Hyaluronic acid filler‐induced vascular occlusion—Three case reports and overview of prevention and treatment

Vascular occlusion induced by hyaluronic acid injections is rare, but can lead to severe adverse events, including necrosis, blindness, and cerebral infarction.

HA fillers involve injections, resulting in lower risks and faster recovery.According to data from the American Society for Aesthetic Plastic Surgery, the number of HA injections increased from 592 930 in 2015 to 749 409 in 2019, an increase of 26.4%. 1 HA offer benefits like sustained volume, biocompatibility, biodegradability, viscoelasticity, and posttreatment correction ease. 2 Typical applications include addressing tissue loss, aging wrinkles, and folds, including cheek and chin enhancement, tear trough correction, and lip augmentation. 3HÀ injections have increasingly been seen by plastic surgeons as the preferred cosmetic method, and they are also the top nonsurgical treatment choice for young women.Although HA injections are generally safe, with a vascular complication rate between 0.001% and 0.005%, 4 severe adverse events related to HA injections occur occasionally due to their widespread use.Minor and self-limited complications are relatively common, including bruising, pigmentation, overcorrection, surface irregularity, and granuloma formation.Serious complications involve vascular occlusion, injecting the filler into the facial arterial circulation, then freely diffusing through the capillary network, causing serious irreversible vascular complications such as skin necrosis, visual impairment, permanent unilateral or bilateral blindness, and even iatrogenic stroke. 5 the case of extensive vascular occlusion, ischemia may occur.
Usually, the damage is local and close to the injection site.However, when high-pressure injection is performed, emboli within the vessels may block distant vessels, even those on the opposite side of the initial injection site, leading to a paradoxical ischemic area. 6If HA vascular embolism occurs and is not treated in time, the natural progression ends with tissue necrosis. 7When retinal vessels are damaged, it can lead to permanent blindness.If the embolus retrogrades into the brain arteries through the orbital arteries, it may lead to subsequent stroke. 8The purpose of this review is to clarify effective methods to prevent serious complications of HA injections through a preoperative, intraoperative, and postoperative review of three cases of HA embolism, and to discuss the prognosis of patients with vascular embolism caused by HA through a systematic and comprehensive treatment.

| CASE SERIES PRESENTATION
We treated three patients who suffered vascular occlusions due to hyaluronic acid injections, each coming from different cosmetic clinics.We managed to retain and display all clinical data from the three patients (Table 1), but couldn't obtain any information regarding the brand, dosage, or cannula used for the hyaluronic acid injections.
Patient 1 is a 30-year-old female.After the injection, she immediately experienced pain, redness, and swelling on her forehead.
Later, she noticed mottled discoloration on the right side of her forehead.By evening, her vision had become blurred, her visual acuity had decreased, and diplopia had set in (Figure 1A).Consequently, she was diagnosed with vascular occlusion.
TA B L E 1 Clinical information on three patients who underwent HA injections.Patient 2 is a 26-year-old female.During the injection process, she experienced a sudden loss of vision in her right eye, accompanied by eye pain, nausea, and vomiting.Upon examination at our clinic, we noted that her vision was impaired, her upper eyelid was drooping, and she had slight periorbital purpura as well as mild edema (Figure 2A).

Age
The injection site was clearly visible, leading to a preliminary diagnosis of periorbital vascular occlusion induced by the HA injection.
Patient 3 is a 24-year-old female.After the injection, she experienced pain from the nasolabial fold to the ala of the nose, and observed a bluish-purple discoloration on her nose and upper left lip (Figure 3A).A recent follow-up showed that her skin and vision were normal.
Patient 2's vision and skin also returned to normal at the one-month follow-up visit (Figure 2B).However, Patient 3 received initial treatment and chose to be discharged from the hospital.She returned to the hospital 3 days later with abscessed granules on her nose and necrotic skin between her eyebrows.After treatment, a one-month follow-up showed scarring between the eyebrows and on the nose (Figure 3B).In contrast, patients 1 and 2, systematically treated with hyaluronidase, exhibited favorable six-month follow-up outcomes, unlike patient 3 whose scars remained evident.

