Detergent solutions

Detergent sclerosing solutions commonly used to treat varicose and telangiectatic veins include sodium morrhuate (SM), ethanolamine oleate (EO), STS, and POL (lauromacrogol 400, laureth-9). They produce endothelial damage through interference with cell surface lipids (Fig. 7.3). Strong detergents, such as STS and SM, produce maceration of the endothelium within 1 second of exposure.²⁰ The intercellular ‘cement’ is disrupted, causing desquamation of endothelial cells in plaques. Because the hydrophilic and hydrophobic poles of the detergent molecule orient themselves so that the polar hydrophilic part is within the water and the hydrophobic part is away from the water, they appear as aggregates in solution (micelles) or fixed onto the endothelial surface (Fig. 7.4). Because the practitioner cannot ensure that the solution is entirely in contact with the endothelial surface (if the injected vein contains blood), the decrease in surface tension on the endothelial cells may not be in direct proportion to the concentration of the solution. Strong detergent sclerosants therefore have a low safety margin.²⁰

Figure 7.3 Diagrammatic representation of the action of a detergent sclerosing solution on the vessel wall, showing formed elements of the blood.

Figure 7.4 Diagrammatic representation of the probable molecular orientation of detergent sclerosing solutions into aggregates.

Detergents act as micelles when injected into a nondetergent environment (blood). Their destructive action on endothelial cells is enhanced when they act as aggregates rather than monomers. Thus, the concentration of the sclerosing solution in the vessel is an important factor regarding endothelial destruction and activity (Fig. 7.5). They have been found to aggregate to a significant extent at lower temperatures as opposed to room temperatures (Fig. 7.6).

Figure 7.5 Diagrammatic representation of the percentage of detergent aggregates versus monomers is a correlation of the solution concentration.

(From Feid C, Presentation at the American College of Phlebology Sclerotherapy Workshop, Atlanta, Ga., November 2000.)

Figure 7.6 Diagrammatic representation of the percentage of detergent aggregates versus monomers is a correlation of the solution temperature.

(From Feid C, Presentation at the American College of Phlebology Sclerotherapy Workshop, Atlanta, Ga., November 2000.)

Detergent sclerosing agents have been studied regarding their direct toxic effects on the formed elements of blood. One study found that the addition of SM, EO, STS, or POL to citrated plasma did not cause clotting nor shorten either the prothrombin time (PT) or the partial thromboplastin time (PTT).²¹ However, all of the sclerosing agents examined were directly toxic to both granulocytes and red blood cells (RBCs) at dilutions of up to 1 : 1000. When tested against cultured endothelial cells, all solutions were toxic to approximately 60% to 80% of cells at 1 : 100 dilutions, but only SM and EO were toxic at a further dilution of 1 : 1000. None of these tested solutions were toxic at 1 : 10,000 dilutions. Therefore, this study confirms that effective endosclerosis occurs through damage to endothelium and not through thrombosis induced by destruction or damage to red and/or white blood cells. Another in vitro study, however, found that the activated PTT was prolonged in proportion to the fall of factor XII and prekallikrein activity when POL was added to citrated serum.²² This indicates that in addition to its action on endothelial cells, POL is capable of acting on blood coagulation through activation of the early phase of the intrinsic pathway. The clinical relevance of this finding is unclear because additional studies have failed to demonstrate its significance, as explained later in this Chapter.^23,24

Osmotic solutions

Hypertonic solutions, such as hypertonic saline (HS), probably cause dehydration of endothelial cells through osmosis, causing endothelial destruction (Fig. 7.7).²² It is speculated that fibrin deposition with thrombus formation on the damaged vessel wall occurs through modification of the electrostatic charge of the endothelial cells.²⁰ For the vessel wall to be completely destroyed, the osmotic solution must be of sufficient concentration to diffuse throughout the entire vein wall.²⁵ In contrast to the immediate action of detergent sclerosing solutions, experimental studies have shown that endothelial destruction with HS 22% or glucose 66% occurs only after 3 minutes.²⁰ The destroyed endothelial cells do not appear to be desquamated as with detergent sclerosing solutions.²⁰

Figure 7.7 Diagrammatic representation of the action of a hypertonic sclerosing solution on the vessel wall, showing formed elements of the blood.

Hypertonic solutions have a predictable destructive power that is proportional to their osmotic concentration. This was demonstrated in a comparative study of multiple hypertonic solutions used on the superficial and internal saphenous veins of 27 dogs.²⁶ The degree of endothelial damage was assessed histologically at multiple times from 30 minutes to 8 weeks after sclerotherapy. The authors ranked the solutions from strongest to weakest as follows:

The authors concluded that maximal endothelial destruction occurred as early as 30 minutes to 4 days after injection, after which time the injected vessel went through either a reparative or a fibrotic process. Because dilution occurs with intravascular serum and blood, osmotic solutions have their greatest effect at or near the site of injection. In contrast, detergent sclerosing solutions can exert effective sclerosis for 5 to 10 cm along the course of the injected vessel. Sadick²⁷ examined the sclerosing effect of HS 23.4% and POL 0.5%. He found equal sclerosing effect (length) for these two solutions injected in a similar type of vein using identical techniques. Unfortunately, HS 23.4% is more potent (about two to three times more) than POL 0.5%. Therefore, he inadvertently demonstrated that detergent solutions have about twice the therapeutic efficacy of osmotic solutions. A better comparison would have been with HS 11.7%.

Chemical solutions

Chemical irritants also act directly on endothelial cells to produce endosclerosis. Lindemayr and Santler²⁸ studied the sclerosing effect of 4% polyiodinated iodine (PII; Variglobin) with standard and immunofluorescent microscopy and demonstrated fibrin deposition on the sclerosed veins only. Platelets fixed only to elastin, collagen, the basement membrane, and the amorphous material of the subendothelial layer, not to intact endothelial cells. It is also thought that the chemical destruction is in part related to the dissolution of intercellular cement, which has been demonstrated to occur after 30 seconds of exposure.²⁰ Thus, this chemical irritant sclerosing solution produces its end result of vascular fibrosis through the irreversible destruction of endothelial cells with resultant thrombus formation on the subendothelial layer (Fig. 7.8).

Figure 7.8 Diagrammatic representation of the action of a caustic chemical sclerosing solution on the vessel wall, showing formed elements of the blood.

