The Hyal dosage required depends on the indication (emergent vs nonemergent complication), location, volume, physical properties of the HAG to be dissolved, and patient factors [9,26]. The use of Hyal often involves a titration approach, where the practitioner assesses the response after each injection. Incremental adjustments of Hyal dosage are recommended—smaller doses and a gradual approach allow for fine-tuning, minimizing the risk of excessive filler degradation.

Vascular complications require larger doses than nonemergent (overcorrection, misplacement, and inflammatory reaction). Thinner skin (eg, lower lids and infraorbital areas) should be treated with lower Hyal doses. Larger filler volumes, larger particle size, higher concentrations of the filler, higher amount of cross-linking, and higher amount of G-prime contribute to increased durability of the filler requiring higher Hyal dosage for dissolution [9,26]. Also, monophasic (without distinct particles) HA formulations are more resistant to degradation than biphasic (particles suspended in gel) [26].

HA fillers have different physical properties that influence their degradation by Hyal in a time- and dose-dependent manner [21]. In an in vivo study using recombinant Hyal, Juvéderm Voluma required higher doses of Hyal than Restylane-L and Juvéderm Ultra for dissolution [11]. Therefore, Juvéderm Voluma may require repeat doses of Hyal for complete reversal.

A study by Rao et al [27] demonstrated Restylane (Galderma Laboratories) dissipated most and Belotero (Merz Pharmaceuticals) was most resistant to degradation. The authors showed that responses were similar for Vitrase and Hylenex, suggesting that these products can be used interchangeably. However, a subsequent study showed that Belotero was the fastest to degrade and Juvederm Voluma (Allergan) and Restylane Lyft were the slowest, with the authors concluding that a high concentration of HA, larger particle size, and increased cross-linking increase filler durability [9]. Jones et al [28] showed that Restylane and Prevelle (Mentor Corp) displayed greater sensitivity to ovine Hyal than Juvederm Ultra and contributed to the degradation resistance of Juvederm Ultra to higher HA content and level of cross-linking.

Drug interactions of Hyal should be considered. Salicylates, anti-inflammatories, cortisone, herbal meds, heparin, vitamin C, estrogens, and antihistamines make tissues resistant to Hyal [5,18]. One should consider a higher Hyal dosage or repeated injections in such cases. Therefore, having a thorough drug history before injecting Hyal is extremely important.

Regarding dosing, there are no accepted standardized guidelines. However, the rule of thumb for treating uncomplicated nodules is 5 iu Hyal for 0.1 mL HAG 20 mg/mL [16]. In the study by Zhang-Nunes et al [11] a cross-linked filler (Juvéderm Voluma, 20 mg/mL) required higher Hyal doses for dissolution, that is, more than 20 iu Hyal per 0.2 mL filler. In another study, in vivo degradation of cross-linked, highly cohesive HA fillers required 30 iu Hyal [29]. Woodward et al [30] recommended 30 iu to dissolve 0.1 mL. However, a study showed no statistical difference between using 20 or 40 iu Hyal in degrading 0.2 mL of various fillers (4-6 mg HA) [9]. Alam et al [10] showed that, although small Hyal doses (1.5-9 IU) can remove HA fillers, slightly higher doses often result in more rapid resolution.

Hyal dose for reversing overcorrection depends on the location and quantity of filler—in such cases, one may inject 15-30 iu in nasal or perioral areas, 3-4.5 in the periorbital area, 10-15 in the infraorbital area, and 1.5 in the lower [5]. However, even lower Hyal doses may be effective in reversing excessive augmentations. More resistant HAGs require higher Hyal doses of repetitive injections [21].

This section reviews the elective use of Hyal for complications such as the Tyndall effect, noninflamed nodules resulting from overcorrection or misplacement of HA filler, inflammatory nodules, and allergic or immunogenic reactions to HA filler (Table 2). It also details the emergency use of Hyal in managing vascular occlusion to prevent tissue necrosis and blindness from periocular emboli. We discuss Hyal dosing for such complications and present our experience with Hyal treatments.

When particulate HA fillers are inappropriately injected too superficially, a bluish discoloration (Tyndall effect) can result and may persist for a long time [1]. Treatment with 30-75 iu Hyal can be effective [34]—a smaller number (10-20 iu) may be used if a small amount of HA needs to be degraded [2]. This will often lead to complete resolution of the complication within 24 hours, although occasionally, a second Hyal treatment may be required [24]. The focus of the provider is on degrading the superficially placed filler. Also, Hyal dosage depends on whether the patient requests the filler to be completely removed or just eliminate the Tyndal effect [35]. The practitioner should follow up with the patient in 3-4 days to check whether additional Hyal is needed. Hyal may be used at any time and has been effective 63 months after the initial injection of HA [36].

