Comparative study of Duplex guided Foam Sclerotherapy and Duplex-guided Liquid Sclerotherapy for the Treatment of Superficial Venous Insufficiency

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1 Original Articles Title of this article Comparative study of Duplex guided Foam Sclerotherapy and Duplex-guided Liquid Sclerotherapy for the Treatment of Superficial Venous Insufficiency Brief title Duplex-guided foam sclerotherapy vs. duplex-guided liquid sclerotherapy The authors: Takashi Yamaki M.D. Motohiro Nozaki M.D. Susumu Iwasaka M.D. Correspondence to: Takashi Yamaki M.D. Department of Plastic and Reconstructive Surgery Tokyo Women s Medical University 8-1, Kawada-cho, Shinjuku-ku, Tokyo , JAPAN TEL: FAX: E-mai:yamaki@prs.twmu.ac.jp Yamakit@aol.com No significant interest with commercial supporters.

2 INTRODUCTION Duplex scanning augmented by color flow Doppler imaging has developed over the last decade, and is now a useful tool for identifying the distribution and extent of venous reflux. Findings obtained by duplex scans correlate well with venography, and the technique is noninvasive, repeatable, and physiologic. 1,2 Recently, duplex guided sclerotherapy has developed, and has been used as an alternative to surgical interruption for control of junctional incompetence. 3-7 More recently, a new method of using a foam agent has been introduced to cause more damage on the intima than liquid form, 8 and foam sclerotherapy is considered to be very promising in the treatment of superficial venous insufficiency Therefore, we recently applied duplex guided foam sclerotherapy (DGFS) in patients with superficial venous insufficiency, and purpose of this study was to confirm the safety and the efficacy of DGFS, and compare the preliminary results of hemodynamic changes between (DGFS) and duplex guided liquid sclerotherapy (DGLS) using non invasive vascular imaging techniques. Materials and Methods Patients Between 2001 and 2002, 77 limbs in 77 patients with isolated GSV incompetence were selected for duplex guided sclerotherapy. Basically, patients who refused to receive surgical interventions were selected for outpatient duplex guided sclerotherapy. The patients comprised 15 males and 62 females, ranging in age from 21 to 84 years (mean 54.6 years). Of these, 37 limbs were treated with DGFS and remaining 40 limbs were treated with DGLS. Limbs were categorized according to the clinical classification for reporting standards in venous disease supported by the North American Chapter of the Society for Vascular Surgery and the International Society for Cadiovascular Surgery. 13 All limbs were classifiable into CEAP (clinical, etiologic, anatomic, and pathophysiologic) C2 (varicose veins), C3 (edema), C4 (skin changes ascribed as pigmentation, eczema, and lipodermatosclerosis), and C5 (healed ulceration). Patients with myocardial ischemia, arterial insufficiency with ankle brachial index of less than 0.8 and, active thrombophlebitis, these with active ulcers were excluded. The follow-up period of the patients was 12 months. Color duplex scanning

3 Pretreatment exam was performed using a color duplex scanner (LOGIQ 500MD: GE Medical Systems, Milwaukee, WI, USA) with a 5 to 10 MHz transducer to detect venous reflux at the sapheno femoral junction (SFJ) and in the greater saphenous vein (GSV). Venous reflux was assessed with the patients in a standing position, by applying distal manual compression followed by sudden release Venous reflux was considered to be present if the duration of reflux exceeded 0.5sec. Pretreatment mapping of the superficial venous system was also performed. Venous obstruction and recanalization were screened by serial posttreatment duplex examinations which were performed 3, 6, 9 and 12 months after the sclerotherapy. Venous obstruction and recanalization were assessed with the patients in a supine position, compressibility of the vein was evaluated on B mode, and no spontaneous flow on color Doppler imaging. Venous reflux was assessed with the patients in a standing position. Air plethysmography Pretreatment air plethysmography (APG) measurements were obtained using APG Model 1000 (ACI Medical Inc., Sun Valley, CA, USA) including venous filling index (VFI), ejection fraction (EF), and residual venous fraction (RVF). 17,18 The VFI is the average rate of increase in the venous volume (VV), which reflects gravitational reflux. The EF is the percentage of the volume ejected after one tiptoe maneuver, and indicates the degree of function in the calf muscle pump. The RVF is a measure of the percentage of the VV remaining in the calf after 10 tiptoe maneuvers, and reflects the ambulatory venous pressure. Posttreatment APG analysis was performed 3, 6, 9 and 12 months after the sclerotherapy. Duplex-guided sclerotherapy The sclerosing foam was produced by Tessari s method using 1% and 3% polidocanol (POL). 7,19 A syringe of 2.5ml was filled with 0.5ml of POL. And 2.5ml of air was aspirated with another syringe of 5ml. Two syringes were attached by a three-way stopcock, and the stable sclerosing foam was obtained by mixing them through multiple passages between the two syringes. After detailed anatomical mapping with duplex scans, patients were placed in the supine position. Each visible varicose tributary vein draining into the GSV was injected first, with 2ml of 1% POL or 1% POL foam. Then 0.5ml of 3% POL or 3% POL foam were injected under duplex guidance, starting 3 4cm distal to the SFJ, 5 and second injection was made 5 to 10cm distal to the initial point with 0.5ml of 3% POL or