The aforementioned mechanism of action has been demonstrated visually with scanning electron microscopy of sclerosed rabbit veins (agent not noted) by Merlen.²⁹ He demonstrated intimal cracks and fissures that left intimal connective tissue fibers and elastic lamina exposed. Ultrastructural damage involving stasis of blood and platelet aggregation on intact endothelial intima occurred in 5 minutes in the dorsal rabbit ear vein.

Sodium tetradecyl sulfate

The mechanism of sclerosis for intravascular STS was elucidated by Schneider⁸ and by Schneider and Fischer⁵⁵ in human varicose veins, by Dietrich and Sinapius⁵⁷ in rabbit external jugular veins, and by Imhoff and Stemmer²⁰ in the dorsal rabbit ear vein. With STS, endothelial damage is dependent on concentration and occurs immediately after injection, with resulting rapid thrombus formation leading to vascular sclerosis.

In two studies, sclerosis with STS produced similar results in a concentration-dependent manner.^43,44 Endothelial damage occurred within 1 hour (Fig. 7.9), followed by the rapid onset of vascular thrombosis with subsequent organization (Fig. 7.10). Histologic recanalization occurred after 30 days with solution concentrations of 0.1% to 0.5%. The histologic findings explained the clinical appearance, which demonstrated initial thrombosis, followed by partial reappearance of the vessel injected with STS 0.1%. Therefore, there may be a concentration gradient in which an ideal concentration depends on many factors, including vessel diameter, rate of blood flow, animal model, and anatomic region within each animal model.

Figure 7.9 Endothelial cells and the vascular wall are entirely destroyed 1 hour after injection of sodium tetradecyl sulfate 0.5%. Hemolysis of red blood cells and early thrombosis are also present. (Hematoxylin–eosin, ×200.)

Figure 7.10 Microangiopathic recanalization is apparent 14 days after injection with sodium tetradecyl sulfate 0.5% (hematoxylin–eosin, ×100).

(From Goldman MP et al: Arch Dermatol 123:1196, 1987.)

Sodium morrhuate

Sodium morrhuate, a mixture of sodium salts of the saturated and unsaturated fatty acids present in cod-liver oil, has been studied in the rabbit ear vein model.⁵⁸ A 0.5% concentration of SM produced no clinical evidence of endothelial damage. Temporary histologic evidence of thrombosis was noted at 1 hour only, with a mild perivascular mixed cellular infiltrate (MCI). There was no evidence for extravasation of RBCs. Vessels injected with SM 1.0% were thrombosed between 2 and 10 days, after which the vessels normalized. Histologically, the SM 1.0%-injected vessel demonstrated a partially destroyed endothelium with extravasation of RBCs. The vessels injected with SM 2.5% demonstrated clinical fibrosis with histologic evidence of microangiopathic recanalization through a fibrotic cord at 45 days after injection. A unique finding noted with injection of SM, both 1.0% and 2.5%, was the presence of large numbers of perivascular mast cells (Fig. 7.11). This finding may correlate with the increased inflammatory nature and allergenicity of SM as compared with other sclerosing solutions.

Figure 7.11 Vessel 2 days after injection of sodium morrhuate 1%. Note the large numbers of perivascular mast cells (hematoxylin–eosin, ×400).

Ethanolamine oleate

A synthetic mixture of ethanolamine and oleic acid, EO is another sclerosing solution that has been studied in the rabbit ear vein model.⁵⁸ No histologic or clinical changes were noted with injection of EO 0.5%. Although an organizing thrombus was produced, complete recanalization occurred in the vessel injected with EO 1%, causing the returned clinical appearance of the injected vessel. Vessels injected with EO 2.5% had a partially destroyed endothelium followed by luminal recanalization. Evidence of phagocytosis of lipid-like material was noted in a vessel injected with EO 2.5% at 48 hours (Fig. 7.12). This may indicate extravasation of sclerosing solution either during injection or with endothelial destruction. Large numbers of perivascular mast cells were also noted 2 days after injection with EO 1% and 2.5%. Extravasated RBCs occurred in vessels injected with EO 1% and 2.5% at 1 hour and 2 days, but not in vessels injected with EO 0.5%.

Figure 7.12 Vessel 2 days after injection of ethanolamine oleate 2.5%. Note the extensive phagocytosis of lipid-like globules (hematoxylin–eosin, ×200).

A previous study comparing EO with STS was performed using the rat tail vein model.⁵⁹ In this model, EO 5% was compared with STS 3% and 1%. Solution measuring 0.1 ml was injected and the veins were biopsied at 4 weeks. In this study, EO 5% was effective in sclerosing only 25% of the treated veins, as opposed to a 73% efficacy with STS 1% and a near 100% efficacy with STS 3%. Therefore, results in the rabbit ear vein compare well with those in the rat tail vein.

Polidocanol

A concentration gradient was also demonstrated in a study of POL in concentrations of 0.25%, 0.5%, and 1.0%.⁴³ Only vessels injected with POL 0.5% and 1% were clinically sclerosed, and only the vessels injected with POL 1% maintained sclerosis without revascularization by 60 days.

An examination of the histologic effects of POL on the endothelium specifically, between 1 hour and 4 days after injection, illustrates the effect of varying the concentration of sclerosing solutions. Endothelial cells exposed to POL 0.25% were at first only partially damaged (Fig. 7.13). Mitotic figures indicating endothelial regeneration were noted 4 days after injection (Fig. 7.14). Likewise, with POL 0.5%, partial luminal recanalization occurred through an initial fibrotic cord in vessels (Fig. 7.15). Only vessels sclerosed with POL 1.0% developed complete endosclerosis (Fig. 7.16). Therefore, POL is probably a weaker detergent type of sclerosing solution than STS, and higher concentrations are necessary to produce complete vascular sclerosis.

Figure 7.13 Partially damaged endothelial cells with thrombosis is seen 8 hours after injection of polidocanol 0.25% in the rabbit ear vein (hematoxylin–eosin, ×40).

Figure 7.14 Endothelial regeneration is apparent 4 days after injection of polidocanol 0.25% in the rabbit ear vein (hematoxylin–eosin, ×100).

Figure 7.15 Advanced luminal recanalization is present 60 days after injection of polidocanol 0.5%, as seen in cross-section. A, ×100. B, ×200; note endothelial lining on recanalized lumen (hematoxylin–eosin).

(A from Goldman MP et al: Arch Dermatol 123:1196, 1987.)

Figure 7.16 Fibrous cord formation is present 30 days after injection of polidocanol 1.0%. The darker areas within the fibrous cord represent hemosiderin-laden macrophages. A, Cross section, ×40. B, Longitudinal section, ×100 (hematoxylin–eosin).

