Table 5.

List of the selected excluded studies and their summary findings

Authors	Follow. up	Study sample Study type	Hyaluronidase ± other medicines	Type of hyaluronic acid dose	Inclusion criteria complication	Outcome adverse effects
Hilton et. al. [56]	Not clear	Retrospective study (N=20) Case series No control 3 male, 17 female. Age range= 32–74 years old mean age= 49.3 years old	20. 75 units (Hylase Dessau®). Diluted in 1.0 mL of normal saline. 0.2–0.5 mL injection	HA brand not reported	Nodule developed after HA tear trough augmentation. Infraorbital Region. 14 patients had HA injection for tear. trough augmentation. 6 patients had no HA injection and idiopathic edema	79% of patients had full nodule resolution with one injection. 3 patients (21%) required an additional injection. No adverse effect observed. There was a loss of original HA treatment effect in two cases (14.3%)
Sadeghpour et. al. [59]	Not clear	Retrospective study (n=5)No control Case seriesOriginal sample of 1,029 patient All femaleAge range 46. 70 years old	All patients treated first with hyaluronidase (Hylenex, no dose given) without significant clinical improvement. Then, a combination of triamcinolone (2. 5 mg/mL) & hyaluronidase (multiple treatment sessions) given.	1,250 Vycross HA filler treatments (1,029 patients) Juvederm Volbella Juvederm Vollure Juvederm Voluma	Delayed. onset nodules (lip) developed in 5 cases (Juvederm Volbella) after 35.8 week on averageSubcutaneous, firm, non. erythematous, and nontender nodule	Combination of triamcinolone and hyaluronidase (multiple treatment sessions) lead to diminution in nodule size.All patients were treated successfully with near. complete or complete resolutionNo mention of adverse effects
Bravo et. al. [10]	Not clear	Retrospective study (n=114)Case seriesNo control 112 females, 2 malesMean age = 43 years old	HYAL (hyaluronidase 2.000 IU, BIOMETILtm, dissolved in 5 ml of the diluent, saline solution, water for injection & mannitol) 400 IU/ml solution 2. 2000 UI injected with a mean dose of 68 UI	HA brand not reportedHA injections were as follows: Eyelid region (n=58) Upper lip (n=10)Lower lip (n=9)Malar region (n=9) Melomental fold (n=5) Forehead (n=4)Nose (n=4)Chin (n=4) Pyriform aperture (n=3) Temple (n=2)Lateral orbit (n=2) Zygoma (n=2)Peri. labial (n=1) Acne scar (n=1)	Over. correction (45%)Tyndall effect (44%)Late nodules (11%)	40 UI of hyaluronidase injection should be enough for each CM2 of HA that needs removalThe main complications were moderate edema and local burning sensation.One case developed lip angioedema and treated with 80 mg oral prednisolone. No dermal or subcutaneous atrophies were observed
Skippen et. al. [61]	Mean follow. up = 11 months (6. 20 months)	Retrospective study n=61Case seriesNo control 59 female, 2 male age range = 21. 78 years mean age=48 years old	HYAL15. 90 IU per eyelid	Had different types of HAHA brand not reported	Had lower eyelids or cheeks HA injection and developed Lower eyelid edema On average 3 years (1. 10 years) after HA filler injection	Single hyaluronidase injection was effective in 92% of patients 8% required another hyaluronidase injection to completely eradicate residual edema6 patients (10%) were satisfied after hyaluronidase only 6 patients (10%) had lower eyelid blepharoplasty. 48 patients (80%) had secondary treatment with HA filler injection No adverse effects mentioned
Dubinsky. Pertzov et. al. [62]	The mean follow. Up = 10.85 months (6. 36 months)	Retrospective study n=17Case seriesNo control Female Age range = 26. 80 years oldMean age=54.9 years old	HYAL3. 90 IU per eyelid	Had different types of HAHA brand not reported	Upper eyelid edema (periocular edema) 6. 24 months after HA filler injection in the supraorbital area.	Edema resolved in all patients after hyaluronidase treatment13 (76.4%)were satisfied and didn’t receive HA filler again4 received additional HA filler.No mention of adverse effects
