Cosmetic Medicine

Aesthetic Surgery Journal

Review Article 33(6) 862–877
© 2013 The American Society for
Aesthetic Plastic Surgery, Inc.
Complications Following Injection of Reprints and permission:
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Soft-Tissue Fillers DOI: 10.1177/1090820X13493638
www.aestheticsurgeryjournal.com

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Cemile Nurdan Ozturk, MD; Yumeng Li, BS; Rebecca Tung, MD;
Lydia Parker, MD; Melissa Peck Piliang, MD; and James E. Zins, MD

Abstract
Background: Soft-tissue filler injection is a very common procedure in the United States. Although the safety profile is favorable, adverse events (AE)
can occur, ranging from mild to severe in intensity.
Objectives: The authors performed a literature search to identify the facial sites most prone to severe complications. They review the course of these
complications and discuss preventive measures.
Methods: The National Library of Medicine, the Cochrane Library, and Ovid MEDLINE were searched, and relevant articles (published through August
2012) were retrieved based on prespecified inclusion criteria. The complications reviewed were limited to “severe” events, such as soft-tissue necrosis,
filler embolization, visual impairment, and anaphylaxis. The filler materials included were those approved by the US Food and Drug Administration at the
time of this study.
Results: Forty-one articles, representing 61 patients with severe complications, were identified. Data collected from these case reports included filler
type, injection site, complication site, symptom interval, symptom of complication, time to therapy, modality of treatment, and outcome. The most
common injection site for necrosis was the nose (33.3%), followed by the nasolabial fold (31.2%). Blindness was most often associated with injection of
the glabella (50%). An estimated incidence of 0.0001% for developing a severe complication was calculated by reviewing society-based filler data and
case reports within same time period.
Conclusions: Although soft-tissue fillers are a popular choice for minimally invasive rejuvenation of the face, physicians should be aware of the serious
potential adverse effects, recognize their presentations, and have appropriate treatments readily available.

Keywords
filler, injectable, complication, blindness, necrosis, cosmetic medicine, literature review

Accepted for publication November 26, 2012.

The use of soft-tissue fillers for cosmetic purposes has

increased dramatically in recent years. According to the Dr Ozturk is an Aesthetic Surgery Fellow and Dr Zins is Chairman
2012 statistics published by the American Society for of the Department of Plastic Surgery at the Cleveland Clinic,
Aesthetic Plastic Surgery (ASAPS), fillers are now the sec- Cleveland, Ohio. Dr Piliang is a staff physician in the Departments
of Dermatology and Anatomic Pathology at the Cleveland Clinic,
ond most common minimally invasive procedure per-
Cleveland, Ohio. Ms Li is a medical student at the Cleveland Clinic
formed among plastic surgeons, behind botulinum toxin
Lerner College of Medicine, Cleveland, Ohio. Dr Tung is Chairman
injections.1 The trend is similar in dermatology practice. of the Division of Dermatology at Loyola University, Stritch School
Data from the American Society for Dermatologic Surgery of Medicine, Maywood, Illinois. Dr Parker is a Clinical Instructor in
(ASDS) demonstrate that injectables are also the second the Department of Dermatology at Case Western Reserve University,
most common minimally invasive procedure performed by School of Medicine, Cleveland, Ohio.
dermatologists (also following botulinum toxin).2 The Corresponding Author:
popularity of fillers is attributable to their ease of applica- Dr James E. Zins, Department of Plastic Surgery, Cleveland Clinic,
tion, significant beneficial effect on appearance, and low 9500 Euclid Ave, Desk A60, Cleveland, OH 44195, USA.
rate of complications. Email: [email protected]
Ozturk et al 863

Although soft-tissue fillers have a very favorable safety Of the 61 cases, the injection site most commonly associ-
profile, adverse events (AE) can occur. Minimal and self- ated with complications was the nose (32.8%; n = 20),
limited complications are relatively common and perhaps followed by the glabella (26.2%; n = 16) and the nasola-
would be more appropriately termed adverse sequelae bial fold (NLF) (26.2%; n = 16). In 4 cases, the injection
rather than true complications. Such events include ecchy- site was not specified.3,4 The distribution of complications
mosis, swelling, and erythema. More significant yet self- according to filler type is shown in Figure 2. Hyaluronic
limited complications also have occurred, including acid was the most common filler implicated in necrotic
overcorrection, irregularities, filler visibility, Tyndall effect, complications, and collagen was the most common filler
and granuloma formation. Complications of greater sever- resulting in visual impairment. Filler type was not reported
ity also have been reported, such as visual impairment, for 2 cases.5,6 One case of anaphylactic shock occurred
skin necrosis, and anaphylaxis. The goal of the present after the eighth injection session of PMMA.7 However,
review is to highlight the more serious complications, neither the specific clinical presentation nor the outcome
identify the areas and techniques most prone to complica- was described.