(B from Goldman MP et al: Arch Dermatol 123:1196, 1987.)

Hypertonic saline

The sclerosing effect of HS was examined histologically in the external jugular vein of the dog by Kern and Angle,⁶³ and in human varicose veins by McPheeters and Anderson.⁵³ These investigators noted endothelial damage with thrombus formation within 1 hour of injection, with ultimate conversion into a fibrous cord within 2 to 4 weeks. This was confirmed in the rabbit ear vein model⁴³ both clinically and histologically. Examination of the marginal ear vein 1 hour after exposure to HS 23.4% demonstrated complete endothelial destruction (Fig. 7.17).

Figure 7.17 The endothelial cells and vascular wall structure are completely homogenized 1 hour after injection of the rabbit ear vein with hypertonic saline 23.4%. Longitudinal section, ×40 (hematoxylin–eosin).

However, subsequent evaluation of HS 11.7% in the rabbit ear vein model⁵⁸ demonstrated an immediate thrombosis that lasted only 48 hours before complete normalization. Endothelial destruction was patchy at 1 hour with perivascular and intraluminal margination of polymorphonuclear cells and eosinophils. There was no evidence of extravasation of RBCs in the veins injected with HS 11.7%, whereas extravasation was noted in 30% of vessels injected with HS 23.4%. Therefore, the degree of endothelial damage and resulting extravasation of RBCs is proportional to the concentration of HS used.

Hypertonic glucose/saline

Sclerodex (SX; Omega Laboratories, Montreal) is a mixture of dextrose, sodium chloride, propylene glycol, and phenethyl alcohol. When SX was studied in the rabbit ear vein model,⁵⁸ it produced an immediate thrombosis that lasted for 2 days, after which the vessel recanalized. At 1 hour, perivascular and intraluminal margination of polymorphonuclear cells and eosinophils were present with patchy endothelial destruction. Endothelial mitoses were present at 2 days within a regenerative endothelium. Extravasation of RBCs was not noted. Therefore, SX has a potency similar to HS 11.7%.

Chromated glycerin and 72% glycerin

The effect of chemical irritant sclerosing solutions has been studied in the rabbit ear model.⁴⁴ Chromated glycerin (CG; Sclérémo, Laboratoires Bailleul, Paris, France), 50% and 100%, was injected into the dorsal marginal rabbit ear vein, producing clinical and histologic thrombosis that lasted only 2 to 8 days, after which the vessel appeared clinically and histologically normal. As noted with POL 0.25% above, the endothelium 1 hour after biopsy was almost undamaged. Therefore, in this experimental model, CG is a weak solution with a sclerosing effect similar to POL 0.25%. This correlates well with its clinical profile. The sclerosing effect of CG is not dependent upon chromium. Excellent results can be achieved in treating leg veins less than 1 mm in diameter with the use of a 72% glycerin solution mixed 2 : 1 with 1% lidocaine with epinephrine, as described later in this chapter.

Polyiodinated iodine

Various iodine solutions, with or without hypertonic solutions, have been examined in the rabbit ear vein model.⁶⁴ Sclerodine (Omega Laboratories, Montreal) is a mixture of iodine USP (60 mg/mL) and sodium iodide USP (90 mg/mL). This solution was compared with an American iodine formula consisting of iodine and sodium iodide, compounded by the Women’s Hospital of Texas in Houston. The two sclerosants were identical in composition. After being mixed with either normal saline, SX (Omega Laboratories), or a solution of dextrose 250 mg/mL and sodium chloride 100 mg/mL (compounded by the Women’s Hospital of Texas in Houston), each sclerosant was injected in concentrations of 0.1% and 0.5%. Thrombosis occurred with all solutions at 1 hour, with an attenuated endothelium and focal endothelial necrosis. A mild perivascular mixed cellular infiltrate consisting of eosinophils and polymorphonucleocytes was present with margination along the endothelial border. With the 0.1% solutions, the endothelium was hyperplastic, with regenerative changes noted by 8 days (Fig. 7.18) and complete normalization by 28 days. With the 0.5% solutions, the endothelium was necrotic with multiple brown spherules approximately 1 µm in diameter seen within the endothelial wall (Fig. 7.19). These may represent iodine crystals. By 28 days, a fibrous cord was present without inflammation. Interestingly, veins treated with iodine/normal saline mix showed a greater incidence and extent of extravasated erythrocytes compared to those treated with iodine/SX (hypertonic saline/dextrose) solutions. The PII 0.1% solution had an experimental efficacy equivalent to HS 11.7%, SM 2.5%, STS 0.25%, and POL 0.5%. The PII 0.5% solution had an experimental efficacy similar to HS 23.4%, STS 0.5%, and POL 1.0%.

Figure 7.18 Regenerating hyperplastic endothelium is present 8 days after injection of the rabbit ear vein with 0.1% polyiodinated iodine diluted with Sclerodex (hematoxylin–eosin, ×20).

Figure 7.19 Multiple brown spherules approximately 1 µm in diameter are noted within necrotic endothelium at 8 days in the rabbit ear vein injected with 0.5% polyiodinated iodine (hematoxylin–eosin, ×40).

Comparative efficacy in the animal model

The mechanism of action for all sclerosing solutions injected into veins in the aforementioned studies was basically similar; that is, endothelial damage and simultaneous thrombus formation occurred almost immediately after injection. Endothelial damage was less in the vessels injected with CG, POL 0.25%, SX, and EO 0.5%, which showed early recanalization and a continued normal clinical appearance. POL 0.5%, SM 0.5% and 1%, EO 1%, and HS 11.7% produced endothelial attenuation, not necrosis. Although an organizing thrombus was produced, recanalization occurred, causing the returned clinical appearance of the injected vessel. Vessels injected with PII 0.1%, STS 0.5%, SM 2.5%, and EO 2.5% also demonstrated recanalization, although endothelial necrosis was demonstrated. In contrast to the luminal recanalization that occurred with POL 0.5% and EO 2.5%, recanalization with STS 0.5% and SM 2.5% occurred with multiple minute vascular channels. Vessels sclerosed with STS 0.25% and 0.5% and with SM 2.5% never totally reappeared clinically in the 60-day span of this study. The only vessels to histologically demonstrate fibrous cord formation that did not recanalize were sclerosed with PII 0.5%, HS 23.4%, and POL 1.0%. Therefore there is a minimal sclerosant concentration (MSC) that is essential to produce endosclerosis. This term, coined by Neil Sadick,⁶⁵ is useful in determining which solution and concentration is best at sclerosing a specific vessel.

