In a recent Letter published in Aesthetic Surgery Journal,1 the incidence of filler-related vascular adverse events (VAEs), which can lead to tissue necrosis and blindness,1–4 was estimated by Schelke et al.1 Based on a national survey among cosmetic doctors, they approximated the total numbers of filler injections in the Netherlands, and considering the number of patients referred to their clinic for filler-induced VAEs, they calculated that the risk of VAE per treatment ranged from 1/5300 to 1/8000.5,6 All of Schelke et al’s patients fully recovered after an outpatient treatment with hyaluronidase injections and no cases of blindness or tissue necrosis were reported.1 Here we present the largest database to date with recent and detailed information on the incidence of complications following botulinum neurotoxin type A (BoNT-A) and dermal filler treatments, which we would like to share with the readers of this Journal. Furthermore, we were able to determine the influence of professional experience and the academic degree of the injector on the incidence of these complications.
To this end, we conducted a retrospective cohort study. Between April 1, 2020 and June 10, 2022 (800 days), data of all consecutive clients of 17 outpatient cosmetic clinics at various locations in the Netherlands (Faceland Clinics, headquartered in Capelle aan den IJssel, the Netherlands) were systematically recorded electronically. These medical records included client demographics, the indication for treatment, the product employed, any related complications, and subsequent treatment. Each single treatment for 1 indication on a certain day (eg, BoNT-A injections for glabellar rhytides, or filler injections for lip augmentation) was calculated as 1 treatment, independent of the total number of units or milliliters injected. The identity of the 60 doctors of medicine (MDs) and 13 registered nurses (RNs) who treated the clients was also recorded. In the Netherlands there are no legal restraints per se to the injection of hyaluronidase or the use of ultrasound by RNs. Within Faceland Clinics, however, only MDs are trained to use ultrasound and hyaluronidase, and therefore only MDs use ultrasound guidance to inject hyaluronidase. In the case of a suspected VAE, an MD at Faceland Clinics diagnosed the VAE and the ultrasounds and salvage procedures were either performed via referral to cosmetic physicians working at the filler complication division of an academic center (Erasmus MC, Rotterdam, the Netherlands), or by a consultant radiologist at Faceland Clinics. Data on the injectors’ professional experience in cosmetic medicine (measured in months) and academic degrees were collected. All injectors were required beforehand to successfully complete a thorough postacademic inhouse training program developed by Faceland Clinics.
As a result, the following data were obtained: a total of 301,804 cosmetic injectable treatments were performed, of which 200,257 were BoNT-A injections, 94,521 were hyaluronic acid (HA) filler injections, 5588 were calcium hydroxylapatite (CaHA) injections, and 1438 were hyaluronidase injections (detailed information is given in Table 1). The injected regions of Profhilo included either the entire facial region or the neck, according to the manufacturer’s injection protocol, and Belotero Hydro (Merz Pharma GmbH & Co. KGaA, Frankfurt, Germany) was used in the entire facial region. A total of 249 complications of varying severity were reported (Table 1). Demographic variables pertaining to clients and their injectors are displayed in Table 2. Data on 14 consecutive patients with filler-related VAEs are displayed in Table 3. Treatment of all of these patients resulted in complete resolution of all signs and symptoms of VAEs through hyaluronidase treatment, with or without ultrasound guidance.7
Table 1.
