Demonstration and comparison of the combined efficacy of hyaluronidase and sildenafil citrate in the management of ischemia DEU to hyaluronic acid filler injections in rabbit ear models

Introduction and Objective: Hyaluronic acid fillers are widely applied in plastic surgery. Unintentional intravascular injections in the facial area can cause hyaluronic acid to progress retrogradely and lead to ischemia by occluding the retinal artery and causing embolism, or by applying external compression in perivascular application and thereby giving rise to complications such as end organ necrosis (blindness or skin necrosis) related to ischemia of the source artery. Reports of such complications are not uncommon in the literature. Ischemia of the retinal artery is a complication that requires urgent intervention as the retinal artery is an end-artery and the retina cannot withstand ischemia for more than a short duration. This complication, which develops in the source arteries that feed the facial area, can cause necrosis in the skin or in composite tissues like those in the nasal region. Development of such complication of arterial ischemia as a result of hyaluronic acid injection applied for aesthetic purposes is quite catastrophic. While there are not enough experimental and clinical studies in the literature, the reported treatment methods mostly consist of author recommendations. Despite the studies conducted on the modes of administration and the dosing of hyaluronidase, and how it combines with thrombolytic agents, a completely therapeutic outcome has not yet been concluded. No studies were found in the literature on vasodilator drugs that could further potentiate this efficacy, and all studies were conducted only for ischemia that would occur through embolization mechanism. The number of clinical and experimental studies in the literature do not suffice for devising an emergency treatment algorithm for vascular complications, for demonstrating the effectiveness of treatment modalities, or for making comparisons. In this study, we aimed to create an ischemia model through intravascular embolization and external vascular compression due to hyaluronic acid filler injections in rabbit ears and examine and compare the efficacy of hyaluronidase, sildenafil citrate and combined treatment with hyaluronidase and sildenafil citrate in two different ischemia models. We thereby aimed to contribute towards creating a treatment protocol according to the physiopathological mechanism. Materials and Methods: In our study we used 28 New Zealand rabbits with similar physical characteristics. The rabbits were divided into four groups of seven subjects each. A composite flap containing skin and cartilage in standard sizes based on the central auricular artery was prepared in each of the ears, and the 56 ears from 28 subjects were divided into eight groups of seven ears each. To create ischemia models, the central arteries of composite flaps in the right ears were embolized with intraarterial hyaluronic acid filler injection, and the central arteries of composite flaps in the left ears were embolized via external compression with perivascular hyaluronic acid filler injection. Thereby, two different ischemia study models were created in each subject. The rabbits in Subject Group 1 did not receive any treatment. Then, the effects on their right ears (Study Group 1E[mbolism]) and left ears (Study Group 1C[ompression]) were examined. The findings were noted as the results of the control group. Then Subject Group 2 was treated with hyaluronidase, Subject Group 3 with sildenafil citrate, and Subject Group 4 with hyaluronidase and sildenafil citrate. Then the right (E) and left (C) ears in each Subject Group were examined for the effects of their respective treatments. After four hours of ischemia study models were created and after two weeks of observation, indocyanine green fluorescence imaging was performed on the flaps. Blood supply to flaps were measured. After the experiment was terminated with euthanasia, the ears were amputated and subjected to histopathological examination. The obtained data were analyzed statistically on parametric and non-parametric scales. Results: As the experimental model was created, the flaps were seen to be pale due to ischemia. However, no necrosis was observed in Subject Group 1 during follow-up. At the same time, fluorescence imaging showed significant decrease in blood supply and decrease in flap sizes. Dimensions of the flaps were measured and noted at the beginning of the experiment and after the experiment. In histopathological examination, inflammation, fibroplasia, edema were evaluated and scaled. Fluorescence imaging data showed that sildenafil citrate enhanced the effect of hyaluronidase and reduced ischemia in both study models. Although sildenafil citrate alone did not reduce ischemia as much as intravenously administered hyaluronidase, sildenafil citrate increased blood supply in both models compared to the control group. Hyaluronidase and sildenafil citrate were more effective in maintaining potency in the embolism model. Flap contraction was seen to be more in the control group, and less in the treatment groups. Discussion: Vascular complications are, without doubt, the most feared side effects of filler injections. Whilst various treatment methods have been proposed to prevent or minimize the harm caused by hyaluronic acid-induced vascular complications, most are author recommendations and their efficacy have not been proven. In ischemia caused by embolization, a plug of thrombocytes and fibrin forms as a result of coagulation and aggregation around the hyaluronic acid and spasm occurs in the artery. Hyaluronidase alone is therefore insufficient. The thrombolytic agent will be helpful in resolving the ischemia. However, we believe that this approach would not have a similar effect on reducing the ischemia caused by external compression. Studies demonstrated that sildenafil citrate increased blood circulation in the skin, the orbit, and the retina. Besides being a vasodilator, it is also a neovascularization agent. We used sildenafil citrate in our study because of such effects as well as its vasodilator effect. In our study, we concluded that sildenafil citrate would enhance the efficacy of hyaluronidase in both ischemia models. Conclusion: Hyaluronidase is the main treatment in the management of embolism caused by hyaluronic acid filler injections and vascular complications caused by external compression. But it is not sufficient by itself because the process involves complex pathways. Sildenafil citrate can be used in combination with hyaluronidase as a maintenance treatment for the management of ischemia. We believe that the data obtained from our study will help to create a treatment algorithm for the management of ischemia complications that occur due to filler injections.