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tions, suggest means for minimizing complications, and
discuss effective methods of treatment.
Soft-Tissue Necrosis and Impending
Necrosis
METHODS
There were 39 cases of significant soft-tissue loss and 9
A literature search was performed to gather information cases of “impending necrosis” (Table 1). The responsible
on severe complications following injection of soft-tissue substances were HA, PMMA, collagen, and CaHa. Common
fillers from reports published through August 2012. The injection sites for these complications were the nose
databases of the National Library of Medicine (PubMed), (33.3%; n = 16),3,4,8-15 NLF (31.2%; n = 15),4,8,13,16-23 and
the Cochrane Library, and Ovid MEDLINE were searched glabella (20.8%; n = 10).17,24-30 Other sites were the
using the following Boolean string: (anaphylaxis OR blind- cheeks and lips (in 1 and 2 cases, respectively).31-33 In 4
ness OR necrosis OR embolization OR scar OR complica- cases (8.3%), the site of injection was not reported.3,4 Of
tion) AND (filler OR injectable). Additional searching was the 16 nasal injections, 5 were in the nasal tip,3,8-10,13 1 was
done using the phrases soft-tissue filler complications, in the lateral nose,4 3 were in the dorsum,10 and 2 were in
dermal filler complications, and injectable complications. the dorsum as well as the tip.11,14 One patient had multiple
The references cited in selected articles also were reviewed injections to the nose, forehead, and glabella.14 For the
to potentially identify additional reports that matched the other 4 cases, the specific nasal location was not
criteria. The search was limited to the English-language reported.3,9,12,15 Details of injection technique and needle
literature and to the head and neck region. size were not described for any case of necrosis.
Reports of “severe” complications following use of The symptom most often associated with intravascular
injectables were selected for this review; these included injection was immediate pain upon administration of the
soft-tissue necrosis, filler embolization resulting in impend- product. Other acute symptoms included blanching, dusk-
ing necrosis, blindness, partial loss of vision, transient loss iness, and ecchymosis. In several cases, no signs were
of vision, and anaphylaxis. Cases of visual impairment noted at the time of injection, and delayed compression of
with concomitant necrosis were counted only once, in the vessels by product was proposed as a possible mechanism
vision loss subgroup. The only filler materials included of injury.20,21,33
were those that had been approved by the US Food and The affected sites showed additional signs of vascular
Drug Administration (FDA) at the time of the review. These compromise within 1 to 2 days, including erythema, white
materials were collagen, hyaluronic acid (HA), polymethyl- or violaceous discoloration, edema, bruising, and ongoing
methacrylate (PMMA) suspended in collagen, calcium pain. In patients with “impending necrosis,” the symp-
hydroxylapatite (CaHa), poly-L-lactic acid (PLLA), and toms and signs improved, sometimes associated with early
injectable dermal matrix. Autologous fat, liquid silicone, intervention, and resolved without sequelae.
and other non-FDA-approved substances were excluded. When soft-tissue loss occurred, slough, ulceration, and
eschar developed within 3 to 7 days after injection. The
tissue loss occurred directly at the injection site in 46.2%
RESULTS of cases (n = 18) and at the site nourished by the com-
promised vessel in 28.2% (n = 11). The latter included
A total of 41 reports representing 61 patients with severe necrosis developing at the forehead and nose after glabel-
complications were identified. A summary of the cases, lar injection26,27,30 and necrosis developing at the nasal ala
therapies, and outcomes is presented in Table 1. The com- and lip after NLF injection.4,8,13,16,18,23 In 10 cases (25.6%),
plications were classified into 3 groups: (1) soft-tissue the data were insufficient to make a correlation between
necrosis or impending necrosis as a result of filler emboli- treatment site and complication site.
zation, (2) visual impairment, and (3) anaphylaxis. Figure A variety of treatments were used, including hyaluroni-
1 shows the distribution of complications by injection site. dase, nitroglycerin paste, warm compresses, intravenous

(text continues on p. 868)

864 Aesthetic Surgery Journal 33(6)

Table 1. Literature Summary: Reports of Severe Complications After Use of Injectable Fillers
Reference and No. Injection Symptom Interval, Time to Therapy, Injecting
of Cases Complication Type of Filler Site Complaints, Location Treatment Utilized Outcome Physician Country

29
Hanke et al, 1991 Necrosis Collagen Glabella NR NR NR Dermatologist United
1 case States

Monheit, 199812 Necrosis Collagen Nose NR NR NR NR United

1 case States

Schanz et al, 200227 Necrosis HA Glabella Minutes: reticular pat- Immediate: low- Complete Dermatologist Germany
1 case tern at injection site molecular-weight recovery
and nose; no pain heparin 5000 IE daily
10 days: ulceration (1 wk)
at injection site,
glabella, and nose

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Friedman et al, Necrosis HA Glabella NR NR NR NR NR
200224
2 cases

Lowe, 200333 Impending HA Lip Venous occlusion; NR NR Dermatologist United

1 case necrosis persistent edema at Kingdom
injection site

Bellman, 200619 Impending HA NLF Immediate: bruising; 2 days: dynacin 100 mg Complete Dermatologist United
1 case necrosis edema at injection PO and prednisone 20 recovery States
site mg PO
2 days: sensitivity; 4 days: hydrogen
pustules; reticulated peroxide, mupirocin
bruising; edema at ointment, and warm
injection site and compress
nasal tip

Narins et al, 200632 Necrosis HA Lip Immediate: bleeding 2 weeks: PO corticoste- Complete NR United
1 case and bruising roid and antibiotics; recovery States
Later: necrosis of left secondary intention
lower lip

Steinsapir and Necrosis HA Glabella NR NR Scarring Ophthalmologist United

Steinsapir, 200625 States
1 case

Gladstone and Necrosis HA Glabella Necrosis at forehead NR NR Dermatologist United

