Management of complications associated with the use of hyaluronic acid fillers. Recommendations of the Aesthetic Dermatology Section of the Polish Dermatological Society

Introduction

The most common treatments in the field of aesthetic dermatology and broadly understood aesthetic medicine include treatments with the use of fillers, which are a popular non-surgical method of face rejuvenation. According to data from the American Society for Aesthetic Plastic Surgery (ASAPS), in 2016, the number of filler treatments in the United States was 2.7 million, more than half of which were performed with the use of hyaluronic acid (HA) preparations. For comparison, about 600,000 such treatments were performed in 2000 [1, 2]. However, referring to the information of the International Society of Aesthetic Plastic Surgery (ISAPS), almost 3.3 million treatments with HA were performed in 2017 [3].
Similarly, the number of treatments in Poland increases from year to year, however, there are no accurate statistics. The lack of precise data is connected with the carrying out of treatments in various treatment rooms, not only medical ones. For many people, HA injections are considered very safe and the effects are predictable. Therefore, on the one hand, the widely recognised reversibility of the effects of HA fillers and the growing variety of approved applications and formulations of these products increase their popularity, and on the other hand, there are also numerous undesirable effects and complications. About 0.01–1% of HA administrations result in complications [4]. The hypersensitivity reactions to HA fillers occur in less than 0.15% of cases [5].
Each HA used has its own unique composition, specific application profile and should be used according to the manufacturer’s recommendations. Despite the best techniques and knowledge of anatomy, undesirable symptoms and complication still can be observed, and their number increases with the number of treatments performed. The injection technique should be based on the type of product, quantity and area of injection. A perfect knowledge of the anatomical areas where individual fillers are best suited is crucial for preventing adverse events. The high-risk areas or hazard zones cover especially the following area: forehead, nose, nasolabial folds, mainly the upper 2/3 of the area, temples, upper lip and eyeball area (fig. 1) [6–8].

Complications of hyaluronic acid

Hyaluronic acid is considered to be the safest preparation used to correct static wrinkles. Hyaluronic acid is a polysaccharide commonly found in mammalian skin and connective tissue. The material of the HA gel matrix acts as a scaffolding for binding structural proteins such as collagen and elastin. From a point of view of safety, HA fillers have several advantages over other fillers: they have better lifting properties (less volume is required to get a lift in the middle of the face), better durability and no requirement to test for skin allergy, and the fact that the effects of HA fillers can be reversed with the use of hyaluronidase. An additional safety-related advantage of HA is the fact that over time they undergo natural degradation by the organism [9].
Undesirable events after its application are rare. The increase in the number of such procedures also results in an increase in the number of complications and adverse effects, especially as these procedures are performed both by unauthorised persons and in inappropriate conditions.
Complications may be related to:
incorrect injection technique,
lack of asepsis of the procedure,
the body’s reaction to the presence of a foreign body,
anatomical variations.
The majority of complications can be reduced or completely eliminated by maintaining sterile conditions and using the proper injection technique [10]. Then the question is, how can we safely perform HA injections? Good knowledge of anatomy is essential. It seems simple to make an aspiration test, but such a test can be misleadingly negative. Aspiration with a syringe of HA with a 12G needle sometimes takes several seconds for blood to appear. If the syringe is equipped with a 21, 23, 26, or 30G needle, it may produce a definitely misleading result, thus asserting the doctor that it is not in the vessel. Injections with thin cannulas, such as 27G, can be dangerous as the cannula can pierce the vessel as well.
Currently it is recommended to administer HA using 25G or thicker cannulas. Most authors recommend administering the substance in small amounts of 0.1ml per passage and relatively slowly [11–13].
Early diagnosis of a complication or adverse effect largely prevents permanent defects. Depending on the time of post-HA administration complications, we can distinguish between early complications that occur immediately or up to 3-5 days after administration and late complications that occur even after several weeks, months or years [9, 14].
A more accurate breakdown would be to separate two groups of complications:
I. Complications following non-vascular administration of HA:
1) nodules,
2) granulomas,
3) chronic oedema,
4) Tyndall effect,
5) infections,
6) biofilm.
II. Complications following vascular administration of HA:
1) ischaemia/necrosis:
a) partial,
b) total,
2) blindness/visual disturbances [15, 16].

Nodules

Nodules are early complications following too shallow (e.g. intradermal) administration of HA or due to inappropriate selection of the filler for a particular patient and surgical area. They usually occur up to 4 weeks after injection, they are firm, limited, remain the same size until they are absorbed, treated or removed. In some cases, a massage, puncture and mechanical extrusion of acid or an injection of 5–150 IU/1 ml of hyaluronidase is sufficient to eliminate the nodule. Most authors recommend upper doses of hyaluronidase [10, 14, 17, 18].