Noninflamed nodules are typically firm, feel rubbery, and tend to be painless. They are not usually associated with redness or significant discoloration. Their incidence is unknown. Noninflamed nodules result from overcorrection, filler misplacement, or migration (Figures 1 and 2). HFUS imaging is a first-line tool to identify the filler, assess its size, and exclude a soft tissue neoplasm (peer-reviewed by Kroumpouzos et al [1]). It may also help identify severe distant filler migration. Treatment of noninflamed nodules is warranted if painful, aesthetically bothersome, or associated with prolonged edema (ie, malar edema for >4 weeks). Hyal is delivered to the skin and subcutaneous tissue by directly infiltrating the visible or palpable HA depot [21]. Massage is recommended to mix the enzyme with HA and promote filler degradation. One may treat with a low dose, that is, 5-15 iu Hyal, and reassess in 1 week. However, higher doses (up to 150 iu) have been reported as effective [21,25]. As mentioned above, the volume and properties of the filler to be dissolved should be considered when deciding the dose to inject. A prospective trial included 8 participants who received 3 injections with 0.2 mL HA, and after 3-5 days each site was injected with 10, 20, or 30 iu Hyal. There were no differences among Hyal doses [8]. However, the study is limited by the small size and not including higher Hyal doses (ie, >50 iu).

The location of the filler should be considered as areas with thin skin, such as the eyelids, require low Hyal dosage (1.5-3 iu). Injecting a low dose helps prevent the loss of the HAG treatment effect. A retouch of another 1.5-3 iu 2-3 days later can be considered. Precautions to prevent ecchymosis should be taken when injecting the eyelids and infraorbital areas, especially as Hyal has been reported to spread the ecchymosis in these areas [37]. One should use a thin needle (30 G or thinner) and a single needle insertion point that helps minimize tissue trauma from the injection.

To prevent suboptimal aesthetic outcomes, the injector should consider patient characteristics, choose an appropriate filler for the area to be injected, avoid overfilling, and inject with a knowledge of anatomy. Overfilling can result in nodule formation and filler migration. Still, asymmetries, nodules, and other contour irregularities can occur even when patients are injected by experienced providers. Hyal is an appropriate therapy for such complications caused by HA fillers. The dosage approach is like that detailed for noninflamed nodules above. One should consider the amount of filler that needs to be degraded and titrate the Hyal dosage according to the response. These authors have used 150-300 iu Hyal for such complications (Table 2).

Inflammatory nodules are often red and may feel warm to the touch. They can be associated with tenderness or pain. Inflammation may result from an immune response to the filler material, infection, or other complications [1]. Delayed-onset nodules (DONs) are usually inflammatory (ie, immune response to filler material), granulomatous (on histology), or related to infection or biofilm [1]. DON formation has a 0.5% incidence, a median time of onset of 4 months, and a median time to resolution of 6 weeks [38]. A subsequent retrospective study reported an incidence of 1% [39]. A skin biopsy and microbiologic testing should rule out granuloma formation and infection. A culture test of a draining or fluctuant lesion can aid in antibiotic selection. If an infection is suspected, oral antibiotic therapy should be administered, and the nodule should undergo incision and drainage if fluctuant. The American Society of Dermatologic Surgery recommended that noninflamed DONs without suspicion of infection might be treated initially with oral steroids for 1 to 2 weeks, rather than Hyal, should the retention of the aesthetic filler effect be desired [40]. The addition of antibiotics (doxycycline or minocycline) can be considered for anti-inflammatory and antimicrobial properties.

Regarding inflamed DONs, an expert panel recommended that high Hyal doses (ie, 500 iu every 48 hours until resolution) be administered after oral antibiotics have been tried for at least 2 weeks [41]. The panelists indicated that Hyal may break down the bacterial biofilm, thus facilitating the spread of infection; therefore, it should not be used as first-line therapy for inflammatory DONs. Another expert panel favored administering Hyal injection (30-300 iu) as first-line therapy with oral antibiotics [42]. Participating experts recommend a watchful approach of 48 hours to 2 weeks after starting antibiotic therapy, unless a more resistant HA (ie, Vycross) has been injected, in which case Hyal must be given as early as possible. Vycross technology has a 1% to 4% DON risk [40]. Highly cross-linked fillers may require higher doses and more sessions of Hyal for effective degradation due to their resilient nature. Early intervention with Hyal is preferred to prevent the development of more persistent complications. The above dose recommendations were made while also acknowledging that the Hyal dose depends on the size of the nodule, location (eg, tear troughs require a lower dose than midface), and filler properties [41,42]. The clinical practice supports injecting Hyal into the center of the nodule with a low gauge (18 or 21 G) needle to disrupt an encapsulated (filler) organization by allowing more penetrations [42]. Subsequent dissolution via Hyal with increasing dosages should be repeated after 2-3 weeks; however, Hyal injections should be limited to 2-3 cycles if there has been no response [42].