Cohen, 200726 States
1 case

Hirsch et al, 200721 Impending HA NLF 2 days: pain and 2 days: aspirin 325 mg, Complete Dermatologist United
1 case necrosis erythema at injec- nitroglycerin paste, recovery States
tion site and warm compress
3 days: hyaluronidase
30 U

Hirsch et al, 200722 Impending HA NLF 6 hours: erythema 6 hours: aspirin 325 mg, Complete Dermatologist United
1 case necrosis and discoloration at nitroglycerin paste, recovery States
injection site warm compress, and
hyaluronidase 30 U

Salles et al, 200813 All 3 cases: All 3 cases: Case 1: Case 1: All 3 cases: NR All 3 cases: Case 1: plastic Brazil
3 cases necrosis PMMA nose 7 days: hyperemia, scarring surgeon
(tip) swelling, and Case 2:
Case 2: necrosis of ala dermatologist
NLF and Case 2: Case 3: plastic
nose Immediate: pain surgeon
Case 3: NLF Later: necrosis of ala
and upper lip
Case 3: necrosis of ala
upper and lower
lateral lip

(continued)
Ozturk et al 865

Table 1. (continued)

Reference and No. Injection Symptom Interval, Time to Therapy, Injecting

of Cases Complication Type of Filler Site Complaints, Location Treatment Utilized Outcome Physician Country

Inoue et al, 200816 Necrosis Collagen NLF Immediate: pain at left 6 days: IV alprostadil Scarring; Plastic surgeon Japan
1 case side of face 120 µg/d for 2 wk; recon-
First hours: reddish surgical debridement struction
discoloration with skin
6 days: necrosis of graft
nasal ala

Grunebaum et al, Case 1: All 3 cases: Case 1: NLF Case 1: Case 1: Case 1: NR United
20098 necrosis HA Case 2: NLF 1 day: skin irritation; 3 days: Bacitracin; complete States
3 cases Case 2: Case 3: numbness secondary intention recovery
necrosis nose 3 days: necrosis of Case 2: Case 2:

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Case 3: (tip) nasal ala Immediate: hydrocolloid scarring
impending Case 2: dressing; hyaluroni- Case 3:
necrosis First hours: pain; dase 40 U complete
dusky erythema Case 3: recovery
12 hours: necrosis of Immediate: nitropaste
nasal ala (for 1 wk) and hyal-
Case 3: uronidase (3 times)
Immediate: erythema
of nose

Georgescu et al, Both cases: Both cases: Case 1: Case 1: Case 1: Both cases: NR United
200917 necrosis CaHa glabella Hours: pain and bruis- 2 days: PO corticoste- complete States
2 cases Case 2: NLF ing at injection site roid; nitroglycerin recovery
2 days: necrosis at paste (1 wk)
glabella 4 months: microderm-
Case 2: abrasion
Same day: pain and Case 2:
swelling over fold; Same day: PO antibiotics
necrosis; ecchy- and steroids
mosis Months: Microdermabra-
sion and hydrocorti-
sone ointment

Winslow, 200915 Necrosis CaHa Nose Immediate: blanching Nitroglycerin paste (tim- Complete Plastic surgeon United
1 case Days: bluish discol- ing not specified) recovery States
oration; ischemic
purpura; edema;
mild epidermolysis
of nose

Bachmann et al, Both cases: Both cases: Both cases: Case 1: NR Both cases: NR Germany
200928 necrosis HA glabella 1 day: erythema; recovery
2 cases inflammation; with
abscess formation scarring
at injection site
Case 2:
Immediate: pain
1 day: erythema and
edema
5 days: discoloration
abscess
3 weeks: ulceration

Humphrey et al, Both cases: Both cases: Both cases: Case 1: Case 1: Both cases: Otolaryngologist United
20099 impending HA nose 12 hours: blanching 12 hours: nitroglycerin partial States
2 cases necrosis (tip) and discoloration at paste (1 wk), warm recovery
injection site compress, and
Case 2: hyaluronidase (15 U;
1 week: discoloration 3 times)
and numbness at Case 2: hyaluronidase
cold temperature (15 U)

Burt et al, 201018 Necrosis HA NLF 1 day: pain and poor NR Complete Plastic surgeon United
1 case perfusion recovery States
3 days: sloughing
and ulceration of
nasal ala

(continued)
866 Aesthetic Surgery Journal 33(6)

Table 1. (continued)

Reference and No. Injection Symptom Interval, Time to Therapy, Injecting

of Cases Complication Type of Filler Site Complaints, Location Treatment Utilized Outcome Physician Country

Kassir et al, 201131 Necrosis HA Cheek First hours: pain; blu- 5 days: massage; IM, Scarring Plastic surgeon United
1 case ish discoloration topical, and PO States
5 days: slough and antibiotics; Valtrex;
eschar of right silicone gel
cheek

Kim et al, 201110 All 4 cases: All 4 cases: Case 1: All 4 cases: Case 1: All 4 cases: Plastic surgeon Korea
4 cases necrosis HA nose Immediate: pain 1 day: hyaluronidase scarring
(tip) Later: reticular skin Case 2:
Cases 2, discoloration and 1 day: hyaluronidase
3, and necrosis of nasal

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4: nose dorsum and tip
(dorsum)

