Sclerosants from the detergent class can be mixed with gases to produce foam sclerosants. Upon injection, foam sclerosants displace the blood in the vessel, forming a “vapor lock,” keeping the drug in contact with the vessel wall and delaying deactivation by circulated plasma proteins. The injected foam sclerosant is in contact with the vessel wall for a longer period of time, which increases the efficacy in comparison to liquid sclerotherapy. Volume and concentration of the sclerosing agent can therefore be decreased, as the active contact time is increased [17].

Advantages of foam over liquid sclerotherapy include its echogenicity with ultrasound, allowing the user to perform sclerotherapy in a precise and controlled manner. In general, foam sclerotherapy is not used for spider vein injections but is utilized for larger veins. Foam sclerotherapy is superior to liquid sclerotherapy in terms of closure rates of varicose veins and truncal veins such as the great saphenous vein (GSV) . A prospective randomized trial by Hamel-Desnos and colleagues in 2003 compared foam sclerotherapy to liquid sclerotherapy (using POL) in the treatment of GSV reflux. This demonstrated that foam sclerotherapy eliminated GSV reflux in 84% and 80% of limbs at 3 weeks and 6 months, whereas liquid sclerotherapy had the same effect in 40% and 26% of limbs during the same time points [18].

Physician-compounded foam (PCF) is considered an “off-label” use of FDA-approved liquid sclerosants as the drug is fundamentally changed by mixing it with a gas. Despite the lack of specific FDA approval, the use of PCFs in the United States, and indeed worldwide, is widespread [4]. PCFs are an effective tool in the treatment of truncal veins, tributaries/branches (replacing microphlebectomy in many cases), venous malformations, and pelvic source varicosities. Treatment is readily performed in an outpatient clinic setting and requires no procedural sedation, and patients return to normal activity levels very quickly with minimal discomfort. PCFs are produced by forcibly mixing a sclerosant of the detergent case with a gas through a small aperture, producing small sclerosant encapsulated gas bubbles. The aperture used is typically either a three-way stopcock or a “female to female” stopcock (double syringe technique). Air or physiologic gases (CO2, O2, or a mixture of both) are typical gases, while the most common choices of sclerosant include POL and STS. Figure 12.1 shows the technique as described by Tessari [19]. Typically the ratio of liquid to gas is 1:3 or 1:4 depending on whether “wet” versus “dry” foam is preferred. The stability of the foam and the size of gas bubbles in the circulation are dependent on the method of foam production, the gas chosen for use (O2 vs. CO2 vs. room air), and other factors including atmospheric pressure and temperature [20]. As the amount of nitrogen in the gas used to create foam increases, the foam is more stable, but the bubbles are also less soluble in the blood [21].

In terms of the use of PCF in the treatment of GSV incompetence, duplex closure rates are highly variable in the literature, ranging from 69 to 91%, depending on the agent used, the concentration, and the number of treatment sessions administered before assessing closure [22–26]. These variables, as well as differing patient populations and disease severities, make comparisons between studies difficult. Additionally, the evaluation of outcome assessments including venous clinical severity scores (VCSS) and quality of life (QOL) instruments is not consistent or uniform. Two more recently randomized trials did assess QOL after ablation of the GSV with ultrasound-guided PCF vs. comparator treatments. Rasmussen and colleagues randomized patients to surgical stripping, endothermal laser ablation (EVLT), radio-frequency ablation (RF) , or ultrasound-guided foam sclerotherapy (UGFS) . Recanalization and retreatment were most common in the UGFS group, but at 3 years, all groups showed similar improvements in VCSS and QOL [27]. A second randomized trial by van der Velden and colleagues compared EVLT and conventional surgery to UGFS. At 5 years, the GSV was obliterated in 85%, 77%, and 23% in the surgical, EVLT, and UGFS groups, respectively. In contrast to the Rasmussen study, QOL scores in the UGFS groups were inferior compared to the other groups [28]. Other studies suggest that UGFS is a cost-effective treatment for GSV reflux, especially when compared to conventional surgery [29].

Venous tributaries associated with saphenous reflux can be treated in either a staged or concomitant fashion. Choices for tributary treatment include stab phlebectomy and UGFS. Recent clinical practice guidelines from the Society of Vascular Surgery and the American Venous Forum recommend either approach as an acceptable treatment (Grade 1B) [30]. Data comparing stab phlebectomy to UGFS in the treatment of tributaries is sparse, and both treatments have proponents. Considerations in treatment choice include vein size, depth, extent, and history of hypertrophic scarring or hyperpigmentation.

