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Chapter
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7
Mechanism of Action of Sclerotherapy
Figure 7.17 The endothelial cells and vascular wall structure are
completely homogenized 1 hour after injection of the rabbit ear vein with
hypertonic saline 23.4%. Longitudinal section, ×40 (hematoxylin–eosin).
Figure 7.19 Multiple brown spherules approximately 1 µm in diameter are
noted within necrotic endothelium at 8 days in the rabbit ear vein injected
with 0.5% polyiodinated iodine (hematoxylin–eosin, ×40).
zation by 28 days. With the 0.5% solutions, the endothelium
was necrotic with multiple brown spherules approximately
1 µm in diameter seen within the endothelial wall (Fig. 7.19).
These may represent iodine crystals. By 28 days, a fibrous cord
was present without inflammation. Interestingly, veins treated
with iodine/normal saline mix showed a greater incidence and
extent of extravasated erythrocytes compared to those treated
with iodine/SX (hypertonic saline/dextrose) solutions. The PII
0.1% solution had an experimental efficacy equivalent to HS
11.7%, SM 2.5%, STS 0.25%, and POL 0.5%. The PII 0.5%
solution had an experimental efficacy similar to HS 23.4%,
STS 0.5%, and POL 1.0%.
Figure 7.18 Regenerating hyperplastic endothelium is present 8 days after
injection of the rabbit ear vein with 0.1% polyiodinated iodine diluted with
Sclerodex (hematoxylin–eosin, ×20).
endothelium 1 hour after biopsy was almost undamaged.
Therefore, in this experimental model, CG is a weak solution
with a sclerosing effect similar to POL 0.25%. This correlates
well with its clinical profile. The sclerosing effect of CG is not
dependent upon chromium. Excellent results can be achieved
in treating leg veins less than 1 mm in diameter with the use
of a 72% glycerin solution mixed 2 : 1 with 1% lidocaine with
epinephrine, as described later in this chapter.
Polyiodinated iodine
Various iodine solutions, with or without hypertonic solutions, have been examined in the rabbit ear vein model.
Sclerodine (Omega Laboratories, Montreal) is a mixture of
iodine USP (60 mg/mL) and sodium iodide USP (90 mg/
mL). This solution was compared with an American iodine
formula consisting of iodine and sodium iodide, compounded
by the Women’s Hospital of Texas in Houston. The two sclerosants were identical in composition. After being mixed with
either normal saline, SX (Omega Laboratories), or a solution
of dextrose 250 mg/mL and sodium chloride 100 mg/mL
(compounded by the Women’s Hospital of Texas in Houston),
each sclerosant was injected in concentrations of 0.1% and
0.5%. Thrombosis occurred with all solutions at 1 hour, with
an attenuated endothelium and focal endothelial necrosis.
A mild perivascular mixed cellular infiltrate consisting of
eosinophils and polymorphonucleocytes was present with
margination along the endothelial border. With the 0.1%
solutions, the endothelium was hyperplastic, with regenerative changes noted by 8 days (Fig. 7.18) and complete normali-
164
Comparative efficacy in the animal model
The mechanism of action for all sclerosing solutions injected
into veins in the aforementioned studies was basically
similar; that is, endothelial damage and simultaneous thrombus formation occurred almost immediately after injection.
Endothelial damage was less in the vessels injected with CG,
POL 0.25%, SX, and EO 0.5%, which showed early recanalization and a continued normal clinical appearance. POL 0.5%,
SM 0.5% and 1%, EO 1%, and HS 11.7% produced endothelial attenuation, not necrosis. Although an organizing
thrombus was produced, recanalization occurred, causing the
returned clinical appearance of the injected vessel. Vessels
injected with PII 0.1%, STS 0.5%, SM 2.5%, and EO 2.5%
also demonstrated recanalization, although endothelial necrosis was demonstrated. In contrast to the luminal recanalization that occurred with POL 0.5% and EO 2.5%, recanalization
with STS 0.5% and SM 2.5% occurred with multiple minute
64
vascular channels. Vessels sclerosed with STS 0.25% and
0.5% and with SM 2.5% never totally reappeared clinically
in the 60-day span of this study. The only vessels to histologically demonstrate fibrous cord formation that did not
recanalize were sclerosed with PII 0.5%, HS 23.4%, and POL
1.0%. Therefore there is a minimal sclerosant concentration (MSC) that is essential to produce endosclerosis. This
term, coined by Neil Sadick,
65
is useful in determining which
solution and concentration is best at sclerosing a specific
vessel.
