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Complications After Using Cyanoacrylate Glue in the Treatment of Venous Insufficiency
© 2024 HMP Global. All Rights Reserved.
Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of Vascular Disease Management or HMP Global, their employees, and affiliates.
VASCULAR DISEASE MANAGEMENT 2024;21(5):E33-E38
Abstract
Venous insufficiency consists of changes in the lower limb and discomfort associated with increased venous pressure. Based on the degree of severity, the condition can range from reticular veins to even an acute ulcer. The use of cyanoacrylate glue for treating this condition is increasingly becoming popular, but there are some complications associated with the method. This review article aims to summarize the information regarding the complications of using cyanoacrylate glue, along with their prevention and management, in detail to help clinicians make informed decisions while administering this treatment method.
Introduction
Venous insufficiency is typically manifested by swelling of the lower limbs, changes in skin condition, and discomfort resulting from increased venous pressure. Disorders associated with venous insufficiency can significantly reduce a patient’s productivity and quality of life. In many cases, this condition is caused by ineffective functioning of the valve of the vein wall. The stages of venous insufficiency can be classified from C0 to C6, according to the clinical, etiological, anatomical, and pathophysiological (CEAP) classification, where C6 denotes the most severe stage. C0 indicates no obvious feature of venous disease, C1 represents the presence of reticular or spider veins, C2 represents obvious varicose veins, C3 represents the presence of edema but no skin changes, C4 represents skin discoloration or pigmentation, C5 denotes an ulcer that has healed, and C6 denotes an acute ulcer.1
Different treatment methods are available for each stage of venous insufficiency.1 Treatments for spider veins include sclerotherapy, intense pulse light treatment, thermocoagulation, and microphlebectomy.2 Treatments for varicose veins include conventional surgical stripping, endovenous thermoablation, radiofrequency ablation, foam sclerotherapy, ambulatory phlebectomy, and cyanoacrylate closure (CAC) procedures.3-5 Treatments for edema include laser ablation, radiofrequency, and steam ablation.6
The CAC procedure involves the delivery of cyanoacrylate glue into the vein. This glue initiates an immediate inflammatory reaction in the vein wall through a polymerization process, which leads to the formation of a protective barrier and the development of fibrosis of the vein tissue. The increased thickness of the glue and the polymerization characteristics allow precise placement in the vein.7 A low rate of complications has been reported.8 These complications include extravasation of the glue, hypersensitivity reaction, septicemia, skin hyperpigmentation, and glue-induced thrombosis. Understanding these potential complications and their appropriate management is essential, especially as the use of cyanoacrylate glue for the treatment of venous insufficiency becomes more widespread.9-14
To our knowledge, there has been no review conducted in the past to summarize all the information available regarding the complications of this procedure. This review article aims to collate the available information and describe these complications, as well as their prevention and management, in detail.
Cyanoacrylate Glue
Cyanoacrylate glue is a liquid embolic material that polymerizes on contact with blood, resulting in blood vessel occlusion. It has found extensive use in the occlusion of cerebral venous and arterial anomalies and cerebral aneurysms, and in treating conditions involving the ovarian and spermatic veins.14 Initial trials for its use in treating venous insufficiency were done in 2013, and by now, its use for the same has been established.15
Benefits of Cyanoacrylate Glue
The CAC procedure does not require the use of tumescent anesthesia and carries no risk of nerve damage from heat. Many studies have demonstrated the safety and efficacy of the CAC procedure for treating superficial venous insufficiency. In a randomized controlled trial comparing surgical stripping with the CAC procedure, both groups showed complete occlusion of the target veins at a 100% rate at 3 months. In addition, both groups showed similar improvements in quality of life, and the CAC group experienced significantly less pain and bruising.14,16
In another trial comparing the CAC procedure with radiofrequency ablation, the CAC procedure demonstrated a 99% closure rate at 3 months, compared with a 96% closure rate with radiofrequency ablation. There was a trend toward a preponderance in favor of the CAC procedure. Pain levels were comparable between the 2 methods, with less bruising observed in the CAC group.14,17
Patients can usually return to regular activities just 1 hour after the procedure. In addition, the shorter duration of the procedure and the absence of tumescent anesthesia can allow the treatment to be performed in a clinic, which leads to time and cost savings.14
Complications of Cyanoacrylate Glue
The CAC procedure is a safe treatment method with potentially no immediate complications, and the patency of the deep venous system may remain intact after treatment has ended. However, some evidence suggests a minimal incidence of complications, including issues such as extravasation, complex hypersensitivity and irritation reaction (CHAIR), septicemia, skin hyperpigmentation, and endovenous glue-induced thrombosis (EGIT). These reported complications are generally mild. They can be effectively managed with noninvasive measures or on an outpatient basis. However, given its relatively recent introduction, health care professionals should exercise caution when using this procedure in clinical practice and watch for rare complications.8-12,14 Patients should be educated about the potential adverse outcomes of the CAC procedure before undergoing treatment.