Reported Complications Related to Cosmetic Injectable Procedures
| BoNT-A complications | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Region and indication | Total N | Percentage of total | Infection | Hypersensitivity reactions | Muscular | Other | ||||||||
| Type I allergy | Type IV allergy | Levator palpebrae ptosis | Asymmetric perioral facial expression | Eyebrow ptosis | Mephisto/Spock | Asymmetry | Malar edema | Scarring | Hyperpigmentation | Diplopia | ||||
| Glabellar (frown lines) | 90,985 | 45.5% | 1 | 1 | 23 | 8 | 11 | 4 | 3 | |||||
| Frontalis (horizontal forehead lines) | 40,733 | 20.4% | 4 | 34 | 4 | 1 | ||||||||
| Orbiculairs oculi (crow’s feet) | 37,955 | 19.0% | 1 | 1 | 1 | 1 | 6 | |||||||
| Orbicularis oculi (brow lift) | 10,915 | 5.5% | 3 | 1 | ||||||||||
| Orbicularis oris (lipflip) | 5504 | 2.8% | 1 | |||||||||||
| Depressor anguli oris (depressed oral commisures) | 3222 | 1.6% | 3 | 2 | ||||||||||
| Levator labii superioris alaeque nasi (gummy smile) | 2405 | 1.2% | ||||||||||||
| Mentalis (chin) | 2337 | 1.2% | 3 | |||||||||||
| Masseter/temporal | 2047 | 1.0% | 6 | |||||||||||
| Nasalis (bunny lines) | 1724 | 0.9% | ||||||||||||
| Orbiculair oris (perioral rhytides) | 581 | 0.3% | 1 | |||||||||||
| Depressor septi nasi (nasal tip lift) | 480 | 0.2% | ||||||||||||
| Axillary (hyperhydrosis) | 328 | 0.2% | ||||||||||||
| Unspecified | 307 | 0.2% | 2 | 2 | 1 | |||||||||
| Platysma (Nefertiti lift) | 304 | 0.2% | 1 | |||||||||||
| Unspecified (tension headache or migraine) | 272 | 0.1% | ||||||||||||
| Total | 200099 | 100,0% | ||||||||||||
| 2 | 1 | 0 | 31 | 18 | 46 | 16 | 7 | 9 | 0 | 0 | 0 | |||
| HA filler complications | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Vascular | Infection | Hypersensitivity reactions | Neurologic | Other | |||||||||||||||
| Region and indication | Total N | Percentage of total | Local signs of impaired perfusion | Necrosis | Blindness | Flare of labial herpes | Type I allergy | Type IV allergy | Neurapraxia | Malar edema | Asymmetric or inhibited perioral facial expression | Scarring | Hyperpigmentation | Uncorrectable nodules | Eczema | Correctable bumps/lumps/irregularities | Correctable asymmetry | ||
| Lips | 44,175 | 46.7% | 4 | 6 | 5 | 3 | 1 | 16 | 4 | ||||||||||
| Unspecified | 11,221 | 11.9% | 1 | 4 | |||||||||||||||
| Nasolabial folds | 7600 | 8.0% | 1 | 1 | 1 | 1 | 1 | 1 | |||||||||||
| Zygomatic/infraorbital | 5544 | 5.9% | 2 | 2 | 1 | 1 | |||||||||||||
| Marionette lines | 5418 | 5.7% | 1 | 1 | 1 | ||||||||||||||
| Profhilo (head and neck area) | 4422 | 4.7% | 1 | ||||||||||||||||
| Chin | 4083 | 4.3% | 6 | 2 | 2 | ||||||||||||||
| Tear trough | 4027 | 4.3% | 1 | 21 | 2 | ||||||||||||||
| Perioral rhytides | 3075 | 3.3% | 3 | ||||||||||||||||
| Cheeks | 1843 | 1.9% | 1 | ||||||||||||||||
| Jawline | 1595 | 1.7% | |||||||||||||||||
| Nasal (with or without BoNT-A) | 648 | 0.7% | 1 | 1 | |||||||||||||||
| Temporal | 388 | 0.4% | 1 | ||||||||||||||||
| Liquid facelift (HA and/or and/or BoNT-A) | 223 | 0.2% | |||||||||||||||||
| Glabellar | 82 | 0.1% | |||||||||||||||||
| Scar | 54 | 0.1% | |||||||||||||||||
| Neck/cleavage | 37 | 0.0% | |||||||||||||||||
| Belotero Hydro (facial) | 37 | 0.0% | |||||||||||||||||
| Forehead | 22 | 0.0% | |||||||||||||||||
| Earlobe | 17 | 0.0% | |||||||||||||||||
| Crow’s feet | 8 | 0.0% | |||||||||||||||||
| Hands | 2 | 0.0% | |||||||||||||||||
| Total | 94521 | 100.0% | 13 | 0 | 0 | 9 | 5 | 1 | 7 | 1 | 25 | 0 | 0 | 0 | 2 | 1 | 29 | 7 | 0 |
| CaHA filler complications | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Vascular | Infection | Hypersensitivity reactions | Other | |||||||||||||||
| Region and indication | Total N | Percentage of total | Local signs of impaired perfusion | Necrosis | Blindness | Flare of labial herpes | Type I allergy | Type IV allergy | Malar edema | Asymmetric or inhibited perioral facial expression | Scarring | Hyperpigmentation | Uncorrectable nodules | Correctable bumps/lumps/irregularities | Correctable asymmetry | |||
| Zygomatic | 2222 | 41.4% | 2 | |||||||||||||||
| Jawline | 1461 | 27.2% | 1 | 3 | ||||||||||||||
| Cheeks | 474 | 8.8% | 1 | |||||||||||||||
| Chin | 394 | 7.3% | 1 | |||||||||||||||
| Nasolabial folds | 279 | 5.2% | ||||||||||||||||
| Marionette lines | 217 | 4.0% | ||||||||||||||||
| Unspecified | 162 | 3.0% | ||||||||||||||||
| Hands | 92 | 1.7% | 2 | 1 | ||||||||||||||
| Temporal | 40 | 0.7% | ||||||||||||||||
| Cleavage | 24 | 0.4% | ||||||||||||||||
| Total | 5365 | 100.0% | 1 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 7 | 0 |
| Hyaluronidase complications | ||||||
|---|---|---|---|---|---|---|
| Hypersensitivity reactions | Infectious | |||||
| Hyaluronidase | Type I allergy | Infection | Correctable bumps/lumps/irregularities | |||
| Total N | ||||||
| 1438 | 0 | 0 | 1 | |||
BoNT-A, botulinum neurotoxin type A; CaHA, calcium hydroxylapatite; HA, hyaluronic acid.
