaluronidase has also been
reports of blindness occurring after filler injec- shown to be effective in vivo in reducing the amount
tion.1,84,85 Clinically, this phenomenon has even of HA present in unaesthetic results.10,106–112 In cases
occurred from the contralateral side where filler of accidental intravascular injection, HYAL is gen-
injected, for example, into the left nasolabial fold erally used to break down the longer, viscous, cohe-
region has resulted in blindness in the right eye, the sive HA chains into small pieces, resulting in a drastic
filler crossing the midline through the extensive vas- decrease in viscosity, so that the HA degradation
cular collaterals in the nasal region connecting the products can pass through vessels such that vascular
periorbital internal carotid vascular territory to those obstruction is relieved. To date, no one has demon-
of the perioral external carotid territory. strated 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,
Hyaluronic Acid and Hyaluronidase
then presumably physicians would have to try to inject
Hyaluronic acid is a high–molecular weight poly- HYAL directly into an occluded vessel, technically
saccharide that has many biologic functions in the challenging as it may be.
extracellular matrix of humans and animals86–88 and
is intimately involved in cell migration, wound
Treatment of Vascular Obstruction
healing, embryogenesis, and even plays important
roles in the pathogenesis of malignant cancers,89–92 to The ultimate goal of treatment, once HA filler is
mention but a few.93 It is a rather viscous substance blocking access of fresh arterial blood, is to restore the
and has many truly remarkable properties.88 At circulation to the affected area to prevent ischemic
physiologic concentrations, it is rapidly degraded (at necrosis (see Table 1 for a list of commonly used
approximately the same rate as serum albumin) in modalities). Current strategies involve the immediate
lymph nodes and the liver.94 By altering the structure use of mechanical means (massage) to break up the
of HA slightly by cross-linking, reduces its embolus and move it so that collateral circulation

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Copyright © American Society for Dermatologic Surgery. Unauthorized reproduction of this article is prohibited.
 DELORENZI

TABLE 1. Emergency Treatment of Accidental Intra-arterial Injection of HA-Based Dermal Fillers

HYAL 300–600 IU injection into ischemic Inject slowly and massage vigorously to maintain HYAL in the region
tissues 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 massage Warm compresses and vigorous massage to help vasodilate and to
break up embolic material into smaller pieces and to open up
collateral vessels
Topical nitropaste Use 1–2 cm under occlusion at site of compromise, monitor vital signs,
and be aware of hypotension
ASA 72 mg by mouth once daily Antiplatelet effect to help reduce intravascular clotting in regions of
decreased perfusion
Hyperbaric oxygen May help to reduce size of necrosis by providing oxygenation to
marginally viable tissues until vessel ingrowth occurs
Prostaglandin E1 injection Usually administered under careful observation. Vasodilation may
lower blood pressure rapidly
Low–molecular weight heparin Risk of bleeding, requires careful monitoring of coagulation profile

See text for context and References 1–6,53,77–90.

might help restore blood flow. Antiplatelet therapy shown promise in similar types of ischemic
(e.g., low-dose acetylsalicylic acid [ASA]) is used, injury.116,117 Prostaglandin E1 injection has also been
which has been shown to be beneficial in other types recommended as a vasodilator (commonly used in
of acute ischemic injury. Typically, low-dose ASA 72 treatment of erectile dysfunction). Prostaglandin E1
mg by mouth is recommended immediately on has been shown to be helpful in various types of
diagnosis (Table 2).7 Systemic anticoagulation has ischemic injuries and ischemia-reperfusion scenar-
also been tried on occasion for filler embolic ios,118 but this treatment is usually provided in hos-
events,113 using the same rationale used for anti- pital under careful supervision. Hylaluronidase has
coagulation in acute coronary syndromes. Warm been recommended2,3,7,9,10 because it is believed to be
compresses may also be helpful to cause vasodilata- clinically effective in reduction of the size of the
tion, and topical nitro paste7,8,11,114 has been shown ischemic lesion by enzymatically breaking down the
to be effective to improve flow in small dermal embolus so that effective circulation can be restored.
arterioles.115 Hyperbaric oxygen has also been rec- A recent laboratory study in a rabbit ear model
ommended to reduce the size of ischemic tissue until clearly showed that HYAL was effective in preventing
vascular ingrowth can occur. Hyperbaric therapy has 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
TABLE 2. Experimental Results (Contents of could penetrate through an intact arterial wall and
Vessels After Immersion) visibly break down HA contained within a human
4 Hours 24 Hours facial artery specimen.