Park et al, 20114 All 3 cases: All 3 cases: Case 1: Case 1: NR Case 1: NR NR Korea
3 cases necrosis HA nose Case 2: necrosis of 3 months: PO antibiotics
(sidewall) mentum Case 2:
Case 2: NR Case 3: necrosis of ala 2 months: surgical
Case 3: NLF excision
Case 3:
1 week: oral antibiotics

Kim et al, 201111 Necrosis HA Nose Hours: swelling and 1 day: filler removal Recovery Plastic surgeon Korea
1 case (dorsum discoloration at (puncture) with
and tip) injection site Days: IV alprostadil and minimal
Days: dark brown and topical antibiotics scarring
purple discoloration
at nasal tip

Dayan et al, 201120 Cases 1 All 3 cases: Case 1: NLF, Case 1: Case 1: Cases 1 NR United
3 cases and 2: CaHa infra- Immediate: blanching Immediate: nitroglycerin and 2: States
impending orbital over left cheek, NLF, paste (for 5 days) complete
necrosis region and left upper lip 2 days: hyaluronidase recovery
Case 3: Case 2: NLF 2 days: edema and 150 U; methylpredni- Case 3: NR
necrosis Case 3: NLF erythema of sone PO; aspirin 325
left lower face; mg/d (2 wk); topical
reticulated vascular oxygen infusion
congestion of upper cream
lip and left buccal Case 2:
mucosa 1 day: Nitroglycerin
Case 2: paste; antibiotic oint-
1 day: tenderness; ment; hyaluronidase
erythema; drainage 20 U; aspirin 325
at fold mg/d; PO antibiotics
Case 3: 4 days: Hyaluronidase
1 day: edema; 15 U; topical oxygen
erythema; bruising infusion cream
at fold and malar Case 3:
region Days: IV and PO antibiot-
Later: ulceration at fold ics; PO valacylclovir;
topical steroid
4 weeks: hyaluronidase
40 U; nitroglycerin
paste; aspirin 325
mg/d, antacids; topi-
cal oxygen infusion
cream

Park et al, 201123 Necrosis HA NLF 1 hour: erythema on 1 day: hyaluronidase 20 Complete Dermatologist Korea
1 case central face U (once) and warm recovery
2 days: Necrosis at compress
nasal tip with pain 2 days: Bacitracin
and tenderness ointment

(continued)
Ozturk et al 867

Table 1. (continued)

Reference and No. Injection Symptom Interval, Time to Therapy, Injecting

of Cases Complication Type of Filler Site Complaints, Location Treatment Utilized Outcome Physician Country

14
Sung et al, 2011 Both cases: Both cases: Case 1: Case 1: Case 1: Both cases: NR Korea
2 cases necrosis HA nose, 1 day: tenderness and Immediate: IV antibiotics; recovery
forehead, erythema hydrocolloid dressing with scar-
glabella 5 days: necrosis of 3 days: adipose-derived ring
Case 2: nasal tip stem cells
nose Case 2: Case 2:
(tip and 1 day: erythema and Immediate: hyaluroni-
dorsum) pain dase 1000 U; steroid
5 days: necrosis injection
of nasal tip and 5 days: IV antibiotics;
dorsum debridement

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11 days: adipose-
derived stem cells

Nettar and Maas, Necrosis HA Glabella Immediate: blanching 1 day: arnica cream and NR Plastic surgeon United
201230 1 day: discoloration; ice compress States
1 case bruising at injection 1 week: surgical
site debridement
1 week: necrosis of
forehead

de Melo Carpaneda All 5 cases: All 5 cases: Case 1: All 5 cases: NR Cases 1, 3, 4, NR Brazil
and Carpaneda, necrosis PMMA nose Immediate: intense and 5: NR
20123 (tip) pain Case 2:
5 cases Case 2: 1-2 days: white to scarring
nose violet discoloration
Cases 3, 4, Later: necrosis
and 5: Case 1: necrosis of
NR nasal tip
Case 2: necrosis
of nasal ala and
dorsum
Case 3: necrosis of
nasal ala and tip
and lips

Castillo, 198934 Blindness Collagen Glabella, NR NR NR NR United

1 case cheek States

Hanke, 199843 Blindness Collagen Glabella NR NR NR Dermatologist United

1 case States

Apte et al, 200336 Visual impair- Injectable Forehead 10 minutes: nausea; NR Vision loss NR United
1 case ment dermal diaphoresis; pain with light States
matrix in left eye; blurred percep-
vision tion

Silva and Curi, Blindness PMMA Glabella Immediate: severe NR Blindness NR Brazil
200440 pain and visual loss and total
1 case in right eye ophthal-
moplegia

Kubota and Hirose, Blindness PMMA Nose (dor- 15 minutes: pain and NR Blindness Plastic surgeon Japan
200538 sum) visual loss in right
1 case eye

Peter and Mennel, Visual impair- HA Glabella, 1 minute: partial loss Immediate: acetazol- Complete NR United
200635 ment cheeks of vision in inferior amide recovery States
1 case right visual field

Kang et al, 20076 Visual loss NR Glabella Immediate visual loss; NR NR NR Korea
1 case and necrosis of glabellar
necrosis region

(continued)
868 Aesthetic Surgery Journal 33(6)

Table 1. (continued)
Reference and No. Injection Symptom Interval, Time to Therapy, Injecting
of Cases Complication Type of Filler Site Complaints, Location Treatment Utilized Outcome Physician Country

