Comparative Efficacy Surgical Interventions Funny Meme

Soft-tissue filler injection is the second most commonly performed cosmetic procedure. ¹ As the procedure is relatively simple and can present immediate results, it is widely performed. Increasing popularity has led to a rise in its documented complications, such as skin necrosis, granuloma, and visual compromise. Vascular compromise by hyaluronic acid causes cutaneous ischemia by compression or embolization of the subdermal plexus, impeding blood flow. Cutaneous ischemia has been reported to be caused by filler-induced compression, but there are still controversies; for example, a recent report showed that it does not cause vascular occlusion. ² However, it is clear that arterial occlusion induces skin necrosis. ³ In patients who develop arterial occlusion following hyaluronic acid filler injection, the skin discoloration may become visible from within a few hours to up to 24 hours.

Hyaluronidases are enzymes that can depolymerize hyaluronic acid, leading to its degradation by hydrolysis; thus, they treat the complications that arise from hyaluronic acid filler injection, such as intra-arterial injection or utilization of excessive filler doses. Previous experimental studies have showed that hyaluronidase can pass through an intact arterial wall to hydrolyze hyaluronic acid filler emboli. ⁴ Several studies have proposed perivascular hyaluronidase injection as a possible treatment for impending skin and soft-tissue necrosis. ^5–7 However, current recommendations of hyaluronidase for prevention and management of arterial occlusion following filler injection are based almost exclusively on expert opinion and consensus reports, and its evidence-based protocol in the management of soft tissue remains undetermined. ⁸ Recently, high-dose pulsed hyaluronidase was reportedly used to treat arterial obstruction. ⁷ The protocol recommends injecting a high dose of hyaluronidase every hour during the 2 days immediately after onset of the ischemic event. The doses of hyaluronidase depend on the extent of skin involvement. Although we mostly agree with this protocol, there are still some issues that we believe need to be addressed before it is actually applied to clinical practice. First, what is being referred to as a high dose of hyaluronidase needs clarification. Second, the need for administering hyaluronidase at hourly intervals needs to be understood. The number of times the injections need to be administered and whether they can be administered more often must be clarified. This experimental study on rabbit auricular flaps aims to address these issues, based on our expert experience. To address the issues concerning hyaluronidase use in hyaluronic acid–induced complications, including appropriate dosage and timing, we induced an iatrogenic arterial embolism on a rabbit island auricular flap and investigated the optimal usage of hyaluronidase to treat the condition.

MATERIALS AND METHODS

Animal experiments were performed according to the good laboratory practice guidelines of the Centralbio Research Institute, Incheon, South Korea. New Zealand white rabbits (Samtako Biokorea, Osan, South Korea), weighing 2.5 to 3.0 kg, were selected. The rabbits were placed under intravenous anesthesia and monitored throughout the study period. Anesthesia was induced by intravenously injecting Zoletil 50 (Virbac, Carros, France) and xylazine (Rompun; Bayer AG, Leverkusen, Germany). Zoletil and xylazine were mixed in a 1:1 ratio and injected intravenously at a dose of 0.1 ml/kg. When the anesthesia had to be extended, an additional of one-half to one-third of the initial anesthetic dose was administered. Rectangular auricular flaps measuring 6 × 2 cm were designed with the central auricular artery as the long axis for both ears (Fig. 1). A full-thickness incision was made along the border of the perichondrium, but the proximal central auricular artery/vein was preserved. After the rabbit auricular flaps were elevated to minimize the effect of collateral circulation, the central auricular artery was revealed. We induced arterial filler occlusion with the flap elevated. Our preliminary study confirmed that it was almost impossible to cannulate the central auricular artery with the flap sutured back, and it was even more difficult to ensure filler occlusion.

Fig. 1.:

Rectangular auricular flaps measuring 6 × 2 cm were designed with the central auricular artery as the long axis for both ears.

A volume of 0.1 ml of hyaluronic acid filler (Chaeum Style No. 1; Hugel Inc., Chuncheon, South Korea) was injected into the central auricular artery at the proximal flap using a 30-gauge needle. [See Video (online), which shows 0.1 ml of filler being injected into the central auricular artery.] The filler is a 1,4-butanediol diglycidyl ether crosslinked monophasic filler with a concentration of 24 mg/ml. The elevated flap was then sutured back.

