Aesth Plast Surg
https://doi.org/10.1007/s00266-020-01759-2
ORIGINAL ARTICLE
The Effect of Hyaluronidase on Depth of Necrosis in Hyaluronic
Acid Filling-Related Skin Complications
Safvet Ors1
Received: 12 February 2020 / Accepted: 30 April 2020
Ó Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery 2020
Abstract
Aim In this clinical study, 16 female patients with vascular
compression and occlusion-related ischemia and skin
necrosis after hyaluronic acid filling injection were ana-
lyzed retrospectively. Dose, timing, and efficacy of hya-
luronidase use in skin necrosis are discussed.
Patients and Methods In a total of 841 cases, aged between
18 and 60 years, hyaluronic acid filling injections were
performed. All patients were followed up for 3–24 months.
Filling injected areas include nasolabial (391 cases), lip
(225 cases), glabella–forehead (90 cases), infraorbital (46
cases), malar region (25 cases), chin (24 cases), and nose
(40 cases). Skin complications occurred in four cases
during the application and in 12 cases 6–24 h after the
procedure. Only palliative treatment was performed in six
cases, while hyaluronidase was used in 10 cases in addition
to palliative treatment. Hyaluronidase injection was per-
formed 30 s after filling injection in four cases and 6–24 h
after the injection in the remaining six cases. A total of
1500 units of hyaluronidase was applied to each case in
average.
Results Recovery period of the patients who received
palliative treatment only lasted 40–60 days. The area of
necrosis was limited in these patients who did heal well
only with some change of pigmentation and no obvious
scar. In the patient group who received hyaluronidase in
addition to palliative treatment, a large necrosis area was
observed at the same time in four patients. Despite the
hyaluronidase treatment in this group, recovery period was
& Safvet Ors
saffetors@gmail.com
1
SO-EP Aesthetic & Plastic Surgery Clinic, Hunat Mah. Nuh
Naci Yazgan Caddesi No:21, 38050 Kayseri, Turkey
NON-SURGICAL AESTHETIC
20–90 days. The affected and necrosis areas were large.
The cause of ischemia depended both on occlusion and on
compression. While four patients healed with a scar, the
remaining 12 patients healed without any significant scar.
Conclusions Hyaluronidase injection provides earlier
recovery of limited skin necrosis. Immediate hyaluronidase
injection allows small damage to heal in a short time;
however, it does not completely eliminate large necrosis,
although it limits the necrotic area.
Level of Evidence IV This journal requires that authors
assign a level of evidence to each article. For a full
description of these Evidence-Based Medicine ratings,
please refer to the Table of Contents or the online
Instructions to Authors www.springer.com/00266.
Keywords Hyaluronic acid
Hyaluronidase
Skin
necrosis
Nitroglycerin
Aesthetic filling
Filler
complication
Introduction
Hyaluronic acid (HA) filling is one of the most common
non-surgical procedures in facial aesthetic applications
[1–4]. HA is frequently applied to nasolabial, nasal,
glabellar areas, jaw line, jowl line, lip, as well as malar,
temporal, and infraorbital regions. It is frequently preferred
by patients due its immediate results, outpatient treatment,
low cost, and reproducibility. Patients generally consider
HA application as a simple procedure with no serious side
effects due to social media coverage and other various
factors. For this reason, in some centers, filling injections
are performed even by individuals who are not physicians.
Although it is a simple procedure, the rate of encountering
complications increases every day [5–8]. As with any
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application performed under the skin, various complica-

tions are present for HA filling applications. While some of
these complications can be treated with existing medica-
tions, some can cause irreversible morbidity [5–13]. Today,
hyaluronidase still maintains its value as the only treatment
against these complications. A consensus has been reached
to start hyaluronidase treatment immediately during the
first 4 h [4, 8, 9, 14, 15].
In this clinical study, a total of 16 female patients
between 2010 and 2019 with vascular compression and
occlusion-related ischemia and skin necrosis after HA
filling injection were retrospectively analyzed. We present
the first six patients treated with antibiotics, local dressing,
aspirin, nonsteroid anti-inflammatory medication, and pal-
liative treatment, as well as 10 patients treated with hya-
luronidase immediately after ischemic skin injury.