| DISCUSS ION
Three patients developed pain and ecchymosis rapidly after hyaluronic acid injections in a beauty facility, and their symptoms continued to worsen.The areas of embolization were frontal, periorbital, and nasal, which are high-risk areas for facial injections. 9All patients were promptly treated with hyaluronidase, but patient 3 chose to be discharged that evening, resulting in scarring between the eyebrows and on the nose.The other two patients followed the prescribed systemic treatment and did well at postoperative follow-up.This in hemodynamics lead to thrombus formation.Eventually, a hyaluronic acid-mixed thrombus occlusion forms, completely blocking the lumen. 14There is a subset of scholars who believe that the cause of vascular embolism is vasospasm, which is sometimes caused by mechanical stimulation or direct stimulation of the vessel when hyaluronic acid injections are performed.Although this spasm is usually temporary, it may exacerbate the formation of an embolism or cause other complications in certain specific contexts. 15

| Measures to reduce vascular occlusion from hyaluronic acid injections
Following our in-depth analysis of the pathogenesis, to prevent vascular occlusion caused by hyaluronic acid injections, we will discuss measures to reduce risks from various perspectives, including health status, expected results, skin condition, pain and sensitivity, and preoperative risk disclosure.
1. Health status: The injecting doctor needs to understand the patient's health status, including past diseases, current oral medications, surgical history (especially facial surgery history, such as The patient 's bilateral nasal alar, nasolabial groove and left upper lip skin showed blue purple changes.(B) One month later, scars were left between eyebrows and bilateral nasal ala.cosmetic rhinoplasty history), past facial injection history (such as botulinum toxin, hyaluronic acid, and facial fat filling), blood transfusion history, and allergy history. 16 Expected effect: The injecting doctor needs to understand the patient's expected outcome of the injection surgery, including the injection site and the desired effect after injection, so that the injecting doctor can control the volume of hyaluronic acid injection and choose the injection method, avoiding the injection risk zone vessels.
3. Skin condition: The injecting doctor needs to evaluate the patient's skin condition preoperatively, including skin elasticity, skin color, subcutaneous fat distribution, etc., which can also help the injecting doctor better determine the injection layer position and injection dosage.
4. Pain sensitivity: The injecting doctor needs to understand the patient's pain sensitivity and tolerance to anesthetics, so as to select the appropriate anesthetic drug and dosage.This helps the doctor judge the patient's pain during injection, determine if occlusion occurs, and its progress.

Preoperative risk disclosure:
The doctor needs to inform the patient of the risks and clinical manifestations that may occur during the hyaluronic acid injection procedure, so that the patient can immediately communicate any occurrences of pain, swelling, or other discomforts to the doctor, allowing for prompt intervention.
The best way to deal with vascular occlusion complications caused by HA filling is to prevent its occurrence.

| Advantages of systemic treatment
The primary drug for treating occlusion currently is hyaluronidase, 12 which mainly works by hydrolyzing HA.Moreover, treatments such as hyperbaric oxygen, nitrate, and massage are often used for treating HA occlusion.Unsystematic treatment may result in problems such as skin blisters, mild to moderate epidermal shedding, and permanent mild dermal scarring and pigment imbalance.Mild scarring was considered a standard of successful treatment in the past.Through treating three occlusion patients, we believe that a comprehensive systemic treatment approach can avoid the aforementioned problems and have summarized a relatively complete treatment plan.This plan includes the use of hyaluronidase, hyperbaric oxygen therapy, local hot compresses, and massages.For special patients with delayed necrosis, the above treatment options can effectively improve the condition and minimize scarring.ronidase, but its potential to cause allergic reactions also requires attention. 18,19 Improving the blood supply to the occluded area in a timely manner is also important.For example, oral vasodilators (isosorbide dinitrate and papaverine) can be used to promote the recovery of blood supply to the occluded area.Although the incidence of vascular occlusion caused by HA is relatively low, with the gradual increase of people receiving HA injections, more and more adverse events are reported.Although hyaluronidase is recognized as a treatment for HA occlusion, 25 the treatment method for occlusion still needs to be improved.We found that hyaluronidase can effectively degrade HA in a short time, but follow-up of patients after the end of the treatment cycle found that most patients still had a poor prognosis (residual scars after skin necrosis, ineffective improvement of visual acuity recovery, etc.).
Therefore, it is of great significance for patients to receive systematic treatment based on hyaluronidase after occlusion for patient prognosis.

