Sclerosing agent and foam: agent selection and technical tips

MAURIZIO GROSSO, M.D. DIAGNOSTIC AND S. CROCE HOSPITAL - CUNEO DEFINITION

Sclerotherapy - the therapeutic use of physical, chemical, and biological properties of an agent in the controlled destruction of a target tissue

Albanese G, Kondo K.L. Pharmacology of . Semin Intervent Radiol. 2010 Dec; 27(4): 391–399.

Sclerosant - an injectable irritant that causes infiammation and subsequent fibrosis, thus obliterating the lumen of the vessel

The American Heritage® Medical Dictionary Copyright© 2007, 2004 by Houghton Mifflin Harcourt Publishing Company.

Sclerosing agent - a compound that acts by irritation of the venous intimal epithelium

Farlex Partner Medical Dictionary © Farlex 2012

Foams - are defined as a dispersion of gas bubble separated by thin liquid films

Nastasa V, Samaras K, Ampatzidis C, et al. Properties of polidocanol foam in view of its use in sclerotherapy. Int J Pharm. 2015;478(2):588-596 SCLEROTHERAPY: HISTORICAL NOTES

Used for over 150 years:

•First reported attempt 1682: Dr Zollikofer in Switzerland injected an acid

•1853: Both Debout and Cassaignaic reported success by injecting perchlorate of iron, Desgranges injected iodine and tannin

•1946: development of sodium tetradecyl sulfate (STS)

•1977: Iaccarino. Transcatheter sclerotherapy of gonadal riv .radiol 1977, 17: 107-110

•1997: Monfreaux, Foam Sclerotherapy SCLEROSING AGENT

• Ethanol SCLEROTHERAPY • Sotradecol® LEG VARICOSE OF CYSTIC • Ethanolamine LESIONS • Hyperosmotic/H ypertonic agents • Polidocanol MALE FEMALE • Sclerogel® VARICOCELE SCLEROTHERAPY VARICOCELE • Boiling Contrast • Sodium Morrhuate • Sclerodex® CONGENITAL PRE-OPERATIVE • Bleomycin VENOUS AND PORTAL VEIN • OK 432 LYNFATIC • Phenol MALFORMATIONS LYNFATIC LEAKAGE SCLEROSING AGENT

ETHANOL: Combination of cytotoxic damage induced by the denaturation and extraction of surface proteins, hypertonic dehydration of cells, and coagulation- when products are present. Since its introduction in 1980, ethanol has been the standard to which all other sclerosants have been compared.

SOTRADECOL®: an anionic surfactant, the only detergent sclerosant approved by FDA for superficial varicosities. Reported cases of varicoceles, limbs , upper gastrointestinal and variceal bleeding, hemorrhagic tumors, gallbladder ablation, lymphoceles, and percutaneous ablation of oral lesions of Kaposi sarcoma and ganglion cysts.

ETHANOLAMINE: induces sclerosis via endothelial damage leading to fibrin product deposition and thrombosis hours after exposure. It is thought that the oleate component functions to induce a further inflammatory response, which extends beyond the vessel to surrounding tissues. It is the only FDA-approved sclerosant for rebleeding of esophageal. Additional uses include treatment of , percutaneous transhepatic portal embolization and AVM.

HYPEROSMOTIC/HYPERTONIC AGENTS: cause dehydration of target cells, inducing cell damage and death. Hypertonic glucose (up to 70%) has been used in treatment of , varicoceles, gastric varices, hydatid cysts, AVMs and lymphatic malformations. Generally not very effective as a single agent, evidence suggests that it may prime or increase the effectiveness of other agents; safety is excellent. Hypertonic saline (available in 23,4% and 11,7%) effective for superficial venous structures such as , varicose veins, and reticular veins. Also used for echinococcosis and abscess cavity. Nearby tissue necrosis including skin ulceration secondary to extravasation from the target vessel is the most concerning complication.

