fillers: complications and their management... · abstract...

Fillers: Complications and TheirManagement

Meire Brasil Parada, João Paulo Junqueira Magalhães Afonso,and Nilceo Schwery Michalany

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408

Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408Clinical Presentation of the Immediate or Early Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . 408Clinical Presentation of Complications and Early

Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409Clinical Presentation of Complications and Adverse

Late Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412Post-Procedure Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414Immediate Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414Treatment of Immediate Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415Treatment of Late Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416Contraindications Post-Permanent Fillers

Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418Treatment of Fillers of Complications in the Back of the Hands . . . . . . . . . . . . . . . . . . . . . . . 418Hyaluronic Acid (HA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418Hyaluronic Acid + Dextranomer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419Hydroxyapatite Calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419Polymethylmethacrylate (Metacril®) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419Polymethylmethacrylate + Collagen (Artecol®) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420L-Polylactic Acid (Sculptra® or Newfill®) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420Silicon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420

Take Home Messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421

M. B. Parada (*) · J. P. Junqueira Magalhães Afonso ·N. Schwery MichalanyUniversidade Federal de São Paulo, São Paulo, Brazile-mail: [email protected];[email protected];[email protected]

# Springer International Publishing AG, part of Springer Nature 2019M. C. A. Issa, B. Tamura (eds.), Botulinum Toxins, Fillers and Related Substances, Clinical Approaches andProcedures in Cosmetic Dermatology 4, https://doi.org/10.1007/978-3-319-16802-9_34

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https://doi.org/10.1007/978-3-319-16802-9_34

AbstractThe fillers are emerging minimal invasive tech-nique for rejuvenation. As the use and applica-tion of fillers grow, it is also important to knowhow to manage possible complications of theprocedures. This chapter describes fillers’immediate, early, and late complications andalso suggestions of management based on evi-dences and author’s experience.

KeywordsComplications · Fillers · Granuloma ·Hyaluronic acid · Infection · Management ·Nodules · Treatment · Vascular occlusion

Introduction

Currently the search for aging delay has been con-stant and growing, leading to the emergence of anew marketing niche for healthcare industries, aswell as for physicians, who have developed prod-ucts and techniques to meet part of the aestheticconcerns of patients. Among these, is the filler, withthe objective of restoring a groove or wrinkle,doing a volumizing treatment or collagen stimula-tion. These procedures are liable to complicationsand side effects which can be classified into early(often expected) and late (often unexpected).Today, there are several types of fillers that can beclassified into temporary, semipermanent, and per-manent. Each filler has physicochemical character-istics, properties, better indications, andcontraindications; however, none of them is totallyfree of risk for complications and adverse effects.Although it is controversial, these authors considerthe permanent fillers as more susceptible to latecomplications, once they definitely remain in thetissue. These complications are difficult to handlebecause with temporary fillers when there are com-plications, time itself can resolve them as the prod-uct undergoes degradation, but this does not occurwith permanent fillers (Amin et al. 2004; Goldanet al. 2007; Jones et al. 2007).Hyaluronic acid is thetemporary filler most commonly used in clinicalpractice. Although it has a lower incidence of com-plications compared to other fillers, its widespread

use produces a significant number of complicationsthat we must be prepared to prevent and treat(Cohen et al. 2013; Duffy 2005).

Classification

The adverse effects of fillers can be classified inseveral ways:

A. Related application time:1. Immediate (<14 days after application)2. Late (> 14 days after application)

B. Related to the procedure: potentially expectedevents (“side effects”)

C. Related to the product (“adverse effects”)D. Related to application technique

(“complications”)

Immediate adverse effects: they are inherent tothe procedure, which are generally expected andare limited to acute or immediate period.

Adverse effects and late complications shouldbe analyzed from the following aspects (Sclafaniand Fagien 2009):

1. Clinical impact2. Aesthetic relevance

As we shall see, the management of these eventsinvolves only expectant management to surgicalmanagement, and these aspects should be, there-fore, considered very well in order to choose thebest conduct for each specific case (therapeuticindividualization) (Alam and Dover 2007; Baileyet al. 2011; Lowe et al. 2005).

Clinical Presentation of the Immediateor Early Side Effects

The immediate and expected changes (side effects)after or during a filler procedure usually are:

1. Erythema2. Swelling3. Pain or tenderness

408 M. B. Parada et al.

4. Bruise5. Itching

The onset of these effects varies according tothe patient and the applicator. It is estimated tooccur in about 80% of applications.

These side effects depend upon some aspectsas the reactivity of the patient, if the patient istaking medications (e.g., anticoagulants), thenumber of punctures and application site, theproduct used, and the applicator technique. Animportant issue in this type of events is toclarify the patient previously of the possibilityof such changes, as well as its transient andmanageable characteristics. Spontaneous reso-lution of these symptoms may take 5–10 days(Winslow 2009).