Comparative efficacy in the human model

In an effort to assess the effect of sclerosing agents in human leg telangiectasias, the author injected 0.1 mL of either POL 0.5% or STS 0.5% into two nearly identical telangiectasias (0.4 mm in diameter) over the anterior tibia in a 65-year-old man. The vessels did not have any associated ‘feeding’ reticular veins, and there was no evidence of associated varicose veins or signs of venous insufficiency. Neither injected vessel was compressed, and a biopsy of each was taken 48 hours after treatment. The vessel injected with POL 0.5% demonstrated a blue thrombus (Fig. 7.20) that was histologically confirmed, and an endothelium that was relatively intact with extensive cellular vacuolization (Fig. 7.21). The vessel injected with STS 0.5% demonstrated a deep blue thrombus (Fig. 7.22). Histologically, the endothelium was totally destroyed, showing extensive intravascular thrombosis and early organization (Fig. 7.23). Therefore, this limited human study correlates with the aforementioned studies on the marginal rabbit ear vein, demonstrating that STS is a stronger sclerosing agent than POL.

Figure 7.20 Anterior tibial telangiectasia. A, Before treatment and, B, 48 hours after injection of polidocanol 0.5%.

Figure 7.21 Histologic examination of vein in Figure 7.11. A, ×40. B, ×100; shows endothelial cell vacuolization with thrombosis (hematoxylin–eosin).

Figure 7.22 Anterior tibial telangiectasia. A, Before treatment and, B, 48 hours after injection of sodium tetradecyl sulfate 0.5%.

Figure 7.23 Histologic examination of vein in Figure 7.22. A, ×40. B, ×100; shows endothelial cell homogenization/necrosis with thrombosis (hematoxylin–eosin).

Osmotic agents

Chemical irritants

Detergent sclerosing solutions

Sodium tetradecyl sulfate

Sodium tetradecyl sulfate (Sotradecol, Bioniche Pharma Group, Inverin, Co. Galway, Ireland; Thromboject, Omega Laboratories, Montreal, Canada; Trombovar, Laboratoires Innothéra, Arcueil, France) is a synthetic, surface-active substance first described by Reiner⁴⁵ in 1946 (Fig. 7.24). It is composed of sodium 1-isobutyl-4-ethyloctyl sulfate plus benzoyl alcohol 2% (as an anesthetic agent) and phosphate buffered to a pH of 7.6. It is recommended that solutions be protected from light. It is a long-chain fatty acid salt of an alkali metal with the properties of soap. The solution is clear, non-viscous, has a low surface tension and is readily miscible with blood, leading to a uniform distribution after injection.¹⁰⁸ It primarily acts on the endothelium of the vein, because, if diluted with blood, the molecules attach to the surface of RBCs, causing hemolysis. The recommended maximum dosage suggested by STD Pharmaceutical Products in a treatment session is 4 mL of a 3% solution or up to 10 mL of lower concentrations (e.g. 1%).^a The recommended maximum dosage from Bioniche Pharma Group and Omega Laboratories is 10 mL of a 3% solution, with intervals between treatments of 5 to 7 days.^b,c

Figure 7.24 Structural formula of sodium tetradecyl sulfate.

The solution just mentioned should not be mixed with other anesthetic solutions because it will become turbid and form a new compound.¹⁰⁹ In addition, heparin should not be included in the same syringe as STS because the two are incompatible (product insert, rev. October 1988). Yet, a paired comparison study of STS with and without heparin disclosed no difference in the therapeutic effect between the two solutions.³⁶

In the United States, STS is available as a 1% or 3% solution that can be diluted with sterile water or normal saline to achieve an appropriate therapeutic concentration. It is also available – with the same pH and preservative – as Fibro-Vein (STD Pharmaceutical Products, Hereford, England), in 5-ml multiuse vials in concentrations of 0.2% and 3% and in 2-ml ampules in concentrations of 0.5%, 1%, and 3%. The Canadian manufacturer recommends dilution with phosphate-buffered saline to preserve the original pH level.^c (This also prevents pain from injection.) It is limpid and does not stick to the syringe cylinder when blood is withdrawn to ensure accurate needle placement. Concentrations of 0.1% to 0.3% are commonly used for the treatment of telangiectatic veins 0.2 to 1.0 mm in diameter; 0.5% to 1% for treatment of uncomplicated varicose veins 2 to 4 mm in diameter; and 1.5% to 3% for the treatment of larger varicose veins, incompetent perforating veins, or an incompetent SFJ.

Advantages

Sodium tetradecyl sulfate became widely used in the 1950s after its introduction in 1946 by Reiner.⁴⁵ Tretbar¹¹⁰ in 1978 first reported the injection of a 1% solution into spider angiomata. He noted excellent results in virtually all 144 patients treated. He also noted an unspecified number of episodes of epidermal necrosis without significant sequelae and a 30% incidence of postsclerosis pigmentation that resolved within a few months.

Shields and Jansen¹¹¹ in 1982 were the first to describe microsclerosis of telangiectasias with STS in the dermatologic literature. They injected STS 1% into 105 patients and reported only one episode of necrosis in more than 600 treatments of vessels less than 5 mm in diameter. There were no systemic reactions, and the majority of postsclerosis pigmentary changes resolved in 3 to 4 months. However, as more experience with its use in the treatment of leg telangiectasias occurred, even further dilutions (0.1% to 0.3%) were recommended, both to achieve clinical efficacy and to limit adverse sequelae (see Chapter 12).

Disadvantages

Approved for use by the FDA for vein sclerosis, STS nevertheless has a number of disadvantages. Epidermal necrosis frequently occurs with extravasation of concentrations higher than 1%; however, telangiectasias and spider veins are usually treated with 0.1% to 0.2% and extravasation at this concentration rarely causes a problem. Allergic reactions occur rarely. Postsclerotherapy hyperpigmentation occurs in proportion to its concentration (see Chapter 8), therefore its dilution is critical. The previously mentioned percentages per diameter of treated vein provide only a preliminary guide for effective treatment. In addition, the Canadian and US manufacturers recommend that as a precaution against anaphylactic shock, 0.3 mL of a 1% solution should be injected into the varicosity, and then the patient should be observed for several hours before proceeding with further injections.^a The reason for this recommendation is unclear, impractical, and potentially hazardous; it is discussed further in Chapter 8.

