The exponential increase in the use of injectable fillers has heralded unique safety requirements, mandating ongoing reappraisal of both procedural method and complication management.
As with the initial 10-point plan for avoiding hyaluronic acid dermal filler-related complications during facial aesthetic procedures and algorithms for management,1 this updated plan aims to establish a simple, user-friendly checklist for optimising patient factors, practical product knowledge and safer technique. Updated treatment and safety algorithms have been added in a visual format (Table 1, Figure 21, 22, 23).
Table 1 A 10-Point Plan for Avoiding Filler Complications
History and Selection
Frequently queried selection criteria include the following:
The Neoplastic Process and Antineoplastic Drugs
Filler safety is frequently queried in patients with cancer or on antineoplastics, cytotoxics, biologicals, or immunotherapy (Table 2). Conversely, the influence of fillers on the incidence, behavior, or aggravation of malignant tumors has been questioned, with the rapidly evolving field of onco-immunology raising awareness around immunity, chronic inflammation, carcinogenesis, and the effects of antineoplastic therapy.2
Table 2 Selection Criteria
Physicians should, however, consider the cumulative psychological burden of altered physical appearance, loss of identity, helplessness to change, and subsequent impact on immunity. Oncologic patients are often concerned about their appearance and fear pitying remarks from outsiders regarding their overall physiognomy. Wearing a cap or a headscarf to hide chemotherapy induced alopecia is an example of the former. Often patients are strongly insistent on maintaining regular aesthetic treatments in order to avoid the perception of suffering or losing their attractiveness. Therefore, the psychological benefits of aesthetic treatments often transcend their potential fear.3 Importantly, risks should be consented upfront.
Active chemotherapy is an accepted contraindication to fillers, with significantly delayed long-term immune changes documented 12 months post-treatment and at least 6–10 months after completing adjuvant therapy for breast cancer.4 Early recovery phases are prone to viral reactivation, with increased bacterial infections during later stages and slower recovery in smokers.5
Increasingly, antineoplastic immunotherapy is causing a unique spectrum of immune-related adverse events. Immune checkpoint inhibitors (ICI)6 remove the brake on activated T-lymphocytes, enabling T-cell attack on normal cells. LOAEs are documented after ipilimumab7,8 and cetuximab,9 and facial swelling and granulomatous reactions with protein-tyrosine kinase inhibitors. However, uneventful HA filler treatment has been described after treatment with imatinib mesylate.10
Carboxymethylcellulose-polycaprolactone, and polylactic acid fillers may induce LOAEs mimicking tumors after nivolumab (ICI), causing staging difficulties on PET-CT scans.11,12
During immunotherapy, filler treatments should preferably be postponed, with vigilant follow-up in patients insisting on psychologically motivated treatments. Standard antibiotic and intralesional steroid treatment of LOAEs is permissible, while oral steroids are contraindicated due to potential interruption of immunotherapy.
The immunological effects of radiotherapy and paradoxical effects of immune stimulation or suppression vary with individual regimes.13 Although no discrete guidelines exist, it is advisable to consider post-radiotherapy patients as being immunosuppressed and to delay fillers for at least 6–12 months.
Physician discretion and vigilant follow-up are advocated in situations where fillers may offer much-needed psychological support after treatment of neoplastic disease.3
In contrast to a 2010 study inferring chronic inflammatory or neoplastic changes due to the pro-inflammatory properties of “low molecular” HA molecules, other reports have queried the actual presence of HA fragments and highlighted varying definitions of “low molecular weight” fragments. (Table 7).14,15
A single anecdotal case has posed a hypothetical correlation between a cutaneous metaplastic synovial cyst and facial HA injections.16 However, large long-term cohort studies demonstrating extensive pharmaco-vigilance have failed to correlate neoplasia with either single or repeated facial HA filler injections.
Autoimmune Collagen Disease: Lupus, Morphea and Systemic Sclerosis
Previous recommendation has been for filler avoidance during active phases of collagen disease, whilst stable or burnt-out disease phases may be treated with relative safety.
Two recent literature reviews state that patients with autoimmune conditions may be safely treated with a variety of fillers.17,18 During active disease stages, we still advise against filler treatments.
Nicotine and recreational drugs such as marijuana, cocaine, and opiates not only alter neuropsychological and pathophysiological responses but also inhibit immune function through direct and indirect mechanisms enhancing susceptibility to infections (Figure 1).19
The potential effect on tissue response, healing, and onset of adverse events should not be overlooked. The negative effect of smoking on cancer rehabilitation is well documented.20
Figure 1 Recalcitrant LOAE in a patient with uneventful previous fillers, developing 6 months after onset of cannabis dependency Note: Image courtesy of Dr Heydenrych.
LOAE protocols may recommend antibiotics or anti-inflammatories prone to drug interactions involving especially hepatic cytochrome P-related medications (eg, clarithromycin, erythromycin, celecoxib, diclofenac) necessitating careful documentation of prior drug intake.
