Servier – Phlebolymphology

XIV. Complications and failures in
phlebological treatment

Underuse, overuse, or misuse of the phlebological treatment? – treatment overuse or insufficiently
trained operators
Martin Schul (US)
Martin Schul presented a clinical case and an example treatment overuse. In one patient, an ablation procedure was performed for three veins, but there was no evidence of reflux in any image. We have benchmarks of 1.6 to 1.7 ablations per patient. Overutilization is widespread and involves every specialty. Underutilization is often in patients with leg ulcers. They required on average 0.37 more ablation procedures vs nonulcer patients. On the other hand, early intervention was associated with lower disease progression. Each 30-day delay was associated with a 7% increase in the risk of progression and a 1% increase in the cost of care. In addition, patients receiving sclerotherapy had the lowest rate of new venous leg ulcers. Martin Schul concluded by saying that we have a collective duty to provide appropriate care using established benchmarks and to promote the “limb emergency for venous leg ulcers” in delivering care. Furthermore, we should provide educational venues for a growing field of wound care centers potentially entering the field.

Matting is the issue – how to avoid and treat
Kurosh Parsi (Australia)
Telangiectatic matting is small telangiectasias <0.2 mm that can appear sporadically or in well-defined patches, commonly on the lower limbs. The incidence of telangiectatic matting is up to in 25% of the patients postsclerotherapy, but it can happen after other venous interventions, such as surgery or laser ablation. Telangiectatic matting is commonly found concurrent with phlebitis and pigmentation; however, they can also happen for no reason, with no prior venous treatment. Matting is an enigma. It can be devastating and it can last for years. Some believe it goes away. Traditional risk factors are procedure related risk factors and patients-related risk factors. Procedure-related risk factors are not treating or incompetently treating the underlying feeding veins, injecting too quickly, using a large volume of injection per site, and using a high concentration of sclerosant. Patient-related risk factors are obesity, estrogen-containing hormones (oral contraceptive pill, hormone-replacement therapy), pregnancy, and a family history of telangiectasias. Inflammation causes endothelial activation and angiogenesis. High-risk areas are the subdermal reticular venous network in the anterior and anterolateral thighs and at the medial knee underlying the great saphenous vein, infragenicular veins, and supragenicular veins. Injection of some of the reticular veins cannot possibly treat and occlude all reticular veins. Ongoing flow from open veins will result in inflammation and matting. Reticular veins are normal vessels and should not be treated. Matting, pigmentation, and inflammation can happen together. Anecdotal observations reported that patients with telangiectatic matting are more often females, report a history of easy bleeding and bruising, and have an urticarial reaction at the site of injection. In a retrospective analysis, the patient-related risk factors were female sex, skin types I, II, and III, and a hypersensitivity and bleeding tendency, but not hemostatic abnormalities. In vitro studies have shown that detergent sclerosants at low concentrations activate cells: endothelial cell, keratinocyte, platelets, and leucocytes. In addition, it has been demonstrated that detergent sclerosant can also activate basophils. Activation of basophils and mast cells results in release of granule contents, including histamine. Histamine causes vasodilatation and induces a inflammatory response, which leads to angiogenesis, pigmentation, reactive dilatation of the surrounding vessel, and target vessel nonclosure. We can prevent inflammation and angiogenesis if we avoid treating high-risk areas. The feeders should be treated, as well as higher and more proximal sources of reflux. We should avoid high concentrations and sodium tetradecyl sulfate in subdermal veins. We should use compression. Patients should avoid strenuous exercise afterward because of inflammation. In a current study, Kurosh Parsi is investigating the effect of pretreatment with antihistamines and Cyklokapron (tranexamic acid) in patients predisposed to matting.

