Incidence of Side Effects Using Carbon DioxideeOxygen Foam for Chemical Ablation of Superficial Veins of the Lower Extremity

Transcription

1 Eur J Vasc Endovasc Surg (2010) 40, 407e413 Incidence of Side Effects Using Carbon DioxideeOxygen Foam for Chemical Ablation of Superficial Veins of the Lower Extremity N. Morrison a, *, D.L. Neuhardt b, C.R. Rogers a, J. McEown a, T. Morrison a, E. Johnson a, S.X. Salles-Cunha b a Morrison Vein Institute, Scottsdale, AZ, USA b CompuDiagnostics, Inc., Scottsdale, AZ, USA Submitted 16 June 2009; accepted 18 April 2010 Available online 23 May 2010 KEYWORDS Ultrasound-guided foam sclerotherapy; Side effects Abstract Objectives: To determine the incidence of side effects following treatment of varicose veins with carbon dioxideeoxygen (CO 2 /O 2 ) foam sclerotherapy, and to compare results with historical controls using CO 2 - or air-based foams. Design: Cohort study with prospective data collection, private clinic setting. Patients: The patient population consisted of one hundred patients, 95% women, age 52 SD 13 years-old, CEAP class C 2 EpAsPr. Methods: Patients underwent ultrasound-guided foam sclerotherapy following thermal ablation of saphenous trunks; 1e3% polidocanol and 70%CO 2 e30%o 2 gas were mixed in a 1:4 proportion. Volume injected averaged 22 SD 11 (range: 2e46) ml. Vital signs were monitored for 1 h; side effects were recorded up to 24 h post treatment. Incidence of side effects was compared to CO 2 - and air-based foam data. Results: Heart rate decreased from 73 SD 11 at the start to 68 SD 9 bpm (p < 0.001, paired t- test) following the procedure. Systolic and diastolic pressures, 127/75 SD 18/14 mmhg, respiratory rate, 15 SD 4 rpm and po 2, 98 SD 2%, did not change significantly. Itching (7) or leg pain (24) reporting was similar to that for air-based foam (p Z NS). Lack of reported chest tightness and/or dry cough was superior to our previous data with CO 2 or air foam (p < 0.05). Reporting of dizziness (1) was less than that for air-based foam (p Z 0.002). The incidence of visual disturbance (2%), was comparable with that for CO 2 (3%) or air (8%) foam, but too few cases were available for meaningful statistical analysis. * Corresponding author at: N. Morrison, MD, Morrison Vein Institute, 8575 East Princess, Drive Suite 223, Scottsdale, AZ 85255, USA. Tel.: þ ; fax: þ address: nickmorrison@morrisonveininstitute.com (N. Morrison) /$36 ª 2010 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. doi: /j.ejvs

2 408 N. Morrison et al. Conclusions: Foam sclerotherapy using CO 2 /O 2 foam was well tolerated by patients and resulted in fewer side effects than similar treatment using air foams. ª 2010 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. Introduction Chemical ablation has become a valuable alternative for the treatment of valvular insufficiency of the superficial veins of the lower extremities. 1e3 A wide range of venous disease has been treated with ultrasound (US) guided foam sclerotherapy (USGFS). 4e16 Foam sclerotherapy can be a primary treatment, or complementary to surgical treatment or thermal ablation by radiofrequency or laser. The gas used to prepare the foam may affect the frequency of adverse reactions associated with the USGFS. Air is used in a 4e1 ratio with a liquid sclerosant and administration of foam volumes of less than 10 ml per treatment session has been recommended. 2 There is evidence that larger volumes can be injected safely and effectively if biocompatible gases (carbon dioxide, oxygen) are employed to make the foam. 1,17e19 In our personal experience, the use of carbon dioxide (CO 2 ) has reduced the incidence of side effects or complications, as compared to the use of air-based foam. 1 This study investigated the incidence of adverse events during CO 2 /O 2 foam sclerotherapy. Materials and methods This study investigated the incidence of side effects and complications of a CO 2 /O 2 -based foam. The results were compared with previously published data for CO 2 - and airbased foam sclerotherapy. 