4 3% POL foam. Immediately after sclerotherapy, compression pads and elastic bandages were applied, and kept on continuously for the first two days. All patients were encouraged to ambulation after the treatment. On postsclerotherapy day 3, elastic bandages and compression pads were removed, and Class II thigh-high compression stocking was applied. Because one the purpose of this study was to determine the efficacy of DGFS, all patients received only one session of sclerotherapy, and these who had multiple sessions of sclerotherapy were excluded. Statistics All data were analyzed using StatView for Windows (Version 5.0, SAS Institute Inc., Cary, NC). Wilcoxon s nonparametric rank sum test and chi-square analysis or Fisher s exact test were used to evaluate differences between group of patients. Statistical significance was defined as p<0.05. Results The baseline characteristics of the two groups are shown in Table 1. There were no significant differences in age, male: female ratio, and clinical presentation between the two groups. Election to include sclerosing foam was not randomized, however, age, female predominance, and CEAP clinical classes were all matched. The incidence of the venous reflux at the 12 month follow up point was shown in Table 2. Duplex scanning demonstrated complete occlusion in the GSV for DGFS in 25 limbs (67.6%), which was a significantly higher proportion than for the DGLS (7 limbs, 17.5%, p<0.0001). There was no statistically significant difference in the proportion of partial recanalization without reflux (p=0.580). Similarly, there was no significant difference in the proportion of partial recanalization with reflux between the two groups (p=0.171). Complete recanalization with reflux was detected in 5 (13.5%) in DGFS group, and 22 (55%) in DGLS group, which was statistically significant (p=0.0001). Recurrent varicose veins were found in 3 patient (8.1%) in DGFS group, and 10 (25%) in DGLS group. This was statistically significant (p=0.048). Table 3 demonstrates the pre and posttreatment APG examinations. The pretreatment APG examinations showed reflux in both groups (4.34 ± 2.22ml/sec and 4.39 ± 2.53ml/sec, respectively). In DGFS, VFI values remained normal during the subsequent follow up examinations, whereas in DGLS, VFI began to increase, and there was a significant difference at 6 months between DGFS and the DGLS (p<0.0005).

5 There was no significant difference in EF value between pre and posttreatment examinations in both groups. At 9 months, there was a significant difference in RVF between the two groups, and RVF value continued to be improved in DGFS (p=0.033). No adverse events were found using both foam and liquid sclerosing solutions in this series. DISCUSSION Compression sclerotherapy has been used for the treatment of varicose veins associated with GSV incompetence for many years. The advantages of compression sclerotherapy include no anesthesia, no hospitalization, and no loss of work. 20 Indeed, sclerotherapy is relatively safe and less costly procedure compared with surgery. But there have been conflicting data on the efficacy of sclerotherapy, and the randomized studies concluded that compression sclerotherapy was inferior to surgery in the presence of GSV incompetence. 21,22. Theoretically, duplex guided sclerotherapy should give improved results when treating a refluxing GSV. Using the duplex guidance, safe injections are carried out by an experienced sclerotherapist. 23,24 Bishop and associates reported a GSV obliteration rate of only 6% when treating the refluxing GSV without duplex guidance. 20 On the contrary, Kanter and associates demonstrated recanalization rates of 24.1% at 1 year and 35.7% at 2 year with duplex guided sclerotherapy, which appears to be superior to that achieved by conventional sclerotherapy. 4 At the moment, wide range of different practices are being performed in sclerotherapy, and duplex guided sclerotherapy is recommended for lesser saphenous varicose veins, anterior saphenous varicose veins, recurrent varicose veins, perforators, and obese patients. 25 No agreement has been reached regarding the need for duplex guided sclerotherapy, or the advantages of this treatment, for the GSV incompetence. 25 In 1950, Orbach described the macrobubble foam preparation with sclerosing solution. 26 Using his technique, however, only 20% of the sclerosant was transformed into foam with bubbles of relatively large and irregular caliber. And side effects caused by this method lead to its abandonment. 27 Therefore, foam sclerotherapy did not become popular till mid 1990s after the introduction of new methods of transforming sclerosing solutions There have been several different methods reported in the production of a foam form. In 1997, Cabrera and associates stated the production of complex foam with CO 2 and an unknown tension-active agent. 8 Monfreux described his technique in the article that generated a simple foam with air in