Comparative efficacy in the human model
In an effort to assess the effect of sclerosing agents in human
leg telangiectasias, the author injected 0.1 mL of either POL
0.5% or STS 0.5% into two nearly identical telangiectasias
(0.4 mm in diameter) over the anterior tibia in a 65-year-old
man. The vessels did not have any associated ‘feeding’ reticular
A B
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Figure 7.20 Anterior tibial telangiectasia. A, Before treatment and, B, 48 hours after injection of polidocanol 0.5%.
A B
Figure 7.21 Histologic examination of vein in Figure 7.11. A, ×40. B, ×100; shows endothelial cell vacuolization with thrombosis (hematoxylin–eosin).
Clinical Use of Sclerosing Agents
A B
Figure 7.22 Anterior tibial telangiectasia. A, Before treatment and, B, 48 hours after injection of sodium tetradecyl sulfate 0.5%.
veins, and there was no evidence of associated varicose veins
or signs of venous insufficiency. Neither injected vessel was
compressed, and a biopsy of each was taken 48 hours after
treatment. The vessel injected with POL 0.5% demonstrated a
blue thrombus (Fig. 7.20) that was histologically confirmed,
and an endothelium that was relatively intact with extensive
cellular vacuolization (Fig. 7.21). The vessel injected with STS
0.5% demonstrated a deep blue thrombus (Fig. 7.22). Histologically, the endothelium was totally destroyed, showing
extensive intravascular thrombosis and early organization
(Fig. 7.23). Therefore, this limited human study correlates
with the aforementioned studies on the marginal rabbit ear
vein, demonstrating that STS is a stronger sclerosing agent
than POL.
1950 and thus have never been subjected to the rigorous toxicity and efficacy studies that would be required by the FDA
today. Hypertonic saline in a 23.4% concentration is available
and approved for use as an abortifacient. However, it is commonly used in various concentrations, with and without the
addition of heparin, procaine, or lidocaine, for sclerosis of
telangiectasias and superficial varicosities. Polidocanol, widely
used in the United States today, has undergone investigative
trials and was approved for use in June 2010. SX, a solution
of dextrose 5% and sodium chloride 10%, is commonly used
in Canada for sclerosis of superficial varicosities and telangiectasias. Chromated glycerin, and now glycerin, is perhaps
the most widely used sclerosing agent worldwide for the treatment of leg telangiectasias. Ouvry
popularized it in the English literature. PII is the most power-
Clinical Use of Sclerosing Agents
ful sclerosing agent and is commonly used outside of the
United States for sclerotherapy of the saphenofemoral junc-
tion (SFJ). It is not yet approved for use by the FDA in the
The only sclerosing agents approved for use in the United
States by the Food and Drug Administration (FDA) are SM,
EO, and STS. All of these agents were approved for use before
United States but is discussed because of its importance in
sclerotherapy. Another solution rarely used now, sodium sali-
cylate, is briefly discussed.
66
and Goldman67 have
165
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7
Mechanism of Action of Sclerotherapy
A B
Figure 7.23 Histologic examination of vein in Figure 7.22. A, ×40. B, ×100; shows endothelial cell homogenization/necrosis with thrombosis
(hematoxylin–eosin).
Osmotic agents
Hypertonic saline
Hypertonic saline was first used to sclerose varicose veins by
20
Linser
advent of more effective, synthetic, detergent sclerosing solutions in the 1940s, its use declined. Renewed interest in its use
occurred in the 1970s, spurred on by numerous publications
in the dermatology literature and multiple lectures on its use
presented at major medical meetings.
centrations of HS, with and without heparin, was performed
in different-sized varicose and telangiectatic leg veins.
found that an 11.7% HS solution was as effective as a 23.4%
solution in treating vessels less than 8 mm in diameter, and
more effective than a 5.8% solution, with less burning, pigmentation, and cramping. The addition of heparin only
decreased thrombosis formation requiring puncture evacuation in vessels greater than 4 mm in diameter. This demonstration of MSC produced superior cosmetic results with an
improved therapeutic-to-complication index.
Advantages
Part of the currently experienced popularity stems from the
lack of allergenicity of unadulterated HS solution compared
with the exaggerated claims of allergenicity associated with all
other sclerosing agents. However, HS is not without significant
adverse sequelae (see Chapter 8).