5
Hwang et al, 2008 Visual loss NR Glabella, Immediate: visual loss Acetazolamide (1 wk) Partial recov- NR Korea
1 case nose, in left eye; erythem- and methylpredniso- ery with
periorbita atous color change lone (3 d) 20/200
at site of injection visual
acuity

Kwon et al, 201042 Blindness, Collagen Nose (sep- Immediate: visual loss Antiplatelet agent and Blindness NR Korea
1 case necrosis, tum) in left eye; head- calcium channel
stroke ache blocker
lesion Later: reticular violet
discoloration

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Sung et al, 201041 Visual loss, CaHa Nose (dor- Immediate: pain in 8 hours: IV antibiotics, Complete Dermatologist Korea
1 case necrosis sum) right eye; ptosis; topical steroids, and recovery
ophthalmoplegia PO corticosteroids with fixed
Later: reddish reticular dilated
pattern in right pupil;
eyelid minimal
scarring

Kim et al, 201137 Blindness, HA Nose (tip) Immediate: visual loss 2 days: IV methylpred- Blindness; Plastic surgeon Korea
1 case necrosis in left eye; pain nisolone; aspirin 100 recovery
in left upper face; mg PO from
ophthalmoplegia ophthal-
2 days: violaceous, moplegia
ulcerative patches

Roberts and Arthurs, Blindness PLLA Periorbital Immediate: visual loss NR Blindness; NR Canada
201239 region and pain in left eye recovery
1 case 1 day: nausea; from
ophthalmoplegia; ophthal-
ptosis moplegia

Lemperle et al, Anaphylactic PMMA NLF NR NR NR NR Italy

20037 shock
1 case

Abbreviations: CaHa, calcium hydroxylapatite; HA, hyaluronic acid; IM, intramuscular; IV, intravenous; NLF, nasolabial fold; NR, not reported; PLLA, poly-L-lactic acid; PMMA, polymethylmethacry-
late; PO, per oral.

(IV) prostaglandins, topical and oral antibiotics, topical

and oral corticosteroids, low-molecular-weight heparin,
topical oxygen, massage, hydrocolloid dressings, and
eventual surgical treatment.* Adipose-derived stem cells
were used in 2 cases of nasal tip necrosis.14 The treatment
choice varied according to when the patient was examined
by the reporting physician. Because the case reports pro-
vided too little detail and the number of cases was small,
it was not possible to establish a correlation between treat-
ment initiation and outcome. Of the 39 cases of soft-tissue
loss, 11 (28.2%) reportedly healed completely, with no or
minimal scarring.8,11,15-18,20,23,27,32 Fifteen patients (38.5%)
had visible scars after complete healing.8,10,13,25,28,31 For the
remaining 13 cases (33.3%), outcomes were not reported.

Visual Impairment
There were 12 cases of visual impairment resulting from Figure 1. Distribution of complications according to injec-
filler embolism to the ophthalmic vasculature (Table 1). tion site and type (necrotic, visual, anaphylactic). Numbers
in blue, red, and yellow circles represent the number of cases
who had necrotic, visual, and anaphylactic complications,
*References 4, 8, 9, 11, 12, 15-17, 20, 23, 27, 31, 32. respectively.
Ozturk et al 869

merely had to meet or exceed the safety and efficacy stand-

ards of collagen products when collagen was injected into
1 NLF and the filler tested in the contralateral fold. Direct
comparisons were then made between the duration of soft-
tissue correction and the complications that occurred. Since
2010, collagen filler products have not been available in the
United States, with the exception of bovine collagen, used as
a carrier for PMMA microspheres.
The FDA has approved a variety of different filler materi-
als, each with a distinct composition, injection profile, and
duration of effect. Many of them are in use off-label at the
discretion of the physician. Currently, HA is the most com-
monly used injectable, followed by CaHa and PLLA.1