1 The fundamental protocols were similar for the three different types of gases used so far but the data reported here do not comprise a randomised study. Patient population All subjects gave written informed consent for treatment with polidocanol and for participation in a quality-assurance research program. Initially, all patients had thermal ablation of the great saphenous vein (GSV), performed either with laser or radiofrequency energy. This treatment also included ambulatory phlebectomy for the treatment of varicose veins. 100 Patients with residual or recurrent varices were treated by USGFS using CO 2 /O 2 -based sclerosant foam. Average patient age was 53 SD 13 (range 19e76) years. Women (n Z 95) outnumbered men (5). The CEAP classification was C2EpAsPr for varicose veins, primary aetiology, and saphenous reflux greater than 1 s. Contraindications Patients with known symptomatic patent foramen ovale (PFO) were not treated. Patients with history of superficial thrombophlebitis, multiple spontaneous abortions, family history of thrombosis, previous deep venous thrombosis underwent thrombophilia screening and were treated with prophylactic low molecular weight heparin prior to thermal or chemical ablation. Diagnostic ultrasound (US) US was used for physiological and anatomical evaluation. 20 The great, small, anterior and posterior accessory saphenous veins were examined. Findings at the saphenofemoral junction, proximal, mid and distal thigh, proximal, mid and distal calf were summarised in a formal report. Out of fascia tributaries and unusual veins were also evaluated. Perforating, intersaphenous, Giacomini, and sciatic veins were examined and noted if reflux was present. Reflux was classified as lasting for 1 sec, 2 s, 3 s or longer than 4 s. Ultrasound-guided foam sclerotherapy (USGFS) Ultrasound evaluation identified residual incompetent segments of the vein. A plan was then developed to a) close recanalised segments of the treated GSV, b) expand ablation distally into the GSV, c) ablate the SSV, d) close incompetent tributaries and perforating veins, and e) ablate remaining incompetent superficial veins. Sclerosant foam preparation The gas used in this study was a mixture of 70%CO 2 and 30% O 2, supplied pre-mixed by the medical gas distributor. The sclerosant used was 1e3% polidocanol, mixed with gas as a 1:4 ratio. The Tessari dual syringe, three-way tap technique was employed to create the foam. 21 Access Direct puncture of incompetent veins was performed under longitudinal or transverse ultrasound visualisation with needle diameters of 0.4 mm (27G). Ultrasound imaging was used to establish whether a further injection of foam was needed for that segment. Injections were stopped once foam approached a connection to the deep system. The GSV was usually punctured in a residual segment in the calf. SSV and tributary injection followed a distal-to-proximal approach. Treatment of perforating veins was accomplished by indirect injection into an extra-fascial tributary or saphenous vein segment. Direct injection of perforating veins was avoided. Table 1 summarises the veins that were treated. The diameter of the treated veins averaged 2.5 SD 1.2 (range 1e6) mm. Only one vein (10 mm) greater than 6 mm was treated. 2 ml of foam was used for most injections. Patients were sometimes instructed to perform plantar and dorsiflexion of the ankle to increase blood flow via the deep veins and speed neutralisation of any foam that may have reached the deep venous system. A total of 648 injections were performed in 176 legs, averaging 6.5 per patient, or 3.7 per leg. Table 1 lists the number of injections per site. The duration of treatment varied, lasting less than 15, 30, and 45 min for 66%, 36% and 8% of the patients respectively. The total foam volume injected per patient was 22 SD 11 ml,

