Abstract
Objective
Cyanoacrylate closure (CAC) is a minimally invasive, nonthermal treatment for varicose veins. However, regarding postoperative skin and soft tissue adverse reactions, their clinical characteristics remain poorly defined. This study compared adverse reactions after CAC and thermal ablation (TA) and characterized their features following CAC.
Methods
We retrospectively reviewed 511 patients treated for saphenous vein incompetence (300 CAC cases and 211 TA cases). Skin and soft tissue adverse reactions, defined as reactions requiring oral medication or surgical intervention, were evaluated.
Results
Baseline characteristics were similar between the groups, and no severe systemic reactions were observed. Skin and soft tissue adverse reactions occurred more frequently after CAC than after TA (34/300 [11%] vs 8/211 [4%]; P = .004). Higher CEAP classes were associated with increased reaction rates. Adverse reactions after TA were mainly related to thermal injury, including burns, phlebitis, cellulitis, and nerve-related symptoms perceived in the skin, whereas hypersensitivity-type reactions were observed only after CAC. CAC-related adverse reactions appeared to involve multiple contributing factors and were classified into five types based on particularly prominent clinical features: allergic contact dermatitis, phlebitis, exacerbated edema with induration, generalized urticaria, and foreign-body granuloma. CAC-related adverse reactions were more frequent in great saphenous vein treatment than in small saphenous vein treatment (59/520 [11.3%] vs 23/302 [7.6%]), and occurred exclusively with below-knee access. Adverse reactions were also more common in patients with hypertension. The onset of CAC-related adverse reactions occurred immediately (2.9%), at 1 week (32.3%), 2 weeks (26.5%), 3 weeks (26.5%), 4 weeks (5.9%), or >4 weeks (5.9%), whereas 75% of TA-related adverse reactions occurred within 1 week. Persistent subjective symptoms lasting ≥1 month, including pain, neuropathy, or discomfort, were less frequent after CAC than after TA (4/300 [1%] vs 14/211 [7%]; P = .0044).
Conclusions
CAC was associated with more complex and delayed adverse reactions compared with TA. Awareness of these characteristic patterns is important for patient selection, counseling, risk assessment, and postoperative management.
Keywords: Ablation, Cyanoacrylate closure, Hypersensitivity reaction, Phlebitis, Varicose veins
Article Highlights.
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Type of Research: Single-center, retrospective observational study
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Key Findings: Skin and soft tissue adverse reactions requiring treatment occurred more frequently after cyanoacrylate closure (CAC) than after thermal ablation (34/300 [11%] vs 8/211 [4%]; P = .004). CAC-related adverse reactions observed in 34 patients appeared to involve multiple contributing factors and were classified into five distinct types based on their clinical features.
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Take-Home Message: Recognizing these characteristic patterns of CAC-related adverse reactions may aid in patient selection, risk counseling, and postoperative management.
The treatment of varicose veins has advanced considerably over the past 2 decades, with a clear shift toward minimally invasive endovenous procedures. Several randomized controlled trials,1 including studies comparing cyanoacrylate closure (CAC) with thermal ablation (TA), have demonstrated comparable closure rates among currently available techniques, indicating that device selection should be based primarily on anatomical characteristics and patient-specific factors rather than efficacy alone.
CAC is increasingly used as an alternative to TA, largely because TA can cause thermal injury to surrounding tissues and nerves, potentially prolonging postoperative adverse events.2, 3, 4 Nevertheless, skin and soft tissue adverse reactions after CAC is not uncommon. Several case reports have documented type IV hypersensitivity reactions confirmed by patch testing,5, 6, 7, 8, 9 and various terms, such as phlebitis-like abnormal reactions and complex hypersensitivity and inflammatory reactions, have been used to describe these manifestations, but these terms remain variably defined. Although the reported incidence of allergic reactions after CAC ranges from 2% to 25%,4,10, 11, 12, 13, 14, 15, 16, 17 detailed clinical characterization remains limited. Thus, the frequency, specific clinical features, and time course of cyanoacrylate-related skin and soft tissue adverse reactions remain insufficiently defined. To address this gap, we conducted a retrospective study of medical records to evaluate postoperative skin and soft tissue adverse reactions in patients treated with CAC and compared the frequency, characteristics, and duration of these reactions with those observed after TA.