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Therefore, it is not surprising that HA products are implicated
most frequently in severe complications. These fillers also
Figure 2. Distribution of severe complications according have different mechanisms of action and different periods of
to type of filler. CaHa, calcium hydroxylapatite; HA, persistence in tissue. Among the temporary materials, HA
hyaluronic acid; PLLA, poly-L-lactic acid; PMMA, remains in the tissue for 4 to 12 months, whereas collagen
polymethylmethacrylate. typically lasts only 2 to 4 months. Recent studies have shown
that reinjection 4 to 5 months following initial treatment sig-
nificantly increases the efficacy of HA products.49-51 CaHa and
The injected substances were HA, PMMA, injectable der- PLLA are considered semipermanent fillers and may last 1 to
mal matrix, collagen, PLLA, and CaHa. Specific details 2 years in tissue. The only FDA-approved permanent filler is
regarding injection technique and needle type were not PMMA. Although the collagen carrier of this filler resorbs
described in any of these reports. The glabella was the over time, the microspheres do not degrade, resorb, or dis-
most common site yielding visual complications (50%; solve, yielding permanent correction of wrinkles.
n = 6), followed by the nose (33.3%; n = 4), forehead Even though soft-tissue fillers are generally safe, unde-
(8.3%; n = 1), and periorbital region (8.3%; n = 1). In 3 sirable effects can occur with any type of filler. Adverse
patients who had injection of the glabella, injections also effects may result from injection techniques (eg, overcor-
were made in the nose, cheeks, and periorbital area.5,34,35 rection, irregularities, Tyndall effect, intravascular injec-
tion) or can be host-initiated local events. Some of these
In all 12 cases, the signs and symptoms of visual loss effects may resolve with time, but others will require
developed within minutes of the filler injection. Visual intervention based on severity and/or the type of filler
impairment was almost always accompanied by pain in the used. Visual impairment, soft-tissue necrosis, permanent
affected eye.36-41 Other immediate symptoms included dia- scarring, and anaphylaxis are rare but severe events.
phoresis, nausea, headache, ophthalmoplegia, and
ptosis.36,37,39,41,42 In 4 cases, a violaceous reticular discolora-
tion was evident several days after the injection, which was Determining the Incidence of
followed shortly by soft-tissue necrosis in the glabella and Complications
nose.6,37,41,42 One patient experienced ischemic stroke in
addition to vision loss.42 Various treatment attempts were The lack of an organized database, combined with the fact
used, including diuretic agents, antiplatelet agents, systemic that the injections generally are not performed in hospitals
steroids, and aspirin.5,35,37,41,42 In 7 cases, no information on or outpatient facilities, makes it very difficult to obtain
treatment was provided.6,34,36,38-40,43 Only 2 of the 12 patients accurate data on complications, although several attempts
(16.7%) had complete recovery of vision,35,41 and 1 (8.3%) have been made to estimate the number. Hanke et al29
had partial recovery.5 Six of the 12 cases (50%) resulted in published data pertaining to a 7-year period (1982-1989)
permanent complete blindness.36-40,42 In 3 cases (25%), the and reported an average annual incidence of 0.09% for
outcome was not clear.6,34,43 necrosis and abscess after collagen treatments. In 2002,
based on a review of manufacturer-supplied data, Friedman
et al24 examined the safety profile of HA injections per-
DISCUSSION formed outside the United States. The overall incidence of
AE was reportedly 0.15% in 1999 and 0.06% in 2000.
The increasing demand for soft-tissue augmentation, using a Narins et al32 used information from spontaneous drug AE
wide variety of fillers, has been documented repeatedly. reporting (SAER) systems to identify the more severe
Since the introduction of collagen as a standard injectable HA-related complications and reviewed the published
material in the 1980s, a number of filler materials have been cases in the United States in 2004. They estimated the
manufactured and approved by the FDA. All FDA efficacy incidence to be less than 0.001%.32 Current statistics on
testing of newer fillers has been based on the collagen proto- fillers and associated complications can be gathered read-
type, using split-face studies.44-48 In other words, new fillers ily from company-based data as well as national societies.
870 Aesthetic Surgery Journal 33(6)

Considering the widespread use of fillers by many special-

ties, the large variety of brands worldwide, and unreliable
methods of data collection, determining an accurate inci-
dence of complications is a challenging task. When com-
bining procedural data from ASAPS and ASDS statistics
from 2010 to 2011, the number of filler treatments per-
formed by plastic surgeons and dermatologists totaled
approximately 4 658 982 for the 2-year period.1,2 In the
same timeframe, the number of cases of severe complica-
tions in the United States reported by the same specialties
was only 5,18,20,31 yielding an estimated incidence of
0.0001%. Until a database is established by our profes-
sional societies, which allows for prospective data entry,

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the true incidence of complications will remain unknown. Figure 3. This 47-year-old woman, who had been injected
with calcium hydroxylapatite at another clinic, presented 4
months later with white nodules along the lower lip. The
Treatment of Mild, Moderate, and Self- granules were palpable and visible (arrows) just under
Limited Complications the mucosa of the lower lip. The patient refused surgical
excision.
A review of the Manufacturer and User Facility Device
Experience (MAUDE) database from 2003 to 2008 demon-
strated that the most common AE associated with fillers
were swelling, erythema, and inflammatory reactions such
as granulomas and nodules.52 Other mild to moderate hyaluronidase (15-300 U). Semipermanent fillers such as
complications included hypersensitivity, infection, bruis- CaHa and PLLA have the advantage of being longer lasting
ing, Tyndall effect, pain, blisters, beading of filler under than HA; however, with this benefit comes a disadvantage.
skin, numbness, and migration. If overcorrection occurs, irregularity and nodule formation
Swelling and ecchymosis may develop at the time of can develop; these problems are more persistent and dif-
injection and usually resolve spontaneously.32,53-55 Erythema ficult to treat. To prevent technique-related complications,
also is commonly transient but, on occasion, permanent injection should be in the subdermal plane, bolus injection
telangiectasias may occur at the injection site. If this hap- should be avoided, and injection sites should be massaged
pens, treatment with intense pulsed light therapy or pulsed after injection.66,67 Treatments for semipermanent fillers
dye laser can be initiated.56,57 Nodules and erythema that include direct excision of the filler, needle disruption and
persist beyond the first few days of treatment may be signs unroofing of lumps, and waiting for the product to
of inflammation.53,57,58 In these cases, massage and admin- absorb.66-70 Lumps caused by PLLA or PMMA respond well
istration of hyaluronidase for HA products have proven to intralesional steroid injections, but steroids are less
helpful.58 After infection is ruled out, intralesional or topi- effective for CaHa.56
cal corticosteroids also may be used.53,57 True granulomas appear late, after weeks or months,
Lumps or beading usually appear shortly after treat- and respond well to intralesional steroids55-57,60,65 or inci-
ment in the form of well-confined palpable lesions, which sion and drainage. The reported rate of granuloma is 0.01%
can result from injection in areas of thin soft-tissue cover- to 1%.48,56 Recently, there has been discussion on the role
age (eg, eyelids, nasojugal region, lips), injection of too of biofilms in causing delayed nodule formation.32,55,71-75
much material, clumping of filler, or dislocation by move- Biofilms are accumulations of microorganisms within a
ment of muscles.56,57,59,60 Common sites for irregularities self-developed matrix, which are irreversibly adherent to
and lumps include the lips and the perioral area. The one another and to a variety of surfaces.75,76 All fillers,
lips are an area of high mobility and thin mucosa. Once especially longer-lasting products, are potential surfaces for
irregularities in the mucosa of the lips occur, they are dif- biofilm formation. Because their growth rate is slow, bio-
ficult to correct if semipermanent fillers have been injected. films usually are not identifiable by culture. They may
Therefore, the use of semipermanent fillers in this area present as sterile abscesses or cause a chronic inflamma-
is discouraged61,62 (Figure 3). The tear trough and perior- tory response.55,75,77-79 Infections resulting from biofilms are
bital regions also are considered high risk and are prone notoriously difficult to treat because of their slow bacterial
to display irregularities if injected superficially.54,63,64 metabolism and their secretion of a protective matrix.77
Measures to avoid visibility of the implanted material Hyaluronidase has been shown to help break down the
include firm massage and meticulous placement of filler in matrix, thereby decreasing the biofilm mass.80 Dayan et al75
the deep supraperiosteal plane.58,65 Relatively short- reported successful treatment of resistant inflammatory
term fillers such as HA products are preferable for these reactions with hyaluronidase regardless of the filler used.
high-risk regions. An additional benefit of using HA Other treatment options for biofilms are prolonged use of
in these areas is that irregularities can be reversed with antibiotics, administration of intralesional 5-fluorouracil,
Ozturk et al 871