Disadvantages
Unlike detergent sclerosing solutions, all hypertonic solutions
act nonspecifically to destroy all cells (including RBCs) within
their osmotic gradients. Osmotic agents damage cellular
tissues and readily produce ulceration if injected extravascularly or if diffused through the vessel extravascularly (see
Chapter 8). Therefore, injection technique is critically important with use of this type of sclerosing agent.
vessel wall, nerves in the adventitia of the vein may be stimulated, causing pain (see Chapter 3). This diffusion may also
lead to transient muscle cramping. Hemolysis of RBCs occurs
166
in 1926 and Kern and Angle63 in 1929. With the
A double-blind, paired-comparison study of various con-
Because HS diffuses to some extent through the blood
65
It was
through hyperosmosis, causing the release of hemosiderin,
which may readily diffuse across the damaged endothelium.
This may lead to post-treatment hyperpigmentation, especially in a punctate pattern. Finally, because osmotic agents
are rapidly diluted in the bloodstream, they lose their potency
within a short distance of injection. Thus, these agents are
only rarely effective in treating veins larger than 3 to 4 mm in
diameter.
Modification of the Solution and the Technique
Various modifications of the HS solutions have been made in
an effort to increase the efficacy and decrease the pain of injection and other adverse sequelae. In 1975, Foley
the microinjection of ‘venous blemishes’ with a 30-gauge
needle using 20% hypertonic saline, 100U/mL of heparin, and
1% procaine, which he patented as Heparsal. He reported no
allergic or anaphylactic reactions and only rare pigmentary
problems in more than 1000 treatments to more than 100
patients. Foley theorized that the addition of heparin helped
to prevent thrombi in larger vessels, and the addition of
procaine helped alleviate the pain on injection. Sadick,
in randomized, double-blind, 800-patient and 600-patient,
paired-comparison studies, found that the addition of heparin
to HS provided no benefit in the treatment of varicose and
telangiectatic veins less than 4 mm in diameter. Bodian,
because of his personal clinical comparison experience, also
did not believe that the addition of heparin was necessary for
effective sclerosis. Finally, it has been demonstrated that the
addition of heparin to the culture medium enhances proliferation and increases the lifespan of endothelial cells.
its use may be counterproductive.
A number of modifications in injection technique have also
been made to limit the pain of HS. Bodian
71
cramps occurring at the site of injection last 3 to 5 minutes
and are relieved with gentle massage or ambulation. To limit
the risk of extravasation, he recommended injecting a small
air bolus before injecting 0.5 to 1 mL of HS; this ensures
undiluted contact of the HS with the intima to produce
maximum irritation of the vessel. He believed that hemolysis
caused by the sclerosing solution may lead to or exacerbate
hemosiderin staining and thus should be lessened by the prior
injection of air, which washes out the RBCs from the vessel.
68
described
65,69
70,71
72
Therefore
found that muscle
73
Finally, regarding the possible exacerbation of hypertension
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with injection of a large sodium bolus, he stated that 1 g of
sodium chloride injected during a ‘long treatment session’
(5 mL of a 20% HS solution) is well tolerated.
Alderman74 was the first to advocate dilution of the HS
solution to better adjust the osmotic damage to the caliber of
the vessel. From his experience with 150 patients with telangiectasias treated over 8 years with 18% to 30% HS, he
recommended the following HS concentrations for sclerosis
of varicose and telangiectatic veins: 18% to 25% HS for
‘venous telangiectasias’ (blue telangiectasias), 22% to 25% HS
for ‘arterial lesions’ (red telangiectasias), and 30% HS for rare,
large ‘arterial’ lesions. He diluted the saline with lidocaine to
achieve a 0.4% concentration of lidocaine. The only adverse
side effects reported were mild, temporary burning at injection
and residual brownish pigmentation that occurred in up to
one-third of patients. The pigmentation usually resolved, for
the most part, over 1 year.
Lidocaine, when used as a diluent, can be used with or
without epinephrine. Animal studies have demonstrated that
solutions with less than a 1% concentration of lidocaine are
vasoconstrictive.
75,76
In addition, the author routinely uses it
with epinephrine as a diluent to enhance vasospasm and partially stabilize perivascular mast cells.
Hypertonic glucose–saline
Sclerodex is a mixture of dextrose 250 mg/mL, sodium chloride 100 mg/mL, propylene glycol 100 mg/mL, and phenethyl
alcohol 8 mg/mL (as a local anesthetic/preservative) at a pH
of 5.9, mainly used in Canada for sclerosis of telangiectasias
and small-diameter superficial varicosities.
77
It is essentially a
hypertonic solution with a mechanism of action similar to HS.
The manufacturer states that the sodium chloride reinforces
the sclerosing potency of dextrose.