Table 2.
Demographic Variables Pertaining to Clients and Their Injectors
| Clients | Professionals | ||||
|---|---|---|---|---|---|
| Overall | Overall | ||||
| N | 131,025 | N | 73 | ||
| Gender | Female | 94.2% | Months of professional experience in cosmetic medicine | Mean | 25.3 |
| Male | 5.8% | SD | 23.3 | ||
| Age (years) | Mean | 39.9 | Range | 2-103 | |
| SD | 12.4 | ||||
| Range | 18-87 | ||||
| Clients with complications | Professionals grouped by academic degrees | ||||
| N | 249 | Doctors of medicine | |||
| Gender | Female | 95.6% | N | 60 | |
| Male | 4.4% | Months of professional experience in cosmetic medicine | Mean | 29.1 | |
| Age (years) | Mean | 42.2 | SD | 23.9 | |
| SD | 12.2 | Range | 3-103 | ||
| Range | 20-76 | Registered nurses | |||
| N | 13 | ||||
| Months of professional experience in cosmetic medicine | Mean | 8.0 | |||
| SD | 8.4 | ||||
| Range | 2-31 | ||||
SD, standard deviation.
Table 3.
Consecutive Patients with Filler-Related Vascular Adverse Events
| Patient | Gender | Age (years) | Region | Impaired perfusion diagnosis | Radiographic diagnosis | Delay in treatment time (hours) | Clincally guided HYase units | Ultrasound-guided HYase units | STSa dose | Injection technique | Product | Injector experience in cosmetic medicine (months) | Injector academic degree |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 27 | Chin | Clinical symptoms | — | 46 | 1000 | 0 | 0 | Needle 27G | HA | 31 | RN |
| 2 | F | 40 | Zygomatic | Clinical symptoms | — | 23 | 1500 | 0 | 0 | Needle 27G | HA | 31 | RN |
| 3 | F | 46 | Lips | Clinical symptoms | — | 0 | 600 | 0 | 0 | Needle 27G | HA | 38 | MD |
| 4 | F | 58 | Nasolabial | Clinical symptoms | — | 26 | 600 | 0 | 0 | Needle 27G | HA | 32 | MD |
| 5 | F | 21 | Lips | Clinical symptoms | — | 24 | 1500 | 0 | 0 | Needle 27G | HA | 31 | RN |
| 6 | F | 31 | Chin | Clinical symptoms + ultrasound | Submental artery (occlusion) | 0 | 3000 | 60 | 0 | Needle 27G | HA | 39 | MD |
| 7 | F | 32 | Nasal bridge | Clinical symptoms | — | 11 | 2250 | 0 | 0 | Needle 27G | HA | 40 | MD |
| 8 | F | 56 | Infraorbital | Clinical symptoms + MRI | Angular artery (occlusion) | 24 | 3150 | 0 | 0 | Needle 27G | HA | 51 | MD |
| 9 | F | 31 | Lips | Clinical symptoms + ultrasound | Inferior labial artery (external compression) | 0 | 150 | 0 | 0 | Needle 27G | HA | 17 | MD |
| 10 | F | 24 | Lips | Clinical symptoms + ultrasound | Superior labial artery (occlusion) | 21 | 2000 | 15 | 0 | Needle 27G | HA | 40 | MD |
| 11 | F | 36 | Chin | Clinical symptoms + ultrasound | Submental (occlusion) | 0 | 700 | 70 | 0 | Needle 27G | HA | 39 | MD |
| 12 | F | 35 | Chin | Clinical symptoms + ultrasound | Submental perforator (occlusion) | 72 | 0 | 120 | 0 | Needle 27G | CaHA | 54 | MD |
| 13 | F | 28 | Chin | Clinical symptoms + ultrasound | Mental artery branch (occlusion) | 15 | 1500 | 20 | 0 | Needle 27G | HA | 32 | MD |
| 14 | F | 29 | Chin | Clinical symptoms | — | 16 | 1200 | 0 | 0 | Needle 27G | HA | 15 | RN |
CaHA, calcium hydroxylapatite; HA, hyaluronic acid; HYase, hyaluronidase; MD, doctor of medicine; RN, registered nurse; STS, sodium thiosulfate. aCurrently not used because of absence of observed effect on CaHA microsphere degradation.15
