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Table11.2 SYMPTOMS OF VARICOSE VEINS AND
TELANGIECTASIAS
Aching Heaviness (on standing, prolonged sitting) Aching Pain (on standing, prolonged sitting) Burning (venous neuropathy) Itching (cutaneous in ammation) Nocturnal Cramps (recumbent edema reduction)
Table11.3 TESTS OF HISTORIC INTEREST
Trendelenburg Test Cough Test Schwartz Test Perthes’ Test
CLINICAL TESTING
 e recent development of an extremely painful area on the lower leg at the ankle associated with an overlying area of erythema and warmth may be indicative of lipo­dermatosclerosis, which may be associated with insu ­ciency of an underlying perforator vein, and examination for this lesion should be performed. Lipodermatosclerosis may precede ulceration and has been shown to be improved by sti compression and certain pharmacologic interventions.
Patients with a history of iliofemoral thrombophlebitis who describe “bursting” pain with walking may be su ering from venous claudication. In these patients an evaluation for persistent hemodynamically signi cant obstruction, possibly treatable with angioplasty and stenting, may be inorder.
PHYSICAL EXAMINATION
Using no special equipment, the practitioner can obtain a degree of information regarding overall venous out ow from the leg, the sites of valvular insu ciency, the presence of primary versus secondary varicose veins, and the presence of deep venous thrombosis (DVT).  e screening physical examination consists of careful observation of the legs. Any patient with the following conditions should be examined more fully:large varicose veins; bulges in the thigh, calf, or the inguinal region representative of incompetent perfo­rating veins (IPVs) or a saphena varix; signs of super cial venous hypertension such as an accumulation of telangiec­tasias in the ankle region (corona phlebectatica); or any of the  ndings suggestive of venous dermatitis (pigmentation, induration, eczema).  is includes patients with obvious cutaneous signs of venous disease such as venous ulceration, atrophie blanche, or lipodermatosclerosis. An obvious but o en forgotten point is the necessity of observing the entire leg and not con ning the examination simply to the area that the patient feels is abnormal.
Finally, because the veins of the leg empty into the pel­vic and abdominal veins, inspection of the abdomen is very important, since dilation of veins on the abdominal wall or across the pubic region suggests an old iliofemoral throm­bus. Dilated veins along the medial or posterior aspect of the proximal thigh or buttocks most o en arise from vari­cosities involving the pudendal or other pelvic vessels, and these can be of ovarian re ux origin.
Historically important tests of venous function have been part of the physical examination of venous insu ciency (see Table 11.3).  ese tests have been laid aside largely because of their lack of speci city and sensitivity.  e continuous-wave Doppler examination has replaced most of these tests, and con rmatory duplex testing has relegated them to an inferior role. However, the educated physician who treats venous insu ciency must have knowledge of these tests and their physiologic background, such as the Trendelenburg test or Brodie-Trendelenburgtest.
TRENDELENBURGTEST
A tourniquet may be placed around the patient’s proximal thigh while the patient is standing.  e patient then assumes the supine position with the a ected leg elevated 45 degrees.  e tourniquet is removed, and the time required for the leg veins to empty, which is indicative of the adequacy of venous drainage, is recorded.
When compared with the contralateral leg, the method just described may demonstrate a degree of venous obstruc­tive disease. Another approach is to elevate the leg while the patient is supine and to observe the height of the heel in relation to the level of the heart that is required for the prominent veins to collapse. Unfortunately, these proce­dures are neither su ciently sensitive nor accurate and do not di erentiate acute from chronic obstruction; thus they are of minimal assistance in current medical practice.
C O U G H  T E S T
One hand is placed gently over the GSV or saphenofemoral junction (SFJ), and the patient is asked to cough or perform a Valsalva maneuver. Simply palpating an impulse over the vein being examined may be indicative of insu ciency of the valve at the SFJ and below to the level of the palpatinghand.
PERCUSSION/SCHWARTZTEST
One hand is placed over the SFJ or saphenopopliteal junc­tion (SPJ), and the other hand is used to tap very lightly on a distal segment of the GSV or small saphenous vein (SSV).  e production of an impulse in this manner implies insuf­ ciency of the valves in the segment between the two hands. Con rmation of the valvular insu ciency can be achieved by tapping proximally while palpating distally.  is test can also
98 • PRIMARY SUPERFICIAL VENOUS INSUFFICIENCY
be used to detect whether an enlarged tributary is in direct con-
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nection with the GSV or SSV by palpating over the main trunk and tapping lightly on the dilated tributary, or vice versa.  e presence of a direct connection results in a palpable impulse being transmitted from the percussing to the palpating hand. As might be expected, these tests are far from infallible.