HYAL 300 IU No gel No gel

Methods
Normal saline Gel Gel

Arterial specimens filled with monophasic HA gel were

After an anatomic teaching session on fresh human
separately immersed in either 4 mL of normal saline or 2 mL of cadavers, the facial arteries were dissected under direct
normal saline plus 2 mL of bovine testicular HYAL (150 IU/mL).
Arterial segments immersed in HYAL contained only watery visualization using loupe magnification (Figure 1).
fluid at both 4 and 24 hours, with no remaining gel, whereas After direct cannulation in situ, the arteries were filled
specimens immersed in saline alone contained apparently
intact HA gel. with Juvederm Ultra Plus XC (Allergan Inc.,
Markham, ON, Canada). Then, I tied off any side

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 DEGRADATION OF HA FILLER BY HYAL

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,
Figure 1. Right fresh cadaver facial artery in situ, filled with
HA filler, before suture of branches of facial artery. Dis- examined under loupe magnification, and
section performed under loupe magnification, and arterial photographed.
branches subsequently tied off with fine suture material.

In addition, while dissecting the facial arteries, I also

branches with fine suture material under loupe
decided to perform the same study with facial vein
magnification. Distending the vessel with filler
segments, using the same experimental and control
material helped to fill these side branches and
conditions. There were 2 specimens in each group for
improved visualization of the entire facial artery,
both the experimental and control groups for 4 and
angular artery, and the collateral vessels in the
24 hours (8 arterial specimens and 8 venous
mid-face. Once the side branches were all tied off and
specimens).
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 Figure 3. Tied-off segment of facial artery, filled with HA
and 300 IU of bovine testicular HYAL (experimental group). filler (HA “sausage”), inside plastic specimen container.

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 DELORENZI

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

Figure 6. Arterial and venous specimens retrieved from

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

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 DEGRADATION OF HA FILLER BY HYAL

Figure 7. Arterial and venous specimens in the experi- Figure 8. Close-up photograph of thick-walled arterial
mental condition contain only thin watery material when specimen after cutting open 1 end. This vessel was
cut open to release contents. No gel is found on visual immersed in 300 IU of HYAL with 2 mL of normal saline for
inspection of vessel contents. Gel appears to have been 24 hours. As seen in the photograph, only watery contents
completely hydrolyzed to a thin watery consistency by drip out from the vessel, with no evidence of HA gel
HYAL effects through the intact arterial and venous walls. 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
The amount of HYAL used (300 IU) approximates arterial wall and supports the current clinical practice of
what I recommended as a preliminary dose of HYAL in flooding ischemic tissues with HYAL after accidental intra-
arterial HA filler embolization.
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 that the clinicians have to deal with in determining the
practical significance to do a dose ranging study with appropriate HYAL dosage, routes of administration,
commonly available HYALs with different HA filler frequency of repetition of HYAL, and ancillary mas-
materials to find the optimal doses of HYAL to use for sage. I stressed that it has not been shown that HYAL
different HA fillers. It is known that HYAL rapidly has this same effect in vivo within 4 hours, and the
degrades in situ, but how fast? This is yet another reader is cautioned that HYAL degrades rapidly
practical problem: we do not know the duration of the in vivo so that the effects seen in vitro do not neces-
in vivo enzymatic effectiveness of the various HYALs sarily correlate directly with clinical practice. More
available in different locations. Canada, for example, work has to be performed to prove the effectiveness of
no longer has a commercial, standardized, pharma- this dosage in the clinical sphere. It may be that the
ceutical grade HYAL on the market, so clinicians are dosage has to be repeated more often because of the
forced to source it from private compounding phar- degradation of HYAL enzymatic function in vivo.
macies (introducing various issues of quality control).
Some formulations may last significantly longer than The weaknesses of this study include the following
others, and this has practical implications because it issues:
would determine the appropriate retreatment interval.
A validated laboratory model is needed to determine 1. In vivo, HYAL undergoes enzymatic degradation,
dose response and retreatment intervals. whereas in this static bench model, the total
amount of HYAL was presumably unaffected
This would give us a valid dose of HYAL to use for during the exposure time. Therefore, it may be
specific forms of HA fillers and clear up the confusion presumed that the concentration of HYAL in the