3 Incidence of Side Effects Using Carbon DioxideeOxygen Foam 409 Table 1 Ultrasound-guided foam sclerotherapy of lower extremity veins as a complement to thermal ablation and phlebectomy (N Z 100 patients). Injection sites Number of injections Percentage GSV tributaries distal to thigh % GSV tributaries at mid thigh % GSV tributaries at proximal thigh % Distal GSV % Distal SSV % SSV tributaries % Proximal SSV % GSV at mid thigh % Proximal GSV % Perforating veins 3 0.5% Total % GSV: great saphenous vein; SSV: small saphenous vein. 2nd numbers is what I have in the data base. varying from 2 ml to 46 ml. The average foam volume injected per leg was 12 SD 6, varying from 1 to 28 ml. Patient monitoring A registered nurse (RN) monitored vital signs pre-procedure, every 15 min during the procedure, and 30 and 60 min post procedure while the patient was still in the clinic. The vital signs monitored were heart rate, blood pressure, respiratory rate, pulse oximetry (po 2 ), and electrocardiogram. Side effects or adverse events were also monitored directly by the RN every 15 min during the procedure and 30 and 60 min post procedure. A telephone interview registered the events volunteered by the patients 2, 6 and 24 h after the procedure. The expected sequelae monitored were: injection site itching, localised leg pain, localised burning sensation, tingling, and localised erythema. The side effects sought after were dry cough, metallic taste, and chest discomfort. The complications monitored included respiratory difficulty, nausea, dizziness, circumoral paraesthesia, visual disturbance, and headache. TTE and TCD monitoring Transthoracic echocardiography (TTE) and transcranial Doppler (TCD) were undertaken for those patients with a history considered suspicious for right-to-left shunt, such as patent foramen ovale (PFO). The aim was to assess the presence of foam in the right and left heart and in the middle cerebral arteries. 22 Asymptomatic patients who reported symptoms possibly attributable to a PFO, particularly migraine with aura, following the first injection would undergo a PFO diagnostic protocol. Further foam sclerotherapy was avoided in patients in whom a PFO was found. Statistical analysis Incidence of adverse events associated with CO 2 /O 2 foam were documented and compared with historical data previously recorded for CO 2 foam or air-based foams. 1 Data are represented by the mean and standard deviation. Paired t-tests of statistical significance were used to compare ordinal data. Contingency table analysis was undertaken using Chi-square tests. Results There were no physiologically significant changes in vital signs or electrocardiogram (Table 2). A 5 bpm heart rate decrease at 60 min post procedure and a 2 mmhg decrease Table 2 Vital signs associated with chemical ablation. Ultrasound-guided foam sclerotherapy Liquid: 1e3% polidocanol Gas: 70% carbon dioxide (CO 2 )e30% oxygen (O 2 ) pre-procedure 15 min into procedure 60 min post procedure Heart rate (bpm) 73 SD SD SD 10 a Respiratory rate (rpm) 15 SD 4 14 SD 4 15 SD 3 Pulse oximetry (%) 78 SD 2 78 SD 2 78 SD 2 Systolic pressure (mmhg) 127 SD SD 16 b 126 SD 17 Diastolic pressure (mmhg) 73 SD SD SD 14 a Significantly lower than pre-procedure heart rate (p < 0.001, paired t-test). b Significantly lower than pre-procedure systolic pressure (p Z 0.043, paired t-test).

