Original Article

Vascular complications from facial fillers with

hyaluronic acid: preparation of a prevention and
treatment protocol
Complicações vasculares dos preenchimentos faciais com ácido
hialurônico: confecção de protocolo de prevenção e tratamento

JOSÉ CARLOS DAHER 1*

SUELLEN VIEIRA DA-SILVA 1 ■ ABSTRACT
AMANDA COSTA CAMPOS 1 Introduction: Over the past two decades, there has been an
RONAN CAPUTI SILVA DIAS 1 exponential advancement in treating signs of facial aging. The
ANDERSON DE AZEVEDO DAMASIO 1 growing demand for less invasive therapies has stimulated
RAFAEL SABINO CAETANO COSTA 1 the development of biomaterials toward better products,
seeking to fulfill safety criteria, such as biocompatibility
and reversibility. Hyaluronic acid (HA) is the most widely
used facial filler worldwide, being routine in plastic surgery
clinics. Even with low complication rates, it is prudent for
the plastic surgeon to be attentive to the signs of vascular
occlusion because the interruption of the progression towards
necrosis and permanent sequelae depends on rapid medical
action. Thus, our service saw the need to create a prevention
and treatment protocol, since such complications are serious
and sometimes even irreversible. Methods: A systematic
review of the literature was conducted from January 2003
to January 2018, using descriptors of vascular complications
after facial filling with HA and its treatment. Results: Filling
with HA presents a low potential for complications when
performed by qualified professionals. Hyaluronidase, which
is currently used off-label, can hydrolyze HA, even in its
cross-linked form. If used correctly in a timely manner, it can
Institution: Hospital Daher Lago Sul, treat possible vascular complications that would progress to
Brasília, DF, Brazil. irreversible damage. Accordingly, we prepared a treatment
protocol given the current evidence. Conclusion: Every plastic
Article received: February 27, 2019. surgeon who works with fillers and HA must have a protocol
Article accepted: October 20, 2019. and be aware of the necessary material for early intervention.
Keywords: Hyaluronic Acid; Hyaluronoglucosaminidase;
Conflicts of interest: none.
Dermal Fillers; Embolism; Necrosis.
DOI: 10.5935/2177-1235.2020RBCP0002

1
Hospital Daher Lago Sul, Brasília, DF, Brazil.

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 Vascular complications from facial fillers with hyaluronic acid

■ RESUMO
Introdução: Ao longo das últimas duas décadas, houve um
avanço exponencial no tratamento dos sinais causados pelo
envelhecimento facial. A procura crescente por terapias
menos invasivas estimulou a evolução dos biomateriais em
direção ao produto ideal, buscando preencher os critérios de
segurança, tais como biocompatibilidade e reversibilidade. O
ácido hialurônico é o produto mais utilizado mundialmente
para preenchimento facial, sendo rotineiro nos consultórios de
cirurgia plástica. Mesmo com baixos índices de complicações,
é prudente que o cirurgião plástico esteja atento aos sinais de
oclusão vascular, pois a interrupção da evolução em direção
à necrose e sequela permanente depende da rápida atuação
médica. Sendo assim, o nosso serviço vislumbrou a necessidade
da confecção de um protocolo de prevenção e tratamento, uma
vez que tais intercorrências são graves e algumas vezes até
mesmo irreversíveis. Métodos: Revisão sistemática da literatura
entre janeiro de 2003 a janeiro de 2018, utilizando descritores
de complicações vasculares após preenchimento facial com AH
e o respectivo tratamento. Resultados: O preenchimento com
AH apresenta baixo potencial de complicação quando realizado
por profissionais habilitados. A hialuronidase, atualmente
utilizada off-label, é capaz de hidrolisar o ácido hialurônico,
mesmo na sua forma cross-linked. Se utilizada corretamente
em tempo hábil, pode tratar possíveis complicações vasculares
que naturalmente evoluiriam para danos irreversíveis. Para
tanto, confeccionamos um protocolo de tratamento à luz das
evidências atuais. Conclusão: Todo cirurgião plástico que atua
com preenchimentos e ácido hialurônico, deve ter em mãos um
protocolo e o material necessário para intervenção precoce.
Keywords: Hyaluronic acid; Hyaluronoglucosaminidase; Dermal
fillers; Embolism; Necrosis.

INTRODUCTION myotomy and can be improved using dermal fillers.