The use of PCF is in general thought to be safe and well tolerated; however, serious adverse events can occur. In particular, neurologic complications such as strokes and transient ischemic attacks, while rare, have been reported. In most of these reported cases, air was the gas used to produce the foam, and the patients were often found to have a structural defect such as a patent foramen ovale (PFO) or atrial septal aneurysm [31–34]. These cases have led some to advocate the use of physiologic gases (CO2 or CO2/O2) rather than air-based foams for the production of PCF [35]. While there is no firm data to support this position in terms of prevention of strokes and TIAs, there is data demonstrating fewer visual disturbances and other side effects when physiologic gases are used [36]. Physiologic gases, which have minimal nitrogen content, are biocompatible and as such are rapidly absorbed. Other than gas canister cost, there is little downside to their use. While there is minimal risk of cerebral embolization in patients without a PFO or large pulmonary shunt, a study of 221 varicose vein patients showed that 58.5% of the individuals had a right to left shunt with bubble testing: much higher than the prevalence of such shunts in the general population (est. 26%) [37]. Although individuals with right to left shunts are ostensibly at higher risk of cerebral embolization with foam sclerotherapy , the overall rarity of these events and the high prevalence of such shunts in this population make screening for shunts prior to foam sclerotherapy impractical and unnecessary. Nonetheless, foam sclerotherapy should be used with caution in patients with a known right to left defect, particularly if the patient has a history of previous events that led to the detection of the defect. The use of good quality foam (no grossly visible bubbles) and limiting injection volumes is recommended. In the case of neurologic symptoms during or after foam sclerotherapy, hyperbaric oxygen therapy has been reported to resolve intracerebral gas in the vasculature [34].

An alternative to the use of PCF for the treatment of incompetence of the GSV, accessory saphenous veins (ASV), and their tributaries is proprietary endovenous microfoam (PEM) , marketed as Varithena™. There are no head-to-head studies comparing PCF to PEM, and extrapolating results from studies of PCF are difficult due to varying study designs, endpoints, and the lack of a standard production method or technique for PCF. The sclerosant drug in PEM is 1%POL, but it is produced with a proprietary canister system containing a very low nitrogen physiologic gas. With in vitro testing in a benchtop vein model, PEM gas bubbles are overall smaller, with a narrower distribution of sizes when compared to PCF bubbles, and the stability of PEM foam is superior to PCF. Theoretically increased stability should improve foam performance in vivo, and smaller circulating bubbles could theoretically improve patient safety [37].

The neurologic safety of the use of PEM for the treatment of GSV incompetence was demonstrated in a Phase II clinical trial published in 2011. Patients with symptomatic GSV incompetence were tested with a transcranial Doppler (TCD) bubble testing for the presence of a right to left shunt. Patients who qualified for the study by virtue of a positive bubble test were then treated with PEM. During treatment, TCD monitoring showed middle cerebral artery bubbles in 61 patients. These patients had diffusion-weighted MRI testing (very sensitive to the presence of edema formation) at baseline and at 24 h and 1 month posttreatment. Patients additionally underwent visual field and neurologic testing. None of the patients were found to have changes in MRI, visual fields, or neurologic examinations after PEM treatment [38].

In the development of PEM, following the Phase II trial, pilot studies were performed to develop a patient-reported outcome tool (PRO) and to test methods of patient blinding leading up to the pivotal Phase III trials in the United States [39]. The reliance of surrogate markers such as duplex closure of veins was deemed by the FDA to be insufficient for approval of PEM, and they required a validated PRO assessing varicose vein symptoms to be the pivotal study endpoint [40]. The VVSymQ^® is the PRO instrument used in the trials. It assesses the severity of the five symptoms (heaviness, aching, throbbing, swelling, and itching) shown to be most relevant to patients with varicose veins.

The two pivotal trials, VANISH-1 (275 patients) [41] and VANISH-2 (230 patients) [42], utilized the VVSymQ^® as the primary study endpoint and change in appearance of the leg as assessed by both an independent physician reviewer and the patients themselves. Patients with symptomatic GSV or ASV reflux were enrolled in the prospective single-blind randomized trials. Duplex closure was assessed, as was patient safety. Both studies compared PEM to placebo, but the VANISH-1 study randomized patients to three differing doses of POL (0.5, 1.0, and 2.0%), while VANISH-2 randomized patients to 0.5 or 1.0% POL. VANISH-2 patients were allowed to have a two treatment sessions, separated by 1 week. At 8 weeks the primary endpoint (improvement in the patient PRO) and the secondary endpoints (including improvement in appearance) were assessed. Both studies showed significant improvement in both PRO scores and appearance, and compared to placebo, these improvements were highly statistically significant (p < 0.0001 for both endpoints). One-year follow-up was reported for the VANISH-2 group, and symptom improvement was sustained [43]. The duplex closure rates at 8 weeks in the 1% POL groups were 80.4% for the VANISH-1 trial [41] and 86.2% for the VANISH-2 trial [42]. There were no significant adverse neurologic events in the trials, other than headache, but 5.4% of patients had superficial thrombophlebitis following the procedure, and 4.7% had a deep vein thrombosis (DVT) on follow-up duplex examination. The majority of these events were asymptomatic and detected because of study protocols requiring detailed post-procedure duplex evaluation, including imaging of all tibial vessels. There were no symptomatic pulmonary emboli, and none of the patients with a DVT later showed signs or symptoms of post-thrombotic syndrome.