Recovery time, width of necrosis area, scar presence,
atrophy, and depigmentation are taken into consideration in
the comparison of cases.

Patients and Methods

Between 2010 and 2019, a total of 841 cases aged between

18 and 60 received hyaluronic acid filling application of
various brands (cross-linked and non-cross-linked) in our
clinical center. All patients were followed up for
3–24 months. Ethical approval for the retrospective clinical
study was granted by the research ethics committee. We
have reported the complications observed in our own
clinic. Patients who were referred to our clinic for the
treatment of complications occurring due to filler applica-
tions in other centers were not included in the study. In our
study, HA filling injections and the treatment of compli-
cations were performed by the senior author who is a
plastic surgeon. Filling injected areas include nasolabial
(391 cases), lip (225 cases), glabella–forehead (90 cases),
infraorbital (46 cases), malar region (25 cases), chin (24
cases), and nose (40 cases). In four cases with HA filling
injection into the glabellar region, color change, capillary
filling loss, coldness, and sudden pain were observed dur-
ing the application in the glabella, nasal area, forehead, and
infraorbital region (Fig. 1a). Skin complications started
during the procedure in four cases and 6–24 h after the
application in 12 cases. Six cases with complications who
had filling injections before 2015 received palliative
treatment only, while patients who had filling injections
after 2015 received 4–6 doses of 300 units of hyaluronidase
each in addition to palliative treatment. In patients with an
open wound, fusidic acid antibiotic was used topically. In
patients with large wounds, amoxicillin–clavulanate were
administered orally for 14 days. Hyaluronidase application
was performed after 30 s of complication onset in four
Fig. 1 a A 38-year-old female patient with oily porous skin. Color
change, loss of capillary filling, pallor in the forehead, nasal back, and
right infraorbital region were observed during glabellar HA filling
application. 300 IU hyaluronidase was applied immediately, b 5th
day after procedure; superficial and deep necrosis in the nasal dorsum,
forehead, and right infraorbital region is observed, c 30th day after
procedure; the surrounding tissue is epithelialized, and the midline
has not healed, d 50th day after treatment. Superficial skin necrosis
has healed, but there is a scar in the mid-necrotic region along the
vascular area. Wound healing has not been completed
patients, while in the remaining six patients hyaluronidase
was applied after 6–24 h. The dose interval was 30 s, 2 h,
8 h, 16 h, 24 h, and 72 h in the former four cases. In the
latter six cases, 4–6 doses of hyaluronidase were applied
with an interval of 4–6 h. Thus, a total of 1500 units of
hyaluronidase was applied to each case. None of the
patients were treated surgically. Complications, filling
areas, and recovery times are summarized in Table 1.
Demographic data of patients are given in Table 2.

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Table 1 Evaluation of hyaluronic acid skin complications
Number Limited Large Recovery Permanent Hyaluronidase; dose
of cases necrosis necrosis time (days) scar starting time interval
6 6 - 40–60 - -
10 6 4 20–90 4 1500 IU first 4 h
4–6th h
Results
Skin damage at various extends was observed in a total of
16 cases (1.9%) as a result of HA filling injections. 50% of
the application areas with observed skin damage was the
forehead–glabella (8 cases), 25% was the nose (4 cases),
and 25% was the nasolabial region (4 cases). Observed skin
damage ranged from hyperemia and mild skin complica-
tion to large skin necrosis (Figs. 2 and 3). While ischemic
skin findings were observed as a result of nasolabial region,
nose, and forehead–glabella fillings, no ischemic compli-
cations were observed in lip, jaw, malar, and infraorbital
region fillings. In 12 patients, skin damage was limited and
small area (Figs. 5 and 6). Recovery time with palliative
treatment was observed to be 40–60 days. The affected
area was limited in these patients and the region healed
with a little pigmentation change, but no significant scar. In
four patients treated with additional hyaluronidase appli-
cation, necrosis in the center of affected area and in the
surrounding area was observed at the same time (Figs. 1, 2,
and 4). The recovery period varied between 20 and 90 days
in these patients, and the affected area was quite wide.