Granulomas

Granulomas appear as a defensive reaction to the foreign body, several weeks, months or even years after the treatment. The cause of lesions is unknown. Sometimes lesions occur during viral or bacterial infection that act as a stimulus, causing the reactivation of macrophages to trigger a sudden reaction to the foreign body. There are also theories stating that this may be a secondary response to the contamination associated with the fermentation process. They may be occur at all points of filler application, are of different sizes, increase in size, and sometimes subside spontaneously. In order to eliminate granulomas we can use combinations of glucocorticosteroid – triamcinolone and 5-fluorouracil in the ratio of 50 : 50. Such treatments are repeated every 4–6 weeks. In case of lack of improvement – excision of lesions is recommended [10, 16, 19].

Chronic oedema

The chronic oeadma lesions usually occur in the orbital area. The oedema itself may be related not only to the hydrophilic nature of HA, but sometimes it may be a type IV hypersensitivity reaction. Lesions may persist for many weeks, sometimes up to complete biodegradation of the substance. Oedema is reduced after massages, use of arnica creams and antihistamines. In case of chronic oedema, a hyaluronidase dose of 5–50 IU/1 ml can be administered [8, 9, 20].

The Tyndall effect

The Tyndall effect is characterised by a bluish colour in the orbital area after the administration of hyaluronic acid. It is usually caused by a too superficial administration of acid or by the migration of the substance. It is more common in people with thin skin and fair complexion [12, 21].

Infections

Bacterial infections, mainly streptococcal or staphylococcal infections, can occur as a result of a discontinuity of the skin. They may result from inadequate pre- or post-procedure asepsis as well as the use of contaminated preparation. Changes occur within a few days or within weeks in the case of biofilm. They are typical of inflammatory changes: erythema, swelling, hardening nodules, soreness or tenderness of the area. Treatment is dependent on the severity of the disease process.
Topical and/or general application of antibiotics with broad spectrum and high skin penetration (tetracycline, doxycycline, clindamycin) is recommended. In severe cases, it is recommended to incise the lesion to remove the purulent content and to perform inoculation and targeted antibiotic therapy [10, 15, 18, 22].

Biofilm

The role of biofilm with respect to skin fillers is currently the subject of discussion by many authors. This diagnosis should be taken into account in case of such symptoms as pain, hardening, erythema, swelling occuring after a few weeks at the site of injection. Classic bacterial cultures do not often reveal the presence of bacteria. The most common strains forming the biofilm include:
Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus viridans, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Pseudomonas aeruginosa. The complex structure of biofim is the cause of their high resistance to various bactericidal agents, including antibiotic resistance [10, 22–24]. The treatment is complicated and long. According to the recommendation of most authors, a thick needle puncture and drainage of the contents should be performed and hyaluronidase should be administered, depending on the extent of the lesion, at a dose of 15–30 IU twice a week for 2–3 weeks. Broad spectrum antibiotics such as ciprofloxacin 500 mg twice daily with clarithromycin 500 mg twice daily or moxifloxacin 400 mg twice daily with clarithromycin 500 mg twice daily for 3–6 weeks are recommended [25, 26].

Vascular complications

The prevalence of vascular disorders remains unknown, however, according to the authors, such a complication may occur even in 3 out of 1000 procedures involving HA. Some recommended injection techniques may minimize the arterial filler injection, but no technique is 100% effective [12, 14]. The most common vascular complications occur in the forehead, nasolabial fold, nose and temple area as a result of the administration of a filler to the facial, labial, upper, angular, supratrochlear and supra-orbital arteries, superficial temporal artery and its branches: zygomatico-orbital and frontal (figs. 2 A, B) [4, 15, 27]. Vascular complications may cause skin necrosis, persistent ophthalmoplegia, permanent loss of unilateral or bilateral vision and stroke [13, 17, 18].
There are three hypotheses regarding pathophysiology associated with ischemia. One of them is vascular compression which refers to high HA pressure on the vessel. Another is the vasoconstriction associated with the tension of muscle layers in the walls of blood vessels in response to a mechanical stimulus. The last one is associated with the occurrence of HA as a embolic material in the lumen of the vessel at the site of injection and the possibility of its migration to distant places. This happens when the material is injected by arterial means or when the vessel is damaged during injection and HA is injected in a farther area but passes back through a tunnel made with a needle or cannula (fig. 3) [7, 8, 27, 28].
Ischemia caused by external pressure or vasoconstriction is relatively simple and quick to treat. Sometimes they appear even a few hours after the injection and exhibit a typical marble-like appearance and pain. After hyaluronidase administration, the pain or pressure sensation usually disappears quickly, while marbling may remain on the skin for up to 2–3 weeks – gradually decreasing, of course [21, 29, 30]. The HA embolic material in the vascular lumen causes immediate frosting effect [31]. If the physician’s reaction is instantaneous and the embolism is small compared to the lumen of the vessel, the reaction can be completely reversible with the vessel regaining its patency. If the physician does not notice or recognise the frosting effect, the patient starts to feel pain and pressure after a few hours. The administration of hyaluronidase is always absolutely recommended even after a few hours or a few days. If there is no immediate reaction and hyaluronidase is not administered, irreversible complications may occur, such as for example tissue necrosis and, in the most severe case, blindness [31–33].