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Eighteen rabbit auricular flaps were used in this study. Three flaps were classified as controls, as they underwent filler-induced vascular occlusion without hyaluronidase injection after 24 hours of hyaluronic acid filler injection. For the remaining flaps, different doses of hyaluronidase were injected. Injection sites were four different points about 5 mm within the central auricular artery (Fig. 2). Hyaluronidase (1500 IU) (Liporase; Daehan New Pharm., Korea) was mixed with 6 ml of normal saline to make a 500-IU solution of 2 ml, a 250-IU solution of 1 ml, a 125-IU solution of 0.5 ml, a 100-IU solution of 0.4 ml, and a 75-IU solution of 0.3 ml.

Fig. 2.:

Hyaluronidase injection sites were four different points about 5 mm within the central auricular artery.

Fifteen experimental flaps were randomized into five groups. In group A, three rabbit auricular flaps were injected with 500 IU of hyaluronidase once. In group B, three flaps were injected with 250 IU of hyaluronidase twice with a 15-minute interval. In group C, three flaps were injected with 125 IU of hyaluronidase four times with a 15-minute interval. In group D, three flaps were injected with 100 IU of hyaluronidase five times with a 15-minute interval. In group E, three flaps were injected with 75 IU of hyaluronidase seven times with a 15-minute interval.

The progress of skin flap changes were observed and photographed at five time points: before the flap was elevated, 24 hours after the flap was elevated before hyaluronidase injection, and on postoperative days 2, 4, and 7. Flap fluorescence angiography was performed at four time points: 24 hours after the flap was elevated and before hyaluronidase injection; on postoperative day 2, which was the same as 24 hours after hyaluronidase injection; and on postoperative days 4 and 7. Fluorescein sodium (fluorescein sodium salt; Sigma-Aldrich, Inc., St. Louis, Mo.) at a dose of 15 mg/kg was injected via the lateral saphenous vein. The flap was photographed under 365-nm ultraviolet light with the Fluorescence-labeled Organism Bioimaging Instrument (NeoScience Suwon, South Korea) after 5 minutes. Zen Digital Imaging for Light Microscopy software (Carl Zeiss, Oberkochen, Germany) was used to calculate the fluorescence area on postoperative day 7. Data were statistically analyzed with R package version 3.4.2 software (R Foundation for Statistical Computing, Vienna, Austria; http://www.R-project.org). The difference in the mean fluorescence area among groups was analyzed using the Kruskal-Wallis test. The difference in the mean fluorescence area between two independent groups was analyzed using the Wilcoxon ranked sum test, and p values less than 0.05 were regarded as statistically significant.

RESULTS

All the rabbits were restored to normal activity and diet 2 hours after the surgery. Flap infection and wound dehiscence were not observed. All the control and experimental flaps demonstrated total occlusion after hyaluronic acid injection. Photographic and fluorescence images showed typical flaps in each group (Fig. 3). Our preliminary study showed that the auricular flap, which was elevated and sutured back without hyaluronic acid filler injection, survived completely (data not shown). Flaps of the control group showed severe skin necrosis, and their average fluorescence area (positive area/total area × 100 percent) was 37.61 percent on postoperative day 7. Group A was injected with a single high dose of hyaluronidase (500 IU). As we injected at four points near the central auricular artery, the amount of enzyme injected at each point would be approximately 125 IU of hyaluronidase. However, this treatment did not completely resolve the skin necrosis. Groups B and C responded better to treatment than did group A, while group D and group E did not show an improvement. The average fluorescence area was 74.83 percent in group A, 81.49 percent in group B, 88.26 percent in group C, 56.48 percent in group D, and 60.69 percent in group E on postoperative day 7. [See Figure, Supplemental Digital Content 1, which shows the progress of skin flap changes in each group. The control group and groups A, B, C, D, and E were observed and photographed at five time points: before the flap was elevated (Preop), 24 hours after the flap was elevated (1D), and on postoperative days 2, 4, and 7(2D, 4D, and 7D). Flap fluorescence angiography in each group was performed at four time points: 24 hours after the flap was elevated and before hyaluronidase injection; on postoperative 2, which was the same as 24 hours after hyaluronidase injection, and on postoperative days 4 and 7, https://links.lww.com/PRS/D994.] A significant increase in fluorescence was observed with all hyaluronidase intervention groups compared with the control group (p < 0.01). The average fluorescence area was significantly smaller in groups D and E than in groups A, B, and C (p = 0.0495). The fluorescence area was significantly larger in group C than that in group A (p = 0.495) and in group C than that in group B (p = 0.0495). There were no significant differences between groups A and B (p = 0.1266).