P E R T H E S ’  T E S T
 e Perthes’ test has several uses, including distinguishing between venous valvular insu ciency in the deep, perfo­rator, and super cial systems and screening for DVT. To localize the site of valvular disease, the physician places a tourniquet around the proximal thigh with the patient standing. When the patient walks, a decrease in the disten­sion of varicose veins suggests a primary process without underlying deep venous disease because the calf muscle pump e ectively removes blood from the leg and empties the varicose veins. Secondary varicose veins do not change caliber (if there is patency of the deep venous system) because of the inability to empty blood out of the veins as a result of impairment of the calf muscle pump. In the setting of a current DVT, they may increase in size. If there is signif­icant chronic or acute obstructive disease in the iliofemoral segment, the patient may note pain (venous claudication) as a result of the obstruction to out ow through both the deep and super cial systems.  e Perthes’ test is now of more his­torical than actual clinical importance.
ACKNOWLEDGMENT
Much of the material in this manuscript was derived and modi ed from the scholarly research of Mitchel Goldman, MD, and was published in his volume on sclerotherapy.
R E F E R E N C E S
1 .  ompson H .  e surgical anatomy of the super cial and perforat-
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3. Arnoldi C .  e heredity of venous insu ciency , Dan Med Bull . 1958 . 5 : 169 .
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5. Arenander E , Lindhagen A .  e evolution of varicose veins studied in a material of initially unilateral varices, Vasa . 1978 . 7 : 180 .
6. Ottley C . Heredity and varicose veins , Br Med J . 1934 . 1 : 528 .
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8 . K i n g E S J .  e genesis of varicose veins , ANZ J Surg . 1950 . 20 : 126 .
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10. Niermann H . Zwillingsdermatologie . Berlin : Springer-Verlag . 1964 .
11. Gundersen J , Hauge M . Hereditary factors in venous insu ciency , Angiology . 1969 . 20 : 346 .
12. Folse R .  e in uence of femoral vein dynamics on the development of varicose veins , Surgery . 1970 . 68 : 974 .
13. Almgren B . Non-thrombotic deep venous incompetence with spe­cial reference to anatomic, haemodynamic, and therapeutic aspects , Phlebology . 1990 . 5 : 255 .
14. Lee S , Lee W , Choe Y , etal. Gene expression pro les in varicose veins using complementary DNA microarray , Dermatol Surg . 2005 . 31 : 391–395 .
15. Coughlin LB , Gandy R , Rosser S , de Cossart L . Factors associ­ated with varicose veins in pregnant women , Phlebology . 2002 .
: 167–169 .
16. Abramson JH , Hopp C , Epstein LM .  e epidemiology of vari­cose veins:Asurvey in western Jerusalem , J Epidemiol Community Health . 1981 . 35 : 213 .
17. Henry M , Corless C .  e incidence of varicose veins in Ireland , Phlebology . 1989 . 4 : 133 .
18. Tournay R , Wallois P . Les varices de la grossesse et leur traitement principalement par les injections sclerosantes, expansion . Paris : Scient Franc . 1948 .
19. McCausland AM . Varicose veins in pregnancy , Cal West Med . 1939 . 50 : 258 .
20. Mullane DJ . Varicose veins in pregnancy , Am J Obstet Gynecol . 1952 . 63 : 620 .
21. Lev M , Saphir O . Endophlebohypertrophy and phlebosclerosis , Arch Pathol Lab Med. 1951 . 51 ( 2 ): 154 .
22. Donovan DL , Schmidt SP , Townshend SP , etal. Material and struc­tural characterization of human saphenous veins, J Vasc Surg . 1990 . 12 : 531 .
23. Bouissou H, Julian M, Pieraggi M- , et al . Structure of healthy and varicose veins. In:Vanhoutte PM, ed. Return circulation and norepi- nephrine:An update . Paris : John Libbey Eurotext . 1991 .
24. Cambell GD , Cleave TL . Diverticular disease of the colon , Br Med J . 1968 . 3 ( 5620 ): 741 .
25. Burkitt DP . Varicose veins, deep vein thrombosis, and haem­orrhoids: Epidemiology and suggested etiology , Br Med J . 1972 . 2 :556 .
26. Myers TT. Varicose veins. In: Barker and Hines, eds. Barker and Hines’s peripheral vascular diseases , 3e. 1962 . Philadelphia : Saunders . 1962 .
27. Fowkes FGR . Prevalence and risk factors for chronic venous insuf­ ciency , Acta Phlebol . 2000 . 1 : 69–78 .
28. Widmer LK . Peripheral venous disorders:Prevalence and socio-medical
importance: Observations in 4529 apparently healthy persons, Basle Study III . Berne, Switzerland : Huber . 1978 .
29. Cotton LT . Varicose veins: Gross anatomy and development , Br J Surg . 1961 . 48 : 589 .
30. Hoshino S , Satakawa H , Iwaya F , etal. External valvuloplasty under preoperative angioscopic control , Phlebologie . 1993 . 46 : 521 .
31. Van Cleef JF , Desvaux P , Hugentobler JP , etal. Etude endoscopique des re ux valvulaires sapheniens, J Maladies Vasculaires . 1992 .