Fillers are also useful in treating grooves during their
The aging process is multifactorial and results in initial stages or as an adjuvant modality to surgery.
simultaneous changes in the various components of the The filling of soft parts is an alternative for
face. The pathogenesis of facial aging can be explained patients seeking facial rejuvenation with minimal
anatomically and is the result of the interaction of downtime. For young patients, this might be the ideal
intrinsic factors (maturity of soft parts, skeletal atrophy/ modality, while for older patients, the combination of
changes and muscular hyperactivity) and extrinsic filling and surgery is more effective. To date, the ideal
factors (gravity and solar damage). Consequently, the filler has not been found, and there is no consensus on
smooth confluent appearance of the face is slowly its ideal characteristics (Chart 1).
replaced by spiked angles, wrinkles, grooves and
prominences. Skeletal changes lead to a general Chart 1. Characteristics of the ideal filler.
decrease in facial height and moderate enlargement Characteristics of the ideal filler
and deepening of the facial structure. The decrease
Non-toxic Produces natural and noticeable changes.
in maxillary height and the increase in orbital volume
results in sunken eyes and less space for the insertion Biocompatible Minimal downtime.
of available soft tissue. Lasting Predictable.
Superficial lines that cross the upper limit of Reversible Work well with ageing.
the dermis are responsive to dermabrasion, peeling, Autologous Not perceptible to touch.
and lasers. However, dynamic wrinkles respond to
Ease of use Safe
muscle inactivation with botulinum toxin or myectomy/

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The history of facial filling began in 1830, when consistency, high viscoelasticity and high degree of
the German chemist Karl Ludwig, in 18301, discovered hydration because of its structural characteristics5.
paraffin. Using this material, in 1899, Gersuny2, an This material was first described in 1934 by Meyer and
Austrian, reported using the substance for esthetic Palmer6, during the analysis of bovine vitreous humor,
purposes, when he created a testicular prosthesis for a which in its natural state is a very good filler but has
patient who had been treated with orchiectomy due to a short half-life. After minimum chemical changes
tuberculosis. After that, paraffin became widely used (cross-linking), it was possible to create a material that
in rhinomodeling, until in 19112 a list of complications was tolerated by the immune system, non-reactive, and
that the use of this material could generate emerged. It had greater longevity. Two techniques were developed
was then abandoned for cosmetic purposes. to produce the acid: bacterial fermentation or extraction
Adipose tissue grafting was initially developed from rooster crest. For large-scale production reasons,
in the late 19th century for facial reconstruction. the first technique is the most widely used today.
Neuber, in 18933, described an autologous fat graft, Since FDA approval in 2003, HA has become the
from the arm, which consisted of fragments of fat most widely used filler in the world due to its properties,
tissue to correct facial defects. However, this method such as biocompatibility and reversibility. According to
only became popular in 1982, after Illouz4 described the American Society of Plastic Surgery, in 2014, soft
the use of cannulas for vacuum aspiration and grafting tissue filling increased by 253% when compared to 2000,
of the aspirated product. Several techniques have with HA accounting for 78.3% of all injectable fillers.
been proposed since then, and this grafting modality
is still widely studied and used by plastic surgeons for METHODS
facial filling and other areas of the body. In the 1940s,
in Japan, injectable liquid silicone was used for breast An extensive search was performed in the
augmentation. This product gained prominence after MEDLINE, Cochrane, and PubMed databases between
being introduced in the United States of America January 2003 and January 2018. The keywords used
in the 1960s, but in the following years, reports of were “dermal fillers”, “vascular complications”,
complications and sequelae of the use of liquid silicone “hyaluronic acid” and “hyaluronidase”. Initially, 49
emerged. Its use for cosmetic purposes was banned by articles were selected.
the Food and Drug Administration (FDA) in 1979. The inclusion criteria were:
Clinical experiments with bovine collagen - Year 2003-2018;
occurred between 1977-1978, to treat age-related - Clinical trials and case studies;
wrinkles. After 6 years of research, the substance was - HA facial filler;
approved by the FDA for aesthetic purposes, under - Vascular complications;
the name Zyderm. Despite the success of this material - Treatment with hyaluronidase.
in the 1980s and it becoming the standard to which all Exclusion criteria:
other injectables were compared, it was not an ideal - Case reports;
product and had a number of drawbacks. As well as - Filling with other materials besides HA;
its short duration, all biological materials were derived - Focus on other complications.
from organic sources, which can lead to sensitization - The results yielded 19 articles.
to foreign animal or human proteins, the transmission
of diseases, and immunogenicity. During the following DISCUSSION
years, there was an evolution of collagen materials, as
shown in Chart 2 below: Although infrequent7, adverse effects related to
the use of HA injections may occur. It is important for all
Chart 2. Evolution of collagen-based fillers. surgeons who work with HA to perfect the infiltration
technique and to recognize early complications and
Collagen-based biological filling master its handling.
Zyderm(1981)/Zyplast (1985) Collagen (bovine) The complications of HA filling can be divided
Dermalogen (1998) Human collagen matrix into early and late, according to the time of appearance.
Surgisis (1998) Pig collagen matrix Those classified as early appear within a period of hours
to days. The most common are edema, pain, hyperemia,
CosmoDerm/CosmoPlast (2003) Collagen (human)
and ecchymosis8. These reactions are usually self-
limiting and do not require major interventions. On
Hyaluronic acid (HA) is a polysaccharide found the other hand, vascular complications that can result
naturally in the connective tissue of mammals (skin, in tissue necrosis and loss of vision can occur rarely.
cartilage, bone, and synovial fluid), with a gelatinous These require further attention and follow up due to