Clinical Presentation of Complicationsand Early Adverse Effects

InfectionAfter fillers injections, in the first days, there isthe possibility of secondary infections due to theprocedure. They can be elicited by viruses (her-pes infection) or bacteria. Bacterial infectionsare presented as skin indurations with redness,pain, or itching that can evolve with fluctuationand even systemic symptoms such as fever,malaise, asthenia, leukocytosis, vomiting, andweight loss.

Hypersenstivity (Allergy)Hypersensitivity to the fillers is unpredictable,except when using fillers of animal origin, suchas the collagen, which is possible to allergicdiagnostic pretesting. Although there isno well-established pretesting for the nonanimalorigin products, allergic conditions may occuras idiosyncrasies. These are characterized byclinical conditions ranging from simple signsas inflammation with erythema, edema, heat,local pain, and itching, without any signs ofinfection, until signs as pus or lumps withfluctuation, angioedema and anaphylacticreactions.

Irregularities Caused by PoorDistribution of the ProductBoth in acute and chronic periods, we can checkvisible or palpable irregularities, due to unevendistribution of filler. In the acute period, however,this problemmay be related to improper techniqueor lack of patient compliance to post-procedurecare such as guidance to do not massage the site ofapplication or do vigorous exercise on the day ofapplication.

DyschromiasMost dyschromias occurs due to improper place-ment of the filler, when applied very superficially inthe epidermis or superficial dermis, thus allowingvisualization. They also may be due to persistentredness and ecchymosis (hemosiderosis) and canprogress to post-inflammatory hyperchromies.

Tissue Necrosis Caused by VascularOcclusionThis is one of the most serious and troublingcomplications that can occur in the acute phaseafter or during the application of fillers.

There have been reports of irreversible blind-ness secondary to vascular occlusion by fillers.

The application site of greatest risk is theregion of glabella that, in our opinion, shouldnot be filled except at a very superficial layer ofthe skin and in small quantities.

Other danger zones are the region of angularartery (near the piriform aperture) and the regionof the temporal artery.

The use of fillers in areas close to medium-caliber vessels of the face leads to the risk of peri(external compression) or intravascular injectionthat can cause sub or total occlusion of thevasculature.

In case of arterial occlusion, it can be noticedimmediately after application a blanching patterndrawing the area of the affected vessel irrigation,whether or not accompanied by severe paindepending on the filler composition (if it containsor not lidocaine), followed by purplish skin tone.In the case of venous occlusion, the symptomonset is slower and will evolve into the violettone and less intense pain. If not noticed, vascularocclusion evolves with a reticular erythema,

Fillers: Complications and Their Management 409

sometimes purpuric, followed by necrosis of theaffected area in about 3–5 days.

Predicting signs of necrosis:

• Skin blanching• Dusky (i.e., grayish blue) skin• Ecchymosis• Reticulated erythema• Intense pain in the treated area

Some cases of vision loss were reported amongthe last years and are often associated with injec-tion on “danger zones.” Some symptoms arelinked with vision loss risk:

• Ocular pain in the affected eye immediatelyafter injection

• Diminished vision• Ptosis• Headache• Dizziness• Nausea• Ophthalmoplegia (i.e., extraocular muscle

palsy) (Lemperle et al. 2006; Lowe et al.2005; Requena et al. 2011)

Clinical Presentation of Complicationsand Adverse Late Effects

Hypertrophic ScarPatients who already tend to hypertrophic scarringmay eventually develop this type of healing pro-cess after fillers injections. Most reported cases arerelated to inadequate injection technique, buthypertrophic scar has been also reported followingthe use of filler at the right level.

Intermittent EdemaIntermittent swelling can occur months to yearsafter fillers injections and is usually related to theconsumption of alcohol, sun exposure, vigorousexercise, and episodes of vasodilation.

DyschromiaSkin color changes may occur when the filler isapplied superficially in the skin. Different wave-lengths of light waves are reflected and scattered

differently by substances present in the tissues: theTyndall effect. As an example we know that theskin red wavelengths penetrate more deeply thanthe blue. Thus, the presence of a filler at verysuperficial skin layers can lead to a dyschromiadue to the change of the reflectance of that tissue(bluish color in the implant area).

MigrationIt can occur with any filler, but more often withpermanent fillers. Migration of a filler may presentclinically as nodules simulating granulomatous orneoplastic diseases. Silicone is the most suscepti-ble product to this complication, and althoughbanned in many countries, we can often encounterpatients with complications arising from their ille-gal use or patients who have used this productmany years ago. Migration to distant sites is notuncommon, for example, from the buttocks to theentire length of the lower limbs.