| CON CLUS ION
By showing the treatment and prognosis of three patients, we believe that occlusion patients receiving a systematic treatment based on hyaluronidase can effectively reverse the damage of vascular occlusion.We have conducted a review from the aspects of the pathogenesis of occlusion, anatomical analysis of dangerous areas of facial injections, measures to reduce its incidence, and precautions for hyaluronidase application.This aims to deepen clinical doctors' understanding of the complications caused by HA and thus reduce the occurrence of this adverse event.Although we analyzed three cases, due to the small sample size, we cannot provide statistically significant conclusions or a reliable basis for the treatment of hyaluronic acid embolism.However, we hope that our analyses will provide helpful recommendations for physicians, minimizing the permanent damage caused by embolisms.
All patients arrived at our hospital within an hour after the onset of occlusion.It is well known that reversing ophthalmic artery occlusion within 90 min is crucial to preventing permanent blindness.Therefore, we promptly administered hyaluronidase injections (Shanghai First Biochemical Pharmaceuticals Corp, Shanghai, People's Republic of China: equivalent to Vitrase in North America, 150 U/h) at the occlusion sites for the patients and developed a comprehensive treatment plan based on the hyaluronidase injections.The treatment involved the use of tobramycin dexamethasone eye drops, vasodilators (Monoketone and papaverine), oral aspirin, intravenous amoxicillin, as well as massage and hyperbaric oxygen therapy for the occluded areas.We also recommended that patients use recombinant human acidic fibroblast growth factor to minimize the formation of scars.Patient 1 and Patient 2 recovered well after treatment as prescribed.Patient 1 was treated for 12 days and had almost healed skin on her forehead and reduced bruising in her eyes (Figure 1B,C).

F I G U R E 1
(A) On the night of admission, the patient had skin patchy changes above the right forehead, conscious blurred vision and decreased vision, and diplopia.(B) and (C).After 12 days of treatment, the forehead skin was healed, and only a small amount of ecchymosis appeared in the eye.F I G U R E 2 (A) The patient had decreased vision in the right eye, ptosis in the right eye, slight purple ecchymosis around the eye, and mild edema.(B) After a month of follow-up, the patient 's vision returned to normal, and the forehead and periocular skin returned to normal.We presented three cases with complete records from symptom onset to posttreatment.These patients, experiencing postinjection pain and swelling, used hyaluronic acid to minimize permanent occlusion damage.Patient 3, who was discharged upon request after initial treatment, returned due to worsening occlusive conditions and promptly sought further care.Although Patient 3 was treated with hyaluronidase injections immediately at the time of the initial consultation, she ended up with scars between her eyebrows and on her nose due to the lack of comprehensive systemic treatment.
article analyzes the risks of hyaluronidase injections and provides insight into the mechanisms of embolization, prevention strategies, and the advantages of hyaluronidase-based systemic therapy.4.1 | PATHOGENESISComplications from HA injections are usually divided into minor and severe.Minor early-stage complications include swelling, bruising, and erythema, while late-stage minor complications are less common, such as delayed hypersensitivity reactions.10Serious complications include irreversible damage caused by embolization, such as skin necrosis, visual impairment, brain infarction, and e death.Current vascular occlusions caused by HA injections can be divided into intravascular and extravascular causes.Intravascular factors include the direct blockage of arteries by large-molecularweight HA fillers, 11 and chemical damage to the endothelium by impurities in the HA or filler. 12Extravascular causes include excessive injection volume causing external pressure on the vein, or edema and inflammatory reactions caused by filler components. 13Chen et al. speculated that the mechanism of arterial occlusion caused by HA is that the intravascular HA causes endothelial damage, activates endothelial cells, and subsequently triggers platelets, coagulation factor XII, and the endogenous coagulation cascade reaction.At the same time, tissue factors are released, activating coagulation factor VIII and initiating the exogenous coagulation cascade reaction.Due to the lumen occlusion caused by HA, changes