Tissue blood circulation deteriorated due to both occlusion
and compression. The damage healed with a scar in four
patients (Figs. 1, 2, and 4), while the remaining six patients
healed without a significant scar (Figs. 5, 6, and 7).
Although the necrosis observed in the patients who did not
receive hyaluronidase treatment was smaller, the healing
period lasted longer than those who received hyaluronidase
treatment.
Discussion
The complications seen after HA filler injections can be
divided into two groups: simple and complicated. Simple
complications include pain, erythema, edema, irregularity,
bruising, overfilling, allergic reactions, and infection
[13, 16–18]. Complicated complications include skin
necrosis due to vascular pressure and occlusion, blindness,
cerebral infarction, diffuse alveolar hemorrhage, perma-
nent scar, atrophy, and pigmentation changes
Palliative Intra- Extravascular Adjacent
treatment arterial pressure tissue
occlusion damage
? - 6 -
? 4 6 4
[5, 6, 9–11, 15]. Simple complications can be resolved with
spontaneous or empirical treatments, while in the compli-
cated ones, time is very limited and emergency interven-
tion is required. Since hyaluronidase use was not quite
common in our country before 2015, only palliative treat-
ment was applied to the first six cases (Figs. 6, 7, and 8).
Palliative treatment consists of antibiotics, local dressing,
acetyl salicylic acid, nonsteroid anti-inflammatory medi-
cation, massage, and hot compress. The treatments applied
in complicated cases are hyaluronidase, acetyl salicylic
acid, corticosteroid, nitroglycerin pads, massage applica-
tion, hot compress, and urokinase [18, 19]. Still, all
researchers agree that the most effective treatment is
immediate hyaluronidase injection [7, 8, 13, 15]. Accord-
ing to the experimental and clinical studies, it is clear that
hyaluronidase injections limit the complications to a cer-
tain extent, although they do not completely eliminate the
skin necrosis and other complications [7, 8, 13, 15]. We
recommend immediate hyaluronidase application when
whitening, capillary filling loss, coldness, or severe pain is
experienced during the procedure (Fig. 1a). Although
reported cases are in the form of isolated case reports, more
than hundreds of studies have been presented in the last
5 years. This reveals the severity of the issue and that the
rate of complications will increase gradually. Some studies
report a complication rate of 1/100.000 after HA filling
injections [5–8]. We have enough experience to believe
that the complication rate is much higher in real life than
reported in the literature.
Hyaluronic acid injections may disrupt vascular circu-
lation by leaking into the vessels or causing pressure
[5, 11, 14, 20–27]. Our observations suggest that when the
filling causes pressure to the vessels, the affected area is
more limited. On the other hand, when the HA filling leaks
into the artery, it affects both the injected area and the
adjacent tissues (Fig. 1). In such cases, the necrotic tissue
becomes larger, the recovery period is extended, necrosis
progresses, and the effect of hyaluronidase is limited
(Figs. 1 and 2). While the findings are immediately seen
during the procedure of HA fillings that leak into the artery,
complications that are caused by the pressure on the vessels
usually appear 6–24 h after the HA injection. Four patients
with HA filling in the glabellar region had a marked
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Table 2 Demographic data of patients
Case Ages Sex Ethnicity Filler volume Skin type Treatments Filler area Smoking Additional disease/ Additional filler/ Hyaluronidase
number (ml) allergy botox allergy

1 18 F Asian 0.7 Normal Palliative ? hyaluronidase Nose No No No No

2 20 F Asian 1 Normal Palliative Nose No No No No
3 25 F Asian 1 Oily and Palliative ? hyaluronidase Nose No No No No
porous
4 20 F European 0.6 Normal Palliative Nose Yes No No No
5 39 F Asian 1?1 Oily and Palliative Nasolabial No No No No
porous
6 35 F Asian 1?1 Normal Palliative Nasolabial No No No No
7 55 F Asian 1?1 Normal Palliative ? hyaluronidase Nasolabial No No No No
8 48 F Asian 1?1 Oily and Palliative ? hyaluronidase Nasolabial No No No No
porous
9 43 F Asian 0.5 Oily and Palliative ? hyaluronidase Glabella Yes No No No
porous
10 38 F Asian 0.5 Oily and Palliative ? hyaluronidase Glabella No No No No
porous
11 29 F European 0.6 Normal Palliative Glabella No No No No
12 35 F Asian 0.7 Oily and Palliative ? hyaluronidase Glabella No No No No
porous
13 50 F Asian 0.6 Oily and Palliative ? hyaluronidase Glabella No No No No
porous
14 60 F Caucasian 0.6 Oily and Palliative Glabella Yes No No No
porous
15 46 F Asian 0.5 Normal Palliative ? hyaluronidase Glabella No No No No
16 51 F Asian 0.6 Normal Palliative ? hyaluronidase Glabella Yes No No No
Aesth Plast Surg
Aesth Plast Surg
Fig. 2 a A 50-year-old female patient HA filler injected to the
glabellar region. Four doses of hyaluronidase (1200 IU) were applied
6–24 h after complication onset. Ten days later, a deep necrosis is
observed in the midline with surrounding superficial necrosis; b the
Fig. 3 A 20-year-old female patient with HA filling on the nose.
