Chapter 7 Chemical Ablation

Historical Background

Historical data suggest that chemical ablation of the great saphenous vein (GSV) using liquid sclerosant delivered percutaneously via syringe and needle will fail (recanalize) in over 50% of cases at 1 year. Sclerotherapy in Europe became less frequently performed in the latter part of the 20th century, at least in part, because of the work of Hobbs.¹ His 10-year randomized controlled study showed the clinical recurrence of varices was common in patients with truncal saphenous reflux managed with sclerotherapy.² Hobbs found that after 10 years, 71% of patients treated with traditional surgery for saphenous incompetence had a good outcome; this compared with only 6% of patients treated by sclerotherapy. Recent scientific evidence has shown that liquid sclerotherapy is not very effective at eliminating truncal saphenous incompetence and failure to eliminate reflux leads to early recurrence of varices. Scientific evidence is limited when comparing sclerotherapy and surgery due to the fact that many of the trials had methodologic flaws such as lack of evaluation by independent observers, high dropout rates, poorly defined outcomes, and the lack of intention-to-treat analyses.^3,⁴ However, despite these defects, most of the studies clearly demonstrated very high recurrence rates of varicose veins after sclerotherapy, ranging from 20% to 70%.

Investigators have shown that if endothelial damage is not extensive, thrombi will form and layer endoluminally. Some thrombus is expected because of platelet deposition and initiation of the intrinsic coagulation pathway once collagen is exposed; however, excessive thrombosis is undesirable because it can lead to recanalization of the vessel. Furthermore, excessive thrombus can lead to perivenous inflammation resulting in patient discomfort on an acute basis and unwanted pigmentation of the surrounding skin thereafter.

Etiology and Natural History of Disease

Sclerotherapy refers to the introduction of a drug into the vein lumen for the specific purpose of producing endoluminal fibrosis and subsequent vein closure. Clinically, the reason vein closure is desired is to mitigate the effects of venous hypertension caused by retrograde venous flow; however, other reasons are also present in clinical practice. The mechanism of action of sclerosing solutions is directed toward complete destruction of the endothelial cells lining the venous lumen, exposure of subendothelial collagen fibers, and, ultimately, the formation of a fibrous cord. In accomplishing this process, sclerosing agents must significantly alter the endothelium and to a lesser extent the media of the vein wall. The most important qualities that a sclerosant should possess are safety, efficacy, and lack of untoward side effects. Other important features should be the ability to produce durable and repeatable results, painless treatments, accurate placement with ultrasound guidance, ease of availability, and low cost.

The efficacy of sclerosing agents is a function of concentration and vein diameter.⁵ If the target vein diameter is greater than 3 mm, liquid sclerosants do not properly reach the vein wall secondary to dilution. Sclerosant in the form of foam has clearly improved the results of sclerotherapy. Foam is more efficacious than liquid⁶^–⁸ and is more readily monitored with ultrasound imaging. Foam is the reason chemical ablation has made a resurgence. Foam will expand and fill a vein of less than 12-mm diameter, offering better contact with the vein wall. Cabrera and colleagues⁹ published a clinical series of 500 lower limbs treated with foam sclerotherapy and reported that after 3 or more years, 81% of treated great saphenous trunks remained occluded and 97% of superficial varices had disappeared. This required one session of sclerotherapy in 86% of patients, two sessions in 11% of patients, and three sessions in 3% of patients.

Sclerosants

Sclerosing solutions are categorized as either detergent, chemical, or osmotic; in the United States, although many are used, only one drug is approved by the U.S. Food and Drug Administration (FDA). Sodium tetradecyl sulfate (STS) was originally approved by the FDA for manufacture by Elkins Sinn in 1946. Under the Elkins Sinn trade name Sotradecol, STS became the preferred agent for sclerotherapy. In Europe, the popular sclerosants are STS 1% to 3% (Fibrovein; STD Pharmaceuticals, Hereford, UK) and polidocanol (POL) 0.5% to 3% (Sclerovein; Resinag AG, Zurich, Switzerland). The sclerotherapy community is therefore limited in its choices of drug, and currently investigators are focused on two methods of enhancing sclerotherapy—one method changes the biologic behavior of the drug, and the other method alters the drug delivery system.

When Elkins Sinn discontinued production of Sotradecol in the United States in 2000, a nationwide shortage ensued. Since no other manufacturer had FDA approval to produce STS, compounding pharmacies were the only source from which physicians could obtain this agent. The shortage of STS and the stopgap role of compounding pharmacies ended in November 2004 when the FDA granted approval to Bioniche Pharma USA, Inc. (Belleville, Ontario, Canada) to manufacture STS in 1% and 3% strengths. Today, FDA-approved Sotradecol is manufactured by Bioniche Pharma in an FDA-approved facility and sold exclusively by AngioDynamics, Inc. (Queensbury, NY). In a study of compounded STS versus pharmaceutical-grade STS, several findings were reported.¹⁰ Compounded STS was found to contain measured levels of impurities, the most important of which was carbitol. Analysis of pharmaceutical-grade STS revealed no detectable levels of impurities. Although the level of STS impurity necessary to precipitate a clinical event is unknown, impurities in other drugs have been linked to significant unexpected adverse events. Concentrations of different compounded STS formulations showed significant variation when measured by an independent laboratory. In one sample, the concentration was 20% below the desired 3% concentration level.

Regarding efficacy, in the compounded STS group 45.7% of treated great saphenous veins demonstrated segments of incomplete ablation some time during follow-up. In the pharmaceutical-grade STS group, incomplete ablation occurred in only 12.5% of veins (p = .02).