Albanese G, Kondo KL. Pharmacology of sclerotherapy. Semin Intervent Radiol. 2010;27(4):391-399. SCLEROTHERAPY - LEG VARICOSE VEINS

STORY AND TECHNIQUES • FOAM PROPERTIES: adhesiveness, compactness, long lasting,  1997 Monfreux: glass syringe filled with 0.3-0.5 echovisibility, enhancement of sclerosing ml of liquid and closed with a sterile plug; hold power and reduction of drug doses tension on the piston until 2-3 ml of foam are

generated  1999 Tessari: two disposable syringes and a three- • COMPACTNESS: related to the size of the way tap; later a dedicated kit was produced, with bubbles: when this size is sufficiently small, no prefilled sterile air syringe or poor mixing with blood occurs in the vein in the first moments after the injection • foam very compact with a very small bubble diameter and dissolve over a period of weeks • US GUIDE chance to push the foam in a • induces severe vein spasm; best dilution ratio 1:4-5 safer way near the sapheno-popliteal or sapheno-femoral junction

 2015 Nastasa: an effort is made to evaluate the effect of adding different substances on the stability of polidocanol foams (0.5% w/w) by altering the surface tension or/and the bulk and interfacial rheological properties of the fluids SCLEROTHERAPY - LEG VARICOSE VEINS

CONVENTIONAL SCLEROTHERAPY

 gold standard preferred over laser for eliminating large spider veins (telangiectasiae) and smaller varicose leg veins

 the sclerosing solution additionally closes the "feeder veins" under the skin that are causing the spider veins to form and recurring

AGENTS

 5- TETRADOCYLSULPHATE (in EU Trombovar 1-3%, Fibrovein 0,2-0,5,1,3%)

 POLIDOCANOL (Asclera, Aethoxysclerol 1-3%)

TIME: about 10 minutes to perform SCLEROTHERAPY - LEG VARICOSE VEINS

CONVENTIONAL SCLEROTHERAPY MODERN SCLEROTHERAPY

• Venous pressure tourniquet • ULTRASOUND GUIDANCE: • Multiple injections of dilute used to visualize the underlying sclerosant into the abnormal vein to deliver and monitor the superficial veins injection (real-time monitoring)

• Leg is then compressed with • FOAM SCLEROTHERAPY: stockings or bandages usually for microfoam sclerosants used to two weeks treat larger varicose veins, including great and small • Patient encouraged to walk saphenous veins regularly during that time

• Usually at least two sessions required separated by several weeks SCLEROTHERAPY - LEG VARICOSE VEINS

LOCAL COMPLICATIONS • Skin necrosis (<4%): if sclerosant injected outside the vein, cosmetically possibly devastating • - (1-3%) • Hyperpigmentation due to intense inflammatory reaction

SYSTEMIC COMPLICATIONS Rare (0-5.7%) • allergic reaction • venous thromboembolism - pulmonary • ischemic lesions: reports of stroke (<0,7%) or myocardial infarction associated to unsually large sclerosant amount

Guex JJ. Complications of sclerotherapy: an update. Dermatol Surg 2010 Jun; 36(2): 1056–1063.

Carrol C et al. Clinical effectiveness and cost-effectiveness of minimally invasive techniques to manage varicose veins: a systematic review and economic evalutation. Health Technol Assess. 2013 Oct; 17(48): 1-141.