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 Vascular complications from facial fillers with hyaluronic acid

the high potential of sequelae9. Late complications Chart 4. Signs of complications x time.
include biofilms, granulomas, depigmentation, and Clinical findings Time after filling
scarring. (Chart 3) Skin pallor Seconds Minutes
Livedo reticularis Hours
Chart 3. Complications related to the use of hyaluronic acid.
Cyanosis Hours to days
Early Tardias
Blisters Days to weeks
Relate to infiltration: Infections
Barrier loss, ulceration Dias a semanas
Edema Granulomas
Pain Nodules the topography, where infiltration of the material
Bleeding Depigmentation occurs. During an initial visit, it is crucial for patients
Ecchymosis Scars to question their experience with previous facial
procedures. Most of the face is supplied by branches
Inflammatory Reactions
of the external carotid artery, except for the forehead,
Allergic Reactions the central part between the eyes and the upper part of
Vascular infarction/Tissue necrosis the nose, which are supplied by the ophthalmic artery,
and a branch of the internal carotid artery. The arteries
Venous obstruction is uncommon but may be involved in complications of the glabella and forehead
observed in some cases where some degree of occlusion are the supratrochlear and supraorbital arteries,
is already present10. It can occur when a large volume both of which can lead to eye-related complications.
of material infiltrates topographies with significant The supra-trochlear artery is constant in most cases,
tension, where the tissue is restricted, with the absence varying its position by a maximum of 5mm. It starts
of the usual elasticity, as with scars. An accidental deep in the superomedial part of the orbit and becomes
intravenous injection may not have repercussions and subcutaneous 15 to 25 mm from the supraorbital
often goes unnoticed. In contrast, the injection of intra- ridge as it moves superiorly. The supraorbital artery
arterial material can result in flow obstruction, leading appears at the supraorbital border, vertical to the pupil,
to hypoxia in a certain territory and tissue ischemia11. becoming subcutaneous 15 to 20 mm above the orbital
The signs of vascular occlusion are immediate ridge, heading towards the forehead. Filling in the nasal
and usually present with: pale tissue, followed by region should be performed in the deep supraperiosteal
livedo reticularis, and ischemia. If no intervention plane, below the SAMS, thus avoiding the anastomotic
is performed, blisters, sores, and tissue necrosis can venous network.
occur (Chart 4). The most serious complication related The use of cannulas for deep injection is another
to vascular obstruction is a loss of vision, which can recommendation since it is less likely that a blind tip
happen when there is occlusion of an ophthalmic thin cannula penetrates an artery compared to a needle.
artery or the retina via a retrograde flow of material It is prudent to always aspire before infiltrating the
injected into the supraorbital area. This is associated material and when withdrawing the needle. Avoid the
with an influx of a large volume at an excessive infusion infiltration of a very large volume (<0.1) of material at
pressure. The symptoms are immediate and include an exaggerated pressure, using smaller syringes for
ocular pain and visual disturbance. Tissue necrosis flow control, to avoid a possible reversal of flow and
occurs more in the so-called risk zone, which is the retrograde embolism14.
nose, mainly in the glabella. The glabella is supplied Even after prevention strategies are undertaken,
by arteries from the supratrochlear, which travels in vascular complications can occur that should be treated
a medial path to the eyebrows. Due to this anatomical immediately. Hyaluronidase is a mucolytic enzyme
course, it is suggested that there is a greater risk that capable of degrading HA in both its natural and cross-
inadvertent intra-arterial injection may occur12. The linked form. It hydrolyzes HA, breaking its bonds,
alar topography of the nose is vascularized by terminal generating increased permeability in the skin and
branches of the angular artery, a site poor in collateral connective tissue. Its plasma half-life is approximately
branches, and is, therefore, a common area of tissue two minutes, with it inactivated during its passage
necrosis. Most of the cases reported in the literature through the liver and kidneys15. However, its effect on
occurred in Asia, where there is a high prevalence of subcutaneous tissue is immediate, with a long duration,
filling in risky facial areas13. ranging from 24 to 48 hours.
The first strategy against vascular complications In 2007, Hirsch16 et al. reported the first case
from using HA is prevention. The doctor must of vascular occlusion by HA filling, which reverted
be knowledgeable about the vascular anatomy of successfully after the use of the enzyme. In 2014,