NodulesThe nodules may be caused by several factorssuch as those immediate after injection, due toovercorrection or poor distribution of the product,or those due to allergic reactions to the filler,which may be early or late. There are still nodulesarising from infections, which may be single ormultiple (Funt 2015).

The nodules may be dermal or subcutaneousand may be or not clinically apparent or palpable.The evaluation of clinical and aesthetic signifi-cance of these cases is the parameter of the treat-ment required or not (Fig. 1).

Recent advances in magnetic resonanceimaging (MRI) studies for filler complicationsdiagnosis described how this exam could helpto differentiate between inflammatory andnoninflammatory nodules which is not alwayspossible with high-frequency US (Di Girolamoet al. 2015).

Foreign Body GranulomasThe granulomas can be clinically classified asnodules if no histopathological study isperformed. The histopathological study will benecessary to clarify the diagnosis and help thetreatment planning. In many cases the result is


compatible with foreign body granuloma, withoutany evidence of infection or hypersensitivity.

The risk of foreign body granuloma formationcannot be predicted and may occur months toyears after the use of a filler. Possible triggerscan be systemic or localized infections.

InfectionThe infection may emerge clinically as nodules,which are different in this case because they areaccompanied by pain, warmth, redness, swelling,and fluctuation. Irregularity, inflammatory fibrouscords, andmultiple nodules are some possibilities.

As the filling procedure involves punctures inthe skin and introducing material into the tissue,the risk of infection will be high, if carefulantiseptic measures are not taken.

We must remember that, due to the lack ofregulation and supervision in some countries,this procedure is being performed by doctorswithout proper training or even by nonmedicalprofessionals. Inevitably the chances that weencounter this kind of complication are growing.

The bacteriamost commonly involved are Strep-tococcus pyogenes and Staphylococcus aureus, butinfections that begin more than 2 weeks after theprocedure are highly suggestive of atypical infec-tious agent such as mycobacteriosis.

Saprobe bacteria can find a favorable microen-vironment for multiplying in the gel formed bythe filler, as this limits the access to the

inflammatory defense cells (neutrophils, macro-phages, lymphocytes) and simultaneously allowspassage of nutrients for bacterial metabolism.

The possibility of the so-called bacterialbiofilms formation should be considered. Theseare complex bacterial biosystems formed byaggregated and adhered bacteria to the surface.This provision in colonies allows greater bacterialresistance and much more difficulty in treatment.

More severe symptoms can occur, includingsystemic symptoms such as hyperthermia, mal-aise, asthenia, leukocytosis, vomiting, and weightloss.

Lipoatrophy After FillersA rare reaction (idiosyncratic) was described afterthe use of fillers, in which the patient hadlipoatrophy similar to that of patients on antiretro-viral therapy for HIV.

Hypersensitivity ReactionsThese reactions are characterized by redness,swelling, warmth, and pain, however withoutany evidence of infection. They are more fre-quent in early stage after filler injection buteventually may arise later. Currently they areless frequent due to increased biocompatibilityof most used fillers but have been a much morecommon reaction during the predominance ofthe use of bovine and human collagen, as well asthe hyaluronic acid of animal origin (roostercrest).

As the current hyaluronic acids are derivedfrom industrial technology that employs a strep-tococcal bacterial fermentation, local hypersensi-tivity reactions may still occur due to the possiblehigh protein level in fillers.

There are two main types of hypersensitivityreactions:

- Angioedema (antibody-mediated edema) thatis due to IgE-mediated immune response that canbe treated with antihistamines

- Nonantibody-mediated (delayed) edema thatcannot be treated with antihistamines but possiblytreated with steroids and the removal of the filler((Hirsch and Stier 2009), Cox and Adigum 2011,(DeLorenzi 2013; Gilbert et al. 2012; Requenaet al. 2011))

Fig. 1 PMMA post-application nodule(polymethylmethacrylate)


Complications in Specific Sites

A-Back of HandsThe rejuvenation of the dorsum of the hand withfillers has been widely used today. Like any otherprocedure, there can be some complications.

Recent review published about this specificsite has compiled the most frequent late compli-cations in this region: permanent swelling notrelieved by classical therapies, tingling and numb-ness, and foreign body granuloma formation(Figs. 2 and 3) (Park et al. 2012).

B-Malar EdemaMalar edema may occur after superficial or deepinjection in this region, but it is far more com-mon when the filler is injected more superfi-cially. The superficial lymphatic cheekdrainage is naturally compromised, and evensmall amounts of filler can worsen it causingpersistent edema. The deep drainage also canbe impaired by bigger amounts of filler. Thenspecial care must be taken when injecting fillersat this site.