Partial vessel patency impairment

Occurs when the embolism material does not completely close the vessel light. This can be recognised when we notice a slight pinkishness after a short massage of the frosty area [15, 30, 32].

Total vessel patency impairment

This complication manifests itself in typical frosting (confluence), marbling and pain in the injection area. It is extremely important for the physician to take appropriate steps, because untreated, it may lead to skin necrosis [30, 32, 33].

Loss of vision

Vascular embolism occurs when the injected material shifts from the distal to the proximal artery of the retina, causing sudden, tearing pain, visual impairment, blindness and further tissue necrosis.
This is one of the most serious complications that can lead to permanent disability, especially in the absence of appropriate treatment. In the literature review, there are not many reliable reports concerning saving vision after its loss due to HA treatment. The procedure is to prevent further complications, e.g. ischaemic stroke [12, 34–37].

Hyaluronidase

It is an enzyme with a molecular weight of 60 kDa. It acts at the site of administration, causing hydrolysis of HA by separating the 1.4-glucosamine bond between C1 of the glucosamine molecule and C4 of the glucuronic acid. Hyaluronidase does not penetrate the blood–brain barrier. There are no large randomised studies on its use in aesthetic medicine and the available knowledge is based on a literature review and practical guidelines from the authors. The use of off-label hyaluronidase in aesthetic medicine was approved by the Food and Drug Administration (FDA) [38, 39].
Hyaluronidase is commercially obtained from sheep or bovine testicles, therefore there is a risk of transmission of a prion disease if the hyaluronidase comes from an unknown source [40]. The first administration of hyaluronidase dates back to 1951, when after adjuvant administration with procaine during local anaesthesia the beneficial effect was obtained [41]. In 1994, Clark and Mellette described the effect after simultaneous administration of hyaluronidase with local anaesthesia during 72 surgeries performed during one year. They demonstrated increased tissue separation during treatments due to reduced tissue oedema [42]. Wohlrab et al. on the other hand, in their study of 44 patients, observed that hyaluronidase combined with lidocaine increases the efficiency and area of local infiltration anaesthesia [43].
After the administration of hyaluronidase, it is immediately dispersed in the tissue and then it quickly returns to its initial state. The time of working of hyaluronidase depends on the area of administration. Immediate effect occurs after contact with the substrate, and its activity time in the skin usually lasts 24 to 48 hours, while in the eye area 60 to 112 hours.
After intravenous administration, hyaluronidase is immediately inactivated and the inactivation mechanism is unknown [44].
Use of hyaluronidase in medicine approved by the FDA:
1) addition to saline solution - subcutaneous irrigation in elderly people,
2) increased absorption of drugs administered subcutaneously,
3) elimination of harmful effects of injected drugs (lidocaine, bupivacaine),
4) preventing the harmful effects of extravascular administration of drugs (antibiotics, oncological drugs),
5) urography – improvement of resorption of contrast agents [44].
Off-label indications for hyaluronidase:
1) treatment of hypercorrection after HA administration,
2) treatment of granulomas of foreign body type,
3) treatment of embolism/necrosis after HA administration [44].