Methods
This retrospective observational study was conducted at the Kannai Medical Clinic and approved by the Ethics Committee of Medical Corporation Keihakukai (Approval No. KEIHAKUKAI20244). We reviewed 300 patients who underwent CAC between September 2020 and April 2023 and 211 patients who underwent TA (radiofrequency or laser) between June 2023 and July 2024 at our institution.
All patients had symptomatic great saphenous vein (GSV) or small saphenous vein (SSV) incompetence with reflux of ≥0.5 seconds on standing duplex ultrasound. The severity of chronic venous disease was classified according to the Clinical–Etiological–Anatomical–Pathophysiological (CEAP) classification. Treatment was initiated at the point of reflux, including the below-knee segments when reflux extended distally. All procedures were performed under intravenous sedation (midazolam, propofol, or pentazocine, alone or in combination).
CAC procedure
CAC was performed using the VenaSeal closure system (Medtronic) according to the manufacturer’s instructions. A 7F introducer sheath and 5F delivery catheter were positioned 5 cm distal to the saphenofemoral junction. After two proximal injections of ∼0.10 mL of glue with manual compression, single injections were administered every 3 cm along the target vein segment. Hemostasis was achieved at the time of catheter removal, and occlusion was confirmed by duplex ultrasound. Direct puncture injection was performed as needed.
TA procedure
Thermal ablation was performed using radiofrequency ablation (ClosureFast; Medtronic) or endovenous laser ablation. Laser ablation was conducted using a 1470-nm system, including the ELVeS Laser 1470 (Biolitec), Endotherme 1470 laser (LSO Medical), and/or Venocure 1470 (Diotech), selected according to anatomical considerations. Tumescent local anesthesia was administered to minimize thermal injury. The radiofrequency ablation times were standardized by level (20 seconds above the knee, 15 seconds at the knee, and 5-10 seconds below the knee). Laser ablation was performed using 7 W with a LEED of 60 to 70 J/cm above the knee and 20 to 50 J/cm below the knee.
Patients were evaluated at 1 day, 1 week, and 1 and 3 months postoperatively; those with persistent symptoms continued follow-up until symptom resolution. Compression stockings were worn for 7 days after surgery.
Definition of skin and soft tissue adverse reactions
Skin and soft tissue adverse reactions were defined as postoperative cutaneous or subcutaneous findings that required systemic treatment with oral medication (including antihistamines, corticosteroids, antibiotics, or nonsteroidal anti-inflammatory drugs) or surgical excision.
Patients whose symptoms were limited in extent (≤100 cm2) and resolved within 1 week with topical treatment alone were excluded from the analysis.
These adverse reactions encompassed inflammatory or infectious skin and soft tissue manifestations, including erythema, edema, induration, urticaria, phlebitis-like reactions, cellulitis, burns, nerve-related symptoms perceived in the skin, and granulomatous changes. Findings attributable to external irritation (eg, compression stockings or disinfectants) were excluded.
Persistent subjective symptoms were defined as pain, neuropathy, or discomfort lasting longer than 1 month.
Medical records were reviewed for demographic data (age and sex), comorbidities (hypertension and diabetes mellitus), CEAP classification, treated truncal vein (GSV vs SSV), and access site (above-knee vs below-knee).
Statistical analysis
Continuous variables are presented as mean ± standard deviation, and categorical data are presented as percentages. Continuous variables were compared using the t-test, and categorical variables were analyzed using the χ2 test or Fisher’s exact test, as appropriate. The significance level was set at P < .05. All statistical analyses were performed using Prism 9 (GraphPad Software).
Results
Baseline patient characteristics
A total of 511 patients were included in the study, comprising 300 treated with CAC and 211 treated with TA. Baseline characteristics, including age, sex, hypertension, and diabetes mellitus, were comparable between the two groups (Table I).