17
: 113 .
32. Sales CM , Rosenthal D , Petrillo ICA , etal.  e valvular apparatus in venous insu ciency:Aproblem of quantity?, Ann Vasc Surg . 1998 . 12 : 153 .
33. Takase S , Lerond L , Bergan JJ , Schmid-Schonbein GW .  e in ammatory reaction during venous hypertension in the rat , Microcirculation . 2000 . 7 : 41 .
34. Takase S , Pascarella L , Bergan JJ , Schmid-Schonbein GW . Hypertension-induced venous valve remodeling , J Vasc Surg. 2004 . 39 : 1329–1334 .
35. van Bemmelen SP , Hoynck van Papendrecht AA , Hodde KC , Klopper PJ . A study of valve incompetence that developed in an experimental model of venous hypertension , Arch Surg . 1986 . 121 : 1048 .
36. Takase S , Pascarella L , Lerond L , Bergan JJ , Schmid-Schonbein GW . Venous hypertension, in ammation, and valve remodeling, Eur J Vasc Endovasc Surg . 2004 . 28 ( 5 ): 484–493 .
37. Takase S , Lerond L , Bergan JJ , Schmid-Schonbein GW . Enhancement of reperfusion injury by elevation of microvascular pressures , Am J Physiol Heart Circ Physiol . 2002 . 282 : H1387–H1394 .
RISK FACTORS, MANIFESTATIONS, AND CLINIC EXAMINATION • 99
12.
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SCLEROSANTAGENTS
MECHANISMS OF ACTION, CLASSIFICATION, AND PHARMACOLOGY
Attilio Cavezzi and Marcello  Izzo
MECHANISM OFACTION
To sclerose a vein means to induce endothelial damage and subsequent thrombus formation (sclerothrombus) by the injection of a chemical into the vein lumen.  e result of this process is occlusion and  brosis of the diseased vein. Modern sclerosing substances act directly on the vein endothelium.  ree hours a er the injection, endothelial swelling with desquamation is detected. A er 15 hours, a deposition of a mixed thrombus takes place and a er about 24 hours it  xes to the vessel wall until its  nal connective organization. Finally  brosis of the vein may occur between 60 and 90days a er the injection.
Perivenous in ammatory reactions can appear when adventitia is involved (which is usually caused by excessive doses of the sclerosant drug), with or without intima and media lesions.
In 1989 Mancini etal. investigated histology of proximal segments of great saphenous vein (GSV), which were sub­mitted to liquid sclerotherapy followed by surgical excision (at di erent time intervals) and investigated by optical and electronic microscopy.  e main  ndings of this study were the following: (1)an endothelial lesion develops immedi­ately; (2)15 minutes a er the injection the  rst  brin con­tent deposits; (3)a er two and a half hours, the formation of a lamellar platelet microthrombus occurs; (4)between the second and third day massive (sclero) thrombosis develops; (5)at two months, the complete occlusion of vein lumen with connective and  brous organization usually occurs.
Sclerosing substances have been experimentally studied on animals since 1920.  e outcomes of animal studies are summarizedhere:
1. Endothelial damage is low in vessels injected with chromated glycerin (CG), polidocanol (POL) 0.25%, dextrose-sodium chloride (DSC), and ethanolamine oleate (EO) 0.5%; an early recanalization takesplace;
2. POL 0.5%, sodium morrhuate (SM) 0.5–1%, EO 1%, and hypertonic saline solution 11.7% do not cause endo­thelial necrosis but only partial damage, and, although an
organized thrombus appears, vessel recanalization invari­ably occurs;
3. Vessels injected with sodium tetradecylsulfate (STS) at 0.5% concentration, or with SM 2.5%, present endothe­lial necrosis and an incomplete recanalization by numerous newly formed microchannels with clinical disappearance of treated venules.
More speci cally the study of Goldman etal. on rab­bit ear veins shows that increasing concentrations of POL and STS (from 0.25 to 1%) result in sclero brosis of the vessel but with recanalization within 14days, and in some cases the reappearance of the vein takes place. Endothelial damage may be caused by the sum of a number of di erent mechanisms depending on the action of the substance used. Changes in surface tension of plasma membranes can be pro­duced; physical, chemical changes in endothelial cells matrix through pH variations or changes of osmolarity may occur; also direct cellular destruction may occur due to caustic chemical actions or other physical factors like cold andheat.
Classi cation of sclerosing solutions:
1. Detergent solutions with decreasing sclerosant
power:STS, SM, POL,EO
2. Osmotic solutions:Sodium salicylate (SS; or potassium
salicylate [PS]), saline hypertonic solutions with very high osmolality (about 7533.8 mOsm/kg),DSC
3. Chemical solutions with a caustic-like e ect on the
endothelium:Iodine solutions.
Currently used sclerosing substances have di erent mechanisms of action and aggression on vein walls, but basically they are all osmotically active and in general, their action on the endothelium may be just irritative, necrotiz­ing, or colliquative.