Endovenous Glue-Induced Thrombosis
EGIT is a common complication of the CAC procedure, which can sometimes prove to be worrisome.11 EGIT is characterized by migrating glue-thrombotic mixture from the proximal part of the great saphenous vein (GSV) toward the sapheno-femoral junction (SFJ) with varying involvement.18 Simply, it means a blood clot spreads into a deeper vein.11
Most cases of EGIT are identified within the first 1 to 2 weeks of follow-up.18 Clinical studies show a variable incidence ranging from 0% to 21.1%. In a retrospective study, it was observed that 11 of 191 patients experienced EGIT, and each had a different pattern of extension of the thrombus into the deep vein. The most frequently observed shape was a slender, threadlike extension of the thrombus into the deep vein, which could be attributed to the pressure applied to prevent migration of the cyanoacrylate glue into the deep vein during the procedure.11
The incidence of EGIT is influenced by various factors, including the composition of the fluid in the vein, the type of vein, and the rate of insertion of the cyanoacrylate glue. This suggests that anatomic variables such as the diameter of the venous vessels, the length of the treated vein, and the mode of branching also contribute to the occurrence of EGIT. A retrospective study described risk factors such as older age, diabetes, hypertension, hyperlipidemia, and lack of anticoagulation.18,19 Another study stated that a small saphenous vein under 5 mm in diameter is a risk factor for the development of EGIT. In addition, the study proposed creating a categorization system and therapeutic regimen for EGIT depending on the extent of thrombus expansion into the deep vein.11 The Kabnick and Lawrence classification system can be used for the same, where level 6 denotes the most severe phase of EGIT. According to this categorization, level 1 means an extension of EGIT below the point where the epigastric vein is located. Level 2 indicates EGIT that extends to the same level as the origin of the epigastric vein. Level 3 means the extension of EGIT to the same level as the SFJ. Level 4 characterizes EGIT that extends into the common femoral vein (CFV). Level 5 describes EGIT that adheres to the adjacent wall of the CFV behind the SFJ. Finally, level 6 indicates the extension of EGIT into the CFV, which is consistent with deep vein thrombosis.18,20
To minimize the risk of EGIT, it is advisable to consistently administer the cyanoacrylate glue in the entire range of the target vein in a uniform concentration.18,21 Although the treatment policy for EGIT has not yet been established, there is a low possibility that EGIT will naturally progress to hematoma expansion. In its initial stages, follow-up observation through ultrasound examination is required, and in an advanced stage, anticoagulant treatment is recommended. A retrospective study stated that usually, this complication does not require a separate treatment model. Instead, its conservative management is the way to cure it.22 On average, its resolution can take up to 5 to 6 weeks after initial detection.18
Complex Hypersensitivity and Irritation Reaction
A significant complication after the CAC procedure is an inflammatory reaction, which results in symptoms such as pain, warmth, itching, localized tissue induration, redness, and widespread skin scarring. Although the exact cause of this complication has not been documented, clinical and pathological observations have suggested that it occurs due to glue injection during the procedure.10 A prospective observational study termed this complication a phlebitis-like abnormal reaction.9 Various terms have been used over the years for this complication until 2021, when a study finally used the term CHAIR to characterize this distinct complication based on the documented clinical manifestations.10
Although first-in-human studies did not mention this complication, the studies conducted after that have reported this complication up to an extent. A study suggests that this complication rate could be substantially higher than previously documented in published research (0-25%).9,15,23,24 Seventy-two percent of these complications are reported to be mild, 22% moderate, and 6% severe.25
A retrospective study reported that no patient who was treated for small saphenous veins was diagnosed with CHAIR. All CHAIR-diagnosed patients were from the group of patients who were treated for the GSV. In all of the CHAIR cases, the site chosen for introducing the glue was placed below the level of the knee joint. A research study documented an adverse event characterized as abnormal skin redness, which was believed to be a delayed hypersensitivity reaction to the cyanoacrylate glue. Despite the similarity to phlebitis, this reaction generally manifested as a more extensive skin disease, appearing 7 to 14 days after the procedure, with a tendency to occur at the GSV site, mainly in women. This condition is self-limiting, and treatment with anti-inflammatory drugs is considered only when patients experience discomfort. The research further clarified that this reaction originates from local inflammation following the injection of the cyanoacrylate glue.10,26,27 The study found no identifiable patient procedural factors, or even a history of previous CAC procedures, as a predictive factor for these hypersensitivity reactions. The only notable observation was a lower risk of these reactions in patients falling into advanced clinical classes of the CEAP classification.25
To reduce the likelihood of CHAIR, it is advisable to refrain from using cyanoacrylate glue in individuals with known allergies to adhesive materials, including those associated with false eyelashes and nails.25 In all cases, the delivery catheter should be removed carefully to avoid leaving adhesives in the subcutaneous tissue.28 Patients affected by CHAIR should use nonsteroidal anti-inflammatory drugs and antihistamines to treat the complication.10 In cases where a patient shows signs of suspected hypersensitivity, the initial course of action should include the administration of topical corticosteroids. Subsequently, oral corticosteroids and antihistamines should be considered. If a hypersensitivity reaction persists despite this treatment, it is advisable to refer the patient for hypersensitivity testing to confirm a specific reaction related to the performance of CAC.24 A 6-day tapered course of oral steroids should be given for the treatment of patients with moderate hypersensitivity reactions; if the symptoms are not completely resolved by the end of the first 6-day course, the patient should be given additional 6-day steroid tapers in sequence.25
