An investigation of side-effects and efficacy of foam-based sclerotherapy with carbon dioxide or room air in the treatment of reticular leg veins: a pilot study

Background

Originally, sclerotherapy was performed utilizing solutions (liquids) to promote sclerosis of the vein wall through a controlled thrombophlebitic reaction. ¹ In the past few decades, foam sclerotherapy, made from mixing room air (RA) with the sclerosing solution, was introduced with the advantage of increased efficacy rates as compared with solution-based sclerotherapy. ^1,2

Recently, carbon dioxide (CO₂) has been used to create foam for sclerotherapy. CO₂ foam bubbles dissipate quicker than RA foam bubbles. A decreased incidence of side-effects including visual disturbances, chest tightness, cough and dizziness have been reported in patients treated with ultrasound-guided foam sclerotherapy of the great saphenous veins (GSV). ^1,3 No studies are currently available to evaluate the safety and efficacy of foam sclerotherapy prepared from CO₂ or RA for the treatment of reticular veins. We sought to perform a pilot study to investigate the incidence of side-effects and efficacy between RA and CO₂-created foam in the treatment of reticular leg veins.

Methods

This was a split-leg, randomized, blinded, investigator-initiated clinical study performed in an outpatient, private physician's office. Only patients with bilateral disease and bilateral colour-venous-duplex ultrasounds negative for underlying GSV and/or small saphenous veins (SSV) reflux and/or deep venous thrombosis (DVT) were randomized. The primary objective of this study was to evaluate the efficacy of foam sclerotherapy using RA or CO₂ in the treatment of reticular leg veins as judged by the disappearance of the reticular veins. Secondary objectives included side-effects, local and distant and the total volume in mL used per leg between these two treatment regimens.

As this was an unfunded pilot study of real-world experience, the sample size was limited to 20 patients. All evaluable patients with reticular and telangiectatic leg veins who met all study inclusion/exclusion criteria were considered for entry into this study. Inclusion criteria were as follows: women or men in good general health aged 18–65 years with reticular leg veins planning to undergo sclerotherapy of their reticular and telangiectatic leg veins. Patients were excluded if they suffered from any uncontrolled systemic disease (systemic disease not yet stabilized); significant history or current evidence of a medical, psychological, or other disorder; history of or the presence of any skin condition/disease that might interfere with the diagnosis or evaluation of study parameters (e.g. atopic dermatitis, eczema and psoriasis); an active bacterial, fungal or viral infection in the proposed treatment area; history of acute deep venous thrombosis; history of thrombophilia; history of hypersensitivity (e.g. anaphylaxis) to the study medication(s); inability to ambulate following the procedure; history of asthma; history of sclerotherapy to the legs in the last 180 days; current participation or participation within 30 days prior to the start of this study in a drug or other investigational research study. Prior to study enrollment, all patients were treated with color-venous-duplex ultrasound to rule out underlying GSV and/or SSV reflux and/or DVT.

Prior to treatment, each patient's leg veins were evaluated for extent, quality and size of their leg veins according to the standard treatment technique within our office. As all telangiectasias are fed by reticular veins, we elected to treat the telangiectasias at the same time. The percent sodium tetradecyl sulphate (Sotradecol [STS], Bioniche Pharma, Belleville, Ontario, Canada) utilized varied according to vein diameter classification (Table 1). Telangiectatic leg veins on both legs, measuring less than 1 mm, were treated with glycerin 72% (San Diego Compounding Pharmacy, San Diego, CA, USA). The patients were randomized to receive treatment to one of their legs with foam sclerotherapy prepared from STS and CO₂ and in a 1:4 (1 mL STS:4 mL gas) ratio using the double-syringe technique, while the other leg received treatment with foam sclerotherapy prepared with STS and RA in a 1:4 ratio using the double syringe technique. During injections, patients were monitored for the development of dizziness, visual changes, aura, migraine, cough, chest tightness or transient ischaemic attack-like symptoms by a blinded investigator. Each leg was treated in a single treatment session, one day apart, and the order of treatment, RA or CO₂ first, was also randomized.