Tissue damage is observed prior to superficial necrosis on the entire
forehead
Fig. 4 a A 25-year-old female patient with HA filling in the supratip
area has hyperemia, superficial and deep necrosis. No hyaluronidase
was applied, b day 45 after procedure, the area with deep necrosis has
healed with an atrophic scar
complication impact on the middle part of the forehead, left
infraorbital region, and nasal area. Intra-arterial hyalur-
onidase injection was not applied to any of our patients,
since it has already been reported in several studies that the
neighboring tissue with superficial necrosis is epithelialized. A scar is
observed in the deep necrosis region, c 4 months after procedure. The
glabellar region has healed with a scar
Fig. 5 a A 55-year-old female with oily porous skin with HA filling
applied to the nasolabial region. Superficial necrosis extending to the
nasolabial and malar region can be observed. Four doses of
hyaluronidase (300 IU) were applied between 6 and 24 h, b 7th day
after procedure. The damage area has expanded, c 40th day after the
HA filler, recovery is about to be completed, d 40 days after
hyaluronidase injection. Healing without scar can be observed
effect of hyaluronidase injection into tissue is similar to
intra-arterial hyaluronidase injection [5–8]. Furthermore,
several experimental studies also report that intra-arterial
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Fig. 6 a A 35-year-old female patient with HA filling in the glabellar
region. Superficial necrosis is observed in the forehead midline and
superior. No hyaluronidase was applied, b limited improvement is
observed 40 days after filling application, c limited improvement is
observed 50 days after filling application, d 60th day after filling
application. Complete recovery without scarring is observed
Fig. 7 a A 60-year-old woman
with oily skin and large pores.
Localized deep necrosis is
observed after glabellar HA
filling. No hyaluronidase was
applied, b 60th day after HA
filling application, c 1st year
after HA filling application
hyaluronidase injection may cause damage to the vascular
endothelium [28]. Diagnosis methods such as conventional
ultrasound, Doppler ultrasound, scintigraphy, and MRI
could be used and are very valuable in the observation of
necrosis effects.
After hyaluronidase injection, limited necrosis areas
heal in a short period of 3–4 weeks on average; however,
the area with large necrosis heals in a longer time such as
3 months (Figs. 1 and 2). This suggests that hyaluronidase
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Aesth Plast Surg
Fig. 8 a A 20-year-old female patient with a superficial reaction after
HA filler injection to the radix nasi, b 6th month view after procedure.
No hyaluronidase was applied
injection recovers capillary circulation without further
damage to the surrounding tissue. Hyaluronidase is also
effective in large necrosis regions; however, we believe
this effect is limited to a certain extend. Perhaps, if hya-
luronidase is not applied to the large necrosis regions, a
full-thickness necrosis will develop, and surgical inter-
vention will be required to remove necrotic tissue.