4 410 N. Morrison et al. in systolic pressure at 15 min into the procedure were observed. Localised itching was reported by 7 of the 100 patients, a proportion similar to that reported by patients treated with air- (6%, p Z NS) but less than that reported by patients treated with CO 2 (15%, p < 0.05). Localised leg pain was reported by 24 patients, a proportion similar to that reported after air- (22%, p Z NS) or CO 2 -based (20%, p Z NS) USGFS. Two patients mentioned leg burning, two mentioned tingling, one mentioned cramping, and one complained of redness following CO 2 /O 2 -based USGFS. Discomfort from compression stockings was mentioned by 5 patients. No patient reported chest tightness or dry cough in this series of 100 cases of USGFS using CO 2 /O 2 gas (Table 3). This finding was a significant improvement over air or CO 2 foams as previously reported (p < 0.05, chi squared). Dizziness was reported once (1%), significantly less than the percentage reported following air- (12%, p Z 0.002) but not statistically different from CO 2 -based (3.1%, p Z NS) USGFS. The patient reporting dizziness also reported headache, hangover, and calf or ankle tingling, numbness and pain. The incidence of visual disturbance was comparable with that observed with CO 2 and air foams (Table 3). However, the small number of events observed in these series prevented meaningful statistical comparison of these events. Overall, 5 patients mentioned non-leg symptoms. One patient mentioned earache and another mentioned metallic/medicine tasting. There were two cases of visual disturbance and one case of dizziness, headache and hangover. All patients had received injections in proximal tributaries, accounting for 8% (5/66) of patients who received proximal tributary injections. Three of these 5 patients had injections in the proximal SSV, accounting for 7% (3/44) of patients who received proximal SSV injections. One patient received bilateral proximal GSV injections, accounting for 7% (1/14) of patients who received proximal GSV injections. 36 Further patients who received more than 25 ml of foam reported no symptom of this type. Discussion Few reports describe the incidence and significance of side effects following USGFS with the use of biocompatible gases. 1 This work makes a contribution toward an understanding of possible side effects following USGFS using a physiological gas, CO 2 eo 2, instead of air. In controlled clinical trials, better efficacy of foam compared to liquid sclerosant has been demonstrated. 23e26 Pain, pigmentation or signs of inflammation, were more common after foam than after liquid injection in one report 25 but other investigators noted no difference in ecchymosis, inflammation or other side effects or adverse reactions. 23,24,26 Review papers have emphasised the superiority of foam versus liquid sclerotherapy for the treatment of patients with varicose veins. 27,28 In our study USGFS was complementary to thermal ablation by radiofrequency or laser ablation. One of the inspiring factors leading to the use of a physiological gas-based foam was CO 2 angiography. 29 Physiological gas-based foam has been injected in larger volumes than those usually recommended for air-based foam. 19 A commercially-prepared foam, composed primarily of CO 2 and O 2, produced smaller bubbles, and avoided arteriolar obstruction (bubbles were seen with both foams, but did not cause obstruction with the commercial product) caused by the home-made air-based foam. 30 CO 2 /O 2 -based foam is more stable than pure CO 2 based foam (Personal Communication: Tessari L, Cabrera A). The European Consensus on Foam Sclerotherapy published by Breu et al. 2 made several recommendations based on the opinions of experts, since little published data existed at the time to address much of this subject. Consensus statement 1 recommends accessing the great saphenous vein at the proximal thigh. In our study, the proximal great saphenous vein had already been ablated, either surgically or thermally so we treated distal veins first. In contrast to consensus 2, we initiated SSV injections distally and found no disadvantage to this approach. Table 3 Side effects following chemical ablation. Ultrasound-guided foam sclerotherapy Liquid: 1e3% polidocanol Gas: air or CO 2 or 70%CO 2 e30%o 2 Condition Gas Air CO 2 CO 2 eo 2 Chest tightness 9 (18%) 4 (3.1%) 0 (0%) Dry cough 8 (16%) 2 (1.6%) 0 (0%) Dizziness 6 (12%) 4 (3.1%) 1 (1%) Visual disturbance 4 (8.2%) 4 (3.1%) 2 (2%) Metallic/medicine taste 0 (0%) 2 (1.6%) 1 (1%) Nausea 2 (4%) 3 (2%) 0 (0%) Circumoral paraesthesia 0 (0%) 1 (0.8%) 0 (0%) Respiratory difficulty 0 (0%) 1 (0.8%) 0 (0%) Total 49 (100%) 128 (100%) 100 (100%) CO 2 : carbon dioxide. O 2 : oxygen. Adapted and expanded from Morrison et al. Comparisons of side effects using air and carbon dioxide foam for endovenous chemical ablation. J Vasc Surg 2008; 47:830e6.

