Introduction

Ageing is a multifactorial, three-dimensional and dynamic process caused by internal (biological) and external (environmental) factors [1,2]. With increasing age, an interplay of changes occurs in all anatomical structures, involving the skeleton, ligaments, muscles, adipose tissue and skin [3]. Some of the facial manifestations of ageing are a result of fat displacement, bone resorption and tissue atrophy that progressively lead to volume loss [4-6]. In turn, facial volume loss is responsible for many of the indications for which patients seek out aesthetic treatments, such as wrinkles, folds (e.g. nasolabial folds) [7] and tissue augmentation (e.g. midface, lips) [8-10].

Facial volume loss can be safely and effectively treated with the use of hyaluronic acid (HA) soft tissue fillers [10-12]. The latest report from the International Society of Aesthetic Plastic Surgery estimates that the number of treatments performed using these devices increased by 11.6% between 2017 and 2018, with 3,729,833 worldwide procedures completed [13]. In 2019, over 749,409 HA-based aesthetic procedures were performed in the United States (U.S.) alone [14]. Treatments using HA fillers are currently the second most popular non-surgical aesthetic procedure performed, following the use of neuromodulators [14]. Based on product, HA dominates the global dermal filler market, accounting for 77.2% of the market share [15]. With the increasing popularity of these procedures, the development of novel products and the expansion of indications, the number of treatments are likely to continue to increase. The growing demand for safe and minimally invasive aesthetic procedures, combined with the increasing geriatric population, will also continue to drive the growth of the global market which is projected to reach over 6 billion U.S., dollars by 2027 [15,16]. Concurrent with this growth, the incidence of adverse events (AEs) following these treatments are predicted to increase as well [1].

Various AEs related to soft tissue fillers have been reported, ranging from mild injection site complications to severe complications [17]. Most immediate-to-short term AEs tend to be related to the injection technique rather than the devices themselves and frequently consist of erythema, edema and pain. Other early-onset AEs include hypersensitivity, infections, surface irregularities, vascular occlusion and more [18]. Delayed and/or chronic AEs may include foreign body granulomas or biofilms, among other complications [18,19].

Familiarity with the AEs possibly associated with HA fillers and guidance to their prevention, treatment and management are imperative to ensuring patient outcomes [15]. AEs can occur due to a variety of contributing factors, such as patient characteristics (e.g. concomitant conditions and/or medications), injection technique (e.g., needle versus cannula), injector’s level of knowledge of anatomy and the biophysical properties of the injectate [19,20]. For example, the degree of crosslinking, gel calibration (particle sizing) and concentration of HA of different products affect therapeutic results [1,20,21]. Hence, achieving optimal outcomes with HA relies on an understanding of these concepts and approaches to AE prevention, treatment and management [1].

Many authors have proposed algorithms and/or created guidelines for the prevention, treatment (addresses the causative agent) and management (addresses the symptoms) of AEs related to HA soft tissue fillers [1,19,20]. However, different recommendations may be based on varying levels of evidence. Therefore, the purpose of this systematic review is to perform an evaluation of currently proposed methods for the prevention, treatment and management of AEs related to the use of HA soft tissue fillers for aesthetic indications, and to develop evidencebased models established on the level of support for each recommendation. These schematics may be used by providers of aesthetic injectable treatments when practicing evidence-based medicine founded on some of the strongest knowledge currently available.

Materials and Methods

The following methods were created in consultation with the Preferred Reporting Items for Systematic Review and MetaAnalysis Protocols-2015 (PRISMA-P) checklist and patient, intervention, comparison, outcome (PICO) items [22,23]. The PICO framework was used to develop the search terms, which were also informed by relevant Medical Subject Headings (MeSH) [24]. As per the Cochrane Handbook suggestion, we altered the PICO model to P, I, S/T (i.e., study type or types of study) and O [25]. PubMed was searched using the following terms: (((hyaluronic acid) AND ((facial) OR (aesthetic)) AND ((safety) OR (adverse event) OR (complication) OR (side effect))). Systematic reviews, literature reviews, meta-analyses, expert consensus statements and guidelines related to AEs following the use of soft tissue facial fillers were selected. Broad and general search terms were chosen as there are relatively fewer publications of the aforementioned categories than individual studies. Inclusion criteria consisted of English language publications; free full-text availability; relating to products approved for use by the Food and Drug Administration and/or Health Canada; use for aesthetic indications, in healthy adults (i.e. above the age of 18 years); and a publication date in the preceding ten years (i.e. from January 2010 and May 2020), prior to the search date.