The first use of hyaluronidase in aesthetic medicine took place in 2004 in the treatment of overcorrection caused by improper administration of hyaluronic acid. At that time, 75 IU of hyaluronidase (Lee Pharmacy, Inc., Fort Smith, AZ, USA; 50 IU/ml) and 1.5 ml of 0.5% lidocaine with epinephrin were used thus reducing 90% of irregularities, nodules and overcorrection within 24 hours [45].
There are still no fixed guidelines for the dosage of hyaluronidase in overcorrection/HA shifts, due to the fact that various HA preparations show different susceptibility to degradation after hyaluronidase administration. On the basis of 30 cases described with the use of hyaluronidase, it has been shown that HA substances using VYCROSS technology are 50% less sensitive to enzymatic degradation by bovine hyaluronidase than other acid preparations. It is believed that in the treatment of facial overcorrection, the efficiency can be achieved using 30–150 IU hyaluronidase per 1 ml HA [46]. In the eye area, the authors recommend small doses of 5–15 IU with possible supplementation of the treatment with the same doses after another 2 weeks [44].
There are different hyaluronidase preparations available on the market demonstrating diversified activity in relation to various HA preparations [47, 48]. Hyaluronidase is also used to treat nodules and granulomas. In such cases, it is recommended to administer 15 to 150 IU hyaluronidase intralesionaly, control after 2 weeks and further hyaluronidase injections depending on the clinical condition. In the risk of necrosis, the authors recommend high doses of hyaluronidase from 500–1,000 IU administering the preparation at the depth of 3–4 mm in the amount of 0.3–0.5 ml per injection point [48–50].
Vascular embolism after HA administration is one of the most serious complications and requires large amounts of hyaluronidase – from 1500 IU. It is believed that the best result is obtained after hyaluronidase administration up to 4 hours after HA injection [51, 52].
Hyaluronidase may cause both immediate and delayed allergic reactions [46]. The reactions described after hyaluronidase administration concern < 0.1% of patients treated and include: erythema, pruritus, treated area oedema, urticaria, angioedema.
Experts' opinions on hyaluronidase allergy testing are divided. Kirby et al. recommend intradermal administration of 0.02 ml (3 IU) hyaluronidase and reading the test after 5 minutes. The presence of wheal response, together with accompanying erythema at the site of administration within 5 minutes after injection is interpreted as a positive reaction. According to the authors, the presence of erythema or vascular spot alone should be considered a negative reaction [51].
Allergy testing is justified for the treatment of overcorrection or nodules and granulomas, as well as the Tyndall effect. In the risk of necrosis, hyaluronidase should be administered as soon as possible; there is no time to perform the test.
Relative contraindications for hyaluronidase administration include:
1) patients with hymenoptera venom allergy - risk of cross reactions,
2) patients allergic to bovine collagen,
3) multiple allergy [52].
The following hyaluronidase preparations are available in Poland:
1) DermaQual-Disolvidase – Hialuronidaza (1500 IU) – powder to be dissolved in 9 ml of saline solution;
2) Liquid hyaluronidase – ZIMOJAL (5 ml) – ready solution 0.05 IU/ml;
3) Hyaluronidase – Liporase (1,500 IU) – powder to be dissolved in 3 ml of saline solution;
4) Desinfiltral – hyaluronidase (1,500 IU) powder to be dissolved in 5 ml of saline solution;
5) Hialuronidase MesoMedica (150 IU/1 ml) – 10 ml.