6 glass syringe. 9 Henriet reported his experience using Monfreux s technique for minor varices. 10 Mingo-Garcia developed a special device for producing a foam form with compressed air. 12 In 2000, Tessari reported a new method for the production of a stable foam with two syringes connected with a three-way stopcock. 19 And recent study on DGFS described the efficacy of foam sclerotherapy with excellent immediate occlusion rate and fewer complications. 8,11 Our present study using Tessari s method revealed that DGFS showed significantly better results in terms of occlusion rate of the GSV and the recurrence rate of varicose veins as well as the venous functions compared with DGLS. The advantages of sclerosing foam include the possibility of reducing the amount of the necessary sclerosing liquid as well as the concentration. The sclerosing foam displaces blood with very little drug dilution of the blood, and active surface of the drug is increased by preparation of the foam. 28 DGFS provides favorable results since sclerosing foam is highly echogenic and immediate spasm in the GSV is obtained by sclerosing foam. Althogh, further follow-up study is required to confirm the validity of this method, DGFS could have great promise in the treatment of superficial venous insufficiency.

7 REFERENCES 1. Szendro G, Nicolaide AN, Zukowski, et al. Duplex scanning in the assessment of deep venous incompetance. J Vasc Surg 1986; 4: Vasdekis SN, Clarke GH, Nicolaides AN. Quantification of venous reflux by means of duplex scanning. J Vasc Surg 1989; 10: Raymond Martimbeau P. Advanced sclerotherapy treatment of varicose veins with duplex ultrasound guidance. Semin Dermatol 1993; 12: Kanter A, Thibault P. Saphenofemoral incompetence treated by ultrasound-guided sclerotherapy. Dermatol Surg 1996; 22: Kanter A. Clinical determination of ultrasound guided sclerotherapy outcome: Part I: the effect of age, gender and vein size. Dermatol Surg 1998; 24: Kanter A. Clinical determination of ultrasound-guided sclerotherapy: Part II: in search of the ideal injectate volume. Dermatol Surg 1998; 24: Tessari L, Cavezzi A, Frullini A. Prelinimary experience with a new sclerosing foam in the treatment of varicose veins. Dermatol Surg 2001; 27: Cabrera Garrido JR, Cabrera Garcia-Olmedo JR, Garcia-Olmedo Dominguez MA. Elargissement des limites de la sclérothérapie: Noveaux produits sclérosants. Phlébologie 1997; 50: Monfreux A. Traitement sclérosant des troncs saphènies et leurs collatérals de gros caliber par le method MUS. Phlébologie 1997; 50: Henriet JP. Un an de pratique quotidienne de la sclérothérapie (veines reticulaires et télangiectasies) par mousse de polidocanol faisabilité, resultants, complications. Phlébologie 1997; 50: Cavezzi A, Frullini A. The role of sclerosing foam in ultrasound guided sclerotherapy of the saphenous veins and of recurrent varicose veins: Our personal experience. Aust NZ J Phlebol 1999; 3: Mingo-Garcia J. Esclosis venosa con espuma: Foam medical system. Rev Espan Med Cirugia Cosmética 1999; 7: Porter JM, Moneta GL. International consensus commitee on chronic venous disease. Reporting standard in venous disease: an update. J Vasc Surg 1995; 21: Labropoulos N, Leon M, Nicolaides AN, et al. Superficial venous insufficiency: Correlation of anatomic extent of reflux with clinical symptoms and signs. J Vasc Surg 1994; 20: Yamaki T, Nozaki M, Sasaki K. Color duplex ultrasound in the assessment of