The intravenous lethal dose in 50% of the population (LD₅₀) is 90 ± 5 mg/kg in mice and between 72 and 108 mg/kg in rats. When tested in the L5178YTK mouse lymphoma assay, STS did not induce a dose-related increase in the frequency of thymidine kinase-deficient mutants. However, long-term animal carcinogenicity studies have not been reported (product insert rev. October 1988).

Historical Manufacturing of STS Injections

Historically, the commercial STS injections were made from a compound manufactured as a high-grade detergent used to clean optical surfaces by Niacet (Niagara Falls, N.Y.). The product is manufactured in an industrial plant and is called NIAPROOF Anionic Surfactant 4, also known as NAS 4 and NIAPROOF 4. It is manufactured to have between 26% and 28% by weight STS with 20% by weight maximum of diethylene glycol ethyl ether (carbitol) and 1% to 2% by weight sodium chloride. During the manufacture, carbitol is added so that the final product is three parts STS to two parts carbitol. This 27% parent compound is the same compound provided to each manufacturer of STS for injection. Each manufacturer then purifies the active ingredient STS to remove the carbitol. Interestingly, analysis performed by an independent laboratory shows that the four major companies that manufacture STS have different levels of impurities, including carbitol. Fibro-Vein contains 0.02% w/v of carbitol; Sotradecol produced by Elkins Sinn until 2000 contains 0.6% w/v of carbitol, and Trombovar contains 2.6% w/v of carbitol. (Analysis performed 4 January 1989, 20 June 1989, and 8 May 1990 by Butterworth Laboratories Ltd, Great Britain. Leberco Testing, Roselle Park, N.J., and County of Avon Scientific Services, Bristol, Great Britain, confirmed these percentages of carbitol content.) Sotradecol produced by Bioniche Pharma USA since 2007 contains no carbitol or any other impurities (analysis performed by ChemCon, Freiburg, Germany, 19 Nov 2007.) What effect the carbitol impurity has on efficacy or toxicity is unknown.

Carbitol has about the same toxicity as ethylene glycol when ingested, which has a mean lethal dose in humans of 3 to 4 oz (90–120 mL).¹¹² The LD₅₀ for intraperitoneal carbitol was 5.39 mL/kg in both rats and mice. The Ames test was very weakly mutagenic for Salmonella typhimurium and Saccharomyces cerevisiae. Carbitol is reported to be teratogenic in rats and mice.¹¹³ Cutaneous contact with carbitol also can produce a dermatitis with both immediate and delayed hypersensitivity.^114,115

Many compounding pharmacies supply STS. Various loopholes in Federal and State regulations allow pharmacies to compound a variety of medications for use in humans. The FDA has no regulatory power over this ‘branch’ of the pharmaceutical industry. Although the compounding pharmacy industry has voluntary standards, no organization exists to test the quality and accuracy of medications provided by the compounding pharmacies. Our analysis found both a discrepancy between the stated concentration and the actual concentration of STS in bottles from all three compounding pharmacies. The concentration of the sclerosing solution should be matched to the size and type of vein treated to produce the minimal sclerosing effect.¹¹⁶

The reason for the difference in concentration may be related to the variability of the percentage of the bulk STS industrial solution. At temperatures below 15°C, the product fractionates so that the concentration of STS is greater than 27% at the bottom of the drum and below 27% at the top of the drum. An analysis of this 27% STS solution by the Professional Compounding Centers of America (PCCA; Houston, Tex) performed in July 2003 found that the 27% STS contained 27.94% of STS. No analysis of the carbitol component or any other component in the industrial solution was performed. The presence of impurities in any intravenous injection is worrisome (Table 7.4).

Table 7.4 Analysis of sodium tetradecyl sulfate (STS) from four sources

Compounding pharmacies manufacture STS from industrial source material. Carbitol is a known contaminant of industrial STS. If a company is going to use an industrial chemical to prepare a pharmaceutical injectable product, then it is duty bound to disclose other chemical compounds present too. However, by far the most important consideration in our opinion is that carbitol, like STS, is a high-molecular-weight organic molecule. The presence of both molecules in an injectable product will increase the risk of unwanted side effects relating to sensitivity and anaphylaxis. It is not a coincidence that Fibro-Vein has displayed a very low incidence of such side effects, but rather that it is due to the very low levels of carbitol that have been present in Fibro-Vein for the last 25 years. We find it very difficult to justify the deliberate administration by intravenous injection of two large-molecule organic compounds when physicians are being led to believe that they are only injecting the one compound, namely STS. In fact, Alemeida and Raines have compared the therapeutic effect of compounded STS with Sotradecol and found that compounded STS was less effective in sclerosing varicose veins.¹¹⁷

Current Manufacturing of STS Injections

In recent years the FDA has made it a requirement that all active ingredients in pharmaceutical products are manufactured according to current good manufacturing practices (CGMP). The same ruling came into effect in Europe on 30 October 2005. The legislation means that a pharmaceutical product manufactured and sold in either the United States or the European Union must have the active ingredient manufactured under CGMP conditions. It is no longer acceptable to purify and dilute an industrial-grade concentrate.

To our knowledge, only two brands of STS injection are currently made using an active ingredient manufactured under the rigorous conditions required by the US and EU pharmaceutical regulations: they are Fibro-Vein and Sotradecol.

Fibro-Vein has the active ingredient manufactured in Europe using the same process as the original Niacet molecule but now manufactured in a pharmaceutical plant.

Sotradecol is manufactured by Bioniche Pharma Group in an FDA-approved facility at Inverin, County Galway, Ireland. The formulation involves preparation of a solution of the active ingredient, STS, and the inactive ingredients, benzyl alcohol, dibasic sodium phosphate, and water for injection. After sampling, testing, and approval of the sample, the product is sterile filtered. Aseptic filling occurs in a class 100 clean room with a class 1000 background.

The Bioniche active pharmaceutical ingredient (API) was tested for the presence of carbitol by gas chromatography analysis.^a A carbitol reference standard was sourced from Sigma Aldrich Inc., St Louis, Mo. USA. The test results revealed that no carbitol was detected.

Accelerated stability studies of Sotradecol 3% and 1% manufactured by Bioniche were performed at 40°C and analyzed for impurities. The results for Sotradecol 3% are shown in Table 7.5.

