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Reversers


Summary and Key Features

  • The increasing popularity of soft tissue augmentation requires knowledge of reversal techniques.

  • Adverse events due to filler injection can be totally or partially reversed depending on the filler type and timing.

  • Nonpermanent fillers are much more forgiving and more easily corrected.

  • Hyaluronidase can be considered a treatment “eraser” for many complications arising from the injection of hyaluronic acid, and small doses can be effective.

  • Vascular occlusion should be rapidly diagnosed and treated, especially if vision loss is involved, and large doses of hyaluronidase should be considered

  • Late-onset inflammatory reactions may require a multifaceted approach, particularly after complications due to permanent filling agents.

  • An emerging treatment for calcium hydroxylapatite filler is the use of sodium thiosulfate.

Introduction

According to the most recent (2019) procedural survey by the American Society for Dermatologic Surgery (ASDS), the use of injectable fillers has increased by 78% since 2012 in the United States. The advent of new, nonpermanent soft tissue fillers, and the resurgence of older, permanent fillers, speaks to the increased demand of the public for soft tissue augmentation. As with all cosmetic procedures, the increase in number of procedures performed increases the chances for complications. Additionally, many of the soft tissue fillers on the market today are injected in locations that are off-label, many of which carry a higher probability of vascular occlusion or other complication. Thus, a profound knowledge of how to reverse filler complications is paramount. Soft tissue fillers can be divided into two categories according to biodegradability: biodegradable (absorbable) or nonbiodegradable (permanent). The innovation of cross-linking techniques with different hyaluronic acid (HA) concentrations determines where fillers may be placed and how long they may provide tissue correction ( Table 38.1 ). Any of the listed products can lead to early or delayed complications, but only HAs can truly be reversed with the use of hyaluronidase. Unlike biodegradable agents, particularly HAs, permanent fillers require a multifaceted approach and can be more difficult to correct in the event of misplacement or serious adverse reactions.

Table 38.1
Products According to Biodegradability, Manufacturer, Type of Cross-link or Vehicle, Type of Product and Concentration, and Regulatory Organs approval for United States, Canada, Europe, South America, and Central America
Biodegradable Products
Product Manufacturer Cross-Link Tech/Vehicle Type Product and Concentration (mg/mL) Approval by Country Biodegradability/erasability
Juvéderm Ultra XC Allergan Hylacross HA-24 All Absorbable/erasable
Juvéderm XC ultra plus Allergan Hylacross HA-24 All Absorbable/erasable
Juvederm Volux Allergan Vycross HA-25 South, Central America/Canada/Europe Absorbable/erasable
Radiesse Merz Carboximetilcelullose 70% Calcium hydroxylapatite 30% All Absorbable/nonerasable
Sculptra Galderma/Sinclair Saline and Lidocaine Poly-l-lactic acid (% depend on dilution) All Absorbable/nonerasable
RHA 2 Teoxane SA Preserved Network HA-23 United States/Europe Absorbable/erasable
RHA 3 Teoxane SA Preserved Network HA-23 United States/Europe Absorbable/erasable
RHA 4 Teoxane SA Preserved Network HA-23 United States/Europe Absorbable/erasable
Juvéderm Voluma XC Allergan Vycross HA-20 All Absorbable/erasable
Juvéderm Volbella XC Allergan Vycross HA-15 South America/Canada/Europe Absorbable/erasable
Juvéderm Volift a Allergan Vycross HA-17.5 South, Central America/Canada/Europe Absorbable/erasable
Juvederm Vollure XC Allergan Vycross HA-17.5 All (Vilify in other countries) Absorbable/erasable
Belotero Hydro Merz No crosslink, contains glycerol HA-18 South, Central America/Canada/Europe Absorbable/erasable
Belotero Balance Merz CPM HA-22.5 All Absorbable/erasable
Belotero Volume a Merz CPM HA-26 South, Central America/Canada/Europe Absorbable/erasable
Belotero Intense a Merz CPM HA-25.5 South, Central America/Canada/Europe Absorbable/erasable
Belotero Soft a Merz CPM HA-20 South, Central America/Canada/Europe Absorbable/erasable
Emervel Classic a Galderma OBT HA-20 South, Central America/Canada/Europe Absorbable/erasable
Emervel Lips a Galderma OBT HA-20 South, Central America/Canada/Europe Absorbable/erasable
Emervel Volume a Galderma OBT HA-20 South, Central America/Canada/Europe Absorbable/erasable
Emervel Deep Galderma OBT HA-20 South, Central America/Canada/Europe Absorbable/erasable
Restylane Galderma NASHA HA-20 All Absorbable/erasable
Restylane Silk/Vital Galderma NASHA HA-20 All Absorbable/erasable
Restylane Defyne Galderma NASHA HA-20 All Absorbable/erasable
Restylane Refyne Galderma NASHA HA-20 All Absorbable/erasable
Restylane Kysse Galderma NASHA HA-20 All Absorbable/erasable
Restylane Lyft Galderma NASHA HA-20 All Absorbable/erasable
Nonbiodegradable products (permanent)
Silikon 1000 Alcon — Polydimethylsiloxane All (not aesthetic uses) Nonabsorbable/nonerasable
Belafill Suneva Medical Bovine collagen PMMA + bovine collagen North America and Canada Nonabsorbable/nonerasable
CPM, Cohesive polydensified matrix; OBT , optimal balance technology; NASHA , nonanimal stabilized hyaluronic acid; PMMA , polymethyl methacrylate.

a Products not US Food and Drug Administration approved.