Genetic Predisposition to Immune-Mediated Adverse Reactions, and Genes Within the Major Histocompatibility Complex
Upfront screening for a propensity to LOAEs, although not currently feasible, would be ideal. In addition to speculation around HLA B*08 and DRB1*03 – subtypes in immune-mediated disorders affecting women with silicone breast implants, Decates et al also examined the major histocompatibility haplotypes in 211 patients where 129/211 demonstrated LOAEs after fillers. A significant correlation was demonstrated between the combined presence of HLA B*08/DRB1*03 and inflammation, with an almost 4-fold increase in immune-mediated adverse events (odds ratio = 3.79, 95% CI 1.25–11.48).18
HLA subtyping poses future possibilities for pre-identifying individuals at risk of delayed reactions.
Our recommendation is for avoidance of fillers in patients with this specific combination of HLA subtypes (B*08 and DRB1*03).
Pregnancy and Lactation
Medicolegally, insufficient procedural or drug-related safety data mandate against use during pregnancy, intended pregnancy, or breastfeeding. Due to the paucity of data and unpredictability of complications and their management, fillers are deemed inadvisable during pregnancy or lactation.21 Should a patient fall pregnant shortly after treatment, no specific action other than routine follow-up is needed.
The safety and timing of re-treatment after previous LOAEs is often questioned. Importantly, previous triggers such as acne, dental procedures, sinusitis, gastroenteritis, flu-like illness, vaccinations or causes of compromised skin barrier should be managed upfront. A recent review cites the majority of patients re-treated with a similar filler product having an uneventful course.22
The authors suggest at least one month between full clearance of LOAE and re-treatment to exclude transient clearance on steroids or antibiotics. For medicolegal purposes, an intradermal test with 0.1ml of the intended product may be performed and checked after 1 and 3 months (Figures 2 and 3).
Figure 2 After 1 month: the test site with Volbella showed a positive reaction. Note: Image courtesy of Dr K De Boulle.
Energy-Based Devices (EBD)
Figure 3 After 3 months: positive reaction for Juvederm Volbella and Volift. Note: Image courtesy of Dr K De Boulle.
EBD treatments are best avoided in areas overlying LOAEs as they invariably impact skin barrier function and may act as external trauma triggers or induce infection in predisposed patients. Radiofrequency treatment (RF) has been documented to result in statistically significant increases in inflammatory, foreign body, and fibrotic responses associated with fillers despite histological absence of immediate thermal effect following RF (Figure 4).23 The use of microneedle RF over recently placed filler should be approached with caution.24
Skin Barrier Function, Infection, and Treatment Timing
Figure 4 Artecoll granuloma (20 years) with exacerbation after Fractional resurfacing and subsequent HA layering. Note: Image courtesy of Dr K De Boulle.
Importantly, skin barrier function may be altered for 3–4 weeks after apparent clearing of conditions such as dermatitis.
Active rosacea implies increased vascularity, impeded barrier function, and antimicrobial peptides, generally taking 12 weeks to stabilize.25 Perioral dermatitis should be pre-treated to full clearance, generally necessitating 6 weeks.
Patients with underlying Staphylococcus aureus carrier status may be treated topically with intranasal mupirocin bd x 5 days, alternatively topical neomycin and bacitracin, chlorhexidine, or bleach baths.26
Herpes simplex (HSV) lesions are infective until disappearance of the last crust. To prevent eczema herpeticum, particularly in patients with a history of or active atopic dermatitis, HSV is best treated prophylactically for 5 days starting one day pre-treatment, particularly when injecting close to HSV areas. Acyclovir (ACV) and related nucleoside analogs (valacyclovir or famciclovir) have long been a gold standard. However, the rapid emergence of ACV-resistant HSV, combined with increasing transplant and cancer patient numbers, mandates a careful treatment history despite this not representing the usual injectable patient cohort.27
LOAEs following influenza-like viral illnesses are documented after treatment with various HA filler brands. The current global COVID-19 SARS 2 pandemic has led to similar reaction patterns, with several publications detailing LOAEs after HA fillers.28–30
The COVID-19 SARS-2 spike protein interacts with dermal angiotensin-converting enzyme receptors (ACE2) which normally regulate the homeostasis between angiotensin 2 (pro-inflammatory) and angiotensin 1 (anti-inflammatory). This induces a pro-inflammatory, loco-regional TH1 cascade thought to promote a CD8+T cell-mediated reaction to incipient granulomas previously formed around residual HA particles.29
As seen in the ASIA (Autoimmune/inflammatory syndrome induced by adjuvants) syndrome, vaccinations may trigger immunological hypersensitivity cascades with subsequent LOAEs.31 Not surprisingly, LOAEs have indeed been reported after various COVID-19 SARS 2 vaccine brands.29 Multiple clinical manifestations ranging from edema, erythema, swelling and tenderness to subsequent painful, indurated plaques and nodules have been documented in patients with fillers placed from weeks to years before either a first or second Covid vaccination.30
Evolving COVID-19 vaccination protocols may well become one of the most common triggers of subsequent HA filler-associated LOAE, with the triad of increasing filler use, escalating COVID-SARS-2 infection rates and progressive vaccine roll-out recently cited as potentially portending a perfect storm.29
Interestingly, ACE inhibitors such as lisinopril have anecdotally been found beneficial in reducing vaccination-induced LOAEs, with lisinopril proposed as pre-vaccination medication in patients prone to LOAEs after HA fillers, or having developed LOAEs following first vaccinations.32 Currently, no controlled study is available to prove either large-scale benefit or the benefit following non-HA fillers. As cited in recent publications, oral corticosteroids constitute initial one-month therapy for Covid vaccination-related LOAE therapy for Covid vaccination-related LOAE.29,30
Patient Expectations and Psychological Screening
Body dysmorphic disorder (BDD) often presents with cosmetic complaints and higher pre-procedural expectations (Table 3). Psychopathology or unrealistic expectations regarding enhanced quality of life (QOL), self-esteem, social interactions or facial beauty should be excluded upfront due to decreased procedural satisfaction.33
Table 3 Body Dysmorphic Disorder (BDD)
Patient questionnaires may serve as valuable screening tools. Concerning answers to the questions in Figure 5 merit completion of a more extensive BDD questionnaire or referral for psychological evaluation (Figure 5).34
Figure 5 Valuable BDD screening questions. Note: Data adapted from Krebs et al.34
Baby boomers (in their 60s) and Gen Zs (born 1994-) currently comprise the largest aesthetic market segments, mandating an understanding of specific needs.35 Aesthetic education of younger generations also bears long-term implications for future patient loyalty. The expert injector’s role lies in communicating insightful facial analysis despite the increasing challenge of selfies, photographic distortion and social media pressure. A systematic analysis of all facial angles, both in repose and animation, helps to establish expertise through irrefutable clinical logic.