Exclusion criteria included articles on the topic of biostimulators (e.g. poly-L-lactic acid, calcium hydroxylpatite), neuromodulators (e.g. onabotulinumtoxinA, incobotulinumtoxinA, abobotulinumtoxinA) or treatments to anatomical areas outside of facial regions (e.g. neck, décolletage, body, hands); use for medical indications (e.g. lagophthalmos, eyelid malpositions, orbital volume deficiency; post-traumatic facial disfigurement); use in immune-compromised individuals (e.g. human immunodeficiency virus-associated lipodystrophy); animal studies; and the following study designs: clinical trials, case report/series, cross-sectional analyses and registries. As the final step in the selection process, the systematic search was supplemented with non-systematic scoping methods for the inclusion of additional key references.

Two reviewers independently performed each stage of the review (screening, eligibility and inclusion) and extracted information using data extraction tables and quality appraisal forms. Variables for which data/information was sought included AE descriptions (signs, symptoms) and prevention, management and treatment strategies. The overall strength of the body of evidence presented in each publication, for each recommendation, was also assessed as per the ratings described by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group (Table 1) [26]. Each reviewer was trained on the GRADE Handbook before beginning their reviews.

The model development group consisted of clinical and methodological experts, including three board-certified plastic surgeons with a combined total of over 40 years of injecting experience, a senior epidemiologist with substantial experience in the aesthetics field, an anatomist and clinical researchers specializing in the fields of aesthetics and dermatology.

Results

Number of articles: The search terms resulted in 878 texts; 94.65% (n = 831) of which were available in the English language. After applying the filters for publication year, full-text availability and article type, nineteen texts remained. The titles and abstracts of these nineteen texts were screened by the two reviewers and then the full texts were assessed according to the eligibility criteria. The reference lists of the eleven resulting texts were consulted, which resulted in 447 references before the removal of duplicates. These additional 447 references were assessed using the same techniques as the original 878 texts that resulted from the search terms. A third reviewer resolved any disagreements. Following this methodology (Figure 1), 46 texts remained. Eight additional references were added to the collection, using non-systematic methods. Following this step, fifty-four texts were included in the present review (Table 2).

Article types: The vast majority of eligible articles included non-systematic reviews (37/54; 68.52%), followed by consensus recommendations (9/54; 16.67%). Systematic reviews (4/54; 7.41%) and guidelines (4/54; 7.41%) were infrequent.

Number of studies and subjects: Only reviews and systematic reviews reported the number of studies and/or subjects that were included in their analyses. The current analyses are therefore based on approximately 251 studies involving 3448 subjects treated with fillers, including 130 studies involving 401 subjects treated with HA (Table 2). However, it remains possible that reviews and systematic reviews may have considered duplicate studies/cases.

Adverse events: All AEs discussed within the included publications (N = 54) are presented in (Table 3). In total, thirty-four AEs were found to be associated with the use of aesthetic soft tissue fillers in the face. Many publications (35/54; 64.81%) examined multiple AEs, with the average number of AEs presented in a single article being 5.02 (SD: 5.56; Range: 1 to 23). Reviews (9/11; 81.82%) and consensus recommendations (2/11; 18.18%) made up all article types that reviewed >10 AEs (N = 11). The most frequently mentioned AEs were blindness/vision loss, disturbances, compromise or impairment (23/54; 42.59%); ischemia/vascular complications (21/54; 38.89%); nodules (18/54; 33.33%); and infection (18/54; 33.33%).

Quality of evidence: The prevention, treatment and management strategies presented in the included articles are summarized in (Figure 2 ) (parts a to z6vi).  There were 8/34 (23.53%) AEs (i.e. abnormal sensation, anaphylactic shock, intra-cranial penetration, urticaria, nerve palsy, scarring, stroke and telangiectasia) for which there was only a single reference providing guidance on its prevention, treatment and/or management. “Common” AEs such as bruising and swelling were widely mentioned in the literature.