Table I.
Baseline characteristics of patients treated with cyanoacrylate closure (CAC) or thermal ablation (TA)
| Characteristics | CAC (n = 300) | TA (n = 211) | P-value |
|---|---|---|---|
| Age, years | 70.1 ± 0.7 | 67.1 ± 1.0 | Ns |
| Sex (male/female) | 91/209 | 87/124 | NS |
| Hypertension | 72 (24.0) | 45 (21.3) | NS |
| Diabetes mellitus | 35 (11.7) | 29 (13.7) | NS |
| CEAP class | |||
| C2 | 5 (1.7) | 34 (16.1) | – |
| C3 | 208 (69.3) | 120 (56.9) | – |
| C4a | 57 (19.0) | 40 (19.0) | – |
| C4b | 12 (4.0) | 10 (4.7) | – |
| C5 | 2 (0.7) | 2 (0.9) | – |
| C6 | 6 (2.0) | 5 (2.4) | – |
| Treated truncal vein segments | 822 | 385 | |
| GSV | 520 (63.3) | 233 (60.5) | – |
| SSV | 302 (36.7) | 152 (39.5) | – |
| Access site for GSV | 520 | 233 | |
| Above the knee | 12 (2.3) | 6 (2.6) | – |
| Below the knee | 508 (97.7) | 227 (97.4) | – |
CEAP, Clinical–Etiological–Anatomical–Pathophysiological; GSV, great saphenous vein; NS, not significant; SSV, small saphenous vein.
Data are presented as mean ± standard deviation for continuous variables and as number (percentage) for categorical variables.
P values were calculated using the t-test for continuous variables and the χ2 test for categorical variables, as appropriate.
No significant differences were observed between groups.
Regarding CEAP classification, the distribution differed between groups. The proportion of C2 patients was significantly lower in the CAC group than in the TA group (5/300 [1.7%] vs 34/211 [16.1%]). In contrast, C3 patients were more frequent in the CAC group compared with the TA group (208/300 [69.7%] vs 120/211 [56.9%]). The proportions of patients with C4a, C4b, C5, and C6 disease were similar between the groups. Overall, the baseline characteristics were comparable except for differences in CEAP classification.
We further analyzed the treated truncal vein segments. A total of 822 veins were treated in the CAC group and 385 veins in the TA group. In the CAC group, 520 veins were GSVs and 302 were SSVs. In the TA group, 233 veins were GSVs and 152 were SSVs. Access sites were also evaluated. In the CAC group, 520 access sites were recorded, including 12 above-knee and 508 below-knee approaches. In the TA group, 233 access sites were recorded, with 6 above-knee and 227 below-knee approaches.
Skin and soft tissue adverse reactions requiring treatment after CAC and TA
We analyzed the incidence of skin and soft tissue adverse reactions requiring treatment in both groups (Table II). Such reactions occurred in 34 patients in the CAC group and eight patients in the TA group. The incidence was significantly higher in the CAC group than in the TA group (34/300 [11.3%] vs 8/211 [3/8%]; P = .0018). In patients presenting with painful erythema and suspected infection based on laboratory findings, oral antibiotics were administered. In cases considered less likely to be infectious, treatment was determined according to lesion size. Oral corticosteroids were initiated for lesions larger than 100 cm2. For lesions smaller than 100 cm2, topical therapy was started, and oral corticosteroids were added if no clinical improvement was observed after 1 week. Two patients in the CAC group (0.7%) required surgical intervention due to persistent symptoms despite ≥3 months of oral medical therapy. The procedure consisted of local excision of granulomatous or lipofatty inflammatory tissue through a 4- to 5-cm incision under local anesthesia (lidocaine with epinephrine). No patients in the TA group required surgical intervention.
Table II.