Social Media and Aesthetic Self-Perception
Obsessive selfie-taking, classified by the American Psychiatric Association as a mental disorder associated with low self-esteem, is ascribed to social competition, attention-seeking, mood modification, self-confidence and social conformity, consequently initiating the development of a psychometric Selfitis Behavior Scale (SBS).36
Selfie-filters may encourage unrealistic expectations through complexion enhancement and altered features such as erased nasolabial folds, tighter jawlines, and bigger lips. Furthermore, normalization of pouting poses has blurred the boundaries between resting and dynamic lip proportions, complicating realistic volume expectations. Only 60–65% of real-world images are differentiated from manipulated images, further encouraging manipulation.37
Importantly, social media has significantly altered the concept of patient confidentiality, with patients increasingly keen to publicize treatment experiences.
The current COVID-SARS2 pandemic has fuelled further perceptual change as remote living and working have forced individuals to view themselves on-screen, unedited, in motion and at the mercy of short focal length webcams. The resulting “zoom face” inevitably depicts a more rounded face, wider set eyes and broader nose, creating a flawed representation of reality which patients struggle to process.38
Asian and African beauty concepts may differ fascinatingly from Caucasian ideals, with perceptions increasingly influenced by the advent of social media and “beauty influencers” (Table 4).39 Whilst the traditional African beauty concept has shifted to more Westernized ideals, with an increasing desire for lower body mass and paler, yellowish skin tone, Chinese aesthetic patients demonstrate a strong desire for retained ethnic identity. A Singaporean study comparing Caucasian and Chinese aesthetic patients demonstrated that Chinese patients were younger and more likely to seek correction or more obvious changes than Caucasian patients. On multivariate analyses, powerful predictors for proceeding with non-invasive facial treatments included rejuvenation rather than correction as a goal, an expectation of an immediate result, and prior aesthetic treatments.40
Table 4 Ethnicities: Features and Management
The expert injector should understand not only universal, cross-cultural beauty ideals, but grasp applicable ethnic nuances.
Asian faces have unique facial proportions, beauty concepts, aging stigmata, and cosmetic demands.40 The frequent need for centro-facial treatment with higher injection volumes merits highly specialized skills and carries a higher risk of intravascular embolic events.
The Indian face is particularly prone to developing early periorbital hyperpigmentation and infraorbital hollowing, with tear trough deficiency the most common filler request between 20 and 40 years.41 Malar volume loss and jowling are common in older individuals, with excess medial soft tissue on a relatively smaller midface mandating initial treatment of lateral vectors to create adequate lift without excess medial volume. The shorter, wider lower face requires 3-dimensional correction and chin augmentation to achieve optimal facial height and the desired oval shape.
Despite escalating demand, few discrete guidelines exist for African phenotypes. Key considerations include a tendency to scarring, keloids or post-inflammatory hyperpigmentation (PIHP).39 Mild and transient hyperpigmentation after nasolabial fold HA fillers in Fitzpatrick Skin Types (FST) IV–Vl is cited in 2–17% of patients (6% of injection sites). Serial punctures, superficial injection depth and fast injection speed predispose to PIHP. Whilst a 27G needle should pose no significant risk of PIHP or keloid formation, a test area with a small 31/33-gauge needle is suggested when in doubt. Keloid tendency is linked to chromosome band 7p11 and the EGFR gene.42
When performed with a clear understanding of male and female features and desired outcomes, facial procedures may greatly enhance overall QOL. Hormonal therapy, especially whilst transitioning from female to male, may induce acne which should be optimally treated before attempting fillers.43
Clinic staff should be trained in using preferred pronouns and identifiers when addressing transgender patients, whilst intake forms should request “gender” rather than “sex” and include a write-in option for “other.”