Septicemia
Septicemia refers to a bacterial infection that affects the bloodstream. It can manifest as increased body temperature and, in more severe cases, can lead to circulatory failure due to dilation of blood vessels, leakage from small blood vessels (capillaries), and a reduction in the heart's ability to contract effectively.29 The occurrence of this complication after using cyanoacrylate glue is more common for bleeding gastric varices than for venous insufficiency. Still, it cannot be ignored as it can prove fatal if not treated in time.2,30-33
In 2022, Nishizawa and Kudo documented a case where a patient developed symptomatic septicemia after a CAC procedure, requiring surgical removal of the treated saphenous veins. Initially, after completing the CAC procedure, no anatomical abnormalities were observed, and postoperative hematoma did not develop. However, in the following days, the patient complained of pain and warmth in the left calf and redness and swelling of the left lower limb. The patient also presented with a fever ranging from 37°C to 38°C. A foreign body reaction, potentially triggered by the CAC procedure, was suspected as the cause. Oral steroids were initially administered for treatment, but 2 blood cultures later confirmed the presence of methicillin-sensitive Staphylococcus aureus. Subsequently, antibiotics were prescribed and surgery was performed under tumescent anesthesia for bilateral excision of both small saphenous veins. This complication can prove to be fatal if not treated in time.12
Skin Hyperpigmentation
Skin hyperpigmentation is a common dermatological condition resulting in a darkening skin tone. These changes in skin color can come from various internal and external influences, such as hormonal fluctuations, inflammation, trauma, acne, eczema, specific medications, exposure to ultraviolet radiation, and other factors.34-37
One of the complications reported after the use of cyanoacrylate glue for venous insufficiency is skin hyperpigmentation, though there is a lack of clinical studies with large patient cohorts.8 This complication can occur in around 3% to 12% of treated patients and remain even after 12 months of the initial treatment.15,38
In 2019, Hwang et al conducted a study to evaluate the effectiveness and safety of CAC of an incompetent GSV and to assess the regression of varicose veins following CAC without a concomitant procedure on 48 patients. The result showed this procedure to be effective in treating varicose veins, but there were some complications as well. Skin hyperpigmentation occurred in 13.3% of the patients compared with CHAIR, which occurred in 16.7% of the patients. However, skin hyperpigmentation stayed longer than CHAIR, even after a 12-month follow-up.39
Extravasation
In rare cases, the CAC procedure may result in extravasation, which may further lead to persistent foreign body reactions requiring surgery. This problem can cause extensive inflammation in the outer layer of the skin and the tissue just below it, characterized by lymphoid clusters, eosinophils, and foamy histiocytes around the leaked glue. This pattern is consistent with a foreign body-like response.8 A study reported the occurrence of subcutaneous granuloma in a patient at the site of vein cannulation in the upper calf as a mildly painful lump with skin erythema around. A duplex ultrasound revealed the glue extravasation with a skin inflammatory reaction. To cure it, glue extraction was done distantly from the cannulation point.40
This complication can occur even when there have been no immediate complications or difficulties after the initial treatment. It has been reported that it can occur up to 9 months after the initial treatment. The etiology of such delayed extravasation remains elusive. However, cases have been documented suggesting a plausible mechanism involving a chronic immunological response to cyanoacrylate glue, leading to subsequent damage to the vessel wall. Another possible explanation could be that when pressure is applied after the glue is installed per the manufacturer's instructions, the glue may be forced into the small branch, causing it to rupture, leak, and subsequently trigger a foreign body reaction. As a result, it is advisable to be careful and apply moderate pressure during this compression process.8
This complication is particularly significant due to the inflammation extending into the nearby skin, necessitating surgery, its unexpected occurrence several months after treatment, and its adverse impact on aesthetic outcomes and patient satisfaction. Studies suggest that doctors should inform patients about this complication before the treatment and include it in the consent form.8,41
Conclusion
The occurrence of complications after the CAC procedure is coming to light more as its use has increased over recent years. These complications cannot be completely ignored because many of them can have long-lasting effects on the quality of life of the patient, even proving to be fatal. CHAIR is the most common complication, with a possible occurrence rate of above 25%. However, the most serious complication is septicemia, as it can prove to be fatal if not cured in time. With proper knowledge and awareness about these complications, many can be treated in the early stages or even prevented from occurring. n
The authors report no financial relationships or conflicts of interest regarding the content herein.
Manuscript accepted April 24, 2024.
Corresponding Author: Mitesh Mohan Hood, Pristyn Care, Capital The Cityscape, Badshahpur, Sector 66, Gurgaon, Haryana, India 122102. Email: mitesh.hood@pristyncare.com
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