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Figure 4. (A) Two weeks after injection of collagen to the nasolabial folds, this 42-year-old woman complained of nodules and
ulceration, which persisted for another 2 weeks. She had multiple erythematous and partially ulcerated lesions (arrows) on
other areas of the face, which suggested factitious disorder. She was treated with oral antibiotics and steroids. (B) Ten months
after excision of the ulcerated lesion and granuloma on the right nasolabial fold (left arrow). The rest of the lesions healed by
secondary intention (right arrow). (C) Pathologic findings of the excised area were consistent with prurigo nodularis (Picker
nodule).

and intralesional laser therapy with a 532-nm or 808-nm Mild to moderate complications are usually self-limited.
laser.77,81-83 With respect to antimicrobials, 2-drug therapy Consensus treatments for complications that fail to resolve
with a quinolone and third-generation macrolide has been within several weeks include hyaluronidase injection,
recommended.55,77 To prevent biofilm formation or other intralesional steroids, and light-based therapies. Systemic
soft-tissue infections, care should be taken to avoid any steroids, systemic antibiotics, and/or surgical excision
contamination during implantation. A sterile technique may be required depending on the extent of the problem.
should be used when reconstituting or diluting the prod- An algorithm for the treatment of mild to moderate com-
uct, the injection site should be prepared with topical anti- plications is presented in Figure 5.
septics, injection to infected areas should be avoided, and
makeup and other potential contaminants on the skin
should be removed before injection.67,74,84 Moreover, the Treatment and Prevention of Severe
following should be avoided: injection of high-volume Complications
bolus material, breaching of mucosa, and injection through
previous filler.75,76 However, it is important to note that Vascular-related events are the complications most likely to
cases of recurrent, unexplained infections can be the result result in permanent sequelae. They can occur from intravas-
of other pathology. Factitious ulceration also should be cular embolism of injected material, direct needle injury to
considered in this setting (Figure 4). vessels, or external compression of vessels by surrounding
Hypersensitivity to fillers may trigger angioedema or filler† (Figure 6). Inadvertent injections of the angular, dor-
anaphylactic reactions.56,63,74,85 Delayed hypersensitivity sal nasal, or supratrochlear artery are most likely to lead to
reactions are usually self-limited systemic events that an ischemic response that results in necrosis.31,54,65
resolve without any sequelae but, depending on the pres- Appropriate treatment should be started immediately
entation, oral steroid treatment may be required. Although upon suspicion of vascular compromise. Injection should
collagen itself is no longer available, other collagen-
containing products (such as PMMA in collagen suspen-
†
sion) require skin testing prior to administration. References 10, 16, 18, 26, 27, 31, 53, 56.
872 Aesthetic Surgery Journal 33(6)

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Figure 5. Algorithm for treatment of mild to moderate complications following filler injections. 5-FU, 5-fluorouracil; HA,
hyaluronic acid; IPL, intense pulsed light; I&D, incision and drainage.