Recommended treatment schemes in case of complications

1. Nodules:
a) injection site massage;
b) an attempt to mechanically remove the administered HA by puncturing the injection site and/or squeezing out the material;
c) administration of hyaluronidase preparation in doses of 5–150 IU per 1 ml of previously administered hyaluronic acid; the authors recommend doses in the upper range; d) control appointment and eventual repeated administration of hyaluronidase the next day [14, 18, 38, 46, 48].
2. Granulomas:
a) administration of triamcinolone at the dose of 40 mg/ml or 5-fluorouracil at the dose of 50 mg/ml; both preparations can be administered simultaneously in a 50 : 50 ratio and the treatment can be repeated every 4–6 weeks ( the use of both preparations is off-label);
b) in case of no improvement – excision of lesions [10, 16, 19].
3. Chronic oedema:
a) injection site massage;
b) application of arnica cream and antihistamines in accordance with the Summary of Product Characteristics, e.g. administration of loratidinum in a dose of 10 mg twice a day; administration of drugs until the lesions recede;
c) in case of prolonged oedema – administration of hyaluronidase preparation in doses 5–50 IU/1 ml of previously administered HA [8, 9, 20];
4. Tyndall effect:
a) injection site massage;
b) an attempt to mechanically remove the administered HA by puncturing the injection site and/or squeezing out the material;
c) administration of hyaluronidase preparation in doses 5–150 IU/1 ml of previously administered HA; the authors recommend doses in the upper range;
d) control appointment and eventual repeated administration of hyaluronidase the next day [15, 21, 46].
5. Infections and biofilm:
a) an attempt to discharge the contents in the case it is liquid and ordering culture thereof;
b) administration of hyaluronidase at a dose of 150–200 IU;
c) if bacterial growth from the culture is demonstrated and biofilm is reasonably suspected, a broad-spectrum antibiotic must be administered for at least 3–6 weeks; a long period of antibiotic therapy is suggested; examples of preparations: ciprofloxacin 500 mg twice a day together with clarithromycin 500 mg twice a day or moxifloxacin 400 mg twice a day together with clarithromycin 500 mg twice a day;
d) if there is no improvement, referral to the hospital to administer vancomycin [15, 21, 23, 24, 26]. In case of infection, glucocorticosteroid administration should be avoided.
Difficult to treat biofilm may also result from the presence of rheumatic and autoimmune diseases, so it is recommended to perform general and specific tests, depending on the individual case.
6. Partial vessel patency impairment: a) performing an intradermal test using hyaluronidase; waiting for at least 5 minutes for its results [50, 51] with special caution in persons declaring an allergic reaction to hymenoptera venom. It should be remembered to have an anaphylactic emergency kit in the medical room;
b) administration of acetylsalicylic acid at a dose of 600 mg;
c) administration of 400 IU of hyaluronidase in several punctures every 3–4 cm into the ischaemic region. It is recommended to administer hyaluronidase using a needle or 25G cannula;
d) use of warming compresses;
e) control after 1 hour; in the case of visible concussion and/or pain, point c should be repeated;
f) control after 6 hours; in the case of visible concussion and/or pain, point c should be repeated;
g) control appointment on the following day; in the case of visible concussion and/or pain, point c should be repeated until concussion and/or pain are completely eliminated [22, 34, 38]. The use of nitroglycerin is not recommended due to its ability to constrict vessels at longer intervals [53, 54].
7. Total vessel patency impairment:
a) in severe cases, due to possible major complications caused by delayed implementation of the patient’s treatment, the intradermal test with hyaluronidase may be waived; great caution should be exercised with people declaring an allergic reaction to hymenoptera venom; it should be remembered to have an anaphylactic emergency kit in the medical room;
b) administration of acetylsalicylic acid at a dose of 600 mg;
c) administration of 1000–1500 IU of hyaluronidase or more in several punctures every 3–4 cm into the ischaemic region; it is recommended to administer hyaluronidase using a needle or 25G cannula;
d) use of warming compresses;
e) control after 1 hour; in the case of visible concussion and/or pain, point c should be repeated;
f) control after 6 hours; in the case of visible concussion and/or pain, point c should be repeated;
g) control appointment on the following day; in the case of visible concussion and/or pain, point c should be repeated until concussion and/or pain are completely eliminated;
h) administration of 400 mg doses of penthoxyphilin twice a day for at least 2 weeks [29, 34, 38].
8. Loss of vision.
In the case of loss of vision caused by HA treatment, we must remember to hand the patient over to the ophthalmological emergency department as soon as possible. There is a principle of the golden 90 minutes counted from the time of performing the treatment. Call for an ambulance.
The following actions shall be taken when waiting for the ambulance arrival:
a) administration of a single hyaluronidase dose of 1000–1500 IU in the area of injection;
b) administration of acetylsalicylic acid at a dose of 600 mg;
c) administration of 2–3 drops of 0.5% timolol solution to the blind eye;
d) inducing hypercapnia in the patient (e.g. by breathing into a bag);
e) performing a firm eyeball massage;
f) retrobulbar administration of 1500 IU of hyaluronidase – only for ophthalmologists or physicians experienced in the scope of this procedure [6, 35–37];
g) handing the patient over to the ambulance team, notifying them about the need to carry out the procedure of retrobulbar hyaluronidase administration in the ophthalmological emergency department and equipping the patient with a hyaluronidase ampoule.

Conclusions

Treatments with the use of HA are relatively safe for the patient, provided that they are performed by a qualified physician and appropriate procedures are applied, as well as tested preparations are used. The total percentage of complications does not exceed 1%. Complications after HA treatments include vascular and non-vascular complications. Vascular complications are particularly dangerous due to the occurrence of an impaired vessel patency, which can lead to skin necrosis or even loss of vision. One of the main therapeutic actions in most of the complications presented in the publications is administration of appropriate amount of hyaluronidase preparation to the patient. It is crucial for doctors and their patients to know the treatment patterns and to implement appropriate treatment in case of specific complications as soon as possible (fig. 4).

Conflict of interest

The article was prepared by the Aesthetic Dermatology Section of the Polish Dermatological Society owing to the educational grant of Galderma Polska Sp. z o.o.

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