SCLEROTHERAPY - LEG VARICOSE VEINS

EFFICACY SAFETY Foam sclerotherapy is safe and FDA Sclerosing foam is an established therapy in the treatment of varicose veins with a high success approved in the USA rate, low cost, and low major complication rate  risks of adverse events were not significantly  1^st Cochrane Collaboration: "sclerotherapy different from liquid sclerotherapy or open surgery, limited to treatment of recurrent varicose veins except in one RCT, where visual disturbance rate following surgery and thread veins" was reported higher (no longer than two hours visual impairment was reported)°  2^nd Cochrane Collaboration 2004: “sclerotherapy was better than surgery in terms according to actual experiences, the safe amount of treatment success, complication rate and cost of foam should not exceed the 3 ml limit and a at one year, but surgery was better after five minimum interval of 7 days between sessions should years” be respected (no significant )

 European Consensus Meeting 2003: "Foam some recent studies seem to favor large quantities sclerotherapy allows a skilled practitioner to of highly active foam with little bubbles, further treat larger veins, including saphenous trunks, advancements could come from standardization of and is effective in controlling reflux from the the foam preparation technique sapheno-femoral and sapheno-popliteal junctions, with mild increase in failure for long term RCTs studies (> 3 years) vs larger size” conventional sclerotherapy and surgery are needed

SCLEROTHERAPY Injecting of a solution into a vein to collapse and sclerose it

Treatment of:

VASCULAR OR LYMPHATIC SYSTEM MALFORMATIONS

CHILDREN AND YOUNG ADULTS (LOW FLOW FAV – MAV)

 BLOOD VESSELS (VARICOSE VEINS AND HEMORROIDS)

ADULTS (MALE AND FEMALE VARICOCELE, PELVIC CONGESTION, LEG VEINS)

 CISTIC LESION

 PRE-OPERATIVE PORTAL VEIN

 LYNFATIC LEAKAGE SCLEROTHERAPY - VARICOCELE

Gonadal Vein Embolization Sclerosing MALE VARICOCELE: SCLEROSING AGENTS EFFECTIVENESS

Gazzera C. Basile A. Gandini R Li L Hawkins CM Grosso M (radiol med (radiol med (Radiology (Vasc. Interv. (Vasc. Interv. (Austin 2006) 2014) 2008) Radiol. Radiol. 2011) Journal of 2010) surgery 2015) foam foam

Type of S S S S S S agent polidocanol polidocanol Sodium Sodium Boiling polidocan tetradecyl morrhuate contrast ol sulfate

Number of 223 100 244 58 16 1646 patients

Relapse 16% / 3.6% 8.6% 5% 1.9%

Complication / 8% 2.6% / / /

SCLEROTHERAPY – MALE VARICOCELE POLIDOCANOL IS A NONIONIC SCLEROSANT THAT CONSISTS OF 95% HYDROXYPOLYETHOXYDODECANE AND 5% ETHYL-ALCOOL

SCLEROTHERAPY CAN BE PERFORMED PAINLESSLY BECAUSE OF POLIDOCANOL’S ANESTHETIC EFFECT

VARICOSE VEINS

SAPHENOUS VEIN

VENOUS MAL. SCLEROTHERAPY – MALE VARICOCELE

• Patient in angiographic room, in anti- Trendelenburg position • Asked to manually compress funicular vein in left inguinal region (exceptionally clamp) • Slow loco-regional injection of 4 vials at max of sclerosing agent (polidocanol 2%) mixed with contrast medium 50:50 in about 30 min SCLEROTHERAPY – MALE VARICOCELE

SPERMATIC VEIN RENAL FLEBOGRAPHY CATHETERISM HOW WE DO IT

POLIDOCANOL INJECTION FINAL CONTROL SHOWS AND MANUAL COMPRESSION CONTRAST STASIS Conclusion

On the basis of our findings, the embolisation of the LSV obtained using injection of sclerosant through an occluding ballooon rather than through a diagnostic catheter seems to be more effective in achieving total embolisation of the vein, as well as allowing a controlled injection of sclerosing agent even in cases of vein rupture. SCLEROTHERAPY WITHOUT BALOON ASSISTANCE EFFECTIVENESS

Technical success: 97.1% FOAM Recurrence of varicocele: 3.6%

MAURIZIO GROSSO Technical success: 98.0% Alberto Balderi Alberto Antonietti Fulvio Pedrazzini Recurrence of varicocele: 1.9% Davide Sortino Claudia Vinay Grazia Giovinazzo James Caridi Marco Manenti SCLEROTHERAPY Vs EMBOLIZATION

“…(Sclerotherapy) results in occlusion of all collateral veins, even those not visible at phlebography….Indeed, mechanical occlusion means or gluing agents can be considered equivalent to surgical vascular ligation….”