be stopped, and the area should be massaged and treatment measures are aimed at dissolving the product,
warm compresses applied to increase vasodilatation.53,58 facilitating blood flow, and promoting vasodilation. Dayan
Utilization of nitroglycerine paste and hyaluronidase et al20 have suggested the use of hyaluronidase in all cases
also is advocated for early presenting cases. Other treat- of vascular compromise, independent of the filler type,
ments include systemic or topical steroids to reduce due to its edema-reducing benefits and theoretical advan-
associated inflammation, thereby mitigating the degree of tage in reducing occluding vessel pressure.
injury.20,32,53,65 Although aspirin and IV prostaglandins Although we were not able to correlate the time of
have been suggested, their efficacy has not been therapy initiation with outcomes due to the insufficient
proven.11,16,21,22 Other options with unproven efficacy are data of case reports, it is well known that prompt interven-
filler removal via puncture and low-molecular-weight tion is crucial. In an experimental study, Kim et al10 found
heparin.11,20,27 Of course, patients with any vascular com- that the use of hyaluronidase within 4 hours of injection
plication should remain under extremely close care. The proved to be a successful salvage procedure for HA fillers.
Ozturk et al 873

Figure 6. (A) This 62-year-old man had inadvertent intravascular injection of poly-L-lactic acid during treatment of the

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cheeks. Warm compresses were applied immediately. (B) Three months after injection. The patient recovered without any
sequelae.

decrease the chance of bruising by constricting the blood

vessels.26,31
Consensus treatment of suspected intravascular injec-
tion includes immediate cessation of the injection, mas-
sage, warm compresses, topical nitroglycerine paste, and
hyaluronidase (regardless of filler type). Other suggestions
(but without proven efficacy) include removal of filler via
puncture, systemic or topical steroids, aspirin, low-molec-
ular-weight heparin, and IV prostaglandins. An algorithm
for the treatment of suspected intravascular injection is
presented in Figure 8.
The underlying mechanism for visual impairment after
facial injection is related to retrograde embolization from
peripheral vessels into the ophthalmic arterial sys-
Figure 7. The use of a blunt-tip cannula during filler tem.5,37-42,86,91 Intra-arterially injected material is displaced
injection reduces the risk of intravascular penetration.
via a high injection pressure past the origin of the retinal
artery, and when the plunger is released, it is propelled
into this system. Even a very small amount of material can
Once necrosis has occurred, debridement and wound care cause embolization of the retinal artery because it is an
are required to minimize scarring. Typically, an eschar end artery with no physiologic anastomoses.86,92 The ret-
develops, which heals over several weeks by granulation ina is also very sensitive to ischemia.86,92 Factors contribut-
and reepithelialization. The means of surgical reconstruc- ing to this phenomenon are high injection pressures, the
tion are site specific. distance between injection site and retinal circulation, and
Vascular complications are best avoided with appropri- the amount of injected material.37,86
ate training and injection techniques. The most important If symptoms of visual impairment occur, the goal is to
controllable factor for practitioners is the speed of injec- reduce intraocular pressure and dislodge the embolus to
tion. Filler should be injected slowly and the needle with- improve perfusion of the retina and optic nerve. There is
drawn using the least amount of pressure.86 Other no single reliable treatment for iatrogenic retinal artery
precautions include aspiration before injection, delivery of embolism.86 Recommended measures include immediate
material at different points, and injection of small volumes ophthalmologic consultation, ocular massage, timolol
per pass.58,67,74,86,87 The use of small-caliber needles has eye drops, diuretics, hemodilution (with hydroxyethyl
been advocated by some since they slow the speed of starch), corticosteroids, calcium channel blockers, anti-
injection.58,86 The use of blunt needles in high-risk regions coagulation, and needle decompression of the anterior
such as the glabella, nose, and NLF is another means of chamber.42,86,93 Other modalities that have been used
reducing injury to vessels88-90 (Figure 7). The injection after fat embolism to the retinal artery include carbon
technique differs with blunt tips: there is less movement dioxide and oxygen therapy,94 thrombolysis with uroki-
and less subcision and consequently less trauma.90 nase,95 and vasodilation.96 However, attempts to reverse
However, these cannulae are prone to bend with multiple retinal artery occlusion are often unsuccessful. It is
passes, and some planes may be difficult to breach with unclear whether the recovery is due to timely initiation
the blunt tip, resulting in excess accumulation of the of therapy, transient embolism, or favorable location of
product. Use of an epinephrine-containing product infarct in the retina. Unfortunately, in cases of vision
has inherent risks and benefits. Although it may mask a loss, the outcome is grave regardless of the treatment
complication because of its blanching effect, it also may rendered.
874 Aesthetic Surgery Journal 33(6)

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Figure 8. Algorithm for treatment of severe complications following filler injections. *Hyaluronidase is recommended
independent of filler type. IL, intralesional; IV, intravenous; LMWH, low-molecular-weight heparin; PO, per oral.

CONCLUSIONS Familiarity with the prevention, presentation, and immedi-

ate treatment of these rare events is essential for attaining
The soft-tissue fillers approved for use in the United States the best possible outcome.
have an excellent safety profile, which is reflected by their
increasing use. Although serious complications are Disclosures
rare, they can occur. Whenever fillers are placed, the prod- The authors declared no potential conflicts of interest with
ucts needed to treat complications should be readily avail- respect to the research, authorship, and publication of this
able. These should include, but not be limited to, article.
hyaluronidase, nitroglycerine paste, and warm compresses.
Physicians also should be aware of the high-risk regions of Funding
the midface, as identified in the present review. Injections The authors received no financial support for the research,
to the nose, NLF, and glabella require additional caution. authorship, and publication of this article.
Ozturk et al 875

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