Insightful understanding of functional anatomy, synergistic and antagonistic muscle balance and both the direct and indirect effects of fillers are essential for natural dynamic outcomes. These principles also underlie the rehabilitation of facial palsy through injectables.44,45
Filler placement may modify muscle behaviour through:
- Stretching muscles to improve tensile strength.
- Expanding the submuscular aponeurotic system (SMAS).
- Providing a mechanical block via intramuscular injection.
- Inducing resistance or support through differential placement above or below the muscle.
Although rare, the potential for allergic reactions, infection, vascular incidents, visual loss, and LOAEs must be stipulated on consent forms and explicitly discussed with the patient.46 Particular care should be exercised when consenting patients with cancer, on antineoplastic treatment or BDD. Importantly, to circumvent treatment delays, upfront consent should be obtained for managing potential complications. Additionally, in certain countries, the aesthetic use of hyaluronidase is off-label and should be clarified.47
The Covid-era has necessitated a new subset of regulations, as well as the initiation of conversation around potential vaccination sequelae. As cutaneous implications of both COVID-19 infection and vaccination emerge, cosmetic patients may benefit from a discussion around COVID-19 vaccine-related planning as a part of pre-procedure counselling for dermal fillers. In the absence of final data, we provisionally suggest waiting 2 to 4 weeks between filler injections and vaccination, with an even longer window in patients with a higher risk profile for developing reactions.32
Upfront financial consent remains mandatory.
The widespread use of HA fillers is driven by the unparalleled advantage of reversibility through hyaluronidase (Table 5). Despite a consensus paper advocating hyaluronidase for calcium hydroxylapatite (CaHa)-induced vascular occlusion due to its anti-edematous and anti-inflammatory properties, it does not dissolve the culprit. While a recent proof-of-concept study has demonstrated potential reversibility of CaHA through intralesional sodium thiosulfate (STS),48 optimal injection concentration, treatment ratio, time to onset, ability to pass through intact vessels, and treatment efficacy for established nodules are still unknown.49,50
Table 5 Hyaluronidase Safety Aspects
A human cadaver study has demonstrated a very limited in vitro potential of STS to dissolve intraarterial CaHa after submerging CaHa-filled arterial segments in varying concentrations of STS.50
Hyaluronidase: Practical Aspects
A 3-fold difference has been cited in the required number of hyaluronidase units per HA volume, with dissolution times varying from 2 to 16 minutes per 0.1 mL aliquot. This underscores the need for knowledge regarding the efficacy of locally available hyaluronidase on preferentially used HA products (Table 6).51
Table 6 Hyaluronidase Practical Aspects
Molecular Weight, Inflammatory Response and Autoimmunity
Although HA has been cited as a potential trigger factor for the ASIA syndrome, recent publications maintain that carbohydrates induce poor antibody responses due to their antigenic incapacity to stimulate T cell responses (Table 7). Carbohydrates preferentially bind to membrane receptors such as immunoglobulins to induce clustering and primary B cell activation, stimulating production of low affinity, short-living IgM, and no induction of memory effect in the absence of T cells.52,53
Table 7 Definitions
Conversely, bacteria act as potent activators of the TLRs (1,4,5,7,9) to induce inflammation, innate immunity, and non-agent-specific autoimmunity (Table 8). This underlines the critical importance of aseptic technique in avoiding late-onset inflammatory and immune sequelae.31,54 In genetically predisposed patients or specific HLA types, inflammasomes are triggered, possibly through an adjuvant role of ionized molecules.
Table 8 HA Filler Degradation
Importantly, acne is present in 10% of the population. Cutibacterium acnes (C.acnes) has a strong immunostimulatory capacity, is found in all stages of acne, and binds to the cytoplasmic nucleoside-binding oligomerization domain-like (NOD-like) receptors to induce inflammasomes and opportunistic infections, thus stimulating both innate and adaptive immune responses.55,56 The “safe injection distance” from individual acne lesions is currently unknown and adequate pre-treatment is mandatory.
Whilst Alijotas-Reig et al initially posed the increased risk of immune-mediated adverse reactions after consecutive injection of different fillers, a subsequent review of 260 cases found no increased risk of local or systemic reactions after repeated injections of different fillers in the same or different sites. When occurring, however, they were more likely to become chronic, systemic, and severe.31
Layering fillers over late or minimally biodegradable products is still deemed inadvisable due to the initial filler being teased into reactivity, which may be histologically proven.57,58
In cases of unknown previous fillers, and to determine the precise nature of fillers, ultrasound may offer a valuable diagnostic tool.59,60
Injection Depth and Immunological Response
Despite questions posed around the differential immunological response with filler depth and subsequent impact on immunologically induced LOAEs in the Covid-era, no data is currently available for risk stratification of intradermal vs deep tissue injections.
Accurate clinical photography, at rest and in animation, is vital for facial analysis, learning curves, and medicolegal purposes. Common consistency pitfalls include inaccurate positioning in the lateral and oblique views, which are avoidable by adhering to basic tenets. Position accurately for lateral views by using the Frankfort Line, thus also facilitating correct angulation for oblique views, in which all 4 canthi should be visible (Figures 6–8).
Figure 6 Frankfort horizontal plane vs natural head position.
Note: Image courtesy of Woodrow Wilson .