HFUS-guided injection can increase the likelihood of response of a nodule or granuloma to Hyal [16]. The inflamed nodule or granuloma has a “capsule” (ie, prominent chronic inflammatory and granulomatous reaction at the periphery); in such case, ultrasound can show in real time that the needle or cannula injecting the medication has penetrated the “capsule” before Hyal is injected [1].

Granuloma is a rare complication (0.01%-1%) of fillers and appears after a latent period, which can be several months to years postinjection [43,44]. Granulomas caused by HAs appear as cystic granulomas [45]. Encapsulation occurs at advanced stages, and histology shows palisaded granulomatous tissue mainly composed of giant cells and macrophages. Biofilm formation has been a suggested trigger [46]. Granulomas can be treated with Hyal dosed up to 150 iu [47]. Multiple Hyal sessions are often required. Granulomas with conspicuous fibrosis and abundant giant cells may not respond to Hyal. Still, most authors suggest using as first-line therapy high-concentration intralesional steroids, such as 20-40 mg/mL of triamcinolone or a combination of intralesional triamcinolone 10 mg/mL, 5-fluorouracil 50 mg/mL, and lidocaine [48]. Intralesional steroids interfere with the activities of fibroblasts, macrophages, giant cells, and collagen synthesis [45]. Intralesional steroids should be considered when inflammation is a significant component of the granulomatous reaction and 5-fluorouracil when there is excessive tissue growth associated with the granuloma. Treatment should be repeated every 3 to 4 weeks until resolution [48]. Surgical excision should be the last resort.

Most reactions to HA fillers are localized and manifest with edema, induration, and erythema at the injection site, pruritus, pain or tenderness, and eruption as early as a few days and as late as years after injection [49,50]. There have been no reports of type II or III reactions. Type I hypersensitivity reactions, such as localized angioedema, are uncommon as are type IV (delayed) reactions that are noted in less than 1% of cases [51]. Type IV reactions can manifest with painful erythematous nodules [50]. A delayed onset facial edema may be caused by type IV reaction and can develop several days to weeks after filler injection [52].

Type I reactions typically respond to oral antihistamines with or without intralesional or oral steroids [1,48,50]. Epinephrine should be administered in systemic reactions such as anaphylaxis or other severe cases. Providers should have an emergency kit containing epinephrine pens, oral steroids, and antihistamines in the treatment room [1]. Type IV reactions may not respond to antihistamines. Degradation of the filler depot with Hyal can be considered when an allergic or hypersensitivity reaction does not improve with a course of antihistamines or systemic corticosteroids. If the reaction is considered moderate or severe, oral corticosteroids should be taken before Hyal use to manage or prevent the potential initial worsening of symptoms due to increased antigens as the HA is broken down [52]. Hyal can be an alternative treatment for delayed facial edema as it does not carry the risks associated with prolonged systemic steroid treatment [52]; however, multiple treatment sessions are typically required, and Hyal can lead to at least partial loss of the filler treatment effect that may not be acceptable by the patient. COVID-19 vaccines have been reported to cause delayed reactions to HA fillers [53]. Two cases of COVID-19 vaccine-triggered delayed inflammatory reaction to HA filler were treated with Hyal [54,55].

The incidence of impending necrosis following dermal filler treatment was estimated at 0.001% (1 in 100,000 cases) in 2013 [56] and increased to 0.009% in 2020 [57]. Vascular occlusion associated with filler injection may be due to intravascular embolism, extravascular compression, and vascular spasm [1]. Pain is the earliest symptom, and coolness, blanching (immediate; may be transient), and livedo pattern are the earliest signs (Figure 3) [57]. A delayed capillary refill (normal, 1-2 seconds) is noted within minutes. A blue-gray appearance follows within tens of minutes to hours due to deoxygenated blood in the tissue. Skin breakdown is noted within days, and the following repair phase lasts days to weeks [57,58].

Vascular compromise requires immediate treatment. However, there is no consensus regarding the Hyal protocol in this complication [7]. Hyal should be administered as soon as possible, optimally within 4 hours [5]. The number of Hyal sessions depends on the severity of the complication and how quickly the intervention occurs. An animal study showed a significant reduction of the ischemic areas within 4 hours of Hyal treatment but no improvement after 24 hours [59]. In a series of patients with impending nasal skin necrosis related to the nose and nasolabial fold augmentation with HA fillers, full resolution of the complication occurred when Hyal treatment was administered within 2 days [60]. In a systematic review, Hyal failed to eliminate the large area of necrosis but played a moderate role in earlier recovery in limited necrosis [61].