Treatment

Prevention

Physicians should prevent complications withfillers by correct selection of eligible patients forthis treatment

If a patient wishes to treat grooves for the firsttime but is unsure of the procedure, one should optfor temporary fillers. If the patient has alreadymade temporary fillers with good results and nolonger wishes to repeat the treatment periodically,only then physicians should think about the pos-sibility of more permanent fillers such as calciumhydroxyapatite and PMMA.

About the selection of patients, the physicianmust actively investigate if the patient has a ten-dency to unaesthetic scars such as hypertrophicand keloid. Investigate autoimmune and granulo-matous diseases, especially collagen diseases andsarcoidosis, which, if present, can lead to

contraindication of the procedure, although thiscontraindication is not absolute.

Investigate the history of procedures alreadyperformed by the patient is very important because,although still controversial, some authors suggestthat injections of different fillers on same areasalready treated with permanent fillers can triggerimmune reactions and adverse events, besidesinfections on permanent fillers. Besides that, previ-ous surgeries on application site could induce ana-tomical variations, and, therefore, the “dangersites” could be different from the usual ones.

Gather information about daily use medicationsand sporadic use medications, because the use of

Fig. 3 Hand back filled with PMMA resulting in “cush-ion” aspect

Fig. 2 Foreign body granuloma after calcium hydroxyap-atite filler


medications that have anticoagulant effects caninfluence the formation of bruises during applica-tion. The suspension or none of these drugs beforethe procedure should be evaluated considering theindication and necessity of the medication in use.

Even before the procedure, it is important toclearly explain to the patient about the procedure,the expected effects, side effects andadverse effects, and duration, assess thepatient’s expectations, and, after these steps, getthe written informed and free consent (Engelmanet al. 2005).

Using the correct technique (tips to avoidcomplications):

1. Visualization of the grayish color of the nee-dle under the skin is warning that the posi-tioning of the needle is too shallow and mustbe repositioned deeply. Exception is madewhen treating acne scars.

2. Intramuscular injection is alsocontraindicated for being a layer at high riskfor formation of lumps and irregularities trig-gered by the migration of the filler when thereis contraction of the injected muscle.

3. Submucosal injections in lips can also triggerirregularities and unaesthetic or uncomfort-able lumps for the patient when injectedvery superficially.

4. Special care must be taken when applyingfillers in areas with very thin skin such aseyelids, for example. The use of fillers to tryto correct fine lines in this region can mistak-enly lead to very superficial injection withvisible irregularities of the skin surface bythe filler’s presence in inadequate dermallayer. In this section we would like to pointout that specific products for fine lines havebeen developed. These products aim to makea “boost” in the dermis, may not possesscrosslinking, or have it in a lesser degree,being less viscous and more rapidly absorbed.They are not therefore called fillers them-selves, but “skin moisturizers,” collagenenhancers, or skinboosters.

5. Groove correction may require more than onesession in order to achieve the desired final

effect. Do not overdo the correction in the firstsession. The patient should come back toshow you the initial result, and a new proce-dure can be done to complement the initialone, if necessary. It should also be remem-bered that the patient does not have technicalor anatomical knowledge to decide whichprocedure is the best for him. The decisionsrelated to the anatomic facial area to betreated and the amount of product for thisarea should be determined by the doctor. Donot let patients interfere in your decision,because sometimes they can have body dys-morphic disorder and can desire much morethan they deserve to have a good clinicalresult.

6. Post-injection guidance is important.Although not proven, the use of coldor frozen compress is often indicated to pre-vent edema, erythema, and post-procedurebruising. Recent evidence may contraindi-cate cold dressings and should be replacedby hot packs in the case of signs of ischemia/vascular occlusion. Massaging is alsogenerally contraindicated but may be neces-sary in the case of ischemia/vascular occlu-sion and poor distribution of the product.Strenuous exercise and exaggeration inmuscle contraction near filler applicationsite in the first 3 days after application canlead to migration and product distributionirregularities.

7. Skin pretests must be made beforehand forthe animal collagen-based fillers. These testsconsist of the intradermal injection of 0.1 mlof the product in the volar forearm and read-ing after 48–72 hours. Some authors recom-mend a second test after 2 weeks based on thepossibility of immune response developmentafter first exposure (similar induction phase ofallergic contact dermatitis). These tests aredispensed when dealing with human origincollagen products. Collagen products are notavailable anymore in Brazil.

8. PLLA when diluted in greater volume andtime between reconstitution and application(36–48 h instead of 12–24 h) and applied


subcutaneously instead of reticular dermisfollowed by massage after application showslower incidence of non-visible but palpablenodules.