Figure 7 Illustration of the Frankfort horizontal plane, which often differs from natural head position, as viewed through a camera grid, superimposed on a skull and translated into pre-and post-photography.
Note: Image courtesy of Woodrow Wilson.
Figure 8 Shooting oblique view: (A) Align nasal tip to mid-pupil; (B) rotate head until all 4 canthi are visible. Note: Image courtesy of Woodrow Wilson.
Due to photographic distortion, mobile photos are inadequate for clinical use.
Selfies taken from a distance of 12 inches increase nasal size by 30% in males and 29% in females, with distortion of the perceived ratio of nasal breadth to bizygomatic width and inaccurate 3-dimensional appearance. Images taken at standard portrait distance render accurate proportions (Figure 9).61
Figure 9 Selfie distortion: the effect of focal length, illustrating wide angle (28mm) distortion as seen with mobile photography. Note: Image courtesy of Dr Heydenrych.
Further studies are needed to establish the role of frequent selfies in increased patient dissatisfaction, and the impact of selfie distortion on future medical decisions.62 Recently, the COVID-SARS −2 pandemic has provoked a surge in patients citing their appearance on virtual platforms as the reason for seeking care, particularly concerning acne and wrinkles.38 The patient is now also the viewer!
When available, computerized photography systems may add additional consistency and finesse to accurate and academic documentation.
Procedural Planning and Aseptic Technique
Aseptic Non Touch Technique (ANTT)
Vigilant aseptic technique is critical in the light of normal non-sterile office circumstances. Most sterility breaches have been proven to occur during the initial procedural phase, mandating pre-planning of product, volumes, and instruments of choice.47,63
Mucosal Cleansing Agents
Whilst chlorhexidine has previously been widely regarded as a good oral antiseptic, the Covid-era has raised new challenges. Preferred alternatives include Na hypochlorite, 1% peroxide, povidone-iodine, cyclodextrin, and succinic acid, with routine oral rinses (2 × 30 seconds) before fillers to decrease viral load.64,65
Intravascular injections, with consequences ranging from tissue necrosis to blindness, constitute the most feared injectable complications. Whilst topographical vessel course is varied (“x and y” axes in graph analogy), vessel depth (“z” vector) is far more predictable, thus bearing great significance in avoiding filler embolism. “Injection anatomy” commonly refers to surface markings in relation to the depth of underlying vital structures.
For effective localization of adjacent vasculature, topographical points are best marked with the patient in the upright position. Important pre-procedural markings may be seen in Figures 10–12 and discussed in Table 9.
Figure 10 Topographical markings of foramina in anterior view. Note: Image courtesy of Dr Heydenrych.
Abbreviations: TC, temporal crest; Z-f, zygomatico-facial; SO, supraorbital; IO, infraorbital.
Figure 11 Oblique view illustrating topographical markings of bony landmarks and adjacent danger areas. Note: Image courtesy of Dr Heydenrych.
Abbreviations: TC, temporal crest; MTV, middle temporal vein; FA, facial artery; STA, superior temporal artery .
Figure 12 Temporal venous danger zone delineated by the upper margin of the zygomatic bone and a parallel horizontal line running from the K Point, at the junction of temporal crest (TC) and lateral orbital rim.
Facial Artery Course
Table 9 Ten Topographical Tracings
The facial artery (FA) crosses the mandible at the antegonial notch just anterior to the anterior border of the masseter, before traveling superomedially, lateral to the modiolus, towards the piriform fossa. Between the risorius and zygomaticus major, it lies coiled and unprotected by muscle cover (“naked”), meriting injection caution. A second naked area lies superolateral from the mouth corner, medial to levator anguli oris (LAO), where the superior labial artery arises from the facial artery. The FA more frequently runs medial to the NLF, starting 1.7 mm medial in the lower portion, crossing beneath the fold at a depth of 5 mm at the superior third, and eventually reaching a point 3.2 mm lateral to the nasal ala (Figure 13).
Figure 13 Naked areas of facial artery. Notes: Reproduced with permission from Pirayesh A, Bertossi D, Heydenrych I, editors. Aesthetic Facial Anatomy Essentials for Injections. Boca Raton: CRC Press; 2020.66 Copyright 2020 Taylor & Francis.
Pinching with the non-dominant hand may serve as injection guide for avoiding inadvertent intravascular placement during temporal fossa injections through altering the tissue layer (Table 10).67
Figure 14 Diagram illustrating the most frequently affected choke anastomotic HA embolic sites.
Functional Vascular Anatomy (Angiosomes)
Table 10 Differences Between “Gentle Pinch” and “Deep Pinch” with Non-Dominant Hand During Temporal Injection
The skin’s three-dimensional functional angiosomes are supplied by a single source vessel and bordered by an anastomotic perimeter of either true or choke anastomoses.68 Whilst extravascular HA is well tolerated, intravascular placement induces severe vessel wall inflammation, predisposing to embolism. Pain may be a warning symptom even in the absence of cutaneous blanching but is not always present. Choke vessels respond with spasm to control or prevent flow across angiosome boundaries, impacting HA spread and necrosis of adjacent angiosomes. Vascular complication sites fall within five specific choke angiosome territories of the facial, ophthalmic, maxillary, and superficial temporal arteries and may sometimes be remote from the primary injection site (Figures 14 and 15).69 These sites are the:
- Nasal bridge
- Nasal tip
- Central upper/lower lips
- Nasolabial/cheek zone
Figure 15 Vascular occlusion illustrating choke anastomotic distributions. Note: Images courtesy of Dr K De Boulle.