Following sclerotherapy, the patient remained supine for five minutes. During that time 0.05% betamethasone dipropionate lotion (E. Foguera & Co., Melville, NY, USA) was applied to the patient's treated leg. Next, 30–40 mmHg graduated compression stockings were applied to the treated leg while the patient was supine. These stockings remained in place for 24 hours a day for the next seven days. The patients were then asked to ambulate for 30 minutes following sclerotherapy injections before returning home.

At 3–4 weeks post-treatment, patients were evaluated by a blinded investigator for the presence of coagulums, telangiectatic matting, ulceration, hyperpigmentation and reticular veins. If present, coagulums were drained at this visit. Statistical analyses were performed on all variables using a two-sample t-test assuming equal variances and two-tail significance was performed for all P values.

Results

Seventy-one patients were screened from February 2010 to June 2010. All patients who qualified for the study were women aged 31–65. Fifty-one patients did not qualify for participation due to: the presence of underlying reflux in the GSV and/or SSV, unilateral disease, bilateral disease with one extremity showing more severe disease than the other, sclerotherapy injections in the last 180 days, current or past participation in another study in the past 30 days, underlying medical condition (see above for exclusion criteria) or non-interest in participating in a research study. Of the twenty patients in the study, one patient was treated with 1% STS CO₂-created foam and 1% STS RA-created foam, six patients were treated with 0.5% STS CO₂-created foam and three patients with 0.5% STS RA-created foam, and 17 patients with 0.25% STS CO₂-created foam and 19 patients with 0.25% STS RA-created foam. Sixteen patients who received CO₂-created foam were also treated with 72% glycerin and 17 patients who received RA-created foam were also treated with 72% glycerin (Table 2). For 55% of patients, this was their first time for any type of vein therapy. The remainder of patients had a history of prior treatments with sclerotherapy, but no invasive procedures or other forms of vein therapy.

A statistically significant difference in the mean total volumes of CO₂ and RA-created foams were 17.5 and 12.35 mL (P value < 0.01), respectively, was found.

No episodes of dizziness, visual changes, aura, migraine, cough, chest tightness or transient ischaemic attack-like symptoms developed for any of the 20 patients during injections with CO₂ or RA-created STS foam. At 3–4 weeks post-treatment 65% of patients had developed coagulums in their reticular veins. Coagulums were present in 55% of CO₂ foam and 60% of RA foam legs (P value = 0.75). A single patient (5%) experienced telangiectatic matting, which occurred on each of her legs treated with CO₂ and RA. No episodes of hyperpigmentation or ulceration developed. There was no difference in the efficacy as measured by resolution of reticular veins. Resolution of telangiectatic veins was not studied since these veins were treated with glycerin solution.

Discussion

In the past few decades, foam sclerotherapy was introduced with the advantage of increased efficacy rates as compared with solution-based sclerotherapy due to an increased time of contact between the sclerosant and the vein wall. ^1,2 The majority of phlebologists utilize readily available RA for foam creation in sclerotherapy; however, CO₂ is becoming increasingly popular. ⁴

Foam stability is affected by foam composition, foam volume and injection technique. ⁵ Composition variables, including the homogeneity of bubble size, viscosity and temperature, all influence the ‘quality’ and longevity of foam. ⁶ CO₂ is 1.5 times more dense than room air; therefore, foam bubbles prepared from CO₂ are smaller than that of air. ⁷ CO₂ also has a much greater diffusibility into blood as compared with nitrogen (the dominant gas in room air); as a result foam half-life is reduced for CO₂. ⁸ As a result, CO₂ foam bubbles quickly disintegrate, ⁷ and this effect is more pronounced as the sclerosant-to-gas ratio is increased. ⁹

Local adverse events can occur from either sclerotherapy solutions or foams and include telangiectatic matting, ulcerations, hyperpigmentation, erythema, oedema, pruritus, pain, urticaria, localized hypertrichosis and allergic reaction. ¹ However, foam-specific side-effects may occur at sites distant to the treatment area due to microbubbles coursing through the circulation.