Skin and soft tissue adverse reactions requiring treatment after cyanoacrylate closure (CAC) and thermal ablation (TA)
| CAC with skin and soft tissue adverse reactions | TA with skin and soft tissue adverse reactions | P-value |
|---|---|---|
| 34 cases (11.3%, 34/300 cases) | 8 cases (3.8 %, 8/211 cases) | .0018 |
Data are shown as the number and percentages of the patients with skin and soft tissue adverse reactions in each group.
Onset timing of skin and soft tissue adverse reactions after CAC and TA
We next examined whether the time to onset of skin and soft tissue adverse reactions differed between the CAC and TA groups. The onset of skin and soft tissue adverse reactions after CAC showed a variable pattern: 2.9% occurred immediately, 32.3% at 1 week, 26.5% at 2 weeks, 26.5% at 3 weeks, 5.9% at 4 weeks, and 5.9% after 4 weeks. In contrast, TA-related reactions developed earlier, 75% within the first week and 25% by 4 weeks (Fig 1). These data suggest that the onset time of the skin and soft tissue adverse reaction in CAC and TA group was different.
Fig 1.
Onset timing of skin and soft tissue adverse reactions after cyanoacrylate closure (CAC) and thermal ablation (TA). Onset timing of postoperative skin and soft tissue adverse reactions in the CAC group (n = 300) and the TA group (n = 211). The adverse reactions occurred at various time points after CAC, whereas most adverse reactions after TA occurred early. Overall, adverse reactions were significantly more frequent after CAC than after TA (P = .004; χ2 test).
Clinical characteristics of skin and soft tissue adverse reactions after CAC and TA
We next analyzed the clinical features of skin and soft tissue adverse reactions in the CAC and TA groups. Among the 34 affected patients in the CAC group, heterogeneous clinical manifestations were observed and classified into five phenotypes (Table III, Fig 2). The proportions reported below are based on the total number of treated patients in the CAC group (n = 300).
Table III.
Classification and clinical course of skin and soft tissue adverse reactions after cyanoacrylate closure (CAC)
| Type | Typical clinical features | Average onset (range) | Average duration (range) | No./total (%) |
|---|---|---|---|---|
| Type I: allergic contact dermatitis | Localized, itchy edematous erythema around the treated area, sometimes extending beyond the vein path | 3.5 weeks (2 days-6 weeks) | 3.2 weeks (1-12 weeks) | 15/300 (5) |
| Type II: phlebitis | Linear painful erythema and induration along the treated vein, with warmth and tenderness | 1 week (All patients occurred at 1 week) | 6.3 weeks (3-8 weeks) | 5/300 (1.7) |
| Type Ⅲ: exacerbated leg edema with induration | Postoperative worsening of preexisting leg edema with firm painful induration of the lower leg | 2 weeks (1-2 weeks) | 6 weeks (4-10 weeks) | 7/300 (2.3) |
| Type IV: generalized urticaria | Widespread, transient itchy eruption involving multiple sites | 3 weeks (4 cases) Immediately (1 case) |
1 week (3 cases) 4 weeks (1 case) 1 hour (1 case) |
5/300 (1.7) |
| Type V: foreign-body granuloma | Localized abscess formation at puncture site, required excision | 12 weeksa 4 weeksa |
22 weeks Interrupted |
2/300 (0.7) |
Onset time and symptom duration are shown as average values with ranges.
Five distinct clinical patterns were identified: allergic contact dermatitis (Type I), phlebitis (Type II), exacerbated edema with induration (Type III), generalized urticaria (Type IV), and foreign-body granuloma (Type V).
These patients underwent surgery after 12 weeks of observation.
Fig 2.
Representative clinical presentations of skin and soft tissue adverse reactions after cyanoacrylate closure (CAC) (A) Type I – Allergic contact dermatitis: 2 weeks after CAC, pruritic and edematous erythema extending beyond the treated SSV segment. (B) Type I – Allergic contact dermatitis with adjacent branch involvement: 3 weeks after CAC, erythema accompanied by pain, pruritus, and warmth along the great saphenous vein (GSV). Ultrasound revealed a branch beneath the central area of erythema on the thigh. (C) Type II – Phlebitis: 2 weeks after CAC, localized linear erythema along the GSV. (D) Type III – Exacerbated leg edema/induration: 2 weeks after CAC in a Clinical–Etiological–Anatomical–Pathophysiological (CEAP) C4b patient, showing painful indurated erythema of the lower leg. (E) Type IV– Generalized urticaria: 2 weeks after CAC, presenting as widespread pruritic urticarial eruptions. (F) Type V– foreign-body granuloma: 7 months after CAC, puncture-site abscess with extrusion of cyanoacrylate material.