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DeLorenzi17 developed an in vitro study to assess and 30G, and a spacing of 3 to 4cm between the points.
whether hyaluronidase was able to cross the intact The application must be repeated after 60 minutes if
human facial artery wall to hydrolyze the HA filler there is no improvement in the initial framework, and
through small segments of the facial artery, which were may be conducted up to 4 times25. The product should be
filled with a monophasic HA, acquiring the aspect of kept cool between 2-8 degrees to ensure its stability. Once
“sausages”. Then, they were immersed in 300IU of opened, the rest of the product should be discarded.
hyaluronidase (manipulated) or saline (control). Only There have been reports of severe allergic
the samples immersed in hyaluronidase displayed reactions to the enzyme. Therefore, patients should be
degradation of the filler at the end of 4 and 24 hours. observed for at least 60 minutes after the application of
Thus, the result indicated that the enzyme could hyaluronidase21. Due to its propagation, it should not
hydrolyze HA even with the vessel wall intact. be infiltrated into areas where botulinum toxin was
Currently, the treatment for vascular accidents by applied in the last 48 hours.
HA requires the use of the enzyme in the entire extension Patients should be reassessed daily to check for
of the lesion. However, there is no standardization of signs of improvement or regression of vascular congestion.
the dose in the literature. In 2007, Soparkar et al.18 used Hyperbaric medicine can be useful, as it acts by carrying
375IU of hyaluronidase to dissolve an HA filler in the oxygen to the tissues and is increasingly being used for
face of a patient. In their opinion, the recommended treating ischemia, which progresses to necrosis26,27.
dose should vary from 150 to 200IU of hyaluronidase The monitoring of affected patients involves
for each 1ml of HA to be removed. In 2014, Rao et al.19 routine care with surgical wound debridement and
exposed four types of HA fillers to various concentrations surveillance of secondary infections. Patients diagnosed
of hyaluronidase in vitro and concluded that the early usually have a satisfactory prognosis. Those with
enzymatic reaction is time and dose-dependent. The a delayed diagnosis are more likely to have major
literature recommends early treatment, demonstrating complications, requiring many weeks of wound care,
a considerable reduction of its effectiveness after 24h of which can result in different degrees of scarring12.
filling20, which may reach 50%.
We feel that a protocol is required that includes CONCLUSION
the treatment of these possible complications and
adopts the abovementioned knowledge carefully. Given Although not very common, complications related
current scientific evidence, we propose the following to the use of HA can be severe and irreversible. The most
protocol for treating possible vascular complications: serious are vascular complications, as they can lead to
1. Immediately stop the procedure; irreversible sequelae. Therefore, any surgeon using
2. Use high doses of hyaluronidase in the HA for facial fillers must have a treatment protocol and
affected area; appropriate medications available.
3. Massage the area;
4. Wait 60 minutes and reassess the possibility COLLABORATIONS
of new infiltration.
JCD Analysis and/or data interpretation, Final
At the first sign of vascular involvement during
manuscript approval
the use of HA, the procedure must be stopped. The ACE
GROUP, in 201821, recommend the immediate infiltration SVS Analysis and/or data interpretation,
of hyaluronidase to prevent the progression to tissue Conception and design study, Data Curation,
ischemia and necrosis, since studies corroborate that Writing - Review & Editing
the best results are with the early use of the enzyme22, ACC Analysis and/or data interpretation
and preferably within the first 4 hours. RCSD Analysis and/or data interpretation
The literature emphasizes that it is important
to avoid a sub dosage, since the progression of the AAD Analysis and/or data interpretation
complication may lead to severe cases, with irreparable RSCC Analysis and/or data interpretation
consequences23. High doses (450-1500IU) should be
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*Corresponding author: José Carlos Daher

Quadra 07 SHIS, QI 7 Conjunto F, Lago Sul, Brasília, DF, Brazil.
Zip Code: 71615-660
E-mail: [email protected]

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