A metanalysis investigating side-effects of foam sclerotherapy for the treatment of varicose veins in over 9000 patients by Jia et al. ² found the median values of visual changes and headache were 1.4% and 4.2%, respectively. Chest tightness and coughing occurred in less than one percent. RA- and CO₂-created foams were included in this metanalysis. In a large, prospective, multicenter study of RA or oxygen foam sclerotherapy in 1025 patients the incidence of migraine was 0.78% (with aura 0.59%, 0.19% without aura), visual disturbance 0.68%, chest tightness 0.68%, chest tightness with visual disturbance 0.49% and transient ischaemic attack 0.1%. ³

A recent study in patients with incompetent GSV treated with ultrasound-guided foam sclerotherapy created from CO₂ versus RA, in a 1:4 sclerosant to gas ratio, demonstrated decreased incidences of foam bubble-related side-effects including chest tightness (3.1–18%), cough (1.6–16%) and dizziness (3.1–12%) in patients treated with CO₂-created foam. There was a trend towards decreased visual disturbances in the CO₂ versus RA group, 3.1–8.2%, though this difference was not found to be statistically significant. There were no differences in vital signs or electrocardiogram changes between the two cohorts. The CO₂ foam creation was attributed to an overall 72% decrease in bubble-related side-effects as compared with room air. ¹⁰

When cerebral emboli were monitored via transcranial doppler ultrasound in patients treated with foam created from RA or a 70% CO₂/30% oxygen mixture, there were no statistical differences in the rate of middle cerebral artery high-intensity transient signals between these two cohorts. ¹¹ One can speculate that the decreased upstream foam-related side-effects are attributable to the short CO₂ foam half-life ⁷ and the increased diffusibilty of this gas into blood as compared with nitrogen and oxygen. ^7,8 Of note, all of the above studies were limited to patients receiving treatment to the great and small saphenous veins, not the reticular veins of the legs.

The only available study investigating the effects of foam sclerotherapy in reticular veins was recently reported by Palm et al. ¹² Overall, there was a low incidence of patient-reported adverse events from RA-created foam sclerotherapy of the reticular leg veins in a retrospective chart review of 325 patients. In this study, the mean volume of foam sclerotherapy per treatment session was 16.9 mL. The incidence of adverse events was as follows: telangiectatic matting 69%, discomfort 24% (though mild) and ulceration 6.8%. Thirty-five percent of patients reported hyperpigmentation; however, on clinical exam there was no evidence of hemosiderin deposition. The authors concluded the patient-reported hyperpigmentation was either temporary or represented coagulum formation. No cases of visual disturbances, migraine, chest tightness, cough, deep vein thrombosis, transient ischaemic attack or cerebral vascular accident-like symptoms were encountered. ¹²

Our study limitations included a small sample size and short-term follow-up of 3–4 weeks. As this was an unfunded pilot study, we hope this study can spur interest for a larger, multicentre study with a more extended follow-up for the assessment of both efficacy and adverse events.

Similar to Palm et al., ¹² we found no instances of distant foam-related adverse events such as visual disturbances, migraine, chest tightness, cough, deep vein thrombosis, transient ischaemic attack or cerebral vascular accident-like symptoms. We speculate the incidence of these distant foam-related adverse events are dramatically decreased as we are not injecting directly into the truncal veins. Our procedure also showed a low incidence of local adverse events, with an isolated case of telangiectatic matting occurring on both the CO₂ and RA foam-treated legs. It is impossible to determine if the matting developed due to treatment of the reticular or telangiectatic veins. In contrast to other reports, we saw no episodes of postinflammatory hyperpigmentation. This adverse event can be decreased via 30–40 mmHg graduated compression stockings postprocedure, topical corticosteroid applied postprocedure and coagulum removal. ¹

Conclusion

In this study, there was no difference in the efficacy, local side-effects or distant side-effects between RA- and CO₂-created foam in the treatment of reticular leg veins. The total volume used was significantly greater with CO₂ foam compared with RA foam. We speculate that this difference can be attributed to the reduced foam stability seen with CO₂-created foam.