Factors that in uence the sclerosing power are:(1)dose and concentration of medication, (2) physical-chemical variables (pH, liquid or foam) of the agents and of the blood, (3)physical-hemodynamic reasons inherent to local
100
SCLEROTHERAPY – ENDOTHELIAL CITOLOGY
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Figure12.1 Endothelial cytology  ndings a er injection of: traditional (top le ) sodium salicylate, alkalinized (top right) sodium salicylate, potassium salicylate (bottom).
 ow conditions, (4)injection technique, and (5)variabil­ity of the factors related to thrombosis and  brosis of the
PHYSICS OF THE
SCLEROSINGAGENTS
treated vessels.
All sclerosant drugs have a di erent mechanism of action, but changing (usually increasing) the pH of a drug renders it a more powerful sclerosant. Dietrich and Sinapsius already demonstrated an increased colliquative action of a higher ph sclerosant drug. More recently Izzo etal. showed a remarkably higher colliquation and aniso­poikilocytosis in cytohistology samples of human umbilical veins treated with 8.4 pH sclerosant drug, when compared to the samples treated with the same sclerosant at an acidic pH (see Figure12.1). Similarly modifying the physical form of detergents (e.g., POL, STS) from liquid to foam increases the sclerosingpower.
 e introduction of the foamy sclerosing form of the drug (foam sclerotherapy or endovenous chemical abla­tion) has led to a kind of mass e ect (sclerosant foam [SF] is a “viscoelastic body”), for which it is possible to inject a nearly empty vein, at least in close proximity of the injectedpoint.
Sclerosing substances are grouped, depending on the power, in three main groups:(1)major sclerosants:iodine solutions and STS; (2)medium sclerosants:POL, SS, and SM; and (3) minor sclerosants: CG, DCS, hypertonic saline solution 23.4%, andEO.
Experimental studies carried out by Stemmer show that blood and sclerosant liquid always move toward the area of lowest pressure according to a pressure gradient. Compression can facilitate movement of the liquid toward a vein segment (e.g., perforator) or increase the contact time with the endothelium; It was also demonstrated that the vessel size of the treated vein in uences the distribution of the sclerosant substance.
In small veins (4mm or less) the injected liquid deter­mines a contact zone with the wall around the injection point and a central streak to the vessel of a few inches; the streak touches the wall only when it encounters an obstacle (e.g., the tortuosity of the varicose veins); medium size vari­cose veins (approximately 6mm) exhibit a laminar  ow of the injected drug, and a central turbulence zone is produced around the needle tip with two streaks of laminar  ow to the extremities;  nally in larger veins (8mm or more) there is a turbulence zone that fades more slowly than the smaller caliber tubes and completely occupies the lumen.  e so-called air block technique (which has been proposed for small varices) involves an injection of a quantity of air before the liquid sclerosant, to displace some blood from the injected segment, obtaining a better contact between
SCLEROSANT AGENTS:MECHANISMS OF ACTION, CLASSIFICATION, AND PHARMACOLOGY • 101
the substance and the endothelium, as shown in Stemmer’s
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studies.
Orbach also proposed the creation of a froth (large bubble foam dispersion) by means of an agitation of STS in a vial, thus obtaining a froth that was aspirated into the syringe with the aim of depositing the drug along the vein in a uniform way and acting longer at the injectionsite.
In Stemmer’s and our own experimental studies, the cali­ber of the needle a ects the dynamics of the injection:at the same injection speed rate and with the same amount of time, the quantity of substance that touches the wall increases or decreases according to the dimensions of the needle.
While Stemmer’s experience demonstrates that the injec­tion rate does not a ect the sclerosis e ect, Zelikovski demon­strated that the rapid injection of labeled iodine solution 4% results in a longer contact time with the vein wall compared to a slow technique. It is agreed that the bending of the needle is completely irrelevant as to liquid injection dynamics.
Chemical and physical constants of blood and of scle­rosant agents interact and are detailed in Table12.1.
An endothelial injury may be caused by alteration of the electrical charge, of blood pH, of osmolality, and of the sur­face tension.  e injection of an alkaline substance modi es the blood/tissue pH and causes endothelial damage, while a solution with acidic pH causes fewer lesions.  is histo­chemical  nding may represent a basic knowledge in the management and exploitation of the sclerosant drugs, with the aim of possibly potentiating their action on the venous wall. In fact, the pH of any single sclerosant drug is di erent, and any possible change of this chemical variable may inter­fere with the  nal outcome as well.  e lowering of surface tension induced by detergent agents and the osmotic varia­tions of hypertonic solutions determine signi cant changes in the endothelium.  e viscosity of the sclerosant agent does not in uence the e ect, but a strong viscosity slows the progression of the product along the venous route (which is the case, for example forCG).
Density is important in the distribution of the liquid in the vessel:if the speci c weight of a sclerosant agent consid­erably di ers from that of blood (mean 1.050) it will tend to  oat or sediment (depending on whether it is lighter or heavier, respectively), which a ects the necrotizing e ect on the endothelium.