Multiple linear regression analyses were performed. No statistically significant regression equations were found to predict the overall complication rate (P = 0.618), BoNT-A–related complications (P = 0.838), or filler-related complications (P = 0.159). However, for the incidence of VAEs, a statistically significant regression equation was found (F(2,72) = 3.898; P = 0.025), with an r2 of 0.100. Injectors’ predicted incidence of filler-related VAEs was equal to 0.014% (constant) + [0.000% × (experience)] − [0.016% × (degree)] where “experience” was measured in months of professional experience in cosmetic medicine and “degree” was coded as 0 (RN) or 1 (MD). The percentage of VAEs increased (95% CI) 0.000% to 0.001% for each month of professional experience and MDs had a (95% CI) 0.033% lower to 0.001% higher incidence than RNs. “Experience” (P = 0.012) was a statistically significant predictor of VAE incidence, whereas “degree” was not (P = 0.069).
In sum, we found the incidence of overall complications to be 0.065% (1/1539) for BoNT-A treatments, 0.106% for HA filler treatments (1/945), and 0.205% for CaHA treatments (1/487), which is in line with earlier reports of filler complication rates (∼0.00%-1.25%).8–14 For filler-related VAEs, the overall incidence in this study was 0.014% (1/7134); with rates of 0.014% for HA fillers (1/7220) and 0.019% for CaHA (1/5365). This VAE incidence is in line with the estimations by Schelke et al.1
Furthermore, our analyses showed that the influence of professional experience and academic degree on the incidence of complications was limited as the regression model only explained 10% of the total variance in VAEs. A statistically significant predictive effect, albeit of limited clinical relevance, of professional experience on VAE incidence was detected, whereas academic degree was found to be insignificant. This suggests that MDs and RNs are both likely to be capable of performing cosmetic injections and able to recognize and treat complications (or refer these for treatment), provided that they have had substantial training (and/or supervision) in cosmetic medicine.
However, the number of reported complications in this study may be underreported. Some professionals may not recognize a problem in their patient, and others may feel reluctant to report a complication.1 Although this study is limited by its retrospective design, currently1,10 these are the most detailed and extensive data on the incidence of complications after BoNT-A and dermal filler treatments.
The risk incidence rates observed in this study indicate that cosmetic professionals will most likely encounter general complications and VAEs more than once during their career.1 As VAEs can lead to skin necrosis or blindness (which in the case of HA is 32% partially to completely reversible),13 these are considered the most alarming complications of filler treatments.1–4 Nevertheless since 2018 a total of 58 VAEs out of a total of ∼240,000 filler treatments in the Netherlands have been reported in the literature by Schelke et al1 (n = 44; January 2018-January 2020) and the present study (n = 14). Interestingly, no cases of blindness were recorded, suggesting a risk of less than 0.0004% (<1/240,000), and all patients with VAEs fully recovered (no cases of tissue necrosis were recorded), indicating that both high-dosed pulsed hyaluronidase16 and ultrasound-guided hyaluronidase7 treatment of VAEs are effective. In conclusion, our data support the emerging body of evidence that cosmetic injections are relatively safe procedures in the hands of adequately trained cosmetic professionals.
Disclosures
The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.
Funding
The authors received no financial support for the research, authorship, and publication of this article.