5 Incidence of Side Effects Using Carbon DioxideeOxygen Foam 411 Consensus 3 recommending indirect injections for treatment of perforating veins was followed as was Consensus 4 recommending the dual-syringe technique for foam preparation. Consensus 5 mentioned air, and mixtures of CO 2 and O 2 as gases to be used to prepare the foam. We have reported the outcomes of these treatments above. Consensus 6, recommending a 1:4 liquid-to-gas ratio was followed. Consensus 7 recommended standardisation of foam preparation for trials but not for daily practice. Our quality-assurance program has been designed primarily for daily clinical practice. Consensus 8 listed concentrations of polidocanol according to specific clinical applications. Our selection of 1% polidocanol matched our primary application, treatment injection of tributary veins. Consensus 9 recommended maximum volumes per puncture up to 4 ml for small saphenous and perforating veins, 6 ml for great saphenous and tributary veins and up to 8 ml for recurrent varicose veins. Yamaki et al. have indicated that multiple small-dose injections of less than 0.5 ml can reduce the passage of sclerosant foam into deep veins. 31 We injected CO 2 eo 2 foam volumes of 2 ml or less. Consensus 10 and consensus 11 recommended a maximum foam volume of 10 ml per leg or per session. Foam prepared with CO 2 appears to be safe when injected in larger volumes. 17e19,32 Our personal experience has indicated that side effects and adverse reactions are not related to foam volume and may occur with injections as little as 2 ml of foam. 33,34. Consensus 12 recommended use of more viscous foams, such as 3% versus 1% polidocanol for large veins. 35 The 3/1 study demonstrated equivalent efficacy for 1% and 3% polidocanol foam for sclerotherapy of GSV less than 8 mm in diameter. 36 In our present study polidocanol 1% was appropriate for the treatment of 2e3 mm veins which comprised almost all the veins treated. According to consensus 16, immediate compression of injected areas was not performed, foam distribution was controlled by ultrasound, and ankle dorsiflexion was performed frequently. Consensus 20 and 21 mentioned recommendations regarding patent foramen ovale. Our philosophy has been to monitor signs and symptoms early during the procedure and to have ultrasound equipment available for TTE and TCD evaluation. Evaluation for patent foramen ovale or thrombophilia before USGFS was not routine. Consensus 23 regarding the use of prophylactic low molecular weight heparin (LMWH) in selected patients was followed. Consensus 24 and 25 regarding provision of patient information on safety and efficacy and informed consent were complied with. Consensus 26 and 27 related to ultrasound guidance and interpretation criteria are routine in our practice. Consensus 28 and 29 were not directly related to this investigation; grading of results and thrombus removal recommendations have been influential in our practice. Our observations indicated that USGFS can be performed safely. Neurological complications have been described 37,38 but are rare and not exclusive to foam sclerotherapy; brain infarct has occurred following saphenous vein stripping. 39 Sylvoz et al. reported a case of polidocanol induced cardiotoxicity after a 7 ml injection, and found 5 cases of cardiac toxicity reported in the literature. 40 Deep vein occlusion has been reported at rates of 1.5% per treatment session or approximately 3% per patient. 41 We have investigated patients with duplicated femoral vein segments: thrombosis was detected in 8.6% of the limbs or 12% of the patients (5/43). 42,43 Extensive, ascending thrombophlebitis following foam sclerotherapy has been suggested as an indication to investigate for malignancy. 44 Figure 1 Transthoracic echocardiography and transcranial Doppler demonstrating bubbles in the left heart and high intensity transient signals (HITS) in the middle cerebral artery: a) four chamber view of heart; b) bubbles filling right atrium and ventricle following injection of foam sclerosant into peripheral leg vein; c) Bubbles (yellow arrow) progressing from right atrium through patent foramen ovale into left atrium; and d) HITS in the middle cerebral artery.