Type I (allergic contact dermatitis) (Fig 2, A and B) was the most common phenotype (15/300 [5%]). It was characterized by localized edematous erythema around the treated area, occasionally extending beyond the course of the treated vein, and was accompanied by pruritus and mild tenderness. Type II (phlebitis) (Fig 2, C) occurred in five patients (5/300 [1.7%]) and presented as linear erythema with induration, warmth, and tenderness along the treated vein. Type III (exacerbated edema with induration) (Fig 2, D) was observed in seven patients (7/300 [2.3%]) and manifested as worsening pre-existing lower leg edema with firm, painful induration. Type IV (generalized urticaria) (Fig 2, E) occurred in five patients (5/300 [1.7%]) and presented as widespread, transient, pruritic eruptions. Type V (foreign-body granuloma) (Fig 2, F) was the least common (2/300 [0.7%]). Both cases presented with puncture-site abscesses requiring local surgical excision. Histopathological examination confirmed foreign-body granulomatous inflammation (Fig 3). The time to onset and duration of skin and soft tissue adverse reactions varied according to clinical phenotype. Type I developed at a mean of 3.5 weeks after the procedure (range, 2 days-6 weeks) and persisted for a mean duration of 3.2 weeks (range, 1-12 weeks). Type II occurred uniformly at 1 week postoperatively in all affected patients and had a mean duration of 6.3 weeks (range, 3-8 weeks). Type III developed at a mean of 2 weeks (range, 1-2 weeks) and lasted for a mean of 6 weeks (range, 4-10 weeks). Type IV showed variable onset patterns. Four cases developed at 3 weeks postoperatively, whereas one case occurred immediately after the procedure. The duration was generally short, with three cases resolving within 1 week, one case lasting 4 weeks, and the immediate-onset case resolving within 1 hour. Type V demonstrated the latest onset, occurring at 4 and 12 weeks postoperatively. These reactions were prolonged, and symptoms persisted until surgical excision 12 weeks after onset. The surgical site was clinically resolved 22 weeks after symptom onset in one patient and the other patient interrupted visiting after surgery. Overall, early-onset reactions were characteristic of phlebitis (Type II), whereas delayed and prolonged courses were typical of foreign-body granuloma (Type V).
Fig 3.
Histopathological findings of foreign-body granuloma after cyanoacrylate closure (CAC) (Type V). Local excision was performed for a puncture-site abscess with cyanoacrylate extrusion related to CAC of the great saphenous vein (GSV) at 7 months postoperatively. Complete wound healing was achieved within 2 months after surgical intervention, with no recurrence observed during 1-year follow-up. (A) Hematoxylin & eosin staining (× 100): A cystic structure forming around vacuolated material (∗) is observed. The intraluminal contents demonstrate vacuolated changes consistent with tissue injury caused by cyanoacrylate. (B) Hematoxylin & eosin staining (× 400): Magnified view of the blue boxed area in panel A, revealing numerous foreign-body giant cells (arrow).
In contrast, skin and soft tissue adverse reactions in the TA group were less frequent (8/211 [4%]) and were primarily associated with thermal injury, including burns, phlebitis (Fig 4, A), cellulitis (Fig 4, B), and exacerbated leg edema with induration (Fig 4, C and D). No hypersensitivity-type reactions were observed after TA. Overall, adverse skin and soft tissue reactions following CAC were more diverse in clinical presentation compared with TA. Although Type V reactions were rare, they were clinically significant because they required surgical intervention.
Fig 4.