Table12.1 CHEMICAL AND PHYSICAL CONSTANTS OF
BLOOD AND SCLEROSANTAGENTS
 e circulating blood and the venous endothelium present
chemical and physical constants that can be considered stable: the pH of venous blood varies between 7.27 and 7.43; the speci c weight is between 1.050 and 1.060; the osmolality is between 275 and 295 milliosmoles; the surface tension of the serum at 37° C is 47 dyn/cm; the endothelium’s electrical charge is negative (glycocalyx)
(Glycosaminoglycans of normal veins and their alterations
in varicose veins and varicose veins complicated by
thrombophlebitis.)
Factors related to thrombosis and  brosis of venous vessels may be di erent from those in Virchow’s triad:the thrombus composition is poor of  brin, and there is a reduced participation of coagulation mechanisms.  e slowdown of blood  ow and hypercoagulability do not play an important role in the formation of postsclerotherapy  brosis and for example, no decrease of the sclerosing POL activity has been reported in anticoagulated patients, as the endothelial injury is the key mechanism that provokes the localized sclerothrombosis.
Wuppermann in 1991 studied the sclerotherapy­coagulation interactions before and a er sclerotherapy, and he concluded that hyper brinolysis occurs immedi­ately a er endothelial destruction (release of tissue activa­tors), together with a denaturation of coagulation proteins; similarly this author showed  brinogen in ltration into the wall and coagulation related to  brinopeptide release (usu­ally between the 5th and 7th day a er treatment) until the  brin degradation products and  brinogen peptides attract chemotaxis cellular in ltration from the supporting tissue and the consequent organization of the sclerothrombus and vein wall altogether.
More recently Parsi accurately investigated several changes in coagulation factors/mechanisms that occur in sclerotherapy. His several in vitro studies and publications highlighted the following interactions between sclerosant agents (namely STS and POL) and the blood components:
1. Higher STS (especially) and POL concentrations
(>0.6%) have anticoagulant properties, and STS, not POL, may enhance heparin activity.
2. Lower concentrations of STS and POL (e.g., 0.1–0.3%)
have procoagulant properties (POL >STS).
3. High concentrations (STS > 0.3%, POL > 0.45%)
produce hemolysis, platelet lysis, and endothelial celllysis.
4. Plasma proteins, especially albumin, neutralize
sclerosants.
To summarize the results of all these heterogeneous tests, STS at high concentration has an antithrombotic e ect, while POL at high concentration is probably neu­tral. Conversely, both STS and POL at low concentrations have a net prothrombotic e ect.  rough these studies Parsi concluded that the e ective sclerosant concentration can be reduced if a lower content of blood/albumin/plasma is obtained in the target vein (which con rms Fegan’s old studies on the “empty vein technique”), but more gener­ally higher concentrations and lower volumes are prefer­able to lower concentrations and higher volumes. Similarly, Parsi speculated on the low incidence of postsclerotherapy deep venous thrombosis (DVT), which could be possibly explained through the neutralization of sclerosants by blood
102 • PRIMARY SUPERFICIAL VENOUS INSUFFICIENCY
proteins in deep veins;  nally, due to the chemical phenom-
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ena reported above, the possible distal neurological/pulmo­nary e ects of the foamed sclerosants should be unlikely related to the presence of the drug on the circulating bubbles.
In another recent publication, furthermore, Watkins showed how approximately 2 ml of a 4% blood protein solu­tion deactivates 1 ml of 3% STS; hence, from his experimen­tal studies it is possible to extrapolate the concept that about
0.5 ml of whole blood should deactivate 1 ml of 3%STS.
Recent in vivo studies from Tessari etal. also pointed out how the chemical activity of STS sclerosing foam is nearly zero a er less than 1 minute (no active STS in the common femoral vein a er STS foam injection in a leg varicose vein; 13th Annual European Venous Forum, 2012, Florence, Italy).
Several physical variables may positively or negatively interfere with the sclerosis process, and the volume of the tar­get vein is one of the most important. When injecting a scle­rosant agent into the vein, the blood dilution plays a major role because of the interaction of blood components (primar­ily proteins) with the sclerosant drugs. Intuitively, the larger the vein, the higher the blood/protein content, the higher the negative interference with the sclerosant drug action on the blood content itself and  nally on the veinwalls.