4. 4 |
The treatment plan 1. Administer hyaluronidase injections promptly in the occluded area.Each vial of hyaluronidase contains 1500 units, divided into three equal doses, and 150 units of hyaluronidase are injected every hour.The 48 h after HA filling is generally considered the ideal time window to use hyaluronidase to prevent ischemic skin tissue injury.Serious complications can be avoided with the use of hyalu-

3 . 5 . 6 . 7 .
Adjuvant treatments such as hyperbaric oxygen and infrared radiation therapy can also be adopted.Hyperbaric oxygen can provide oxygen pressure in hypoxic tissues to promote healing of necrotic tissues.The treatment typically involves setting the atmospheric pressure at 200-250 kPa and administering pure oxygen in cycles of 30 min with 5-min rests in between, once a day for a period of 10 days.20 Infrared radiation therapy, by irradiating infrared rays to body parts, can stimulate local heating in the tissue, thereby producing various physiological effects such as vasodilation, promoting blood circulation, alleviating pain, and stopping bleeding.4. Magnesium sulfate, applied locally in the occluded area, can alleviate inflammation by inhibiting the release of mediators like interleukin-1 and tumor necrosis factor.It also promotes healing by increasing blood flow and oxygen supply through vasodilation, aiding in tissue regeneration and repair.Intravenous or oral β-lactam antibiotics or penicillin antibiotics were used to prevent and control the symptoms of infection complicated with vascular occlusion.If the patient has no contraindications to aspirin, it can be taken orally.As an antiplatelet agent, aspirin can inhibit platelet aggregation and thrombus formation.If the occlusion is located in the ocular circulation, causing ischemic retinal damage, ophthalmological measures should be taken, such as retrobulbar or peribulbar injection of high-dose hyaluronidase21 (operated by professional ophthalmologists), combined with reducing intraocular pressure (through ocular massage and the use of carbonic anhydrase inhibitors) and increasing retinal blood flow (through ocular massage, use of carbonic anhydrase inhibitors and corticosteroids.22Although HA filling can improve the appearance of facial skin, it is not absolutely safe.Even experienced injection physicians may encounter various unpredictable reactions when performing injections on patients.Minor adverse reactions include bruising, pigmentation, overcorrection, irregular surfaces, and granuloma formation,23 while severe adverse reactions include skin necrosis, impaired vision, permanent unilateral or bilateral blindness, and even iatrogenic cerebral infarction.24Vascular occlusion caused by HA injection is the direct cause of severe adverse reactions, and its pathogenesis is due to the direct injection of HA into blood vessels or injection around blood vessels, causing pressure and subsequently inducing occlusion.Through the review of the medical records of three patients, we believe that occlusion patients receiving timely treatment based on hyaluronidase can reverse the irreversible damage caused by occlusion and improve patient prognosis.By comparing the treatment methods of three patients, we concluded: patients who received HA filling and then caused vascular occlusion, immediate treatment based on hyaluronidase can improve the irreversible damage caused by thrombosis and can even lead to the patient's recovery.