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 DELORENZI

experimental container was higher than which techniques used to assess small quantities of
would be normally achieved in vivo with the same material. Ideally, the material contained within
dosage parameters. the vessels would have been measured for viscosity
2. A possible source of experimental error concerns and molecular weight before and after the exper-
the possibility that some of the smaller side imental condition and compared with the control
branches of the facial arteries and veins dissected groups. Qualitatively, the HYAL-exposed speci-
from the cadaver specimens were missed, despite mens showed that the viscosity was drastically
the use of a surgical telescope during the dissec- reduced, as is seen in direct in vitro experiments
tion. Therefore, it is possible that the HYAL could when the HA is directly in contact with HYAL in
have entered the lumen of the vessels through my unpublished work. Gel permeation chroma-
undetected small openings causing spurious tography and capillary viscometry would be useful
results. I was conscious of this possibility, and to measurements to evaluate the degradation of the
reduce the risk of this error, I put the HA material HA material in this situation because this would
inside the vessels under some considerable pres- give numerical values rather than simple qualita-
sure, so that the segments could be examined for tive results of “liquid or gel” as was performed in
leaks (see the distended facial artery filled with HA this study. Similarly, measurement of the molec-
in Figures 1–3). If leaks were present, but the HA ular weight of the product before and after
material was too thick to pass through them, then I degradation would be useful to get a numerical,
would have expected that the thin watery hydro- quantitative result rather than a much weaker
lyzed material inside the “HA sausages” would qualitative result.
have leaked out through these openings during the
hydrolysis phase. As shown in Figure 6, the small In this study, a popular monophasic filler was used
segments were still turgid after exposure to HYAL, (Juvederm Ultra Plus XC; Allergan Inc.). It has been
indicating that the contents were still under some demonstrated in my unpublished work that polyphasic
pressure. This suggests that no material had leaked compounds (such as Restylane; QMED, Uppsala,
out in the experimental condition (or passively Sweden) respond much more quickly to HYAL than
leaked in). monophasic products in vitro. It is hypothesized that
3. Ideally, the vessels could have been left in situ, and this observation is because of the fact that enzymatic
the HYAL injected around the vessels to more degradation is likely to be orders of magnitude faster in
closely approximate the clinical scenario. How- polyphasic compounds because the exposed surface
ever, this would have required a large number of area of cross-linked HA is orders of magnitude greater
fresh cadaver specimens (which were simply not in polyphasic compounds.121,122 The greater surface
available to me). Removing the vessels and area exposed allows for rapid degradation. The
separating them into short tied-off specimens analogy would be melting an ice cube in comparison
allowed for control of the length exposure time to melting ice chips in water. It would be of significant
to saline or HYAL (of known concentration). clinical importance to replicate this study comparing
4. Laboratory analysis of the filler material before monophasic to polyphasic products to see whether the
and after exposure to HYAL was not performed, behavior of the HA products in this model is similar to
and only qualitative results were obtained in this what is observed in vitro. This might indicate, for
study. Numerical results of molecular weight, example, that lower doses of HYAL might be indi-
viscosity, and other basic properties would clearly cated for cases of embolic obstruction with polyphasic
be of greater value in future studies because these products such as Restylane (Medicis Aesthetics Can-
could then be plotted on to a graph to determine ada Ltd., Toronto, ON, Canada).
optimal treatment parameters.120 Other detection
methods of HA degradation products include In this study, common bovine testicular HYAL was
capillary viscometry, mass spectrometry, gel per- used, prepared by a local formulating chemist because
meation chromatography, and other sophisticated standard pharmaceutical grade HYAL (such as the

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 DEGRADATION OF HA FILLER BY HYAL

ovine sourced Vitrase [ISTA Pharmaceuticals, Irvine, acid injection embolus and a proposed algorithm for management with
hyaluronidase. Dermatol Surg 2007;33:357–60.
CA]) is not available in Canada. It would be of practical
10. Hirsch RJ, Brody HJ, Carruthers JD. Hyaluronidase in the office:
interest to repeat the study using different commonly a necessity for every dermasurgeon that injects hyaluronic acid.
available HYAL types found in other countries. It may J Cosmet Laser Ther 2007;9:182–5.

be of great practical importance if it is found that one 11. Glaich AS, Cohen JL, Goldberg LH. Injection necrosis of the glabella:
protocol for prevention and treatment after use of dermal fillers.
particular type of HYAL is more effective than another Dermatol Surg 2006;32:276–81.
for a given HA filler material. Until then, clinicians are 12. Grunebaum LD, Bogdan Allemann I, Dayan S, Mandy S, et al. The risk
forced to treat to effect, or in other words, to use as of alar necrosis associated with dermal filler injection. Dermatol Surg
2009;35(suppl 2):1635–40.
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13. Sclafani AP, Fagien S. Treatment of injectable soft tissue filler
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reactions to a hyaluronic acid-derived dermal Filler. J Clin Aesthet
In an in vitro model of human cadaveric–sourced Dermatol 2010;3:32–5.
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