Artzi et. al. [58]	Not clear	Retrospective study n=17No controlCase seriesOriginal sample of 400 patients and 17 developed complications	17 patients were first treated with oral ciprofloxacin (500–750 mg, bd, for 3. 4 weeks), which treated 6 patients with no recurrence11 patients had recurrent episodes and received broad. spectrum antibiotics (ciprofloxacin or rifampicin for a minimum of 3 weeks) and multiple intralesional injections of hyaluronidase (30–100 unit/mass or nodule)	400 patients (360 females, 40 males; average age = 49.6 years) received Juvéderm Volbella (HA. Vb) filler into the tear trough area (n=351) or lips (n=49).Other HA. fillers were also used in other areas of the face	Late inflammatory cutaneous reactions in tear trough area & lips17 (4.25%) patients 13 in tear trough area (n. 13) and lips (n=4)Patients developed prolonged (up to 11 months) and recurrent (average: 3.17 episodes) late inflammatory cutaneous reactions (average onset: 8.41 weeks following HA filler injection, range: 5–12 weeks)	All symptoms & signs receded in 6 patients who received initially antibiotics and did not recur.Recurrent episodes (11 patients) were treated with repeated courses of broad. spectrum antibiotics and multiple intralesional injections of hyaluronidase. Oral, intramuscular & intralesional administration of corticosteroids were less effective.No mention of adverse effects
Sun et. al. [57]	Not clear	Retrospective study n=20Case control study20 consecutive referrals with nasal skin necrosis following nose and/or nasolabial fold augmentation with HA fillersAge range 21. 52 years old19 female, 1 male	18 received hyaluronidase [ovine testicular hyaluronidase (Shanghai First Biochemical Pharmaceuticals Corp., Shanghai; equivalent to Vitrase in North America, 150 to 300 units] from 0 hrs. 7 days after developing skin problemsAlso given antibiotics, tanshinone, papaverine, topical magnesium sulphate, infrared irradiation, and hyperbaric oxygen. Patients were also given aspirin, unless contraindicated.	HA brand not reportedHA was injected into the nasion area (n=14), nasolabial fold (n=5) or both (n=1)	Skin necrosis after HA injection in nose, nasolabial fold, glabella & forehead, or lip	7 patients (%35) developed skin necrosis.13 patients (%65) recovered fully following combination treatment with hyaluronidase.Early (<2 days) combination treatment with hyaluronidase was associated with the full resolution of the complicationsNo mention of adverse effects
Ors [14]	Followed up for 3–24 months	Retrospective study n=16No controlCase seriesAge range= 18. 60 years oldAll female	6 patients only received palliative treatment 10 patients received 1500 units (300 U with every 4. 6 hrs) hyaluronidase [30 s after HA injection (n=4) or 6. 24 h after HA injection] and palliative treatment.Patients with open wounds received topical Fusidic acid antibiotic. Patients with large wounds received amoxicillin–clavulanate orally for 14 days.	HA brand not reportedoverall, 841 cases received HA filler Nasolabial area (391)Lip (225)Glabella–forehead (90)Infraorbital (46)Malar region (25)Chin (24) Nose (40)	Vascular occlusion. related ischemia and skin necrosis after HA injectionComplications occurred in 16 cases [Nose (n=4), Nasolabial area (n=4), Glabella (n=8) area]Skin complications presented in 4 patients during HA injection and in 12 patients 6–24 h after the procedure.	Recovery time for patients who received palliative treatment and had limited necrosis was 40. 60 days, without obvious scar.Patients who received hyaluronidase and palliative treatment, had larger necrosis areas, and at the end a large necrosis area was observed in 4 patients. The recovery period in this group was 20. 90 days.Overall, 4 patients healed with a scar and 12 healed without any significant scar.Authors suggested Hyaluronidase injection provides earlier recovery of limited skin necrosis. Immediate hyaluronidase injection allowed small damage to heal in a short time; however, it did not eliminate large necrosis, but limited the necrotic area’No adverse effect observed