Why do we Need Reversers?

Reversers are necessary secondary to improper placement on depth of filler, overcorrection, vascular occlusion, and late-onset immune-mediated reactions. Looking from the perspective of filler permanence, only HA and collagen can be completely erased by two different enzymes: hyaluronidase and collagenase. An emerging treatment for dissolving calcium hydroxylapatite (CaHA) fillers is the use of sodium thiosulfate (STS), although its use is not as well studied as hyaluronidase and collagenase. If we look at all the adverse events after filler application, especially with nonabsorbable fillers, there are complications that can be partially reversed or at least treated with a variety of substances, lasers, or oral medicines (those will be mentioned but not discussed in this chapter). This chapter will focus on the use of substances, procedures, or technology that can alter or change not only the permanence of filler itself, but also change the elements involved in a specific adverse event.

Filler Complications and Reversibility

Adverse effects following soft tissue augmentation are generally classified as early onset (up to 2 weeks after injection), late onset (> 14 days to 1 year), or delayed onset (> 1 year) ( Box 38.1 ). Late- or delayed-onset reactions are more commonly associated with nonabsorbable filling agents but have been more recently described with HA, CaHA, and poly-l-lactic acid (PLLA). Early-onset adverse events are easier to treat and more common than late-onset ones. According to reversibility classification, HA and collagen injection may be a clear advantage over other substances ( Figs. 38.1–38.5 ).

Box 38.1
Adverse Events Following Soft Tissue Augmentation According to Onset

  • 1.

    Early onset (immediate to 14 days)

    • Injection site reactions including purpura and edema

    • Noninflammatory nodules (overcorrection or misplacement of injected material)

    • Infection (bacterial, viral)

    • Hypersensitivity reaction/anaphylaxis

    • Vascular occlusion

  • 2.

    Late onset (from 15 days to 1 year) and delayed (> 1 year)

    • Inflammatory nodules (immune-mediated vs infection/biofilm)

    • Persistent or recurrent edema

Fig. 38.1, Immediate-onset adverse events totally reversible. 5FU , 5-Fluorouracil; I&D , incision and drainage.

Fig. 38.2, (A) Patient after 6 months of hyaluronic acid filler for tear trough correction and (B) 15 days after 8 U hyaluronidase each side (4 U per lump).

Fig. 38.3, How to perform retrobulbar injection of hyaluronidase if occlusion of ophthalmic artery of retinal artery is suspected.(Original image attribution goes to Patrick J. Lynch, http://commons.wikimedia.org/wiki/Category:Medical_illustrations_by_Patrick_Lynch .)

Fig. 38.4, (A) Before and (B) 3 months after 1 cc of hyaluronic acid filler to upper cutaneous vertical lip lines showing granuloma formation. Treated with 1 cc Hylenex, 0.5 cc 1% lidocaine, doxycycline 100 mg BID × 10 days, prednisone 40 mg × 5 days. (C) 4 months, worsening, treated with 2 cc Hylenex, 0.5 cc 1% lidocaine, 0.7 cc ILK 5 mg/cc, prednisone 40 mg × 3 days, 20 mg × 3 days, 10 mg × 3 days. (D) 4.5 months, granuloma resolved.

Fig. 38.5, Skin biopsy stained with colloidal iron to compare the amount of hyaluronic acid in normal skin and after 10 and 20 U of hyaluronidase showing no natural hyaluronic acid difference.

Early Adverse Events Treated Without Reversers

Expected early reactions are most commonly injection site reactions, including purpura and edema. Vascular lasers are effective in the treatment of postprocedure purpura. Infections are much less frequent, with herpes virus being the most common. Hypersensitivity and angioedema are very rare but can occur with all fillers composed of foreign body material. Anaphylaxis reaction symptoms are pruritus, erythema, urticarial lesions, angioedema, nausea, vomiting, breathlessness, dizziness, syncope, hypotension, or even cardiorespiratory arrest. The physician must be prepared to deal with anaphylaxic reactions. Epinephrine is the most important drug in this clinical emergency, maximally effective when injected promptly. H1-antihistamines are not drugs of choice in initial anaphylaxis treatment because they do not relieve life-threatening respiratory symptoms or shock, although they decrease urticaria and itching. Diphenhydramine can be administered, and glucocorticoids remain in use for anaphylaxis because they potentially prevent biphasic anaphylaxis, reducing the risks of late symptoms. If symptoms are mild, oral prednisone can be prescribed, but more severe cases need intravenous methylprednisolone. It is important to have an oxygen cylinder and β2 agonist medication, such as salbutamol, in the clinic in case of hypoxemia. After clinical stabilization, the physician must decide whether the patient should be taken to the hospital.

Intravascular Occlusion

Among all the adverse events related to filler placement, intravascular injection and its consequences are most concerning and can be devastating. Chapters 35 and 37 discuss the various types of vascular occlusion events and present the relevant anatomical considerations. This section will review the treatment protocols for reversers in more detail. The mechanism of action of hyaluronidase in the setting of HA vascular occlusion is bathing the artery in hyaluronidase, which can then readily diffuse across the vessel wall and be carried by arterial flow to the embolism. Selective angiography has also been described, but this technique is highly specialized and requires interdisciplinary care.

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