8 primary venous leg ulceration. Dermatol Surg 1998 ; 24: Yamaki T, Nozaki M, Sasaki K. Quantitative assessment of superficial venous insufficiency using duplex ultrasound and air plethysmography. Dermatol Surg 2000; 26: Nicolaides AN, Christopoulos D. Quantification of venous reflux and outflow obstruction with air plethysmography. In: Bernstein EF, editor. Vascular diagnosis. St. Louis: Mosby, 1993: Nicolaides AN, Hussein MK, Szendro G, et al. The relation of venous ulceration with ambulatory venous pressure measurements. J Vasc Surg 1993; 17: Tessari L. Nouvelle technique d obtention de la sclero-mousee. Phlébologie 2000; 53: Bishop CCR, Fronek HS, Fronek A, et al. Real time color duplex scanning after sclerotherapy of the greater saphenous vein. J Vasc Surg 1991; 14: Hobbs JT. Surgery and sclerotherapy in the treatment of varicose veins. Arch Surg. 1974; 109: Jakobsen BH. The value of different forms of treatment for varicose veins. Br J Surg 1979; 66: Schadeck M. Ultrasound guided sclerotherapy In: Schadeck M, ed. Duplex and Phlebology. Napoli: Gnocchi, 1994: Zummo M, Forrestal M. Sclerotherapy of the long saphenous vein: a prospective duplex controlled comparative study. Phlebology 1994; Suppl. 1: Baccaglini U, Spreafico G, Castoro C, et al. Consensus conference on varicose veins of lower extremity. Phlebology 1997; 12: Orbach EJ. Contribution to the therapy of the varicose complex. J Int Coll Surg 1950; 13: Henriet JP. History of foam In: Foam sclerotherapy: state of art. Editions Phlébologique Françaises. Paris: Cavezzi A, Frullini A, Ricci S, et al. Treatment of varicose veins by foam sclerotherapy: two clinical series. Phlebology 2002; 17: 13-18

9 Foam Liquid n=37 n=40 p value Age (yr) 54.3 ± ± a Female sex (%) 30 (81.1) 32 (80) b CEAP clinical class* C2 (%) 27 (73.0) 31 (77.5) b C3 (%) 2 (5.4) 4 (10) b C4 (%) 5 (13.5) 3 (7.5) b C5 (%) 3 (8.1) 2 (5) b Foam: duplex-guided foam sclerotherapy Liquid: duplex-guided liquid sclerotherapy *CEAP Clinical classification: C0, no visible or palpable signs of venous disease; C1, telangiectases, reticular veins; C2, varicose veins; C3, edema without skin changes; C4, skin changes ascribed to venous disease (pigmentation, venous eczema, or lipodermatosclerosis); C5, skin changes with healed ulceration; C6, skin changes with active ulceration. Values expressed as mean ± SD. a Wilcoxon s non parametric rank sum test. b Pearson s 2 X test or Fisher s exact test. Table.1

10 GSV Foam Liquid n=37 n=40 p value Occluded (%) 25 (67.6) 7 (17.5) < Partial recanalization with no reflux (%) 3 (8.1) 2 (5) Partial recanalization with reflux (%) 4 (10.8) 9 (22.5) Complete recanalization with reflux (%) 5 (13.5) 22 (55) Recurrence (%) 3 (8.1) 10 (25) Foam: duplex-guided foam sclerotherapy Liquid: duplex-guided liquid sclerotherapy Table.2

11 Pretreatment 3 Months 6 Months 9 Months 12 Months Venous Filling Index (VFI), ml/s Foam 4.3 ± ± ± 0.4* 1.2 ± ± 0.8* Liquid 4.4 ± ± ± ± ± 0.7 Ejection Fraction (EF), % Foam 51.0 ± ± ± ± ± 13.5 Liquid 47.7 ± ± ± ± ± 40.4 Residual Venous Fraction (RVF), % Foam 39.6 ± ± ± ± ± 26.1 Liquid 36.7 ± ± ± ± ± 16.8 Foam: duplex-guided foam sclerotherapy Liquid: duplex-guided liquid sclerotherapy Values expressed as mean ± SD. *Foam versus Liquid, p < Foam versus Liquid, p < Foam versus Liquid, p < Table.3

12 LEGENDS Table1: Baseline characteristics of the study patients. There were no statistical differences in age, gender, and CEAP clinical manifestations between the two groups. Table2: Incidence of occlusion, recanalization, and recurrence rate after treatment. There was a statistically higher proportion of occlusion in DGFS, and there was a statistically higher proportion of reflux in DGLS. Recurrence was statistically predominant in DGLS. Table3: Comparison of hemodynamic variables before and after treatment. VFI began to increase in DGLS, and there was a significant difference at 6 months between the two groups. At 9 months, there was a significant difference in RVF between the two groups, and RVF value continued to be improved in DGFS.