Fig. 3.:

The progress of skin flap changes was observed and photographed on postoperative day 7 (left). Flap fluorescence angiography was performed on postoperative day 7 (right). (Top row) Filler-induced vascular occlusion without hyaluronidase injection after 24 hours of hyaluronic acid filler injection was classified as the control. Three rabbit auricular flaps in each group were injected with hyaluronidase as follows (in 15-minute intervals in groups B through E): (second row) 500 IU once (group A); (third row) 250 IU twice (group B); (fourth row) 125 IU four times (group C); (fifth row) 100 IU five times (group D); and (bottom row) 75 IU seven times (group E).

DISCUSSION

We induced an iatrogenic arterial embolism in rabbit island auricular flaps and investigated the optimal usage of hyaluronidase to treat hyaluronic acid filler–induced occlusion. In this animal study, we found that a better prognosis could be obtained by administering repeated doses rather than a single dose of hyaluronidase, even when the single dose administered an equally sufficient amount of hyaluronidase.

Skin necrosis induced by soft-tissue fillers is a serious complication. There are several facial zones that are dangerous for filler injection, and an understanding of the vascular anatomy is needed in order to avoid arterial confrontation. ⁹ As there are several arterial variations, vascular complications can occur at any time after soft-tissue filler injection. Fortunately, hyaluronic acid filler can be dissolved to some extent by hyaluronidase, and the clinical course can be improved with this pharmacological intervention. When there are symptoms and signs indicating vascular occlusion after hyaluronic acid filler injection, hyaluronidase should be injected as soon as possible near the obstructed vessels. ¹⁰ [See Figure, Supplemental Digital Content 2, which shows cutaneous ischemia at the nasolabial fold. A 25-year-old woman was injected with 0.8 ml of hyaluronic acid filler at the nasolabial fold 24 hours earlier. Erythematous lesions were found on her forehead, nasal dorsum, cheeks, and nasolabial fold (left). These symptoms were associated with arterial occlusion, such as that of the angular, lateral nasal, dorsal nasal, and supratrochlear arteries. A hyaluronidase dose of 1500 IU was injected into her nasolabial fold, forehead, and nose, based on symptoms that the facial artery had been occluded by the filler (right), https://links.lww.com/PRS/D995.] Therefore, it is essential that physicians are aware of effective protocols of hyaluronidase flushing for vessels suspected of being obstructed.

Hyaluronidase may prefer degrading the body's natural hyaluronic acid rather than the foreign hyaluronic acid filler that has been injected, which is crosslinked to prevent its natural breakdown. ⁴ An enzymatic degradation of hyaluronic acid involves exclusive scission of glycoside linkages. ¹¹ Hyaluronidases begin to degrade hyaluronic acid upon injection at a rate depending on the tissue location and the proximity of the hyaluronidase to the occluded vessel. Massaging the area helps spread hyaluronidase along the areas of occlusion. ^{4 , 12}

There are more than 20 hyaluronidase products available. The unit dose of hyaluronidase commonly used in different countries varies. Vitrase (Bausch and Lomb, Bridgewater, N.J.), distributed in the United States, is 200 USP (1 IU = 1 USP). Hylenex (Halozyme, Inc., San Diego, Calif.), a purified human recombinant hyaluronidase product, is 150 USP. Three to four bottles are used to treat complications such as cutaneous ischemia or impending skin necrosis. In South Korea, however, products with 1500 IU per bottle are available. Therefore, one bottle might be sufficient for one treatment session. For example, when a 750-IU dose is injected, five ampoules with 150 IU per ampoule or half of a 1500-IU ampoule can be administered. While the former can be considered a relatively high dose, the latter can be considered a relatively low dose.