Hyperpigmentation after vein treatment. Dermatologists point of view
Eberhard Rabe (Germany)
The incidence of pigmentation is 10% to 30% of patients following sclerotherapy of vessels between 0.1 and 5 mm in diameter. Risk factors are solution strength, vessel fragility, injection pressure, and type of solution used. Histology data suggest that there is no melanocytic alteration. Pigmentation is secondary to extravasation of red blood cells into the dermis following rupture of fragile vessels with resulting deposition of hemosiderin. Therapy has included bleaching agents (hydroquinone), trichloroacetic acid, and phenol peeling agents with variable success. In 80% of cases, pigmentation will clear spontaneously within 6 to 24 months. The remaining patients will have persistence of pigmentation for up to 5 years, with a small number of patients having pigmentation persisting 5 years after therapy. Skin laser treatment has shown different results with 42% to 92% of the lesions lightened after treatment. In a study where deferoxamine mesylate was used, depigmentation was observed in 81% to 100% of cases. In another study, complete regression of hyperpigmentation was reported in 90.48% of the women after using an intense pulse light generator. In a multicenter, randomized trial, microthrombectomy was shown to reduce postsclerotherapy pigmentation. Eberhard Rabe summarized by saying that hemosiderin pigmentation is a common finding after sclerotherapy. Most of the studies are not controlled or they use small patient numbers. The only bigger randomized control trial shows a benefit of early microthrombectomy in small vessels.

Hyperpigmentation after vein treatment. Phlebologist point of view
Neil Khilnani (US)
Residual pigmentation after C1 sclerotherapy is common (1% to 10% of the population). In the EASI randomized control trial, 0.5% polidocanol liquid was compared with placebo. Pigmentation usually improved over 12 months, but was permanent in 10% of cases. There is only retrospective evidence about pigmentation after C2 sclerotherapy and the incidence is less precise because it is self-reported by patients. The primary biological mechanism is by deposition of hemosiderin. Melanin is responsible for postinflammatory hyperpigmentation. Inflammation stimulates increased melanin production with increased melanin leakage from melanocytes. Melanin pigmentation is more common in large diameter veins with more inflammation. Pigmentation can be related to the technique if the sclerosant is too strong (or even too weak) (thrombosis rather than sclerosis). It is more common with darker skin. Current strategies to minimize pigmentation are to treat the patient in a supine position, which minimizes hemolysis and bleeding, phlebitis, and intravascular coagulum. In terms of compression, there is a weak recommendation with low quality evidence. Removal of intravascular coagulum is recommended by most. Avoiding sun for 1 week is recommended, but the evidence is limited. Light-based (q-switched laser, intense pulse light/radiofrequency) have been tried. Neil Khilnani summarized by saying that pigmentation is common. The risks are higher with large-diameter veins and darker skin. The evidence in the literature is poor regarding compression, removal of trapped blood, and avoiding the sun. Microphlebectomy is an alternative for C1 and C2. There are many opportunities for research in this field, for example, new means of compression, new mechanical means for telangiectasia, and drugs.

Visual and neurological complications of sclerotherapy
Birgit Kahle (Germany)
If performed properly, sclerotherapy is an efficient treatment method with a low incidence of complications. Transient migraine-like symptoms may be observed after any kind of sclerotherapy. They occur more commonly after foam sclerotherapy than after liquid sclerotherapy. It has been suggested that a right-to-left shunt (eg, patent foramen ovale), which is present in approximately 30% of the general population, might be a factor allowing foam bubbles to pass into the arterial circulation. The frequency of occurrence is estimated around 1.5%. Visual disturbance symptoms, flickering lights, spots, lines, or scotoma in one or both eyes, are reversible. They correspond to migraine with aura, but no transient ischemic cerebrovascular events. Visual disturbances can be associated with paresthesia and dysphasic speech disturbance depending on the extension of cortical spreading depression in the cerebral cortex. Cortical spreading depression is a short lasting depolarization wave that moves across the cortex at a rate of 3 to 5 mm per minute. Cortical spreading depression is the pathophysiological correlate of migraine with aura.

Visual disturbances following sclerotherapy are similar to a migraine with aura after sclerotherapy in patients with a relevant patent foramen ovale. Triggers for cortical spreading depression include the release of endothelin 1 and microembolization with a decrease in cerebral oxygen saturation. Following sclerotherapy, there is a higher amount of endothelin 1 release because of larger volumes of sclerosant or basal augmented release from the endothelium. The presence of a patent foramen ovale with fast passage of endothelin 1–rich blood into the left ventricle could be a causal factor. Other factors are incomplete vein spasm immediately after injection, causing a prolonged release of endothelin 1 from the endothelium, patient variability (migraine patients), and concomitant drugs with an anti-endothelin action.

Strokes related to paradoxical clot venous embolisms usually occur with late-onset symptoms (liquid and foam). Strokes related to paradoxical air embolisms occur with early-onset symptoms, which is a specific complication of foam sclerotherapy. In early onset neurological disturbances (“strike”), no intracerebral clots and no correspondence with thromboembolic pathology have been found. Air bubbles in brain arteries have been reported with (nearly) complete recovery.