It is interesting to note that a similar product was manufactured by Abbott Laboratories (Abbott Park, Ill.) in the
1950s and 1960s under the trade name Varisol. This compound consisted of 30% invert sugar and 10% sodium chloride, with a mixture of preservatives and stabilizers (benzyl
carbonate phenethyl, propylene glycol) in water. It was withdrawn from the market in 1963 in conjunction with the FDA’s
new requirements for efficacy and toxicity testing. The author’s
correspondence with Abbott Laboratories has not spurred
their interest in development or production of this solution
(Diane Rennpferd, Coordinator, External Technology Evaluation, 15 August 1991).
The manufacturer of SX recommends that the maximum
quantity to be injected during one visit is 10 mL in divided doses,
with a 5-cm interval between each site of injection.a (The
maximum recommended amount to be injected at any one
site is 1 mL.) The average dose per treated vein varies between
1 mL in the upper thigh and 0.1 mL in the lower leg. The reason
for these recommended doses by the manufacturer is unclear.
Advantages
Omega Laboratories, which produces SX, claims that the addition of dextrose allows for a reduction in the concentration of
sodium chloride, thereby minimizing the pain and local discomfort that would occur with injection of sodium chloride
a
alone.
However, it is probably the decrease in osmolarity
relative to 23.4% HS that allows SX to produce less pain and
muscle cramping.
Disadvantages
Despite the lower osmolarity of SX, like HS, it is slightly
painful for the patient on injection.
occur rarely, with an incidence of less than that with HS.
78
Superficial necrosis may
a,77,79
The author has noted postsclerotic pigmentation occurs with
a frequency similar to that of other sclerosing agents, although
79
Mantse
noted a decreased incidence of complications with
SX as compared with POL and STS (see Chapter 8).
Another disadvantage of SX use is that the solution becomes
sticky in the syringe when blood is withdrawn to ensure an
intravenous position. Unfortunately, unlike unadulterated
HS, allergic reactions may occur to the phenethyl alcohol
component of the solution.
a
Mantse77 noted one allergic
reaction in 500 patients treated with SX, giving an incidence
of 0.2%.
Sodium salicylate
Sodium salicylate (SS; Saliject, Omega Laboratories, Montreal,
Canada) is provided in a 10-mL multiuse vial. Each milliliter
contains 570 mg of SS, with benzyl alcohol 1% and sodium
metabisulfite 0.1% added as preservatives. Because SS is
painful on injection, especially if it diffuses or is injected
extravascularly, it is recommended to be diluted with lidocaine 1% without epinephrine. The manufacturer recommends a maximum daily total quantity of 8 to 10 mL. It may
also be added to other sclerosing solutions such as glycerin to
achieve a final concentration between 6% and 30%. In this
concentration, it can be used for telangiectasias less than
1 mm in diameter.
Recommended concentrations are 20% for reticular veins
of 2 to 4 mm in diameter and 15% for telangiectasia 1 mm
or less in diameter. To make 30 mL of a 15% solution, dilute
5 mL of Saliject with 12 mL of 1% lidocaine and 13 mL of
normal saline. To make 30 mL of a 20% solution, mix 10 mL
of Saliject with 10 mL of 1% lidocaine and 10 mL of normal
saline.
This solution causes muscle cramping after use, especially
if volumes greater than 0.1 mL are injected in a single location. Like other osmotic agents, SS produces necrosis on
extravasation in a concentration-dependent manner. Because
of the intense pain produced with arterial or extravascular
injection, SS is often mixed with STS to ensure that injection
of STS is intravascular (STS is nearly painless when injected
extravascularly). Anaphylactic reactions are possible since,
albeit rarely, patients can be allergic to salicylates.
Chemical irritants
Chromated glycerin/glycerin
Chromated glycerin 72% (Sclérémo, Laboratories Bailleul,
Paris, France; Chromex, Omega Laboratories, Montreal,
Canada; Skleremo, Elvetium-Alet Laboratorios, Buenos Aires,
Argentina) is a sclerosing solution that is popular in Europe,
whereas clinical experience in the United States remains
limited. The maximum recommended amount per injection
session is 10 mL of pure solution. Concentrations of 25% to
100% have been used.80 Its clinical efficacy has been shown
to be dose dependent. Although not approved by the FDA,
CG is a widely used sclerosing agent for leg telangiectasias in
the world; 500,000 vials were sold in 1986.
information is not available from the manufacturers.
The glycerin component of CG is rapidly absorbed by the
intestine and transformed into carbon dioxide or glycogen or
is directly used for the synthesis of fatty acids.
solution must be used with caution in diabetic patients. One
case of reactive hypoglycemia to an infusion of glycerol
occurred in a child, resulting in a comatose state within 4
minutes of infusion.