9. Avoiding infections: washing hands beforestarting any procedure, remove all makeupand other topical products before theprocedure, clean the application sites withantiseptic before the application, take theappropriate antiseptic care, and select the nee-dle or appropriate cannula to perform theprocedure. This will prevent infections andbiofilm formation in the applied product.

10. Biofilms are commonly present in dentalbacterial plaques. Consequently, intraoralinjections of fillers are at increased risk ofinfectious complications and should beavoided. Furthermore, the massage for a bet-ter distribution of the filler with fingersinside the mouth should be avoided. Thisprocedure contaminates the gloves and,therefore, should only be made after treat-ment, and the gloves should not come incontact again with the needle entry holes,where applications have been made. Ifneeded one should proceed the exchange ofgloves after this move.

11. Never inject the filler on areas withactive infection, such as acne, cold sores, orimpetigo, avoid using on patients withrecent dental surgery, Inject on previousimplants of other materials, as well asintraoral application as mentioned in theprevious topic.

12. For prevention of vascular occlusions, somesteps can be taken:– Take care with risk factors such as danger-

ous zones, large volumes of injection,small sharp needles or blunt cannulae(smaller than 27 gauge), previous scarringsites, and type of filler (permanent onesworst than temporary ones).

– Aspirate with the syringe before injecting.– Inject small amounts in high-risk areas or

do not apply in these areas.– Inject more in superficial planes using

products listed for each plan.

– Manually occlude the origin of importantvessels with the nondominant finger.

– Pinch the skin to provide more spacesbetween superficial branches of mainarteries and tomove away from underlyingvasculature.

– Take special care with high-risk areas suchas glabella where anastomosing arteriesand veins have great anatomical variability(Lemperle et al. 2006; Lee 2014; Sánchez-Carpintero et al. 2010; Sherman 2009).

Post-Procedure Care

The commonly used cold compress or ice has notpresented any evidence of prevention of early orlate complications such as swelling, redness, orbruising. However, it offers comfort to the patient,which is the reason for their acceptability as post-procedure care.

The hot compresses are formally indicatedwhen there is evidence of vascular occlusion inan attempt to obtain thermal vasodilation andreestablishment of blood flow.

Immediate Side Effects

Often only local observation and care will be morethan sufficient for the resolution of erythema,edema, bruising, local pain, and tenderness afterthe procedure. If necessary, as described above,one may employ the cold compresses (at first) orhot compresses (as second step).

Persistent erythema can be treated with corti-costeroids or intense pulsed light devices.

The cold packs may be useful for patient com-fort in the case of pain. The use of Arnica andBromelain before and after the procedure has beenreported as helpful, although there are no studieson this use.

In the case of bruises, early compression can beuseful.

The recent introduction of fine gauge cannulaalso shows promise in preventing the eventsdescribed above.


Treatment of Immediate AdverseEffects

Infection TreatmentIn the case of herpes infection, oral antiviralshould be immediately initiated (acyclovir,valacyclovir, penciclovir), with full cycle andfull dose.

In the case of acute bacterial infections, empir-ical treatment could be used with antibiotics whosespectrum covers skin biota bacteria. In case of noimprovement, further investigation like the one inlate infectious complications should be made.

Hypersensitivity TreatmentAccording to hypersensitivity of severity, antihis-tamines and corticosteroids can be employed.

Treatment of Irregularities Caused byPoor Distribution of the ProductIn the case of immediate irregularities, the appli-cator can try a more vigorous massage modelingand better distributing of the product, which willonly work in the early hours after application.Another option is the removal of localized quan-tities of product through needle punctures on theaffected site.

In the case of hyaluronic acid, the use of hyal-uronidase may be tried.

Treatment of Vascular Occlusion/NecrosisAs soon as one notices an early sign of vascularocclusion, one should immediately suspend theprocedure. If cold compresses are being used, thisshould be immediately suspended and replacedwith hot compresses to promote vasodilation.

A quick light massage in circular movements,not compressive, must be made on site.

The use of topical nitroglycerin derivatives isindicated and can be of great help (Kleydmanet al. 2012). Patients should be advised that thismedication can trigger headaches and even hypo-tension in susceptible patients.

When the product used is hyaluronic acid, theuse of hyaluronidase is indicated to attempt toremove the cause of vascular occlusion.

The low molecular weight heparin can be usedas a treatment modality for vascular embolicocclusions, as well as acetylsalicylic acid.

Hyperbaric oxygen therapy can be used whenavailable.

A follow-upwithin a very short period should bemade to detect early signs caused by necrosis and, ifthis is so, treat properly with daily care, debride-ment, and dressing to try to prevent scarring.

If a scar is formed, it should be treated at thecorrect time for its minimization, which will be onaverage after three months, when new adequatecollateral circulation can be formed.