Overall, the quality of evidence in support of the proposed prevention, treatment and management techniques was poor; consisting largely of D (very low) and C (low) GRADE scores. Prevention and management techniques were described less often than treatment techniques; with 14/34 (41.18%) AEs having no provided prevention techniques, 21/34 (61.76%) AEs having no accompanying management techniques, and 5/34 (14.71%) AEs having no methods of treatment (i.e. abnormal sensation, bleeding, intra-cranial penetration, pain and stroke). There were only three strategies that met a GRADE A (high) quality of recommendation, each of which were preventative strategies. These included: i) knowledge of anatomy (e.g., knowing the location and depth of facial vessels and the common variations) and injection techniques are imperative; ii) injectors should wear gloves; and iii) skin should be disinfected (see Figure 2, parts i and t). A small subset (i.e. < 15%) of recommendations corresponded to B (moderate) GRADE scores, with the remaining ~85% being classified as either a C (low) or D (very low). Many of the D recommendations were founded strictly on expert opinion, with no accompanying supporting evidence.

Discussion

In this review, we aimed to summarize currently available data on the prevention, treatment and management of AEs related to HA soft tissue fillers. We then evaluated the quality of evidence in support of each recommendation and assigned to it a corresponding GRADE score, accordingly [26-29]. Overall, thirty-four distinct AEs were identified as being associated with soft tissue fillers used for facial aesthetic indications, in the literature. When attempting to summarize prevention, treatment and management strategies for each AE, twenty-five (73.53%) AEs lacked information pertaining to at least one of the given care categories. Furthermore, almost a quarter of the AEs had but a single reference providing guidance. This review also demonstrated that there have been few advancements or changes to expert recommendations in AE action protocols in the last decade (e.g., High Dose Pulsed Hyaluronidase).45 This is a significant limitation of current guidelines, given product refinements over the last few years, and the increase in novice injectors and subsequent number of treatments being performed worldwide, all of which may effect AE risk [30,31]. Moreover, as there were relatively few AEs described in the literature until 2010,[35] updated guidelines would likely be more representative of real-world data.

In many aspects, standards in aesthetic medicine are set forth by health and safety legislation. However, currently there is no standard for handling AEs associated with the use of HA fillers. Practitioners in different medical fields are performing these procedures and they have varied educational backgrounds and levels of expertise [35]. Consequently, there is an urgent need to evaluate currently proposed guidelines in order to provide clinicians with guidance [20]. In fact, Signorini et al. (2016) [20], professed that complication management is the largest unmet need with HA fillers. In response to this call-to-action, the present review critically appraised the available evidence for validity, based on a hierarchy of strength.

Herein, it was found that a number of approaches alternative to established consensus have been published and most complication guidelines rely on expert opinion with no direct evidence or very low quality studies with severe limitations. This poses a dilemma as a theory or conceptual model of therapy may be perfectly reasonable, but the resulting predictions it enables are limited, if not validated by research. Additional limitations of the current literature include: describing vague safety techniques (e.g. prevent AEs via “meticulous technique”) or in insufficient detail for replication (e.g. suggesting topical steroids for reducing erythema [1,37], hyaluronidase for nodules, or antimicrobials for biofilms but not indicating specific products, doses, or frequency and duration of use; recommending to stop anticoagulant use prior to treatment in order to prevent bruising, but not specifying for how long beforehand [38], providing general safety measures for any/ all AEs, without relating the recommendations to any specific AE [39], referring to different AEs as if they are the same, when in fact they significantly differ based on etiology and thus, prevention, treatment and management (e.g. ecchymosis occurs because small veins and capillaries break under the skin, but a hematoma occurs when a collection of blood pools outside of a large blood vessel; yet some authors refer to them as if they were indistinguishable) [39], failing to make the distinction between treating AEs or their signs and symptoms (e.g. treatment of the emboli causing vascular complications versus the necrotic tissue that results from the interruption of blood flow); providing recommendations but limiting it to a certain anatomical area [40] and as mentioned, most importantly many authors provided no evidence to support their recommendations, or relied on case-control, or cohort studies, with a high risk of confounding bias, non-analytic studies (e.g. case reports, case series) or expert opinion; such are the lowest grades of study designs based on multiple grading schemes, even those not implemented herein [41]. Although, the authors do appreciate that the true rarity of some AEs may precede the ability to develop analytical studies. The literature is also fraught with inconsistencies in the language used, for example: nodules should not be interchanged with the terms “lump”, “bump” or “contour irregularity”; nodules, papules and granulomas should be distinguished from each other as their etiology and treatment differ; “hypersensitive reactions” should be described by their symptoms, such as swelling and inflammation and may actually involve many AEs; swelling and inflammation are distinct AEs; some authors consider Tyndall effect as skin discoloration [42], but only changes to melanin should be considered in hyper/hypopigmented disorders; and vague terms such as “general”, “local” or “site reactions” should be avoided.