6 412 N. Morrison et al. Bubbles, not necessarily sclerosing foam, 45,46 travel to the deep system despite leg positioning, leg immobility, or volume of foam injected. Bubbles consistently reach the right chambers of the heart and may traverse to the left chambers in patients with patent foramen ovale or right-toleft pulmonary shunts (Fig. 1). 22,47 HITS, commonly associated with air embolisation, have been detected in the middle cerebral artery with transcranial Doppler (Fig. 1). 33,34,43 The question pertinent to this investigation is if the type of gas would influence the number of HITS. This investigation demonstrated that USGFS using a70e30% gas mixture of CO 2 and O 2 is at least as safe as airbased or CO 2 -based foams. Vital signs were not physiologically affected during the procedure. Leg symptoms were no different from those seen with air foams but chest tightness or dry cough was reduced in patients treated with CO 2 eo 2 foam. Visual disturbances were reported infrequently in this study but overall too few cases were encountered for statistical analysis. A word of caution is warranted regarding interpretation of our findings. We have used historical data for comparison and this was not a randomised study. Factors such as patient education or awareness or even degree of internet interaction could affect response to investigation of symptoms. However, we compared results with the same protocol for each of the patient cohorts included in the analysis presented above. In summary, USGFS with foam prepared using a physiological mixture of carbon dioxide and oxygen was well tolerated by virtually all patients, and resulted in fewer side effects than in our historical data using air foam. Conflict of Interest/Funding None. Acknowledgements The authors thank Kathy Melphy, RN, BSN, Christine Hall, RN, BSN, Pam Norris RN, BSN, Sharon Olbert, RN, BSN, Barbara Deusterman RN, BSN, Ellen Allen, RN, Janice Moreno, RN, BSN, CVN, Shanon Levin, RVT, and Kristin Hansen, RVT References 1 Morrison N, Neuhardt DL, Rogers CR, McEown J, Morrison T, Johnson E, et al. Comparison of side effects using air and carbon dioxide foam for endovenous chemical ablation. J Vasc Surg 2008;47:830e6. 2 Breu FX, Guggenbichler S, Wollmann JC. 2nd European consensus meeting on foam sclerotherapy 2006, Tegernsee, Germany. VASA 2008;37(S71):3e29. 3 O Hare JL, Earnshaw JJ. The use of foam sclerotherapy for varicose veins: a survey of the members of the Vascular Society of Great Britain and Ireland. Eur J Vasc Endovasc Surg 2007;34: 232e3. 4 O Hare JL, Parkin D, Vandenbroeck CP, Earnshaw JJ. Mid term results of ultrasound guided foam sclerotherapy for complicated and uncomplicated varicose veins. Eur J Vasc Endovasc Surg 2008;36:109e13. 5 Yamaki T, Nozaki M, Sakurai H, Takeuchi M, Soejima K, Kono T. Prospective randomised efficacy of ultrasound-guided foam sclerotherapy compared with ultrasound-guided liquid sclerotherapy in the treatment of symptomatic venous malformations. J Vasc Surg 2008;47:578e84. 6 Creton D, Uhl JF. Foam sclerotherapy combined with surgical treatment for recurrent varicose veins: short term results. Eur J Vasc Endovasc Surg 2007;33:619e24. 7 Nitecki S, Bass A. Ultrasound-guided foam sclerotherapy in patients with KlippeleTrenaunay syndrome. Isr Med Assoc J 2007;9:72e5. 8 Myers KA, Jolley D, Clough A, Kirwan J. Outcome of ultrasoundguided sclerotherapy for varicose veins: medium-term results assessed by ultrasound surveillance. Eur J Vasc Endovasc Surg 2007;33:116e21. 