Birgit Kahle concluded by saying that sclerotherapy is safe. Documented severe neurological complications (transient ischemic attack, stroke) are very rare – only isolated case reports. Visual disturbances following sclerotherapy are very rare (<0.01%) when liquid sclerosants were used and uncommon (0.1% to <1%) when foamed sclerosants were used. Visual disturbances are reversible. We should take care when treating patients with migraines. EHIT and ostial thrombotic complications after saphenous ablation – do we need routinely follow up the patients with US? Lowell Kabnick (US) There are 4 classes of endothermal heat-induced thrombosis (EHIT): (i) in class 1, there is a thrombus extension up to saphenofemoral and saphenopopliteal junctions; (ii) in class 2, there is a thrombus extension into the deep venous system, with a cross-sectional area <50%; (iii) in class 3, there is a thrombus extension into the deep venous system, with a cross-sectional area >50%; and (iv) in class 4, there is a compete occlusion of the deep vein. The incidence of EHIT is low: total for all classes is 3% to 4% and the total for class 2 is 1% to 2%. The incidence of pulmonary embolism with EHIT is a maximum of 0.03%. In a short series by Lowell Kabnick, 9 patients were followed up with class 2 EHIT and all patients were monitored with serial duplex. Of these patients, 8 were placed on therapeutic low-molecular-weight heparin and all patients obtained resolution of EHIT within 14 days. After resolution of EHIT, chest CTs showed a pulmonary embolism in 2 of the 9 patients, but all patients were asymptomatic. None suffered significant sequelae. The rate of closure in the immediate postoperative period is around 99%. If we do not look for EHIT, we can save 300 000 duplex scans per year in the US alone (ie, $100 to $150 million). With the data and the unclear clinical significance of EHIT, the policy of universal screening after endovenous ablation should be revised in the near future. At most, 30 patients a year will have a clinically significant pulmonary embolism. However, 72 patients will bleed from therapeutic low-molecular-weight heparin. Refraining from mandatory duplex screening would save approximately 150 million US health care dollars. Postoperative morbidity and mortality rates would not change. Duplex screening in the postoperative period is wasteful and not efficacious for the prevention of complications or treatment failure.

Lowell Kabnick finished with the statement that routine postthermal ablation duplex screening is a waste of time, effort, and money.

A multicentric study on the role of heparin prophylaxis of thrombotic complications in foam sclerotherapy (the Prosclep study)
Alessandro Frullini (Italy)
In a retrospective study, assessment of thrombotic adverse events and treatment patterns associated with varicose vein treatment was conducted with health care claims data. The incidence of deep vein thrombosis was 4.4% after radiofrequency, 3.1% after laser ablation, 2.4% after surgery, and 0.8% after sclerotherapy. The incidence of pulmonary embolism was 0.3% after radiofrequency, 0.3% after laser ablation, 0.3% after surgery, and 0.2% after sclerotherapy. Thrombotic complications after sclerotherapy are the result of two different conditions: progression of the sclerus in the deep venous system and occlusion of a deep vein not in continuity with the sclerus. Progression of the sclerus in the deep venous system is usually a self-limited condition. It is usually asymptomatic and very rarely causes total occlusion. It usually follows with full resolution or resolves after a short treatment with low-molecular-weight heparin. Occlusion of a deep vein not in continuity with the sclerus manifests itself as an occlusion of a muscular vein, with a lower tendency for spontaneous resolution and it is often painful.

Thrombotic complications after sclerotherapy may have no or poor clinical evidence. The Prosclep study, a multicenter prospective study on sclerotherapy, was conducted at 16 vein centers. Sclerotherapy was performed with polidocanol or sodium tetradecyl sulfate (1% to 3% (liquid or foam). Low-molecular-weight heparin prophylaxis was given in 56.3% of the patients, whereas there was no prophylaxis in 43.7%. Deep vein thrombosis after sclerotherapy of the great saphenous vein was found in 0.31% of the patients with prophylaxis and in 1.91% without prophylaxis (significant results). Deep vein thrombosis after sclerotherapy of the small saphenous vein was found in 2% of the patients with prophylaxis and in 1.88% without prophylaxis (not significant results). No complications were observed after sclerotherapy of the accessory anterior vein, recurrences, and large tributaries. In conclusion, sclerotherapy carries a very low risk of thrombotic complications. Heparin prophylaxis is advised in sclerotherapy of the great saphenous vein, as it significantly reduces the risk of thrombotic complications. There are not enough data on the role of heparin prophylaxis for the treatment of perforators and small saphenous vein sclerotherapy. There is no need for heparin prophylaxis in sclerotherapy of recurrences, large tributaries, and the accessory anterior vein. The Prosclep study confirms that thrombosis after sclerotherapy is a rare and minor complication that resolves after a short course of anticoagulation.