Currently and to the best of the authors’ knowledge, this is the most comprehensive review of the quality of evidence supporting recommendations to AE prevention, treatment and management. This review provides information on a large majority of currently known potential AEs of HA, where other authors have only considered a subset. For example, the majority of included articles only reviewed an average of ~five AEs, which often corresponded to specific anatomical regions; and the most comprehensive review evaluated twenty-three, whereas herein we describe thirty-four. Moreover, as some authors have only focused on either prevention, treatment or management strategies, we have summarized all three facets of patient care.

The methods employed herein included founding recommendations based on the strength of the supporting literature, using four levels of analyses. Strict inclusion and exclusion criteria were set, and the inclusion of articles and data extraction were performed in duplicate. The models we present were developed by a multidisciplinary expert group and have the potential to directly impact practice by offering aesthetic providers with evidencebased guidelines. Familiarity with the content of the models described herein are an essential requirement of any aesthetic practice and to upholding the integrity and responsibilities of clinicians performing injectable procedures.

Despite significant strengths of the current systematic review, there are some limitations to its methods. Given that PubMed was the only search engine searched systematically, it is possible that some relevant publications were not considered for inclusion. Furthermore, as non-English-language publications and texts related to products licensed outside of Canada and the United States were not considered, the international applicability of these findings are limited. There are hundreds of HA-based filler products available worldwide and counterfeit or illegally imported HA is widespread in some countries [43]. However, only approximately one-fourth of this amount is approved by the FDA and/or Health Canada [44]. Therefore, these findings may not be applicable to all soft-tissue fillers available on the world market. In addition, almost one-third of the AEs had but a single publication providing guidance on its prevention, treatment or management. Therefore, the resulting models are likely extremely limited. Lastly, no-to-small sample sizes and a lack of homogeneity in the included studies precluded any quantitative analysis of effect size, confidence interval estimates or a confirmation of the presence/ absence of statistical significance.

Conclusions and Future Research

Most complication guidelines for AEs related to HA soft tissue filler use rely on expert opinion with no direct evidence or very low-quality studies with significant imitations. Moreover, there have been few advancements or changes to expert recommendations in AE action protocols in the last decade, despite a growing number of novice injectors and treatments being performed, and varying product technologies entering the global market. Consequently, there is an increasingly urgent need to re-evaluate currently proposed guidelines in order to provide clinicians with more accurate guidance [20]. To date, the original call-to-action for increased evidence-based AE management by Signorini et al. (2016) [20] remains unaddressed.

In an early attempt to address this call-to-action, we first graded and summarized evidence-based methods for the prevention, treatment and management of AEs associated with the use of HA fillers for aesthetic facial indications. The findings of these quality assessments are summarized herein and provide a foundational framework for evaluating the current body of evidence. To further assess the quality of these methods, prospective studies are required to systematically evaluate outcomes following complication management. For example, a prospective registry could evaluate the true incidence rates of AEs, establish the real-world timeline between treatment exposure and signs and/or symptoms of late-onset AEs, establish standards (e.g., the mean number of hyperbaric oxygen sessions recommended for cases of vascular compromise, the ideal number and frequency of hyaluronidase sessions recommended to dissolve an emboli), and assess the suitability and applicability of the recommendations proposed to date. To the authors’ knowledge, there exists only one such registry, the physician-researcher-initiated “Global Registry of Adverse Clinical Events (GRACE)’, which is a multi-year, prospective AE registry (2018-2020; results in press). To increase participant engagement in these types of registries, governing bodies or specialty groups should consider developing public registries or online portals for tracking AEs. Following future research, modifications to the current AE prevention, treatment and management models may be required.

Figures

Tables

References

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