Following the pivotal trials, the FDA approved Varithena for use in November of 2013 [44]. The product was released for commercial release in August of 2014. Advantages over traditional endothermal ablation techniques for truncal saphenous ablation include the avoidance of tumescent anesthesia with its attendant pain and bruising [45, 46] and the ability to treat side branch tributaries quite simply in a concomitant fashion. It can be used to treat tortuous veins and in this way can treat a broader spectrum of anatomic presentations compared to EVLT and RF. As such, it provides an attractive option for treating recurrent varicose veins and neovascularization. It does not have an indication for treatment of the small saphenous vein (SSV) , so its use in this disease pattern would be considered off-label. Primary disadvantages compared to endothermal ablation include dosing limitations which may limit the number of veins that can be treated in a single session, a lower rate of duplex closure, and a higher rate of thrombotic events (DVT and superficial thrombophlebitis), when compared to historic endothermal ablation data. While data to support the safety and efficacy of PEM is robust compared to data for PCF, it is significantly more expensive.

One of the main barriers to the use of PEM at the time of this publication is the lack of a dedicated current procedural technology (CPT) code for billing. Payor coverage and reimbursement rates are variable and regional, with some insurers still considering PEM “investigational.” Over time, carrier coverage has become more widespread, and issues of coverage and reimbursement should become more certain when a CPT code specific to PEM is approved.

A thorough history and physical examination should be taken prior to treatment of either varicose veins or telangiectasias with sclerotherapy. Patients should be queried about previous treatments and response to those treatments including any adverse events they may have encountered. Special attention should be paid to the patient’s goals—are they being treated for cosmetic reasons, for symptoms, or for both? It is imperative that the risks and benefits of the procedure be addressed, and the pretreatment consultation is key to avoid unrealistic expectations on the part of the patient. Multiple sclerotherapy sessions may be required for the patient to achieve their goals.

Special considerations in the pretreatment consultation include review of medications and medical history. Sclerotherapy should not be performed in pregnant women or women who are breast-feeding unless the benefit clearly outweighs the risk, which is seldom if ever the case for venous treatment. Patients who are taking minocycline should not be treated with sclerotherapy as permanent hyperpigmentation can occur [47]. If a patient has had a previous reaction to a sclerosing agent, they should not receive that agent again. Small dose skin testing with subsequent in-clinic observation can be performed and would be recommended in any patient in whom there is concern for allergic reaction. STS is contraindicated in patients with asthma. All locations where sclerotherapy is performed should have a readily available and up-to-date emergency kit in the event of an anaphylactic reaction to a sclerosant.

Prior to foam sclerotherapy with PCF or PEM, patients are queried about a known history of a structural heart defect (such as an atrial septal defect or a PFO), and if present, alternative therapies may be suggested. As sclerotherapy may cause visual disturbances or migraine headache [48], patients with a history of migraine (especially migraine with aura) are cautioned that therapy could possibly trigger symptoms. They are advised to bring any medications that they would usually take in the event of a migraine with them to their sclerotherapy session.

STS is available in 1 and 3% concentrations, and POL is available as 1 and 0.5%. Both STS and POL have a maximum volume per session of 10 cc. Small volumes should be injected, and the concentration of sclerosant injected will depend on the vein size. Table 12.3 lists suggested sclerosant concentration by vein diameter. The lowest effective dose and concentration that will reliably achieve vessel occlusion should be used in order to minimize adverse effects such as matting, ulceration, and venous thrombosis.

Prior to sclerotherapy of either telangiectasias or varicose veins, photo documentation of the intended treatment area(s) is recommended. Photographs of the same area(s) should be repeated in follow-up to assess results and progress. Injection sites, type, and volumes of sclerosants should be documented at the time of treatment. In the author’s practice, “before and after” photos are shared with the patient at every visit. With the treatment of telangiectasias in particular, the main reason for treatment may be the patient’s dissatisfaction with visual appearance of the limb, making photography a necessary tool. The widespread availability of digital cameras and software programs to store medical images has simplified the use of photography in a vein practice.

Sclerotherapy of spider telangiectasias, while both safe and effective, can take a great deal of practice before mastery is obtained. The sclerotherapist should position themselves in a favorable ergonomic position in relation to the target vein. As the target vein may be a millimeter in diameter or less, any extraneous movement will dislodge the needle from the vein. When performing sclerotherapy, bracing the elbow, wrist, and hypothenar eminence of the dominant hand against a solid surface will ensure stability. The non-dominant hand is used to stretch and stabilize the skin. Such positioning is shown in Fig. 12.2. A small needle (30 or 32 gauge) and a small volume (3 cc) syringe are typically used. During injection the needle angle is very shallow with the bevel is up. Bending the needle can be helpful to facilitate shallow vein entry. The sclerosant is “dripped” into the vein with a minimal amount of pressure to avoid extravasation. There are many options to improve visualization of small veins from simple (magnification lenses, loupes) to more complex. The Syris™ system, Veinlite^®, and Venoscope^® are all transillumination aids, while the Veinviewer^® utilizes projected near infrared light to visualize subdermal veins.