NTNT ablation complications can happen – how to deal with it?
Frantisek Zernovicky (Germany)
Thermal tumescent operations include lasers with different wavelengths, radiofrequency, and hot steam. They cause complete transmural lesions of the vein wall. Tumescence protects surrounding tissue and requires identification of the saphenous compartment, safety function of the compartment, and compression of the saphenous compartment. Nonthermal nontumescent operations include mechanochemical ablation (Clarivein, Flebogrif), cyanoacrylate glue (Venaseal, Variclose), V-Block (VVT Medical), and duplexguided foam sclerotherapy (Varithena BTG). Clinical data on these methods showed good outcomes, noninferiority to endovenous thermal ablation, and an improvement in venous clinical severity score and Aberdeen Varicose Vein questionnaire. VenaSeal procedures may have preferable indications for immobile, hypomobile patients, for patients with unfit anatomy, the Giacomini vein, extremely obese patients, patients with lymphedema, patients with lipedema, patients with severe posttraumatic changes and mixed leg ulcers. A summary of clinical evidence with VenaSeal system concluded with an acceptable safety profile; side effects were minor and infrequent. One disadvantage is that the system is still not as precise as laser or radiofrequency ablation. Another disadvantage is postoperative redness. Cyanoacrylate glue is a permanent implant with nonequal degradability, with filling of a foreign body, tension during movement, persistent tangible resistance. Glue can cause fast progressing granulomatic reactions.

Frantisek Zernovicky presented a clinical case of a 54-old female, polymorbid with a high risk of bleeding and development of a granulomatous reaction. Immunohistochemical visualization showed a necrobiosis lipoidica–like reaction. It was necessary to perform saphenectomy in this patient. The first symptoms of a granulomatous reaction are an indication for an immediate saphenectomy. The warning signs are painful resistance in the previous position of the vein, hypoechogenic brightening around the treated vein, a moving shadow of the glue, a growing granuloma deforming the saphenous compartment, and negative microbiology.

Granuloma formation following cyanoacrylate glue injection in peripheral veins and arteriovenous malformations
Kurosh Parsi (Australia)
Kurosh Parsi presented the n-butyl cyanoacrylate (n-BCA) products available for the treatment of peripheral veins: VenaSeal, Venablock, Veinoff, and Variclose. The long-term pathological reactions to cyanoacrylate glue are unknown in human veins. A histology study showed that perivascular mast cell degranulation occurred 10 minutes after glue injection, and a recent clinical case report demonstrated suppurative granulomas with extrusion of n-BCA 4 months after bilateral great saphenous vein treatment with VenaSeal.

The aim of a study by Kurosh Parsi was to characterize the late tissue reactions to n-BCA injection and determine whether this process involves a granuloma formation and immune activation. Two patients were included. On ultrasound, the injected glue appeared echogenic and produced a shadow artifact. On histopathology after 1 week, glue was seen in the vein lumen, presenting as a homogeneous eosinophilic material that was crystallized to produce a snowflake-like appearance. Six weeks later, histiocytes, but no granulomas were evident. One year later, fibrosis, cavitated granulomas, extrusion of glue, and lymphocytic infiltrate were present. This study was the first longitudinal histological study in humans following the use of n-BCA in the treatment of peripheral vessels. Tissue response to cyanoacrylategine is as follows: mast cell degranulation occurs after 10 minutes, followed by acute inflammation, polymorphonuclear cells after 1 to 2 days, foreign body giant cells after 2 to 3 weeks, fibrosis and wall thickening after 8 weeks, and extrusion of n-BCA to the perivascular space, extravascular cavitated foreign body granulomas, lymphoid hyperplasia, and fibrosis of the surrounding tissue after 1 year.

Kurosh Parsi concluded by stating that n-BCA causes delayed extravascular granuloma formation, glue extrusion, and lymphoid hyperplasia in the absence of clinical signs.