Zhang et. al. [16]	Average follow. up = 5 months (3. 12 months)	Retrospective study n=17No controlCase series19. 52. year. oldMean age=33 years old14 female, 3 male	13 patients had 1500 IU hyaluronidase (Shanghai Shangyao No. 1 Biochemical Pharmaceutical Co., LTD.) injected into facial artery 4 patients had 1500 IU hyaluronidase injected into supratrochlear artery Received intra. arterial thrombolysis therapy 2 hours to 7 days after the onset of symptomsPatients also received;1. glucocorticoid pulse therapy (dexamethasone sodium phosphate, 10 mg, ivgtt, qd, 3 d)2. neurotrophic treatment (mecobalamin injection, 0.5 mg, ivgtt, qd, 90 d)3. anti. allergy treatment (loratadine, 10 mg, pol, qd).	HA brand not reportedHA filler was injected in the nasolabial fold (n=7) or forehead (n=5)	Vascular complications of HA fillerAll had skin necrosis or skin ecchymosis spreading along the surface branches of facial artery or supratrochlear artery4 had severe ptosis and weakness in eye opening, ocular pain, and skin numbness. 2 had ocular motility disordersNone had visual impairment and life. threatening injuries (hypertension, coagulopathy, intracranial and external haemorrhaging)The colour doppler flow imaging was used to locate the facial and supratrochlear arteries	The skin necrosis of 16 patients was completely healed and 1 patient left with small, superficial scarsThe ptosis and ocular motility were completely resolved.No mention of adverse effects
Zhang et. al. [60]	Average follow. up = 3 months (1 month to 1 year)	Retrospective study n=24no controlCase seriesMean age=26 years old23 female, 1 male	11 patients received intra. arterial injection of hyaluronidase (500. 1500 units) 13 patients received intra. arterial injection hyaluronidase (750. 1500 units) and urokinase (100,000. 250,000 units)	HA brand not reportedHA was injected into the nasion area (n=12), followed by the frontal (n=10), glabella (n=1) & temporal (n=1).	Severe visual impairment (unilateral, 10 right & 14 left eyes were affected) after cosmetic facial hyaluronic acid injectionsAll had ptosis & mydriasis with pupil diameter larger than 5 mm 22 patients had ocular motility disorders. 20 patients had skin lesions in the corresponding region of artery occlusion, being pale, piebald, or necrotic.None had life. threatening injuries or interventional contraindications (hypertension, coagulopathy, intracranial & external haemorrhaging)	10 (42%) patients had improved visual acuity after treatment, 14 patients had no visual impairment improvement The ptosis in 24 patients were all healed. 3 patients had secondary embolization, sudden headache, ocular pain, and decline in vision on the 1st or 2nd day after the first intraarterial thrombolysis therapy and had 2nd course of intraarterial thrombolysis therapy with less success. Partial or total ocular motility limitation healed in 8 patients and ameliorated in 14 patients Intra. arterial thrombolysis therapy significantly improved skin necrosis and ecchymosis, and nearly restored the patients’ appearance to normal, leaving only some superficial scars in several patients.Authors suggested that combined hyaluronidase and urokinase may have a better thrombolysis effect on hyaluronic acid embolismIn addition, early hormone shock (high. dose glucocorticoid), local hyaluronidase injection, oxygen inhalation, Mannitol, and melilotus extract tablets were necessary to reduce tissue edema.Earlier treatment was associated with the higher vision improvementNo mention of adverse effects
Wang et. al. [63]	30 days follow. up	Retrospective study n=30Case seriesNo control 1 male, 29 femalesAge range= 18. 35 years old	30 had local injection of hyaluronidase at the HA injection site immediately after the onset of vision loss and 25 received retroocular hyaluronidase injection at other hospitals.28 had one and 2 patients had 2 intra. arterial thrombolysis(Using microcatheter, 1500 units of hyaluronidase diluted in 1 mL of saline and were slowly infused followed by infusion of 1 mL papaverine diluted in 2 mL saline)	HA brand not reported	Presented 20. 120 hrs after the onset of blindness (median, 59.5 h).Had monocular blindness due to HA injection in the forehead (n=3) and nasal bridge (n=27) regions 26 had ptosis 23 had ocular motility disorders. 3 had light perception 27 had no light perception with varying degrees of vascular occlusion in the retina	The ptosis disappeared and 18 patients had normal eye movement after the intra. arterial therapy.5 patients had visual improvement 4 patients with complete vision loss gained some light perception.