Figure 16 Vascular obstruction: 60 IU hyaluronidase under ultrasound guidance (A) pre-Rx (B) 2h post -Rx (C) 1-week post- Rx. Yellow circle denotes injection area. Note: Images courtesy of Dr Stefania Roberts.
Scant upper facial and periorbital venous valves may cause arteriovenous shunting after choke vessel spasm, with resultant embolization to the ophthalmic vein, cavernous sinus, and brain.
True anastomoses, in contrast, link adjacent territories without caliber loss to potentially allow unimpeded embolic passage to remote or contralateral facial sites.69 Three common true anastomotic connections are:
- Angular artery with dorsal nasal or supratrochlear artery
- Across nasal tip
- Across upper or lower lips
When injection pressure is lower than systemic arterial pressure, anterograde vascular occlusion causes downstream flow to vascular tributaries, resulting in predominantly skin surface changes. Displacement against arterial blood flow causes retrograde vascular occlusion, with emboli traversing back to a vascular bifurcation to cause anterograde occlusion in more posterior locations upon stabilization of arterial pressure, effecting more distal capillary non-perfusion.70
Nitroglycerin Paste During Vascular Occlusion
A recent overview advocates the adjuvant use of nitroglycerin in pending vascular occlusion.71 However, choke vessel spasm is deemed a major determinant for the location and extent of tissue necrosis and because nitroglycerin paste may induce choke vessel dilation to alleviate flow-limiting spasm, allowing expansion of the number of affected angiosomes and increasing the area of tissue necrosis, the use of nitroglycerin paste is discouraged.69
The Use of Diagnostic Ultrasound
Although technically intricate, accurately performed and interpreted ultrasound may offer a valuable risk reduction tool during blinded injection procedures (Figures 16 and 17).59
- Upfront vessel localization for prevention of intravascular injection:54
- Localization and treatment of acute vascular occlusion:
The amount, location, and depth of injected HA fillers may be identified, enabling targeted delivery of hyaluronidase.
3. Product identification during late-onset events.59
It is advisable to align with an expert referral center in this regard.
Figure 17 Ultrasound-guided Hyaluronidase treatment illustrating resolution of obstruction over 2 minutes (60 IU) Hyaluronidase. Note: Ultrasound images courtesy of Dr Stefania Roberts.
Abbreviations: HA, hyaluronic acid; R inf, right inferior; H-ase, hyaluronidase; U, international units.
Figure 18 Needle Skills Worksheet. A laminated copy is used for regular extrusion practice utilizing sonar gel/expired products. Proprioceptive memory regarding volume control, needle resistance, and positional angulation may be refined. (A) Refining of volume control (B) refinement of needle course stability and angle.
Unlimited online access to procedural techniques may blur the boundaries between possibilities and capabilities. It is important to grasp that acquiring motor hand skills involves both cognitive spatio-temporal and motoric learning components. Especially during initial learning phases, cognitive representation accrues more rapidly than muscle-specific representations which develop only after extensive practice.72 Attempting injection procedures after online instruction only thus carries inherent risks. Considering the potentially grave sequelae of incorrect placement through minute variations in needle positioning, angulation and plunger control, it has never been more relevant to develop methods for gauging inherent hand skills. Needle skills training forms an integral component of the author’s teaching practice and is useful in refining differential dexterity for controlling factors such as needle position, angle, volume and injection speed (Figure 18).
Volume and Speed
Figure 19 For upper forehead injections, the avascular subgaleal plane may be accessed with needle at 45 degrees to bone. Perpendicular injection may cause bevel height to extend to the vascular supragaleal plane.
Dexterous hand control, slow injection speed, and constant vigilance for undue pain which may portend intravascular placement are vital. Watershed perfusion areas such as the glabella or nasal tip should be constantly observed for fleeting blanching, mandating immediate cessation of injection. Blindness has been reported with volumes as low as 0.2 mL of HA filler, whilst 0.085 mL may fill the supratrochlear artery from skin to orbit.73 Large boluses carry a higher risk for biofilm, with recommendation being for bolus size of less than 0.2–0.3 mL.
The Aspiration Controversy
Although the real-time clinical utility of pre-injection aspiration is controversial,74–80 all injectors are ultimately aligned in avoidance of intravascular incidents. No single method guarantees safety, despite individual preference for aspiration or constant needle movement, thus the following should be borne in mind.
Injection Angles vs Placement Depth (Needle/Cannula)
- Negative aspiration does not guarantee safe injection – slow, careful, low-volume injection is mandatory.
- Adequate aspiration time should be allowed (5 −7 seconds).
- Waiting times for visualizing flashback may be affected by physiochemical and rheological properties, with some products requiring longer negative pressure.
- Not all injectors are equally able to maintain a steady needle position on bone.
- Awareness of bevel angle (eg, 45 degrees vs perpendicular) in relation to tissue plane and vascularity is vital.