Table 7.5 Analysis of impurities in Sotradecol* 3%

Pharmaceutical-grade STS is sourced by Bioniche under an exclusivity agreement from a supplier who holds a Drug Master File (DMF) for the API. The API is a white to off-white solid and meets the following specifications for chromatographic purity:

7-Ethyl-2-methyl-undec-3-ene/7-Ethyl-2-methyl-undec-4-ene	NMT 0.15%
7-Ethyl-2-methyl-4-undecanol	NMT 0.10%
Individual unknown	NMT 0.10%
Total impurities	NMT 1.0%
Assay	96.0% to 100.0%

Forced degradation of the API at 80°C for 2 hours increased the impurities:

7-Ethyl-2-methyl-4-undecanol	5.0%
7-Ethyl-2-methyl-undec-4-ene	2.1%
7-Ethyl-2-methyl-undec-3-ene	0.4%

If a temperature of 80°C was required to distill out carbitol (which is not the case with the Bioniche product), then there is an increased likelihood that the above-mentioned impurities would appear. A full discussion on the toxicity of carbitol is found in Chapter 9.

Polidocanol

Polidocanol, manufactured by Kreussler & Co., GMBH (Wiesbaden-Biebrich, Germany) and sold under the names of Aethoxysklerol and Asclera, distributed by Bioform Medical (San Mateo, Calif. in the US), is composed of a mixture of hydroxypolyethoxydodecane dissolved in distilled water, to which 96% ethyl alcohol is added to a concentration of 5% to ensure emulsification of POL micelles (which provides a clear solution) and to decrease foaming during the production process. Thus, 1 mL of POL contains 40.5 mg of ethanol, and patients taking disulfiram (Antabuse; Wyeth-Ayerst Laboratories, New York, NY) should be warned about a possible alcohol–disulfiram reaction.

Varying from one country to another, POL is available in 2-ml ampules in concentrations of 0.25%, 0.5%, 1%, 2%, 3%, and 4%, as well as multiuse 30-ml vials in 0.5% and 1% concentrations. In the US, it is available as 2 mL ampules of 0.5% and 1.0%. The other ingredients are disodium hydrogen orthophosphate dihydrate and potassium dihydrogen orthophosphate. Sclerovein (Globopharm, Switzerland) contains chlorobutanolum as a preservative, 0.5g/100 mL. Its pH varies from 4.8 to 6.1. The manufacturer has no stability data on POL when it is diluted with bacteriostatic water or normal saline, but Sadick and Farber¹¹⁸ have determined that it remains sterile for at least 3 months following dilution. The sterility is confirmed even when used daily through a multiuse vial. Manufactured by Craveri (Buenos Aires, Argentina), AET is diluted in absolute alcohol and is available in 2-ml ampules of 0.25%, 0.5%, 1%, 1.5%, 2%, 3%, and 4%, as well as in 2-ml syringes at concentrations of 0.25%, 0.5%, and 1%.

POL was synthesized by BASF and introduced in 1936 as a local and topical anesthetic under the tradename Sch 600. Unlike the two main groups of local anesthetics – esters (procaine, benzocaine, and tetracaine) and the amides (lidocaine, prilocaine, mepivacaine, procainamide, and dibucaine) – POL has a noncyclic chemical structure. The anesthetic effect is not a direct function of its concentration but is optimum at a concentration between 3% and 4%.^a Animal trials on its use as a local anesthetic demonstrated the occurrence of obliteration of vessels as a side effect.

Henschel, the former Medical Director of Kreussler Pharma, first started clinical trials of several concentrations of POL to treat varicose veins (correspondence from B. Olesch, 1992).The maximum daily dose recommended by Kreussler Pharma is found in Table 7.6. Blenkinsopp¹¹⁹ recommended a higher maximum daily dosage of 10 mL of a POL 6% solution for an average person based on toxicity experiments extrapolated from rats. However, rats are much less sensitive to POL. Since the LD₅₀ in rabbits is approximately 11.7 mg/kg, Blenkinsopp’s minimum dose may be toxic (Pfahler B, Kreussler: Personal communication, 29 March 1990).

Table 7.6 Maximum daily dose of polidocanol (POL)

POL is unique among local anesthetics in its lack of an aromatic ring. As an aliphatic molecule, it is composed of a hydrophilic chain of polyethylene glycolic ether and a lipo-soluble radical of dodecylic alcohol. It is used as a topical anesthetic agent in ointments and lotions for mucous membranes, including hemorrhoidal treatment.¹²⁰ It is also used as a local anesthetic for skin irritation, burns, and insect bites and as an epidural anesthetic.^121–123 The subcutaneous anesthetic effect of a 0.4% solution is equal to a 2% solution of novocaine.¹²¹ The LD₅₀ in rabbits at 2 hours is 0.2 g/kg, which is three to six times greater than the LD₅₀ for novocaine.¹²² The LD₅₀ in mice has been found to vary between 110 mg/kg (personal correspondence from Kreussler Pharma, 1992) and 1.2 g/kg.¹²¹ The systemic toxicity is similar to that of procaine and lidocaine.¹²⁴ Thus, POL was considered an ideal local anesthetic. However, it soon became apparent that intravascular and intradermal instillation produced sclerosis of small-diameter blood vessels and ‘moderate, clinically unimportant reversible damage to healthy tissue’.^a Therefore, compound Sch 600 was considered for use as a sclerosing agent. The polidocanol preparation Aethoxysklerol was registered at the German health authority, the Bundesgesundheitsamt (BGA), in 1967.¹²³

Experimental evaluation of absorption, distribution, metabolism, and excretion of POL has been studied in dogs, rats, and humans.¹²³ It is rapidly distributed throughout the body within minutes of injection.¹²³ The compound is rapidly metabolized and eliminated, having a terminal elimination half-life of 1.4 to 1.7 hours in dogs. After 72 hours, 97% of the administered compound is excreted (61% in urine, 37% in feces).

In humans, the elimination half-life is 4 hours, with 89% of the dose eliminated from the blood within 12 hours. Amounts excreted in the urine and feces are equal, and almost 80% of the injected compound is excreted via respiration through a breakdown into low-molecular-weight products. Polidocanol is completely eliminated from body organs whether the patient receives one dose or repeated doses. Therefore, no accumulation takes place, nor does POL cross the blood–brain barrier.¹²³ Sixty-four percent of POL is bound to protein, with a volume of distribution of 24.5 L/hour. The total clearance is 11.7 L/hour, with renal clearance of 2.01 L/hour and biliary clearance of 3.08 L/hour.^b

The capacity of POL to cross the placental barrier was investigated in rats.¹²³ Of radioactivity from labeled POL, 15% to 87% was recovered from fetal tissue after 13 days. The striking variations in an earlier differentiation phase may come from weight differences between fetuses. The fetus of day 19 accumulated less activity per gram of tissue than those of day 13 and showed only 18% to 19% of the maternal blood values. From the data obtained, the placenta is evidently only a partial barrier for POL, and its penetration capacity declines on increasing differentiation of the fetus.