9 Smith PC. Chronic venous disease treated by ultrasound guided foam sclerotherapy. Eur J Vasc Endovasc Surg 2006;32: 577e Darke SG, Baker SJ. Ultrasound-guided foam sclerotherapy for the treatment of varicose veins. Br J Surg 2006;93:969e Kakkos SK, Bountouroglou DG, Azzam M, Kalodiki E, Daskalopoulos M, Geroulakos G. Effectiveness and safety of ultrasound-guided foam sclerotherapy for recurrent varicose veins: immediate results. J Endovasc Ther 2006;13:357e Masuda EM, Kessler DM, Lurie F, Puggioni A, Kistner RL, Eklof B. The effect of ultrasound-guided sclerotherapy of incompetent perforator veins on venous clinical severity and disability scores. J Vasc Surg 2006;43:551e6. 13 Bergan J, Pascarella L, Mekenas L. Venous disorders: treatment with sclerosant foam. J Cardiovasc Surg (Torino) 2006;47:9e Bountouroglou DG, Azzam M, Kakkos SK, Pathmarajah M, Young P, Geroulakos G. Ultrasound-guided foam sclerotherapy combined with sapheno-femoral ligation compared to surgical treatment of varicose veins: early results of a randomised controlled trial. Eur J Vasc Endovasc Surg 2006;31:93e Frullini A, Cavezzi A. Sclerosing foam in the treatment of varicose veins and telangiectases: history and analysis of safety and complications. Dermatol Surg 2002;28:11e5. 16 Cavezzi A, Frullini A. The role of sclerosant foam in ultrasound guided sclerotherapy of the saphenous veins and of recurrent varicose veins. Aust NZ J Phlebol 1999;3:49e Wright D, Gobin JP, Bradbury AW, Coleridge-Smith P, Spoelstra H, Berridge D, et al. Varisolve polidocanol microfoam compared with surgery or sclerotherapy in the management of varicose veins in the presence of trunk vein incompetence: European randomised controlled trial. Phlebology 2006;21: 180e Cabrera J, Redondo P, Becerra A, Garrido C, Cabrera Jr J, Garcia-Olmedo MA, et al. Ultrasound guided injection of polidocanol micro-foam in the management of venous leg ulcers. Arch Dermatol 2004;140:667e Cabrera J, Cabrera Jr J, Garcia-Olmedo MA, Redondo P. Treatment of venous malformations with sclerosant in microfoam form. Arch Dermatol 2003;139:1409e Breu FX, Guggenbicher S, Wollman JC. Second European consensus Meeting on foam sclerotherapy. Duplex ultrasound and efficacy criteria in foam sclerotherapy from the 2nd European consensus Meeting on foam sclerotherapy 2006, Tegernsee, Germany. VASA 2008;37:90e5. 21 Tessari L, Cavezzi A, Frulini A. Preliminary experience with a new sclerosing foam in the treatment of varicose veins. Dermatol Surg 2001;27:58e Hansen K, Morrison N, Neuhardt DL, Salles-Cunha SX. Transthoracic echocardiogram and transcranial Doppler detection of emboli after foam sclerotherapy of leg veins. J Vasc Ultrasound 2007;31:213e6. 23 Ouvry P, Allaert FA, Desnos P, Hamel-Desnos C. Efficacy of polidocanol foam versus liquid in sclerotherapy of the great

7 Incidence of Side Effects Using Carbon DioxideeOxygen Foam 413 saphenous vein: a multicentre randomised controlled trial with a 2-year follow-up. Eur J Vasc Endovasc Surg 2008;36:366e Rabe E, Otto J, Schliephake D, Pannier F. Efficacy and safety of great saphenous vein sclerotherapy using standardised polidocanol foam (ESAF): a randomised controlled multicentre clinical trial. Eur J Vasc Endovasc Surg 2008;35:238e Alós J, Carreño P, López JA, Estadella B, Serra-Prat M, Marinel- Lo J. Efficacy and safety of sclerotherapy using polidocanol foam: a controlled clinical trial. Eur J Vasc Endovasc Sug 2006; 31:101e7. 26 Hamel-Desnos C, Desnos P, Wollmann JC, Ouvry P, Mako S, Allaert FA. Evaluation of the efficacy of polidocanol in the form of foam compared with liquid form in sclerotherapy of the greater saphenous vein: initial results. Dermatol Surg 2003;12: 1170e5. 27 Bergan J. Sclerotherapy: a truly minimally invasive technique. Perspect Vasc Surg Endovasc Ther 2008;20:70e2. 