Patient Selection

Sclerotherapy is a good choice for the treatment of nonsaphenous varicose veins, residual veins after surgical correction of axial vein reflux, and recurrent varicose veins secondary to neovascularization or incompetent perforating veins. Sclerotherapy is also the treatment of choice in spider telangiectasias, venectasias, and isolated reticular veins.¹¹ The mode of action is induction of irritation of the vein wall followed by inflammation and fibrosis. Different agents are used such as hypertonic glucose that act by dehydrating the endothelium and substances like ethanolamine oleate⁸ that have a detergent effect in the endothelial layer.

Operative Steps

The three different methods of injecting large veins are:

1. Fegan’s method: In this method the distal perforators are injected first followed by the proximal veins.¹² The saphenous trunk and the junctions are not injected. This is followed by prolonged strong compression with bandaging from bottom to top in order to minimize thrombophlebitis and induce fibrosis.

2. Tournay’s method: In this method the proximal points of reflux are injected, including the saphenofemoral and saphenopopliteal junctions (SFJs and SPJs, respectively). The final step is distal injection. Short periods of local compression are used.¹³

3. Sigg’s method: In this method, the most distal varicose vein is injected first, followed by proximal stepwise injection until the most proximal reflux point is reached. Following the procedure, prolonged compression is used ¹⁴ (Figs. 7-1 through 7-5).

Fig 7–1

Fig 7–2

Fig 7–3

Fig 7–4

Fig 7–5

Imaging

Recent trends have demonstrated a growing use of duplex-guided sclerotherapy, which was first described in 1989.¹⁵ It not only minimizes the chances of intraarterial injection and extravasation but also allows the estimation of the degree of spasm, length of vein treated, and position of the deep veins (Figs. 7-6 and 7-7).

Fig 7–6

Fig 7–7

Foam Sclerotherapy

A recent revolution in the treatment of venous disease has been the emergence of foam sclerotherapy. Egmont James Orbach in 1944 first proposed the use of foam generated by a simple process of shaking a sclerosant with air. However, interest faded because it could only be used for small veins owing to large bubbles and a high air-to-liquid ratio.¹⁶ The renaissance of foam sclerotherapy is credited largely to the work of Cabrera et al.¹⁷ and Monfreux et al.¹⁸ in the 1990s.

Foam for the purpose of vein wall destruction is a nonequilibrated dispersion of gas bubbles in a sclerosing solution in which the gas fraction is 0.5221 or greater. The foam is composed of tiny bubbles of gas covered by a tensioactive liquid.¹⁹ Small bubbles make the foam highly interactive, whereas large bubbles produce ineffective foam. The foam mechanically displaces the blood and comes into contact with the endothelium. Therefore, the same concentration of the sclerosant is suitable for large and small veins. There is sufficient clinical evidence to demonstrate several advantages of foam preparations over conventional liquid sclerotherapy^6,²⁰:

1. Liquid sclerosants are diluted by blood, thus reducing delivered concentration to the vein wall. Foam, on the other hand, displaces the blood and allows direct contact with the endothelium. It follows that the efficacy of a given concentration of a sclerosant can be enhanced with foam therapy.

2. There is increased safety with foam preparations as lower concentrations of sclerosants are used.

3. Extravasated foam is much better tolerated than liquid extravasation.

4. The air contained in the foam is echogenic and thus increases the visibility and accuracy of placement when performing duplex-guided sclerotherapy.²¹

Variables like type and concentration of the sclerosing agent, gas, gas-to-liquid ratio, bubble size, and time between preparation and use determine the efficacy of the agent.²¹ An ideal foam should be durable enough to allow injection before separating into gas and liquid components.²² It is accepted that microfoams with bubble diameters less than 250 µm are commonly used and the ideal effective choice (macrofoams have bubbles larger than 500 µm and minifoams have bubbles ranging from 250 to 500 µm). There are various techniques in the literature that describe effective ways to produce microfoam.

In reference to the biologic behavior of STS, Schneider and Fischer ²³ showed that endothelial damage is concentration dependent and occurs immediately after injection, with resulting rapid thrombus formation leading to vascular sclerosis. Importantly, 3% STS foam has not yielded 100% GSV closure when injected with a standard needle and syringe; therefore, catheters that can enhance the interaction of drug to vein wall are under investigation.

Foam is an option for controlling saphenous reflux in veins of less than 12 mm and has been shown to be a viable treatment for sclerosis of perforators. Foam is of value in the treatment of varicosed tributaries, tortuous vessels, and venous malformations. Foam also has limitations and carries liability concerns. In veins larger than 12 mm, the sclerosant–blood interface compromises treatment.²⁴ It has been recommended that a 10-mL limit be placed with regard to total foam volume injected because of possible paradoxical embolization via the patent foramen ovale.¹⁹ For this reason there has been some interest in maximizing sclerosant contact time with the vein wall through the use of catheters. Future studies will likely focus on maximizing results of liquid or foamed sclerosants through innovations in catheter technology. The known methods of producing foam sclerotherapy include the following:

Cabrera method: Juan Cabrera in 1997 published his 7-year experience of excellent results with special foam that is prepared with a sclerosing agent, CO₂, and an unknown tensioactive agent.¹⁷

Monfreux method: In this method, foam is produced in a glass syringe with the tip closed by a sterile plug; tension is applied by compressing the piston. While the foam is long lasting, the larger bubbles formed by this method can reduce the effectiveness of the therapy.¹⁸

Tessari method: Described in 1999 by Lorenzo Tessari, high-quality foam is produced with two disposable syringes and a three-way tap.²⁴ STS was initially described with this method. The advantages of this method are use of disposable materials, compact foam with small bubble diameter, and the ability to reconstitute the foam if the treatment session takes more time.

Frullini method: Described by Frullini and Cavezzi in 2000, the foam generation uses the same turbulence effect as the Tessari method.¹⁸ Foam is generated by a vial and syringe joined by a connector.