Representative clinical presentations of skin and soft tissue adverse reactions after thermal ablation (TA). (A) Thermal ablation-related reaction: 1 week after TA, brown painful pigmentation along the great saphenous vein (GSV), diagnosed as thermal burn injury with associated phlebitis. (B) Thermal ablation-related reaction: 1 week after TA, painful erythema around the knee, diagnosed as cellulitis. Blood tests showed elevated C-reactive protein and white blood cell levels. The symptoms resolved within 1 week after the start of oral antibiotic therapy. (C) Thermal ablation-related reaction: 1 week after TA in a Clinical–Etiological–Anatomical–Pathophysiological (CEAP) C4b patient, indurated erythema and leg edema mimicking cellulitis, resolving within 3 months with oral corticosteroid therapy. (D) Thermal ablation-related reaction: 1 week after TA in a CEAP C4b patient, showing progressive swelling with indurated erythema of the lower leg.
Risk factors for skin and soft tissue adverse reactions
We next investigated potential risk factors associated with the development of skin and soft tissue adverse reactions in the CAC and TA groups. Patient characteristics were analyzed according to hypertension, diabetes mellitus, CEAP classification, treated truncal vein segment, and access site for GSV treatment (Table IV). In the CAC group, hypertension was significantly associated with the occurrence of adverse reactions, whereas diabetes mellitus was not. No significant associations were identified in the TA group. In CEAP-stratified analysis, patients with C3 disease demonstrated a significantly higher reaction rate after CAC compared with TA (25/208 [12.0%] vs 4/120 [3.3%]; P = .0076). Although the number of advanced cases was limited, patients with C4b disease showed relatively high reaction rates in both groups (CAC, 25.0%; TA, 20.0%). From an anatomical perspective, adverse reactions after CAC were more frequent following GSV treatment than SSV treatment (59/520 [11.3%] vs 23/302 [7.6%], per treated vein). Notably, all GSV-related reactions in the CAC group occurred in cases treated via below-knee access. These findings suggest that hypertension, C3 disease severity, and GSV treatment—particularly with below-knee access—may be associated with an increased risk of adverse reactions following CAC, whereas no clear risk factors were identified for TA.
Table IV.
Patient characteristics associated with postoperative skin reactions requiring treatment after cyanoacrylate closure (CAC) or thermal ablation (TA)
| Characteristics | CAC with skin and soft tissue adverse reactions 34 cases/300 cases |
TA with skin and soft tissue adverse reactions 8 cases/211 cases |
P-value |
|---|---|---|---|
| Age, years | 68.6 ± 2.1 | 70.3 ± 3.6 | NSa |
| Sex (male/female) | 10/24 | 5/3 | NSb |
| Hypertension | |||
| Present | 17/72 (23.6 %) | 1/45 (2.2 %) | .0027b |
| Absent | 17/228 (7.5 %) | 7/166 (4.2 %) | .21b |
| Diabetes mellitus | |||
| Present | 4/35 (11.4 %) | 1/29 (3.4 %) | .37b |
| Absent | 30/265 (11.3 %) | 7 (7/182, 3.8 %) | .0048b |
| CEAP class | |||
| C2 | 0/5 (0 %) | 1/34 (2.9 %) | NSb |
| C3 | 25/208 (12.0 %) | 4/120 (3.3 %) | .0076b |
| C4a | 5/57 (8.8 %) | 3/40 (7.5 %) | NSb |
| C4b | 3/12 (25.0 %) | 2/10 (20.0 %) | NSb |
| C5 | 0/2 (0 %) | 0/2 (0 %) | NSb |
| C6 | 1/6 (16.7%) | 0/5 (0%) | NSb |
| Treated truncal vein segments | 82/822 (10.0 %) | 20/385 (5.2 %) | .0053a |
| GSV | 59/520 (11.3 %) | 13/233 (5.6 %) | .0152a |
| SSV | 23/302 (7.6 %) | 7/152 (4.6 %) | .32b |
| Access site for GSV | |||
| Above the knee | 0/12 (0 %) | 0/6 (0 %) | NSa |
| Below the knee | 59/508 (11.6 %) | 13/227 (5.7 %) | NSb |
CEAP, Clinical–Etiological–Anatomical–Pathophysiological; GSV, great saphenous vein; NS, not significant; SSV, small saphenous vein.