Compared with embolization sclerotherapy has the same results withuot any risk of coils or glue migration or coils resorption. Moreover is not expansive SCLEROTHERAPY – FEMALE VARICOCELE FEMALE VARICOCELE: SCLEROSING EFFECTIVENESS

Gandini R. Tinelli A. Gandini R. Kim et al Pieri S Venbrux AC (Cardiovasc (Eur Rev Pharm (Cardiovasc Intervent (J. Vasc Interv (Radiol Med 2003) (J Vasc Interv Intervent Radiol Sci 2012) Radiol 2008) Radiol 2006) Radiol 2002) 2013)

Embolic Agent STS Foam Atossisclerol STS Foam Sclerosant STS Foam Sclerosant 3% and Coils and Coils

Number of 26 28 38 127 33 56 patients Technical 100% 100% 100% 97% 100% 100% Success

Complication No 7,1% No No No 3,5%

Clinical Significant relief in Significant relief in Significant relief in Significant relief in Significant relief in Significant/partial Outcome 100%; 100%; 100%; 83%; 100%; relief no relief in 13%; in 96%; no relief worsened in 4% in 4% Balloon yes no no / / no assistance SCLEROTHERAPY – FEMALE VARICOCELE SCLEROTHERAPY – FEMALE VARICOCELE “Transcatheter Foam Sclerotherapy of Symptomatic Female Varicocele with Sodium-Tetradecyl-Sulfate Foam”

Gandini R. et Al. Results

 Technical success: 100%.

 3 patients reported pelvic colicky pain after sclerotic agent injection with spontaneous resolution within a few minutes

 At follow-up no recurrences after 12 months

 At 1-3-6-12 months improvement of symptoms PELVIC CONGESTION SYNDROME (PLS): DIAGNOSIS

 High-flow pelvic varicocele is diagnosed with venography when the contrast medium injected through the ovarian vein is rapidly washed out through a high- outflow venous collateral, without opacification of the varicocele.

2013

30,8%

15,4%

26,9% 11,5%

15,4% PELVIC VENOUS INSUFFICIENCY : SCLEROSING WITH BALOON ASSISTANCE SCLEROTHERAPY – PORTAL EMBOLIZATION SCLEROTHERAPY – VASCULAR MALFORMATION

Sclerotherapy is a mainstay in the treatment of low-flow vascular malformation.

Sclerosant agents used: • Absolute ethanol. • Detergent sclerosant : STS, POL, EO (ethanolamina oleato). • Ethanol Ethylcellulosa. • Ethiblock. • Ok-432. • Doxycycline. • Bleomycin A prospective study 44 patients with mucosal cutaneous muscolar malformationes No systemic complication Embolization:

Under general anesthesia. From the peripheral venous right leg access was performed phlebographic study that confirms the presence of the VM cluster. After placing a stringer pressure at the root of the thigh, at an approximately pressure of 100 mm Hg, was performed the direct puncture of the lesion and the injection of embolic solution with Lipiodol. Not complications and good final result reached. Were administered approximately 5 ml of Sclerogel inside the malformation

Cortesy of Dr. Meloni SCLEROTHERAPY – CYSTIC LESIONS

Hepatic cystis SCLEROTHERAPY – CYSTIC LESIONS kidney cystis SCLEROTHERAPY CONCLUSIONS

Sclerosant agents can be used in both vascular and non- vascular procedures and should have an important position in the Interventional Radiology Armamentarium.

It is important to understand concepts such as the mechanism of action, methods of delivery and contact time to ensure safe use of these agents in clinical practice. Thank you for your attention