- With the needle in perpendicular position, the bevel tip still may be in a dangerous vascular plane despite a stable needle tip on bone as in the forehead or temple (aSTA).
- Intravascular placement is possible with a cannula, especially with < 25G, and in the presence of underlying fibrosis or skin tethering.
- Insightful knowledge of vascular anatomy is mandatory, especially pertaining to “z-axis” or vessel depth.
- Constant vigilance of watershed areas such as nasal tip and glabella is mandatory as these areas often demonstrate early, fleeting blanching.
- Pain is not invariably present with intravascular injection.
Angulation dictates injection depth and safety, mandating constant awareness (Figure 19, Table 11).
Figure 20 Early occurring symptoms.
Table 11 Angles vs Depth (Needle or Cannula)
Algorithms and Checklists
A thorough pre- and post-procedural history, with careful clinical examination, should elucidate predisposing factors and facilitate categorization of adverse events. After accurate diagnosis, the majority of problems may be managed through algorithms for:
- Allergic hypersensitivity reactions
- Vascular events
- Late-onset adverse events (LOAEs)
Early occurring symptoms and algorithms include factors as illustrated in Figures 20 and 21:
Late occurring adverse events may be classified according to symptoms as non-inflammatory, inflammatory or edema, and treated according to algorithms as shown in Figure 22. Anatomical factors, such as decreased muscle tonus of the orbicularis oculi, can cause symptoms such as the shelving illustrated in Figure 23. Edema may have a variable clinical presentation as demonstrated in Figure 24 and be classified according to temporal onset as seen in Figure 25. Post-procedural swelling (Figure 26) should be clinically differentiated from type 1 hypersensitivity reactions (Figure 27). Importantly, sterile abscesses may occur either as early or late-onset events, mandating targeted antibiotic therapy with incision and drainage in order to avoid tissue necrosis (Figure 28). The differential diagnosis of skin discoloration after fillers is varied (Figure 29). It is critically important to recognize the mottled or livedoid pattern of early vascular occlusion and not to confuse subsequent pustulation with herpes simplex infection.
Figure 21 Late-occurring symptoms of LOAEs.
Abbreviations: HDPH, high-dose pulse hyaluronidase; Resp, respiratory system; CVS, cardiovascular system.
Figure 22 Classification of LOAEs.
Figure 23 Patient demonstrating shelving Rx: surgery. Note: Image courtesy of Dr De Boulle.
Figure 24 Differential diagnosis of swelling. 1 = edema; 2 = malar edema; 3 = late inflammatory response syndrome; 4 = late onset nodules (LON); 5 = persistent intermittent delayed swelling. Notes: Adapted with permission from Pirayesh A, Bertossi D, Heydenrych I, editors. Aesthetic Facial Anatomy Essentials for Injections. Boca Raton: CRC Press; 2020.66 Copyright 2020 Taylor & Francis.
Figure 25 Temporal onset of post-procedural swelling. Notes: Reproduced with permission from Pirayesh A, Bertossi D, Heydenrych I, editors. Aesthetic Facial Anatomy Essentials for Injections. Boca Raton: CRC Press; 2020.66 Copyright 2020 Taylor & Francis.
Abbreviations: LIRS, late inflammatory response syndrome; LON, late-onset nodules.
Figure 26 Patient demonstrating postprocedural swelling. Note: Image courtesy of Dr De Boulle.
Abbreviations: LIRS, late inflammatory response syndrome; LON, late-onset nodules.
Figure 27 Patient demonstrating Type I hypersensitivity. Note: Image courtesy ofDr De Boulle.
Figure 28 Evolution of a sterile abscess during the first-week post -filler. Rx: targeted antibiotic therapy, with incision and drainage, is vital to prevent tissue necrosis. This presentation may also occur as a late-onset event. Note: Image courtesy of Dr Heydenrych.
Figure 29 Differential diagnosis of skin discoloration: 1. Hematoma; 2. Ecchymosis; 3. Neovascularization; 4. Hyperpigmentation; 5. The Tyndall effect; 6. Ischaemia. Notes: Adapted with permission from Pirayesh A, Bertossi D, Heydenrych I, editors. Aesthetic Facial Anatomy Essentials for Injections. Boca Raton: CRC Press; 2020.66 Copyright 2020 Taylor & Francis.
Figure 30 The clinical spectrum of LOAEs includes inflammatory or non-inflammatory manifestations, including swelling, induration, and nodules. Onset is usually after > 4 weeks.
Country-specific Covid guidelines should be adhered to.81
Patient adherence to the factors as noted in Table 12 should be encouraged.
Table 12 Suggested Inclusions for Post-Procedure Checklist
Aesthetic practices should be geared for efficient management of hypersensitivity events, albeit rare (Table 13).82 Computer reminders are suggested for emergency drug expiry dates.
Table 13 Management of Anaphylaxis with Emergency Crash Cart
Sufficient hyaluronidase should be available for the management of intravascular events, with high-dose pulse hyaluronidase (HDPH) currently deemed the gold standard (see Table 14). Dosage is according to tissue volume or areas involved. At least 5×1500 IU (or equivalent dosage in other format vials) should be available in-clinic. Check expiry dates.