Brennan in 2014 summarized this procedure intopics:

• No ice.• Warm immediate compresses.• Massage or tap the area to facilitate vasodila-

tion and dispersion of material.• Aspirin (80 mg).• Topical nitroglycerin derivatives.• Hyaluronidase (only if using HA).• Corticosteroids.• If ischemia is not reversed, and necrosis is

unresponsive, contact a plastic or reconstruc-tive surgeon.

• Subcutaneous injections of low molecularweight heparin may be helpful.

• Antibiotics.• Antivirals (if impending necrosis is around the

mouth).• Hyperbaric oxygen for 1 month may be

required.• Multiple laser treatment after 3-month

postinjection.

There are five existing phases that might occurafter vascular occlusion:

1. Pallor or blanching (mediated by arterialcontraction)

2. Livedo (indicates that oxygen supply is beingconsumed)

3. Blue or gray-blue (oxygen was consumed anddeoxygenated blood predominates)


4. Demarcation (ischemia progresses to necrosisand a margin of hyperemia surrounds a zone ofnecrosis)

5. Repair and remodeling (inflammation subsidesand tissue repair and remodeling occurs)

Treatment of Late Complications

Treatment of Hypertrophic ScarThe treatment of hypertrophic scars should be donein the same way as that of postsurgical or traumatichypertrophic scars, i.e., the use of intralesionalcorticosteroid injections to generate atrophy withthe aim of improving aesthetic results.

Treatment of Intermittent EdemaIntermittent swelling will occur only in “crisis,”and corticosteroids or tacrolimus topical creamscan be used.

Treatment of DyschromiaTyndall effects will be treated according to thefiller used. In the case of hyaluronic acid, it canbe solved with intense massage, as you may needthe use of hyaluronidase (an enzyme that degradeshyaluronic acid). Visible white spots after usingcalcium hydroxyapatite can be solved with smallincisions and removal of the product because it isvisible. Permanent fillers have more complicatedmanagement and may require surgical removal ofthe applied product.

Post-inflammatory hypochromia can be man-aged with topical hydroquinone, and other hypo-chromias are more difficult to treat. One can try

the whitening of the skin around to decrease thecontrast using laser and chemical peels, mostoften however, with poor results.

Migrated or Poorly Positioned FillerRemoval or OvercorrectionNodules can be treated with vigorous massage tobetter repositioning when forming in the recentperiod after application of the filler. Late nodulesrespond less to this technique because it is alreadyintegrated in the tissue.

In much fewer cases, the fillers may eventuallybe removed when causing unsightly effects bydisplacement, malposition, or overcorrection.This can occur even later when, for reasons notwell clarified, integration or encapsulation of theentire filler to the biological tissue does not occur.The extraction of the substance after an incisionwith a scalpel blade and light expression with twoswabs or digital pressure can be resolute (Fig. 4)(Sclafani and Fagien 2009).

Another option is the use of hyaluronidase ifthe product used is hyaluronic acid. Although thecorrect doses have not been well established, thisenzyme has been shown to correct unsightlyeffects. Besides being very useful in acute vaso-occlusive events, it can also be applied at latertimes for the complications in question (Fig. 5)

Use of HyaluronidaseHyaluronidase, hyalozima, or hialuronogluco-saminidase is an enzyme that facilitates the dif-fusion of injected fluids, extracted from bovinetesticles. The hyaluronidase term is also usedto describe two different enzymes, which

Fig. 4 Nodule caused byHA migration that has beenremoved through anincision and the contentsremoved. Palpationobserved that the producthad not been“encapsulated”


act in various parts of the hyaluronic acidmolecule, which are hialuronoglicuronosidaseand hialuronatoliase.

Hyaluronidase acts reversibly depolymerizinghyaluronic acid in the existing cement around theconnective tissue cells, thereby temporarily reduc-ing the viscosity of this tissue and making it morepermeable to the diffusion of liquids. Based on thismechanism of action, hyaluronidase has been usedfor promoting the degradation of HA injected incases of complications and/or adverse reactions,such as treatment with improvement.

Repeat the application, if necessary, 10–15 dayslater. After dilution, remainder must be totallydiscarded and should not be saved and appliedunder any circumstances. The need and usefulnessof skin testing for its allergenic power isquestionable.

Before using hyaluronidase, the patient shouldbe interviewed about the use of drugs like furose-mide, benzodiazepines, phenytoin, dopamine, andα-adrenergic agonists, anti-inflammatory agents(e.g., indomethacin, dexamethasone, and salicy-lates), numerous plant-based drugs (e.g., flavo-noids and antioxidants), antihistamines, mast cellstabilizers, heparin, vitamin C, and dicumarene.The interaction with these drugs must mimic tissueresistance to hyaluronidase.Some reactions can becaused by hyaluronidase injection, but urticaria andangioedema are reported in less than 0.1% of cases(Brody 2005; Cavallini et al. 2013).