Data are shown as the number of cases and percentages of the total number of patients in each group.
Hypertension, but not diabetes mellitus, was significantly associated with skin reactions. Skin reaction rates varied by CEAP class and treated truncal vein.
Boldface P values indicate statistical significance.
P values were calculated using the χ2 test.
P values were calculated using the Fisher’s exact test.
Systemic and persistent adverse reactions after CAC and TA
Finally, we evaluated systemic and persistent adverse reactions in both groups. No severe systemic reactions were observed, including anaphylactic shock, pulmonary embolism, or deep vein thrombosis, occurred in either group (Table V). We observed the proportion of the patients that expressed symptoms (pain, neuropathy, discomfort) in the CAC group was more than that in the TA group (1% vs 7%). In the detail, pain persisting for ≥1 month was observed in 1% of CAC cases (3/300) and 4% of TA cases (9/211). Neuropathy (10 cases [5%]) and discomfort (2 cases [1%]) occurred only in the TA group.
Table V.
Frequency of severe systemic symptoms, persistent subjective symptoms (>1 month) and skin and soft tissue adverse reactions after cyanoacrylate closure (CAC) or thermal ablation (TA)
| Symptom category | CAC (n = 300) | TA (n = 211) | P-value |
|---|---|---|---|
| Severe systemic symptoms | 0 case | 0 case | |
| Persistent subjective symptoms (>1 month) | 4 cases (4/300 [1]) | 14 cases (14/211 [7]) | .0044a |
| Pain | 4 cases (4/300 [1]) | 6 cases (6/211 [3]) | |
| Neuropathy | 0 cases | 10 cases (10/211 [5]) | |
| Discomfort | 0 cases | 2 cases (2/211 [1]) |
Data are presented as number of cases and percentages.
No systemic reactions were observed in either group. Persistent subjective symptoms included pain, neuropathy, and discomfort, and were more common after TA than CAC.
Some patients experienced more than one symptom.
Boldface P values indicate statistical significance.
Statistical comparisons were performed using Fisher’s exact test.
Discussion
Although CAC and TA are widely used minimally invasive treatments for varicose veins, their detailed clinical characteristics of postoperative skin and soft tissue adverse reactions have not been fully described. In this study, such adverse reactions occurred more frequently after CAC than after TA, and CAC produced a broader spectrum of clinical manifestations. We identified five reproducible types—allergic contact dermatitis, phlebitis, exacerbated edema with induration, generalized urticaria, and foreign-body granuloma—each with onset timing and duration.
The mechanisms underlying CAC-related skin and soft tissue reactions remain incompletely understood. Although Type IV hypersensitivity has been reported,5, 6, 7, 8, 9 other factors such as phlebitis, local chemical irritation, patient comorbidities, baseline skin condition, procedural technique, and anatomical features may also contribute. Formaldehyde, a known degradation product of cyanoacrylate, can cause local tissue irritation or injury.18 In our cohort, hypertension was significantly more common among patients who developed reactions, whereas diabetes mellitus was not. The frequent use of calcium channel blockers in patients with hypertension may exacerbate peripheral vasodilation and edema,19 potentially increasing susceptibility to inflammatory responses.
Disease severity also appeared relevant. Inflammation in CEAP C3 disease may extend through subcutaneous tissues, whereas in C4b disease it may remain more localized, with inflamed areas becoming particularly hypersensitive. Reaction rates were also higher in GSV than SSV treatment, and all reactions occurred when below-knee access was used, suggesting that shallow vein depth increases tissue exposure to cyanoacrylate. Moreover, longer treated segments may theoretically result in greater cyanoacrylate exposure to the intravascular surface area. Further studies are needed to clarify the clinical relevance of these associations.