Vein caliber reduction, prior to any injection is hence suggested in liquid or foam sclerotherapy, to maximize the sclerosant e ect on the vein walls.  is simple statement brings most sclerotherapists to inject patients only in supine position; in this position vein size decreases by about 50% from standing position and according to Feied’s reports, the
dilution of the sclerosant drug at 5cm from the injected site is about three times lower.  e possibility of raising the limb before any sclerosing treatment commences, may lead to a further reduction of the dilution of the sclerosant drug 5cm away from the injected site (eight times higher concentration in comparison with a standing position); similarly, with a limb elevated at 30°–50°, a 60–80% caliber reduction is expected in the saphenous and tributary veins (personal unpublished data; Figure12.2). To overcome the possible di culty of cannulating a vein in a raised limb, many physicians prefer to raise the limb a er entering the vein in supine position and a er  xing the needle/catheter to the skin. Limb elevation does not necessarily pertain to sclerotherapy of minor varicosities, as the latter reduce in size much less (or not at all) because of their location in the dermal space and the minor changes in inner pressure with postural changes. For reticular varices and telangiectasias a possible option to improve the blood reduction/clearing e ect in the treated segment could be to inject and retrieve the sclerosant drug within the vessel a few times. In our empirical experience this procedure seems to reduce clot retention while increasing the sclerosing power even of low concentration drugs (e.g., POL 0,25%, STS 0,1%, SS8%).
As vein caliber and blood content are strictly regulated by the transmural pressure (external pressure versus inner vein pressure), it is possible to increase external pressure through stockings or bandages (with or without pads to increase local pressure according to Laplace’s law), which is more easily achievable for varicose tributaries or for subcutaneous veins in general. In the case of major veins
Figure12.2 I n uence of limb position on the vein sizes.
SCLEROSANT AGENTS:MECHANISMS OF ACTION, CLASSIFICATION, AND PHARMACOLOGY • 103
(e.g., GSV, small saphenous vein [SSV], anterior accessory
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saphenous vein, Giacomini vein, thigh extension of SSV, groin or popliteal fossa recurrence, etc.), which are deeper, Partsch’s studies showed high pressure is needed to occlude a saphenous vein, or to signi cantly reduce its caliber (i.e., 70–80mm Hg for GSV at mid thigh in standing position).
 ibault proposed another mechanical method to mini­mize blood content and vein size.  rough the in ltration of saline solution in the subcutaneous space or in the saphe­nous compartment a er a sclerosant foam injection, he got a prolonged decrease of vein size (decrease of blood reappear­ance in the treated area). Fewer side e ects and ultimately better results have been shown by the author through this adjuvant procedure.
A further reappraisal of this proposal led Parsi and Cavezzi to inject tumescent saline solution (with or with­out anaesthetics, with or without adrenaline inclusion, the latter drug having the ability to minimize vein diameter) immediately prior to the sclerotherapy session. In fact if a long catheter is inserted in the target vein (GSV, SSV, etc.), the tumescence in ltration is performed before sclerosant foam (or liquid) is delivered into the vein through the cath­eter retrieval; similarly tumescence is possibly applicable to previously cannulated varicose tributaries. In a preliminary study Ramelet proposed the tumescence in ltration also in sclerotherapy of resistant reticular varices/telangiectasias, with some contrasting evidence.
 ese procedures, though not scienti cally validated so far, may increase the obliteration rate also in larger veins, while decreasing the necessary dose of SF or liquid and possibly decreasing the side e ects. In our experience, addi­tional tumescence has resulted in improved outcomes in patients treated with long catheter foam sclerotherapy of GSV or SSV or AASV + phlebectomy of the varicose vein tributaries.
Di usion of the sclerosant drug from the injection site and blood (re-)entrance in the treated vein/s is another major factor that may in uence the extension of the sclerothrombus.
A er Stemmer’s experiments and Feied’s published data, the movement of the sclerosant liquid drug (and of SF, though in a lesser extent) from the injected site has been elucidated as another factor that may jeopardize the sclerosant drug e ect. Passariello and Schadeck in the early nineties highlighted the “erasure” e ect from the local tributaries/veins on the sclerosis process of the saphenous stem; when injecting a vein, the washing e ect of the local tributaries will interfere with the extension of the sclero­thrombus, for mechanical and chemical reasons: open veins  ush and limit the proximal segment of the sclero­thrombus where these enter the sclerosed vein (and pro­vide fresh lytic factors).  is is the case, for example with thrombosis of the GSV and common femoral vein or just with epigastric/abdominal veins and endovenous proce­dures onGSV.
Since the introduction of foam sclerotherapy and its worldwide diffusion thanks to Tessari’s method, a signifi­cant reappraisal of sclerosant drug chemical and physical activities has been proposed. Some of the considerations and data that have been mentioned above for liquid drugs, may not necessarily be pertinent to the injections of sclerosant foam. In fact foam dynamics significantly differ from liquid dynamics, both in supine and raised limbs. Apotentiated action of SF over a liquid drug has been proven in different studies, which can be referred to the prolonged contact between drug and vein wall, to the great multiplication of the active surface of the drug over the microbubble surface, to the reduced blood con­tent in the injected segment and to many other factors that intervene in foam activity and that are still under investigation.
 e role of air as the gas component of the scle­rosant foam has been questioned, as to the possible nitrogen-based distant side e ects of the microbubbles. More biocompatible gases, such as CO2 and O2, prefer­ably in a 70% to 30% combination, have been proposed in place of air to form sclerosant foam. Morrison’s stud­ies showed an overall improved safety for CO2, alone or in combination with O2, over room air, as to a few side e ects.