The hyaluronidase dosage required for an intervention is dependent on the size, the amount of crosslinking, and the hyaluronic acid concentration. In addition, a larger vascular embolic event caused by a filler requires a longer hydrolysis period. ¹³ Previous articles have suggested that 500 IU should be injected when arterial occlusion is suspected in the nasolabial fold based on clinical evaluation. ⁷ A hyaluronidase dose greater than 100 IU per each injection point and 500 IU in total in a single fully compromised area, such as the nasolabial fold, glabella, and nasal dorsum, has been considered a high dose in clinical practice. In our experimental model, a total dose of 500 IU was determined to be sufficient for the experimental flap occlusion site induced by 0.1 ml of hyaluronic acid filler. We designed experiments in which the total amount administered was the same but the number of repetitions was different, to investigate the effect of repeated administration of a high dose. Although the total administered dose was the same, the efficacy of single compared with repeated administration of hyaluronidase was different. Results of this experiment imply that repetitive injection may be required for effective flushing with hyaluronidase and to reverse filler-induced arterial obstruction, even if the single-pulsed dose is sufficient in quantity. However, groups D and E, in which 500 IU of hyaluronidase was divided into five and seven injections, respectively, showed extensive skin necrosis compared with groups A, B, and C. Group D was injected with 100 IU at four points a total of five times; thus, 25 IU was injected at each point. A previous study reported that at least 30 IU of hyaluronidase is needed to degrade hyaluronic acid filler in the subcutaneous tissue. ¹⁴ Perivascular injection might be needed at higher doses to pass through the arterial walls and degrade filler particles in the arteries. Perivascular injection of less than 25 IU of hyaluronidase once to each point degrades the occlusion to some extent; however, it may be insufficient to effectively degrade hyaluronic acid filler–induced arterial obstruction. Our results imply that there may be a minimum dose to induce effective perivascular action. When filler-induced occlusion is suspected, previous studies have recommended that high doses should be administered with an emphasis on the total dose only. We believe that it is possible to obtain a relatively significant effect with 100 IU of hyaluronidase at each injection point. The results of this experiment, which controlled the amount of hyaluronidase administered, indicated that significantly increased flap fluorescence area can be expected by repeating a dose of more than 30 to 50 IU of hyaluronidase at each point close to the affected artery.

In this experiment, the hyaluronidase administration time was designed to be 24 hours after filler-induced occlusion. Cutaneous ischemia is expressed 4 to 6 hours after filler injection. Patients start to report symptoms of necrosis approximately 24 hours after filler injection. We set the time as 24 hours in our experimental study because treatment is usually attempted to treat tissue ischemia damage in clinical cases at 24 hours after filler injection.

At the moment of injection, a significant portion of the hyaluronidase can be absorbed into the surrounding tissue, and it is not known how much of it is delivered to the obstructed blood vessels. Hyaluronidase is actively metabolized and deactivated by physiological inhibitors at a specific rate as soon as it is injected. Hyaluronidases differ in their catalytic efficiencies and are more active in acidic conditions. ¹⁵ In addition, hyaluronidase enzymatic activity depends on temperature; it is twofold higher at 37°C than at room temperature. Increasing amounts of hyaluronidase cause higher substrate turnover, illustrating the presence of higher enzymatic activities. ¹⁶

Noncompetitive inhibition is a type of enzymatic inhibition where the inhibitor reduces enzyme activity regardless of substrate binding. Crosslinking modifications can potentially increase resistance in enzyme degradation by preventing the enzyme from accessing the substrate. ¹⁷ In this case, hyaluronidase cannot easily break down the intermolecular bonds between hyaluronic acid macromolecules as it is blocked by the crosslinking of hyaluronic acid molecules. The crosslinking of hyaluronic acid in fillers causes noncompetitive inhibition of the hyaluronidase function. Consequently, the extent of inhibition depends only on the hyaluronidase concentration. ¹⁸