Polidocanol belongs to the class of detergent sclerosing solutions that are nonionic compounds. It consists of an apolar hydrophobic part (dodecyl alcohol) and a polar hydrophilic part (polyethylene-oxide chain) that is esterified (Fig. 7.25). In solution, POL is associated as macromolecules through electrostatic hydrogen bonding between the H⁺atom of the OH– group in one molecule, and the free electron-pair of an oxygen atom of a second molecule. This bonding results in the formation of a network (see Fig. 7.4). The sclerotherapeutic activity results from this double hydrophobic and hydrophilic action, and thus POL is a ‘detergent’. The optimal efficacy of the compound coincides with the highest concentration that still permits the existence of nonaggregated molecules, 3%.^a However, Kreussler Pharma states that POL 4% is also optimal and soluble (personal correspondence, 1992).

Figure 7.25 Structural formula of polidocanol.

Telangiectasias are treated with concentrations of 0.25% to 0.75%. A randomized study determined that a 0.5% concentration may be ideal for sclerosis of leg telangiectasias.¹²⁵ Varicose veins are treated with concentrations of 1% to 4%. Small vessels and telangiectasias respond well. Efficacy is decreased in the treatment of large or medium-sized varicose veins. Kreussler Pharma^b recommends the use of POL 4% for treatment of varicosities greater than 8 mm in diameter. A 3% solution is recommended for varicose veins 4 to 8 mm in diameter, 2% is recommended for varicose veins 2 to 4 mm in diameter, and 1% for veins 1 to 2 mm in diameter. The practitioner should take care not to exceed the maximum dose of POL, which is 2 mg/kg per day.

Advantages

The safety and efficacy of this agent is such that in the 1950s the Vick Chemical Company developed a derivative of POL, polyoxyethylene dodecanol, as a mucolytic wetting agent for use in vaporizers.¹²⁶ Toxicity studies on rats demonstrated a lack of sensitization to cutaneous application and no toxicity with oral ingestion or with exposure to steaming electric vaporizers. A clinical study carried out on 168 infants and children treated with this compound in vaporizers showed no harmful effects.¹²⁷

Henschel^c stated that the selective activity on damaged endothelium results from the steric structure of POL: ‘The macromolecules retard the individual molecules and thus shield the tissue from their uninhibited action.’ This damage is therefore said to be reversible in normal tissue. Henschel goes on to claim that since the surface-active-induced absorption on the varix wall is greatest at the point of injection and falls off rapidly with increasing distance, large quantities can be injected without danger of damage to the deep venous system. He recommends the injection of a maximum of 2 mL of POL 3% at each site, with a maximum of 6 mL of POL 3% injected in one sclerotherapy session. However, Goldman et al⁴³ have demonstrated that POL scleroses normal vessels (rabbit ear vein) and that the concentration injected is critical to the final outcome of vein sclerosis. Polidocanol is a weaker detergent-type of sclerosing solution than STS. These experimental studies indicate that its sclerosing power is approximately 50% of the strength of STS.

Polidocanol is unique among sclerosing agents in that it is both painless to inject and does not produce cutaneous ulcerations, even with intradermal injection of concentrations less than 1.0% (see Chapter 8). Allergic reactions rarely have been reported. The degree of pigmentation produced may be less than that of other detergent sclerosing agents (see Chapter 8).

An open clinical trial comparing POL with STS and HS was conducted in Australia by 120 physicians.¹²⁸ The results at 2 years showed that 55 of 65 physicians considered that POL had a better efficacy than STS, with two claiming decreased efficacy and eight seeing no difference. When compared with HS, 49 of 58 claimed better efficacy for POL, with one physician reporting decreased efficacy and eight physicians finding no difference. Pain on injection with POL was less than with STS in the experience of 54 of 65 physicians, and was less than with HS as reported by 56 of 58 physicians. Finally, 58 of 65 physicians considered that, overall, POL caused fewer complications (pigmentation, ulceration, phlebitis, telangiectatic matting) than STS, and 43 of 58 considered that it caused fewer complications overall when compared with HS.

A double-blind prospective comparative trial between POL and STS in 129 patients found no therapeutic difference between the two agents.¹²⁹ Concentrations of POL were twice that of STS for comparable-sized veins. Adverse effects were also not statistically different. All patients had an average 70% improvement with one treatment. An Italian study which did not mention exact numbers of patients treated or concentrations of solutions also compared POL with STS.¹³⁰ This study found an increase in closure from 66% to 89% in favor of POL. The adverse reaction of skin inflammation was also increased with STS compared to with POL. Thus, POL may have better efficacy than STS as well as fewer adverse effects. In Japan, a 6-year study of 261 patients treated in 21 centers found a 70% to 100% efficacy of POL in treating variably sized leg veins.¹³¹ No subject developed any treatment-related systemic adverse effect.

Sclerosing solution combinations

As mentioned in the introduction and previously in this chapter, almost any caustic substance can be or has been used to sclerose blood vessels. Although this chapter has detailed those commonly used commercially available solutions, it is by no means complete.

Another method for sclerosing varicose veins is to combine solutions either together or in a sequential manner. Certainly, diluting PII with HS or SX increases the potency and localizes the sclerosing effect to the point of injection. This technique may be useful when sclerosing junctions between the superficial and deep systems (saphenofemoral-saphenopopliteal junctions and/or perforating veins).¹³²

Stemmer (personal communication, 1993) found that a mixture of 0.30 mg of sodium salicylate and 1.80 mg of glycerin in 5 mL of distilled water, giving a final concentration of 6% sodium salicylate and 26% glycerin, is an excellent sclerosing solution for telangiectasias of less than 1 mm in diameter. The author’s limited experience with this solution in humans confirms Stemmer’s observation. According to the rabbit ear model, this solution has an equivalent clinical and histologic effect to undiluted CG 72% (Goldman MP, unpublished observations, 1994).

Adding 66% glucose as a diluent can modify the viscosity of POL. This increases the sclerosant endothelium contact time, which in turn increases the surfactant action of the detergent. Making the solution thicker lowers the force of injection and minimizes the diffusion of the sclerosing solution. A mixture of one-third POL 0.5% with one-third glucose 66% and one-third sterile water has been found to decrease thrombosis and telangiectatic matting in the treatment of telangiectasias.¹³³

Sequential injections of different sclerosing solutions

Sequential injections may be useful to enhance the efficacy of a milder sclerosing solution, either by increasing its potency or by the act of sequentially damaging endothelium. After mechanical trauma, endothelial cells are unable to generate various substances or to respond to circulating or locally produced substances.¹³⁴ In this damaged state, further injury may produce irreparable damage. In addition, combining a solution with another may produce an additive effect on its potency.