28 Coleridge Smith P. Saphenous ablation: sclerosant or sclerofoam? Semin Vasc Surg 2005;18:19e Cabrera J, Cabrera Jr J. Nuevo método de esclerosis en las varices tronculares. Patol Vascul 1995;4:55e Eckman DM, Kobayashi S, Li M. Microvascular embolisation following polidocanol microfoam sclerosant administration. Dermatol Surg 2005;31:636e Yamaki T, Nozaki M, Sakurai H, Takeuchi M, Soejima K, Kono T. Multiple small-dose injections can reduce the passage of sclerosant foam into deep veins during foam sclerotherapy for varicose veins. Eur J Vasc Endovasc Surg; 2008 Oct 13 [Epub ahead of print]. 32 Redondo P, Cabrera J. Microfoam sclerotherapy. Semin Cutan Med Surg 2005;24:175e Neuhardt DL, Morrison N, Salles-Cunha SX. Emboli detection in the middle cerebral artery concurrent with treatment of lower extremity superficial venous insufficiency with foam sclerotherapy (CO 2 eo 2 ). Congress Syllabus-Abstract Materials of the American College of Phlebology 22nd Annual Congress, Marco Island, FL, USA; Nov 6e9, Neuhardt DL, Morrison N, Salles-Cunha SX. Emboli detection in the middle cerebral artery during and following foam sclerotherapy (room air) of lower extremity veins. Congress Syllabus-Abstract Materials of the American College of Phlebology 21nd Annual Congress, Tucson, AZ, USA; 2007 Nov 8e11, p Ceulen RP, Bullens-Goessens YI, Pi-VAN DE Venne SJ, Nelemans PJ, Veraart JC, Sommer A. Outcomes and side effects of duplex-guided sclerotherapy in the treatment of great saphenous veins with 1% versus 3% polidocanol foam: results of a randomised controlled trial with 1-year follow-up. Dermatol Surg 2007;33:276e Hamel-Desnos C, Owvry P, Bdenigni J-P, Boitelle G, Schadeck M, Desnos P, et al. Comparison of 1% and 3% polidocanol foam in ultrasound guided sclerotherapy of the great saphenous vein: a randomised, double-blind trial with 2 year-follow-up. The 3/1 study. Eur J Vasc Endovasc Surg 2007;34:723e9. 37 Bush RG, Derrick M, Manjonev D. Major neurological events following foam sclerotherapy. Phlebology 2008;23:189e Forlee MV, Grouden M, Moore DJ, Shanik G. Stroke after varicose vein foam injection sclerotherapy. J Vasc Surg 2006;43: 162e4. 39 Harzheim M, Becher H, Klockgether T. Brain infarct from a paradoxical embolism following a varices operation. Dtsch Med Wochenschr 2000;125:794e6. 40 Sylvoz N, Villier C, Blaise S, Seinturier C, Mallaret M. Polidocanol induced cardiotoxicity: a case report and review of the literature. J Mal Vasc; 2008 Nov 17 [Epub ahead of print]. 41 Myers KA, Jolley D. Factors affecting the risk of deep venous occlusion after ultrasound-guided sclerotherapy for varicose veins. Eur J Vasc Endovasc Surg 2008;36:602e5. 42 Morrison N. Studies on safety of foam sclerotherapy. In: Bergan J, Cheng V, editors. Foam Sclerotherapy: A Textbook. London: Royal Society of Medicine Press; p. 183e Morrison N. Foam sclerotherapy: how to improve results and reduce side effects? Phlebology 2008;34:211e Kobus S, Reich-Schupke S, Pindur L, Altmeyer P, Stucker M. Ascending thrombophlebitis after foam sclerotherapy as first symptom of breast cancer. J Dtsch Dermatol Ges; 2008 Nov 18 [Epub ahead of print]. 45 Guex J-J, Raymond-Martimbeau P, Simka M, Passariello F. Letter regarding article titled Microembolism during foam sclerotherapy of varicose veins in the New England. J Med Phlebol 2008;23: Ceulen RPM, Vernooy K. Reply to letter regarding article titled Microembolism during foam sclerotherapy of varicose veins in the New England. J Med Phlebol 2008;23: Ceulen RPM, Sommer A, Vernooy K. Microembolism during foam sclerotherapy of varicose veins. N Engl J Med 2008;358:1525e6.