References
- 1. Schelke L, Decates T, Kadouch J, Velthuis P. Incidence of vascular obstruction after filler injections. Aesthet Surg J. 2020;40(8):NP457–NP460. doi: 10.1093/asj/sjaa086 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Cho KH, Pozza D, Toth G, Gharb B, Zins JE. Pathophysiology study of filler-induced blindness. Aesthet Surg J. 2019;39(1):96–106. doi: 10.1093/asj/sjy141/5033292 [DOI] [PubMed] [Google Scholar]
- 3. Beleznay K, Carruthers JDA, Humphrey S, Carruthers A, Jones D. Update on avoiding and treating blindness from fillers: a recent review of the world literature. Aesthet Surg J. 2019;39(6):662–674. doi: 10.1093/asj/sjz053/5364893 [DOI] [PubMed] [Google Scholar]
- 4. Ozturk CN, Li Y, Tung R, Parker L, Piliang MP, Zins JE. Complications following injection of soft-tissue fillers. Aesthet Surg J. 2013;33(6):862–877. doi: 10.1177/1090820X13493638 [DOI] [PubMed] [Google Scholar]
- 5. Decates T, de Wijs L, Nijsten T, Velthuis P. Numbers on injectable treatments in the Netherlands in 2016. J Eur Acad Dermatol Venereol. 2018;32(8):e328–e330. doi: 10.1111/jdv.14877 [DOI] [PubMed] [Google Scholar]
- 6. Decates TS, Velthuis P, Zarringam D, Bruin L, Schepers RH, van der Lei B. Upward trend in number of injectable treatments in the Netherlands 2016-2019. J Cosmetic Dermatol. 2021;20(9):3049–3051. doi: 10.1111/jocd.14339 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Schelke LW, Velthuis P, Kadouch J, Swift A. Early ultrasound for diagnosis and treatment of vascular adverse events with hyaluronic acid fillers. J Am Acad Dermatol. 2019:S0190-9622(19)32392-8. doi: 10.1016/j.jaad.2019.07.032 [DOI] [PubMed] [Google Scholar]
- 8. Stojanovič L, Majdič N. Effectiveness and safety of hyaluronic acid fillers used to enhance overall lip fullness: a systematic review of clinical studies. J Cosmet Dermatol. 2019;18(2):436–443. doi: 10.1111/jocd.12861 [DOI] [PubMed] [Google Scholar]
- 9. Abduljabbar MH, Basendwh MA. Complications of hyaluronic acid fillers and their managements. J Dermatol Dermatol Surg. 2016;20(2):100–106. doi: 10.1016/j.jdds.2016.01.001 [DOI] [Google Scholar]
- 10. Alam M, Kakar R, Nodzenski M, et al. Multicenter prospective cohort study of the incidence of adverse events associated with cosmetic dermatologic procedures: lasers, energy devices, and injectable neurotoxins and fillers. JAMA Dermatol. 2015;151(3):271–277. doi: 10.1001/jamadermatol.2014.2494 [DOI] [PubMed] [Google Scholar]
- 11. de Boulle K, Heydenrych I. Patient factors influencing dermal filler complications: prevention, assessment, and treatment. Clin Cosmet Investig Dermatol. 2015;8:205–214. doi: 10.2147/CCID.S80446 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Signorini M, Liew S, Sundaram H, et al. Global aesthetics consensus: avoidance and management of complications from hyaluronic acid fillers—evidence- and opinion-based review and consensus recommendations. Plast Reconstr Surg. 2016;137(6):961e–971e. doi: 10.1097/PRS.0000000000002184 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Chatrath V, Banerjee PS, Goodman GJ, Rahman E. Soft-tissue filler-associated blindness: a systematic review of case reports and case series. Plast Reconstr Surg Global Open. 2019;7(4):e2173. doi: 10.1097/GOX.0000000000002173 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Requena L, Requena C, Christensen L, Zimmermann US, Kutzner H, Cerroni L. Adverse reactions to injectable soft tissue fillers. J Am Acad Dermatol. 2011;64(1):1–34. doi: 10.1016/j.jaad.2010.02.064 [DOI] [PubMed] [Google Scholar]
- 15. Danysz W, Nowag B, Hengl Tet al. Can sodium thiosulfate act as a reversal agent for calcium hydroxylapatite filler? Results of a preclinical study. Clin Cosmet Investig Dermatol. 2020; 13:1059–1073. doi: 10.2147/CCID.S271760 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. DeLorenzi C. New high dose pulsed hyaluronidase protocol for hyaluronic acid filler vascular adverse events. Aesthet Surg J. 2017;37(7):814–825. doi: 10.1093/asj/sjw251 [DOI] [PubMed] [Google Scholar]