Treatment of Foreign Body GranulomasThe foreign body granulomas that have clini-cal or aesthetical impact can be treated

successfully with the use of intralesionalor systemic corticosteroids that are the firstchoice in these cases. These medicationscan have side effects such as atrophy andtelangiectasia.

Other therapeutic options already reported inthe literature are minocycline, 5-fluorouracil,hydroxychloroquine, bleomycin, isotretinoin,allopurinol, azathioprine, tacrolimus, andimiquimod. For single circumscribed granulomas,surgical excision can also be an option.

Application of the laser with wavelengths of532 and 1064 nm has been described for small andlarge noninflammatory granulomas and inflam-matory granulomas, respectively. The effects ofthese lasers are decreasing telangiectasias andneovascularization and reducing volume and stiff-ness of the nodes.

It has been reported the use of etanercept tocontrol granulomatous reaction to silicone.

Treatment of InfectionGenerally short cycles of antibiotics with cov-erage for bacteria associated with skin and sub-cutaneous tissue infections are sufficient tosolve these complications (e.g., cephalosporinssuch as cephalexin). However, if the suspicionis of an atypical agent, one must try, if possible,to identify it with cultures to better guide thechoice of antibiotics. In such cases it will oftenbe necessary for a broader spectrum coverage,with antibiotic associations (e.g., macrolidessuch as clarithromycin, fluoroquinolones suchas ciprofloxacin, and tetracyclines such asminocycline).

Fig. 5 Hyaluronidaseapplication forovercorrection insupralabial wrinkleswith AH


Contraindications Post-PermanentFillers Application

There are reports of patients with severe inflam-matory adverse reactions years after application offillers when these patients were exposed to thera-pies with interferon use. It has been suggested sothat patients with these types of fillers have con-traindication to the use of interferon. Yet it is goodsense to ponder that, often, the use of interferonmay be important to treat major diseases. So thiscontraindication should be relative, analyzing therisk X benefit of interferon use ((Fischer et al.2007)).

Another recommendation is that patients withpermanent fillers should always receive systemicantibiotics when they are affected by any infectionfor a period of 10 years after application in orderto prevent late cross-immune responses.

Treatment of Hypersensitivity ReactionsHypersensitivity reactions can be dealt either withclose observation, if they are mild and little impactas with the use of drugs such as topical,intralesional, or even with systemic corticosteroidsbesides topical tacrolimus. Hyaluronidase rarelyneeds to be used in these cases, also because it isof a heterologous origin and there is relative risk oftriggering allergic reactions. There is already arecombinant human hyaluronidase whose potentialfor allergic reactions is much lower.

Treatment of Fillers of Complicationsin the Back of the Hands

Park TH et cols. suggested an algorithm fortreating such complications:

First of all, put ice on the back of the hands, domassage, and keep hands high.

After this, if necessary, use two types of anti-biotics. If the reaction persists, the next stepdepends on the type of filler used:

– Hyaluronic acid – treat with hyaluronidase– Calcium hydroxyapatite – surgical removal– Others fillers – infiltration with corticosteroids

If the treatment with hyaluronidase and corti-costeroids infiltration failed, it’s necessary to havesurgical removal.

The most important point is the follow-up ofthe patient in a short period of time. The compli-cations not mentioned hereby can be treated asdescribed above.

Histological Aspects of Fillers AdverseReactionsThe histopathological findings allow us to specif-ically identify the agent used in the dermal filler.This is necessary because only the histopatholog-ical examination can identify precisely whichfiller is involved and determine what kind ofinflammatory reaction can optimize the treatment.

Whenever two different products were injectedon different occasions, the histopathological eval-uation can be used as a proof to identify whatproduct caused the reaction (Christensen 2007).

Hyaluronic Acid (HA)

Two types of adverse reaction to HA can beobserved: hypersensitivity reaction and foreignbody reaction.

The cases of hypersensitivity reactions aremuch less frequent than the foreign body and arecharacterized by diffuse inflammatory infiltrationthroughout the dermis represented by lympho-cytes and plasma cells intermingled with a largenumber of eosinophil leukocytes (Fig. 6). In thiscase the HA gel is not observed even with the aidof special stains as alcian blue or colloidal iron.The diagnosis of this reaction can only be carriedout with the clinical information of filler applica-tion in the biopsied area provided.

In cases of granulomatous foreign body reac-tion, which is more frequent in the dermis, areobserved a large number of multinucleated giantcells surrounding large amount of amorphousextracellular material and basophilic correspondsto HA gel injected (Fig. 7). A small amount of thismaterial can be seen in the cytoplasm of giantcells. In some cases large number of eosinophilleukocytes can be observed among the giant cells.