Table 14 High-Dose Pulse Hyaluronidase (HDPH) for Intravascular Events.
Hyaluronidase treatment for intravascular placement should be instituted as soon as possible, with cut-off time regarded as 4 days. Later treatment options include anti-inflammatory medications, antibiotics, hyperbaric oxygen, and standard wound care.
There is a paucity of local management guidelines for visual complications after dermal fillers. A recent study cited widespread unawareness of existing protocols despite awareness of the complication in 75% of respondents, underscoring the urgent need for multidisciplinary collaboration and structured protocols.83
In contrast to previous studies, a recent systematic review detailing HA fillers only showed no cases after lower face treatment, with 32/44 events occurring after injection of the glabella and nose.84 Blindness has been reported with volumes as low as 0.2 mL of HA filler, whilst 0.085 mL may fill the supratrochlear artery from skin to orbit.73
Visual loss is often instantaneous and may be painless. Early, accurate documentation of visual signs is mandatory for subsequent decisions in the retinal referral centre (Table 15).
Table 15 Prognosis
There is currently a lack of indisputable evidence for reversal of injection-related visual compromise (IRVC), with conflicting reports regarding the merits of retrobulbar, supraorbital, and supratrochlear hyaluronidase and an urgent need for multidisciplinary collaboration.85
Many studies are flawed by incomplete documentation. It is imperative that vision is documented upfront in order to establish prognosis.
Given the 24% incidence of concomitant cerebral involvement, the exact mechanism of which still needs elucidation, a multi-speciality approach including neurological and neurosurgical examination is vital.
Practice Protocol for Injection-Related Visual Compromise (IRVC)
Although no universal protocol exists, factors as noted in Table 16 should be considered and documented. Upfront medico-legal advice may be advisable.
Table 16 A Suggested Practice Protocol for Managing Ophthalmic Incidents in the Aesthetic Practice
Late-Onset Adverse Events
LOAEs may present clinically as swelling, induration, nodules, or intermittent swelling (persistent intermittent delayed swelling = PIDS) (Figures 30–32).
Figure 31 Patient with LOAE (nodule). Despite lack of improvement on long-term antibiotics, total resolution was affected with colchicine.
The ASIA Syndrome (Autoimmune/Inflammatory Syndrome Induced by Adjuvants)
Figure 32 Patient with PIDS successfully treated with 0.1 mL of hyaluronidase. Note: Image courtesy of Dr A De Almeida.
In genetically predisposed hosts such as HLA B8 or HLA DRB1*- positive individuals, biomaterials may trigger delayed immune responses, eventually progressing to granulomatous or autoimmune disorders falling into the ASIA diagnostic complex (Table 17).31 Two or more stimuli increase the risk of abnormal immune responses and include:
- Local trauma
- Filler injections
- Dental amalgams
- Menstrual exacerbations
Table 17 ASIA Syndrome: Summary
HA is thought to trigger the immune system via adjuvant effect rather than primary antigenic immune response, being cited as potential trigger in 340/350 patients with previous filler treatments where filler removal effected improvement in 60% of cases. The adjuvant effect of microbial molecules may determine a limited autoimmune response vs evolution to full-blown disease.
Ciprofloxacin now carries an FDA black box warning and should not be prescribed for longer than 60 days (British National Formulary). Potential quinolone side-effects, including colitis and prolonged QT interval, merit recommendation as third-line agents in case of intolerance, allergy, or contraindication to macrolides and tetracyclines. Dual antibiotic therapy should continue for four weeks, followed by patient re-assessment (Table 18).86
Table 18 Antibiotic Choice by Infection Origin (Adhere to Country-Specific Microbiotic Guidelines)
Facial filler treatment is a constantly evolving field mandating continuous reassessment and improvement. New challenges (eg, the COVID 19 SARS 2 pandemic) prompt new insights, with resultant evolution in the understanding, prevention, diagnosis and therapeutic approaches to filler complications.
The updated 10-point plan aims to empower aesthetic physicians to perform optimally through prudent patient selection, knowledgeable product choice, and attentive procedural planning. The most dreaded adverse events are vascular complications and filler-induced blindness. However, with a systematic approach, in-depth knowledge of facial anatomy, and appropriate algorithms, the majority of adverse events are avoidable or manageable.
This updated version of our former publication attempts to illuminate salient background knowledge, whilst still embodying a practical reference guide to the cosmetic health-care practitioner. Hopefully, an increased understanding of safety factors may serve to protect not only our patients but also the future of aesthetic medicine.
Written informed consent for publication of their clinical details and/or clinical images was obtained from the patients. No ethical concerns were raised in this paper.
The authors would like to express deep gratitude to PhD candidate, Elizabeth Rademan, Centre for Research on Evaluation, Science and Technology (CREST), Stellenbosch University, South Africa, for the invaluable writing and editing assistance serving to significantly improve the manuscript.
Dr Izolda Heydenrych reports honoraria for advisory boards and lecturing from Allergan, outside the submitted work; and being a consultant for Allergan/AbbVie, LÓreal, LaRochePosay, SkinCeuticals, Genop Healthcare. Dr Koenraad De Boulle reports grants and personal fees from Allergan and Genévrier, outside the submitted work. The authors report no other potential conflicts of interest in this work.
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