Sodium tetradecyl sulfate 3% is currently the strongest sclerosant approved by the FDA. When treatment with this alone may prove ineffective, such as in patients with a large varicose vein or an area of high reflux, sequential use of HS produces a stronger, synergistic effect. This technique has been reported recently using ultrasound guidance to sclerose the SFJ.¹³⁵ One-year follow-up of 66 patients treated with STS 3% alone under ultrasound guidance at the SFJ demonstrated a recanalization rate of 25%. When a second group of 70 patients with similar pathology were treated with STS 3% immediately followed by HS 23.4%, only 12% demonstrated recanalization at 1-year follow-up. Thus, the sclerosing effect was enhanced. A second report of the identical technique performed on 100 patients reported that a ‘small number’ of treatment failures have occurred.¹³⁶ Unfortunately, when the author reported on the 1- to 2-year follow-up in a response to a ‘letter to the editor’,¹³⁷ he noted that gradual recanalization was the rule on duplex evaluation, even though the clinical outcome was good.

Volumes, concentrations, and progressive dilution of sclerosing agents

A sclerosing reaction is induced by the contact of a sufficiently concentrated agent with the venous wall for a sufficient period of time. This adequate/effective concentration remains theoretical and ranges between a too strong, ‘aggressive’ concentration (responsible for transparietal burn and adverse reactions) and a too low, ineffective concentration (not inducing a sclerosing reaction). Contact should be even and homogeneous along the whole length of the vein being treated, and around the complete circumference of the vein. However, injection of liquid in a vein which is full of blood leads to some dilution, and in situ adequate concentrations are difficult to obtain. In veins smaller than 3 mm, a laminar flow of sclerosing agent replaces blood in the vein and no dilution occurs, but in bigger veins, a turbulence occurs and is responsible for dilution of the sclerosant.

The following is a method to compute theoretically how much sclerosing agent is necessary to fill up a vein. The inner volume V of a vein segment is: V = L × π × (D/2)², where L is the length, and D the inner diameter. It is very simple to calculate that – for example – a length of 10 cm of a vein of 0.7 cm inner diameter has an inner volume of 3.85 cm³. Other examples are computed in Table 7.7 (Fig. 7.26). It is interesting to note that since volumes are proportional to the square of the radius, it is possible to inject a very long vein of small diameter with a small volume of liquid. Figure 7.27 emphasizes the fact that the injection of 0.5 cm³ has very different diffusions in veins of different diameters. This leads us to understand that when deciding the injected volume, the most important reference is the venous diameter (Fig. 7.28).

Figure 7.26 Volume and injected length.

Figure 7.27 Proportional representation of a 0.5 cm³ injection volume.

Figure 7.28 How much to inject? (theoretical)

For all these reasons, we presented a theoretical model that is useful for predicting subsequent sclerosing reactions from a given dilution (Fig. 7.29).¹³⁸ The concentration of sclerosing agent decreases progressively when drifting away from the point of injection (Fig. 7.30A). Practically, when the liquid sclerosing agent is injected at a single point, the injected concentration is usually too high (in order to obtain a sufficiently long sclerosed zone, despite some dilution), and can induce side effects. To some extent, the problem can be addressed by injecting a greater volume of a milder solution (Fig. 7.30B) or by injecting small volumes in multiple points close to each other (Fig. 7.30C). If a venous spasm occurs, or if some means allows a reduction in the vein diameter, the laminar flow will further improve the phenomenon (Fig. 7.30D). The ultimate evolution of this thinking is the use of foam, as described below.

Figure 7.29 Effects of concentration.

Figure 7.30 A–E, Theoretical modeling of dilution of sclerosing agents in several conditions.

Foam sclerosants (foamed sclerosing agents, sclerofoam)

The first foam sclerosants were described 60 years ago, and Wollmann¹³⁹ has demonstrated well that it is hard to tell who really invented the technique. However, it remains obvious that two authors – Cabrera in Spain¹⁴⁰ and Monfreux in France¹⁴¹ – have boosted its use in the past 15 years.

The first advantage of foam is that it does not mix much with blood, and, therefore, little dilution occurs in the body. Provided the diameter is not too large, the foam ‘pushes’ the blood like liquid does, ensuring an even effect on the endothelium (Fig. 7.30E). However, when diameters are too high, the foam floats and only the upper wall is in contact. In these cases, additional maneuvers should be undertaken in order to ensure a full contact (alternative massages, compression, elevation, creation of spasm).

Dilution of foam occurs anyway through two distinct phenomena: dilution of the sclerosing agent bound to the microbubbles – leaving plain gas bubbles – and dispersion of microbubbles after coalescence into larger bubbles.

Many different types of foam have been used and presented, using different sclerosing agents (only detergent solutions like STS, POL and morrhuate can foam), different gases (room air, sterile air, CO₂, O₂, CO₂ + O₂, N₂O), different gas/liquid ratios, different preparation tools, etc. At present, two techniques are predominant: the Provensis, which has been manufactured and standardized, and the double-syringe technique. The double-syringe method mixes gas and liquid through either a three-way stopcock (Tessari) or a female–female Luer lock connector (DSS technique). The DSS has been mechanized by use of an automated device: Turbofoam (Kreussler France, Paris) (Fig. 7.31).

Figure 7.31 Turbofoam.

(Courtesy i2m-labs, Caen, France.)

Foam sclerosants also offer the advantage of being an excellent contrast medium for B-mode echography since ultrasounds are scattered by the multiple air/liquid interfaces and foam is recognized by its white cloud aspect and dark shade cone. Thanks to this property, control of diffusion within the desired vein is simple and accurate.¹⁴² In veins smaller than 3 mm, theoretical advantages of foam sclerosants are less obvious, since experiments have demonstrated that a laminar flow ensures replacement of blood by injected liquid sclerosants. The increased sclerosing power must be taken into account with care, and adverse reactions caused by transparietal burn are common. Chapter 9 details the use and Chapter 8 describes side effects related to the use of foam for the treatment of varicose, spider, and reticular veins.

A complete discussion on the use of foam in sclerotherapy treatment of varicose veins is found in Chapter 9.