The HA gel is heavily stained by alcian blue andalso by colloidal iron.

(Dadzie et al. 2008; El-Khalawany et al. 2015;Parada et al. 2005; Requena et al. 2011; Zimmer-mann and Clerici 2004).

Hyaluronic Acid + Dextranomer

Dense inflammatory infiltrate of granulomatousforeign body type, sometimes nodular and

sometimes diffuse, is observed in the dermiswith large numbers of giant cells of foreign bodyinvolving or containing cytoplasm spherical par-ticles of a blue-magenta color, corresponding tothe microparticles dextranomer amid numerouseosinophil leukocytes, macrophages, and fewneutrophils leukocytes (Fig. 8).

Hydroxyapatite Calcium

The lump is made up of large numbers of giantcells of foreign body phagocytizing or involvingmicrospheres blue-brown and refractive materialwith the characters of calcium hydroxyapatitesurrounded macrophages and fibroblast prolifera-tion and especially thin collagen fibers (Fig. 9).

Polymethylmethacrylate (Metacril®)

Dense sometimes nodular and diffuse inflamma-tory infiltrate is now observed in the dermis andhypodermis and consists of foreign body granu-loma represented by multinucleated giant cellscontaining the cytoplasm regular cystic spaces ofvarious sizes, some containing non-birefringentand translucent spherical microspheres, and

Fig. 7 Restylane (hematoxylin-eosin, original magnifica-tion x200). Foreign body type giant cells surroundingbasophilic amorphous material; eosinophils are seen besidethe giant cells

Fig. 8 Dense inflammatory infiltrate of granulomatousforeign body type is observed in the dermis with giantcells of foreign body involving or containing cytoplasmspherical particles of a blue-magenta color, correspondingto the microparticles dextranomer amid. (hematoxylin-eosin, original magnification x200)

Fig. 6 Hypersensitivity reaction to Restylane that is notvisualized in this case with mixed inflammatory infiltratethroughout the dermis represented by lymphocytes andplasma cells intermingled with a large number of eosino-phil leukocytes. (hematoxylin-eosin, original magnifica-tion x400)


epithelioid granuloma represented by epithelioidhistiocytes and giant Langhans type giant cellsforming granulomas sometimes nodular and dif-fuse and sometimes being permeated by numer-ous lymphocytes (Fig. 10).

Polymethylmethacrylate + Collagen(Artecol®)

The histological picture is similar to that observedin the case of Metacril®, the only difference lies inthe fact that with this filler cystic spaces are largerand of the same size while with Metacril variablesizes are seen (Fig. 11).

L-Polylactic Acid (Sculptra® or Newfill®)

The node is represented by inflammatory infiltratecomposed almost exclusively by giant foreignbody type giant cells containing in the cytoplasmtranslucent particles of variable sizes with mostfusiform or oblong shapes (Fig. 12) being bire-fringent when subjected to polarized light(Fig. 13). Often, asteroid bodies in the cytoplasmof giant cells are also observed. There are smallnumbers of macrophages and lymphocytespermeating.

Silicon

The adverse reaction caused by silicon variesaccording to the type of silicon injected. Thesilicon which is used by most dermatologicaland plastic surgeons is dimethyl-siloxan whoseadverse reaction is characterized by diffuse orfocal macrophage infiltration with multiple cyto-plasmic vacuoles of different sizes and irregularand basophilic nuclei and large clear spacesdelimited by macrophages (Fig. 14). The infiltrateis distributed among the collagen fibers oftenreplacing the entire dermis and often also presentin the hypodermis.

Fig. 11 Artecoll (hematoxylin-eosin, original magnifica-tion x100). Foreign body-type giant cells with round andregular vacuoles, beside nodular tuberculoid granuloma

Fig. 10 Metacril (hematoxylin-eosin, original magnifica-tion x200). Foreign body-type giant cells with multipleround and irregular size vacuoles, beside nodular tubercu-loid granuloma

Fig. 9 Granulomatous Foreign body type reaction withgiant cells phagocytizing or involving microspheres blue-brown and refractive material with the characters of cal-cium hydroxyapatite (hematoxylin-eosin, original magni-fication x200)


Take Home Messages

• There are three main complications with fillers:immediate, early, and late complications.

• The immediate complications are common andexpected. Their treatment is simple and theresolution in hours or days.

• The early complications are potentially seri-ous, and the most feared is vascular occlusion.

• The late complications are insidious and unex-pected. Their management can be difficult, andthe resolution slows such as some kind ofinfections, nodules, and granulomas.

• The use of temporary fillers is recommendedbased on the complications described above.

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