A high-dose (total of 450-1500 iu in up to 4 Hyal cycles) pulsed Hyal protocol should be adopted [18,21,62]. Delorenzi suggested a simplified determination of Hyal dosage in the high-dose protocol considering the size of the ischemic area [62]. For a “single area” (eg, one-half of the upper lip) low-volume vascular event (by definition, <0.1 mL of filler embolus) Hyal dose should be about 450 iu; if a second area is affected, such as the nose, then the dose would be 900 iu. Hyal should be infiltrated diffusely into the ischemic tissues, including the vessel’s course. Perivascular Hyal will permeate vascular walls. Delorenzi showed ex vivo that cross-linked HA contained within the intact artery is susceptible to hydrolysis by Hyal found outside the vessel in its immediate surroundings [63]. Hyal injections should be followed by warm compresses and vigorous massage of the areas to improve drug diffusion and enhance blood flow. Then one should observe and reassess skin color and capillary refill after 60 minutes [62]; however, other authors recommend assessment every 15-20 minutes [24]. If vascular compromise persists, repeat Hyal treatment for up to 4 cycles should be administered [18,62]. Daily follow-up should occur, and more Hyal treatment performed until there is a satisfactory resolution. If treatment is completed within 72 hours of the onset of ischemia, success is possible [62].

An important study by Schelke et al [6] showed that when Hyal is injected under HFUS guidance, lower dosages (35-50 iu) than those in current “high dose” protocols (>500 iu) can be used. This is due to the higher accuracy of Hyal injections performed under HFUS guidance. Also, the study showed that a single Hyal injection yields a full resolution of the vascular complication compared to hourly injections over several hours in the current, high-dose protocol.

The patient should be kept under observation in the clinic for any adverse reactions—when anaphylaxis to Hyal occurs, it is usually within minutes, but there have been cases of delayed onset [18]. All patients should be warned about allergic or anaphylactic response symptoms and instructed to seek medical attention promptly.

This is a rare but severe complication. A literature review by Beleznay et al [64] identified 146 cases in 2019. In recently reported cases, the nasal region (56.3%) was at the highest risk, and HA filler was the most common (81.3%) cause of this complication. Blindness due to periocular embolism of HA is instant and associated with excruciating ocular pain. The mechanism of action of blindness after filler injection is thought to involve intra-arterial injection of filler followed by subsequent retrograde embolization into the ophthalmic artery system [64]. The retinal circulation needs to be restored within 60 to 90 minutes if the retina is to survive. Blindness is an emergency; the patient should be transferred immediately to the nearest hospital ophthalmology department [65].

Currently, there is no evidence-based, accepted standard of care for treating visual compromise caused by filler [64]. Treatments that have been used vary widely and successful attempts are rare. If an HA filler was used, Hyal should be injected into the skin at the injection site and along the path of anastomosing arteries. Retrobulbar Hyal (RBH) injection (150-200 iu in 2-4 mL of diluent) into the inferolateral orbit should be considered by practitioners who have appropriate experience and competence while waiting for an ambulance [66]. A total of 3 cases experienced partial or complete vision recovery after treatment with RBH, although only 1 case directly attributed success to the RBH [64]. In that case, full vision restoration was achieved with Hyal (450 iu as retrobulbar injections and 300 iu to surround the supraorbital and infraorbital foramina) in a patient who received HA fillers in the midface [67]. RBH did not improve vision in other reports [68,69]. Zhu et al [68] failed to show any improvement in visual loss following 1500 to 3000 iu RBH in 4 patients. The authors indicated that Hyal is ineffective at recanalizing the retinal artery occlusion or improving the visual outcome after 4 hours of the onset of blindness.

However, other authors have challenged the RBH approach because Hyal did not demonstrate the ability to cross the dural sheath of the optic nerve and reach an occlusion of the central retinal artery [70,71]. In a cadaver model, Hyal could not cross the optic nerve’s dura into the space where it could bathe the central retinal artery [70]. Most importantly, hardly 5 mm of the ophthalmic artery is exposed in the orbit that is not covered with dura. An alternative approach was suggested, injecting into the supraorbital or supratrochlear artery. In the supraorbital method, Hyal is injected into the supraorbital artery in the supraorbital foramen [72]. The supraorbital approach is less invasive than the retrobulbar and can be effective in cases where the blood vessel blockage is closer to the skin’s surface. This technique has resulted in 2 cases of immediate vision recovery [72,73]. This approach requires no special skills compared to retrobulbar injections which are technically difficult procedures even for a competent ophthalmological surgeon. Still, other authors have challenged the feasibility and practicality of the supraorbital approach as the supraorbital and supratrochlear arteries are difficult to cannulate [64,74]. However, ultrasound guidance may facilitate this approach [75].