Although many CAC-related adverse reactions resemble type IV hypersensitivity, most resolved without excision, differing from classical type IV allergy in which symptoms persist until antigen removal. This discrepancy may be explained by two factors.
First, not all reactions are immunologically mediated; many involve phlebitis or nonspecific inflammatory pathways. Second, immune responses in the vascular tissue may differ from those in the cutaneous tissue. Understanding these mechanisms is important for improving diagnosis and management.
The five-type clinical classification further supports the idea that CAC-related adverse reactions arise from multiple pathogenic pathways. In reactions dominated by allergic contact dermatitis, concomitant phlebitis-like features may have been present but masked by more extensive and prominent cutaneous manifestations.
Cyanoacrylate can persist intravascularly for long periods, allowing delayed acquired hypersensitivity. Experimental studies show a progression from acute inflammation to vasculitis and then granulomatous reactions,20 and foreign-body granulomas after CAC have been reported to persist for years, including a case reported 5.5 years after treatment.21,22 Whether these represent allergic, foreign-body, or mixed mechanisms remains uncertain.
Careful patient selection therefore remains central to prevention. Although preoperative patch testing could theoretically identify cyanoacrylate allergy, it is unreliable in patients without prior exposure and may itself induce sensitization. Moreover, it lacks sufficient diagnostic accuracy for screening.23 Cyanoacrylate is also widely used on the skin for surgical wound closure and in cosmetics, such as eyelash and nail extensions, where reports of type IV allergic reactions are increasing.23, 24, 25, 26, 27
Consequently, particular attention should be paid to a patient’s history of prior cyanoacrylate exposure when considering CAC treatment. However, prior exposure is insufficient for risk stratification, as cyanoacrylate can induce sensitization even upon first exposure,7 and first-exposure type IV reactions are also recognized in dermatology.27
Therefore, CAC should be avoided in patients with a history of adhesive allergy or multiple allergies, for whom TA remains a suitable alternative. Furthermore, other non-cyanoacrylate non-thermal devices such as foam sclerotherapy and mechanochemical ablation are valid alternatives to patients with history of allergic reactions. Although minimizing skin contact with glue is ideal, complete avoidance is not feasible because of the transdermal injection technique. Premedication may help the early inflammatory responses,4 as suggested in other clinical contexts, including transplantation and ischemia-reperfusion injury. Further studies are needed to develop strategies that mitigate postoperative reactions.
This study has several limitations. First, it was a single-center retrospective analysis without standardized grading of skin symptoms. In addition, mild adverse reactions that were resolved spontaneously or with topical treatment alone were excluded; therefore, the true incidence of skin and soft tissue adverse reactions may have been underestimated.
Most patients in our cohort were CEAP C3 or C4, so results may differ in other CEAP classes. Furthermore, the follow-up duration of up to 1 year may be insufficient to evaluate delayed or persistent reactions, particularly granulomatous responses. Prospective studies with extended follow-up are warranted.
Conclusions
CAC was associated with more complex and delayed skin and soft tissue adverse reactions, with variable onsets and durations compared with TA. Although the underlying mechanisms and preventive strategies remain incompletely understood, patients with hypertension, CEAP C3 disease, and those undergoing GSV treatment via below-knee access are at higher risk for CAC-related adverse reactions. We classified these reactions into five distinct clinical types, each demonstrating characteristic patterns of onset and duration, highlighting the heterogeneous nature of CAC-related adverse reactions. Recognizing this spectrum is crucial for patient selection, counseling, procedural techniques, and postoperative monitoring. Further long-term studies are warranted to clarify the biological behavior of intravascular cyanoacrylates and to develop effective strategies for preventing CAC-associated skin and soft tissue complications.
Author Contributions
Conception and design: KS, TM
Analysis and interpretation: KS
Data collection: KS, MY, TM
Writing the article: KS
Critical revision of the article: KS, MY, TM
Final approval of the article: KS, MY, TM
Statistical analysis: KS
Obtained funding: TM
Overall responsibility: TM
Funding
None.
Disclosures
None.
From the American Venous Forum
Footnotes
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest.
References
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