Higher hyaluronidase concentrations are far more effective in indirect diffusion, as they are resistant to the hyaluronidase inhibitor. ⁴ A hyaluronidase inhibitor, detected in mammalian circulation, was the first to be identified recently. ¹⁹ All tissues have different rates of antihyaluronidase activity, depending on the location and tissue type. ⁷ A previous study suggested that hyaluronidase loses its effect in the dermis and subcutaneous fascia within 3 to 6 hours after injection. ²⁰ Hyaluronic acid degradation is the rate-limiting step in several physiological and pathophysiological processes, ranging from embryogenesis to aging. ¹⁸ Patients with burns, septicemia, or shock have a rapid increase in circulating hyaluronic acid levels. Hyaluronic acid and its enormous hydration volume, occupying 10,000 times the volume of the original polymer, may be a naturally occurring intravascular volume expander to prevent circulatory collapse. The production of hyaluronidase inhibitors, as a part of the acute phase response, may suspend rapid hyaluronic acid degradation and prolongation of the rate of hyaluronic acid turnover. ^{19 , 21}

Furthermore, as it is difficult to effectively maintain the hyaluronidase dose required for flushing, we hypothesized that it would be worth considering repeated dosing for 1 hour to maintain the effective dose required to be delivered into the blood vessels. Although previous protocols have recommended repeated injections at 1-hour intervals, we set the dose interval at 15 minutes on the assumption that repeated treatment within at least 1 hour may be more effective at maintaining the hyaluronidase dose required for flushing. Repeated doses at 15-minute intervals were intended to simulate a continuous infusion of hyaluronidase. In this study, we could not compare the effectiveness of our protocol of injections at 15-minute intervals with injections at 1-hour intervals used in existing literature. However, repeated injections every 15 minutes were more effective than a single high dose. It is necessary to further study the differences in effectiveness of protocols with varying intervals between injections.

Several commercial hyaluronic acid fillers are now available, and each product has different molecular weights and crosslinking properties. The ease of dissolution of the hyaluronic acid filler depends on its rheological properties, crosslinking modification strategies, amount of crosslinking agent, and other manufacturing processes. ²² Differences in sensitivity to enzymatic degradation not only affect tissue residence time of the filler but also the speed at which the product is dissolved. Biphasic fillers, which have distinct particles, would be more susceptible to enzymatic degradation than monophasic fillers. ²³ Biphasic fillers might be easily destroyed because they contain smaller amounts of crosslinking agent. ^{17 , 24} The degradation time of the filler in this study is shown in Figure 4. Higher hyaluronic acid concentration and degree of crosslinking, along with a more cohesive nature of the filler, which creates a dense three-dimensional hyaluronic acid network, can contribute to greater resistance to enzymatic degradation. ²⁴ Hyaluronic acid fillers manufactured for deep dermal and subcutaneous injections generally have higher concentrations and elastic modulus, and tend to contain more crosslinking agents than those for superficial dermal injections. ²⁵ Even if the same amount of hyaluronidase is administered, the dissolving effect will vary depending on the nature of the filler. Therefore, when hyaluronic acid filler–induced vascular obstruction is caused by a relatively hard filler, a higher dose of hyaluronidase and repeated injections should be considered to degrade filler particles.

Fig. 4.:

Degradation time of the hyaluronic acid filler Chaeum Style No. 1. Chaeum Style No. 1 is a 1,4-butanediol diglycidyl ether crosslinked monophasic filler designed for superficial dermis injection. The concentration of hyaluronidase is 1 IU/ml. For comparison, the degradation time of Juvéderm Voluma (Allergan, Dublin, Ireland) is indicated.

CONCLUSIONS

Through our study on an animal model, we conclude that a better prognosis can be obtained by administering repeated doses—rather than a single dose—of hyaluronidase, even when the amount of the single administered dose is the same as that of hyaluronidase. Furthermore, when there is cutaneous ischemia or impending skin necrosis due to hyaluronic acid filler injection, it is recommended that hyaluronidase be injected as soon as possible and that a high dose of hyaluronidase be repeated at less than 1-hour intervals. Further studies are required to determine the effective dose and intervals for the treatment of vascular compromise following filler injections.

PATIENT CONSENT

The patient provided written consent for the use of her images.

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Source: https://journals.lww.com/plasreconsurg/fulltext/2020/04000/comparative_effectiveness_of_different.23.aspx

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