PHARMACOLOGY OF
SCLEROSANTAGENTS:AN
OVERVIEW
C H R O M A T E D G L Y C E R I N   C G 
Glycerin or glycerol is a glycol (bivalent alcohol) used as an osmotic diuretic and it is a sclerosant liquid, when com­bined with chrome alum, with strong coagulating prop­erties. Today a bluish-colored and oily sterile solution of chromated glycerin is commonly used, composed of 72% glycerin and 1.11% chrome alum; alternatively, in a few countries the single glycerin or glycerol is used as a com­pound drug.  anks to Kern’s studies CG has regained some popularity in the scienti c community, as it proved to achieve good results in the treatment of telangiectasias over the use of POL, STS, or sclerosant foam. CG has an irritating chemical action on the endothelium, and it is a weak, viscous sclerosant that may result in some minor local side e ects such as pigmentation, perivenous in am­mation (rarely necrosis), skin redness, and/or short-lasting pain in the surrounding area. Systemic reactions are those common to all sclerosant agents plus a dark colored urine emission in rare cases. Generally, CG dose per session and per injection never surpasses 10 ml and 3 ml respectively (usually a few drops per injection in telangiectasias), and this “weak” drug is used for telangiectasias and reticular varicesonly.
104 • PRIMARY SUPERFICIAL VENOUS INSUFFICIENCY
SALICYLATES SS ANDPS
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 e salicylates, an ancient remedy known to Hippocrates and Galen and also in the Middle Ages, exist in nature (e.g., salicylic and methyl salicylate). Used in 1876 in rheumatic fever, and as the basic components of acetylsalicylic acid (ASA) 20years later, salicylates were introduced by Jean Sicard in 1919 in France (SS) in sclerotherapy of varicose veins. SS has been used worldwide (mainly in France, Italy, Canada, and Argentina) in the last 60years, basically for minor varicosities only, more frequently under the form of a compounddrug.
SS is usually used at 10–20% concentration, with xylo­caine included to compensate the hyperalgesia that SS may generate in the  rst seconds a er the injection. Mariani and Izzo introduced PS to potentiate salicylate ion activ­ity on endothelial cells, using an alkaline pH formulation (Figure 12.1); this also resulted in a lower pigmentation rate in the authors’ experience. SS and PS have also shown a bene cial e ect on venous symptoms such as cramps and heaviness, though a short-lasting painful injection is asso­ciated with higher concentrations. Side e ects include skin necrosis (if injected extravenously) and rarely pigmentation. Allergy to ASA and deafness are common contraindications to usage of SS or PS. Ten ml of SS 20% is the recommended maximum dose per session, while 0.1–0.5 ml of SS or SP are commonly used per injection.
 e combination of glycerin and SS has been proposed by Capurro in treatment of minor varicosities to exploit the mildness of the  rst drug and the low-pigmentation propertyofSS.
HYPERTONIC SALINE SOLUTION
HSS 23.4%
HSS damages endothelial wall and induces a thrombus within 1 hour a er injection, while the sclerosis is com­pleted in 2–4 weeks. Addition of heparin to HSS resulted in more “matting,” probably due to the angiogenesis action of heparin, without any improvement of the outcomes.
Local side e ects are similar to those of salicylates, while the lack of selectivity of action of HSS on the diseased ves­sel walls may explain the higher incidence of DVT and pulmonary embolism (PE) in literature. Finally caution is recommended if large amounts are injected in hypertensive patients. Generally, 15 ml is the suggested highest dose per session, and 1 to 3 ml of HSS is the dose per injection, while few drops are used in telangiectasias.
D S C
DSC is a mixture of dextrose 250 mg/ml, NaCl 100 mg/ ml, phenethylic alcohol 8 mg/ml, propylene glycol 100 mg/ ml, and water up to 10 ml.  is hypertonic solution with
5.9 pH value causes dehydration and necrosis of endothelial
cells, 3 minutes post injection.  e deposition of  brin and thrombus formation occurs because of a change of electro­static charges in the endothelium. Local side e ects of DSC may include pigmentation and rare skin necrosis, while, like HSS, a lack of the selectivity of action may raise the risk of DVT/PE if large amounts are injected (total volume of 10 ml per session is recommended).  e dose per injection is up to 3 ml, and DSC is usually recommended in telangiec­tasias and reticular varicesonly.