Although skin necrosis is limited and small in patients
without hyaluronidase application, the recovery time is
significantly longer, which may extend up to 2 months
(Figs. 4, 6, and 7). It is quite clear that hyaluronidase
application accelerates healing in small area necrosis.
However, in both cases, the recovery time is quite long.
Considering the length of recovery time, surgical inter-
vention may be considered, but this will deteriorate heal-
ing, and more scar will remain.
In an experimental study, various doses of arterial
hyaluronidase were applied after HA injection into the
artery of the rabbit ear [14]. Similar to our study, the
researchers observed that hyaluronidase did not completely
prevent necrosis occurrence as a result of arterial occlusion
but reduced the necrosis area. It is recommended to start
Aesth Plast Surg
hyaluronidase application within the first 4 h after com-
plication onset [9, 14]. Considering the four cases reported
here in which hyaluronidase injection was applied at 30th
second of complication onset, for which the affected areas
healed with a significant scar, it can be observed that even
the effect of immediate hyaluronidase application is limited
in large necrosis. Still, in such cases, we strongly recom-
mend immediate hyaluronidase application, since we
believe that hyaluronidase limits the expansion of necrosis
and helps adjacent small area necrosis to recover faster.
The end branches of the supraorbital and supratrochlear
arteries are positioned superficially in the glabella
[21–23, 25]. Even in intradermal HA filling applications,
arterial occlusion and compression can occur. In four cases
where we administered intradermal glabellar HA filling,
the leakage of filling into the artery confirms this. We have
observed more skin complications significantly in patients
with oily and porous skin. Almost half of the 16 cases
reported here had this type of skin (Figs. 1, 3, 5, and 7).
Therefore, they are more affected by HA filling, which
suggests extra caution for such cases. In some studies, it
was reported that tissue damage did not disappear com-
pletely even though vascular occlusion was eliminated in
the early period with hyaluronidase [29]. Tissue damage
may be caused by the chemical structure of HA in addition
to vascular pressure and occlusion. During HA filling
application, negative pressure could be applied to the
injector to test if the injector tip is located inside the vein or
not, which is a routine practice we perform in all of our
patients. However, this does not always give correct
results.
Conclusions
Skin complications due to pressure to the artery or intra-
arterial injections could be observed after HA filling
applications. Hyaluronidase injection can provide faster
recovery of limited, small area necrosis in such cases.
Although immediate hyaluronidase injection allows this
small area damage to heal in a short time, as well as lim-
iting the large necrosis area, it cannot completely eliminate
necrosis. Patients with large area necrosis who received
hyaluronidase treatment have smaller remaining scars
compared to necrosis area.
In case of complication onset, hyaluronidase injection
should be performed immediately if possible. While the
complication rate is 1.9% in all facial HA filling applica-
tions in our center, the observed complication rate is much
higher in glabella. Glabella and nasal areas should be
considered as the high-risk regions and should be avoided
if possible. The most high-risk areas in HA filling appli-
cations are glabella–forehead, nose and nasolabial area, but
lip, chin, and malar region are a little safer. In HA fillings
to the infraorbital area, most commonly observed compli-
cations are edema and overfill. Hyaluronidase is most
commonly used in the infraorbital region for excess filling.
Therefore, this region should be kept in mind as the region
with more frequent complications. Although the filler
injection procedures seem quite simple, serious complica-
tions could occur during the procedure. Therefore, we
suggest untrained doctors or other personnel shouldn’t
perform these applications. Hyaluronidase should be kept
ready at the table in the room where HA filling is applied.
Hyaluronidase use might cause several very serious side
effects such as anaphylactic shock. Therefore, its applica-
tion must be performed in a medical setting and by the
medical staff. The treatment of skin complications should
be done by doctors who are experts on wound healing.
Therefore, the patients should be referred to medical cen-
ters with great expertise.
Acknowledgements The authors declare no financial interest in any
of the products, devices, or drugs mentioned in this manuscript.
Compliance with Ethical Standards
Conflict of interest The authors declare that they have no conflicts of
interest to disclose.
Ethical Approval Ethical approval of the retrospective clinical study
was granted by the research ethics committee.
Informed Consent Informed consent form was used for this study.
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