POL OR LAUROMACROGOL400
POL is an alcohol that was introduced in 1936 as a surface anaesthetic.  e basic molecule (hydroxy­poliethoxy-dodecane) is formed by a lipophilic and by a hydrophilic part, and the amphipathic properties of POL explain the interaction with veins and skin. In 1960 Henschel used POL in varicose vein treatment; since 1967 this usage has spread worldwide, and several clinical trials have been performed to test this molecule in small and large varices. Di erent concentrations of POL (0.25–3%) are available on the market, to treat from telangiectasias to larger saphe­nous veins. POL is an alcohol with the characteristics of a nonionic surfactant or detergent substance, which makes POL well transformable in foam; furthermore POL revers­ibly inhibits the sensory receptors and the conductivity of the sensory nerve  bers (anaesthetic proprieties). POL dilu­tion with distilled water is possible thanks to its long car­bon chain; and Lauromacrogol 400 is the stabilized POL preparation at neutral pH. Experimental and in vivo studies demonstrated that placenta is an e ective barrier for POL and 64% protein binding of POL molecules has been calcu­lated in humans; similarly no teratogenicity, mutagenicity, or carcinogenicity have been shown. Local reactions com­monly include urticaria-like reactions, pigmentation due to clot retention, perivenous in ammation, and skin necrosis. Systemic reactions are those common to all sclerosant agents (allergies, nausea, etc.), while major neurologic, cardiac, and thromboembolic complications have been rarely reported for POL both in liquid and foamyform.
S T S
STS is an anionic “surfactant” with corrected pH that was discovered by Reiner in 1946 and since then di used in several countries worldwide.  is detergent drug can be easily transformed in foam form and has been extensively used in foam sclerotherapy since 1997. With reference to sclerosant foam, STS microbubbles basically have smaller size than POL bubbles, whereas their half-liquid time is shorter compared with POL foam. Its 7–8.1 pH helps to cause endothelial maceration within 1 hour a er injection, and STS quickly combines with serum and endothelial proteins.  e possible local side reactions are rare: pain, urticaria-like skin reactions, pigmentation, perivenous
SCLEROSANT AGENTS:MECHANISMS OF ACTION, CLASSIFICATION, AND PHARMACOLOGY • 105
in ammation, and necrosis. Hemolysis, transient fever,
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nausea, and vomiting are possible systemic reactions when large doses are employed. Cerebral and thromboembolic complications have been reported in literature for STS as liquid or sclerosant foam.  e drug is available in di erent concentrations (0.2%, 0.5%, 1%, 3%) and it is mostly used for medium-large size veins, though 0.1% STS is proposed in sclerotherapy of telangiectasiastoo.
POLYIODIDE SOLUTIONS
reactions, hemolytic reactions, and the activation in vitro of coagulation (which accounts for the risk of disseminated intravascular coagulation, occasionally associated to EO). Beside the typical local and systemic complications, an acute renal failure was reported in treating an obese patient with high doses.  e injected dose should not exceed 10 ml per session, and normally no more than 2 ml per injection site is used. EO is mostly used for esophageal varices, but lower-limb medium-large varicose veins are also an indica­tion for the use of liquid (or foamed) EO sclerotherapy.
Iodated solution (IS) was of major importance for large-vessel sclerotherapy in the last decades (especially in Sigg’s tech­nique), being gradually replaced by detergent agents, both liquid and foam. IS is a dark brown stabilized aqueous solution of monoiodic and polyiodic ions, sodium ions in various concentrations with the addition, in some prepara­tions, of benzyl alcohol. IS has always been recommended for medium-large varices only. IS has a cell-damaging action on the venous endothelium, a marked and time-lasting toxic e ect because it acts as a sort of vital dye stuck to the wall. Lindemayr and Santler indicate that IS does not likely pro­duce activation of blood coagulation, resulting in low risk of thrombosis propagation induced on the damaged venous segments. IS necrotic and algesic power is extremely high if injected into the extravascular space, but high concentra­tions o en result in painful intravenous injections. IS shares similar local and general complications with POL and STS, while visual disorders, dizziness, and iodine taste sensation are more typical for IS. Atypical general contraindication to IS usage is hyperthyroidism, and the total dose of 2–8% IS per session should never exceed 3–4ml.
S M
SM is a mixture of saturated and unsaturated fatty acids of sodium salts of soap-like cod liver oil, synthesized for intra­venous use by Ghosh and Cutting (1926) with surfactant (detergent) characteristics and a 6.9–9.6 pH; SM causes endothelium maceration through an action on membrane lipids, with subsequent thrombosis between the 2nd and 10th day. Typical local reactions are:cramp-like pain, burn­ing sensation in the injection area, remarkable perivenous in ammation, and necrosis, whereas systemic reactions are those of the other sclerosants.  e usual dose in adults to sclerose small-to-large varicose veins is 50 to 250 mg (1–5 ml 5%). SM is not generally recommended for sclerother­apy of spiderveins.
E O
EO is a viscous detergent aqueous solution containing eth­anolamine oleate at 5%, with a 8–9 pH. EO causes endo­thelium maceration, intense extravascular in ammatory
ACKNOWLEDGMENTS
 anks to Fabrizio Mariani and to Lorenzo Tessari for their invaluable scienti c inputs and thanks to Elio Concettina for her help in the literature review.
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