82
The sclerosing quality of glycerin was first studied in 1925
by Jausion et al,83 who found that it induced a mild, rapid,
a
More recent
81
Therefore, this
Clinical Use of Sclerosing Agents
a
Correspondence received from Laboratories Ondee Ltee, 280 Milice
Longueuil, Montreal, Canada (1986).
a
Correspondence received from Laboratories Ondee Ltee, 280 Milice
Longueuil, Montreal, Canada (1986).
167
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7
Mechanism of Action of Sclerotherapy
168
and complete endosclerosis. Isosmotic glycerol (2.6%m/v)
produces 100% hemolysis in 45 minutes.
81,84
This usually
occurs with rapid infusions of 60 g in 15 minutes, 70 g in 30
minutes, and 80 g in 60 minutes.85 However, a review of 500
patients who received glycerol intravenously (at 50 g/500 mL)
6 hours a day for 7 to 10 days demonstrated hemoglobinuria
in less than 1% of patients.
86
The chromium alum component of CG is a potent coagulating factor that increases the sclerosing power of glycerin. It
also prevents the mild hematuria induced through the use of
glycerin alone.
81,87,88
Mihael Georgiev (personal communication, 1994) has produced a 70% glycerin solution, sterile for injection, and has
seen a sclerosing effect with this agent that is identical to CG.
Hobbs (personal communication, 2000) has confirmed this
effect with a 72% solution mixed with lidocaine 0.5% (Laboratorio Terapeutico M.R., Firenze). Since glycerin is obtainable
on formulary for use in cerebral edema and acute glaucoma,
its availability makes it a promising alternative to more caustic
sclerosing agents. Its use for these applications indicates that
glycerin alone has an osmotic effect as well.
We compared the effects of STS 0.25% with those of glycerin 72% mixed 2 : 1 with lidocaine 1% with epinephrine in
13 patients, to determine the relative safety and efficacy of the
two sclerosant solutions.
67
Each patient’s leg veins from 0.2 to
0.4 mm in diameter that did not have incompetence from the
SFJ, and whose feeding reticular veins had been already treated
in a prior sclerotherapy session, were randomly treated with
either STS 0.25% or glycerin 72% solution. Patients were
evaluated from 2 to 6 months postsclerotherapy for overall
clinical improvement and incidence of adverse sequelae. We
found that glycerin was comparable to STS in the discomfort
of injection, but demonstrated a significant decrease in bruising, swelling, and postprocedural hyperpigmentation. Glycerin also demonstrated a better, more rapid clearance of
treated telangiectasias. Thus, the chromate salt addition to
glycerin was not necessary for effective sclerotherapy.
Advantages
The relatively weak sclerosing power of CG corresponds to its
promotion as a mild sclerosing solution with more versatile
use and a low incidence of side effects. Pigmentation and cutaneous necrosis are exceedingly rare at recommended dosages,
and minimal extravascular injection causes only a small
temporary ecchymosis without any cutaneous damage.
Reportedly, the incidence of adverse sequelae is very low.
89,90
a,41,80
Disadvantages
The disadvantages of CG are its high viscosity and local pain
at injection.
partially by dilution with lidocaine. Hypersensitivity is a rare
complication.
occur transiently after injection of large doses. Ocular manifestations, including blurred vision and a partial visual field
loss, have been reported by a single author, with resolution in
less than 2 hours.
result of excessive, nonspecific destruction of RBCs.
A case of fatal anaphylaxis has recently been reported with
chromated glycerin.
doubt is left regarding responsibility of the sclerosing agent.
This case is the only one published and no known cases of
anaphylaxis with glycerin alone exist.
91,92
Both of these drawbacks can be overcome
93,94
Hematuria associated with ureteral colic can
95
These latter two complications may be a
96
The case is well documented and little
Ethanol
Ethanol is a sclerosing agent most commonly used for treating
arteriovenous malformations. It kills cells by fixation, preserv-
a
Sclérémo product information from Laboratories E. Bouteille, 7 Rue
des Belges, Limoges 8100, France (1987).
ing cell morphology, and is thus listed as a ‘chemical’ sclerosing agent. The precipitant thrombus-forming effect makes it
useful for high-flow lesions. Using an in vitro model, Mol et al
found that almost all cells die within 5 seconds when exposed
to a 30% concentration.
97
A 3% concentration, to which cells
were exposed for 12 hours, did not cause any damage. As a
comparison, all cells exposed to 0.025% POL for 5 seconds
also died. As discussed previously, POL kills cells by disrupting the cell membrane through protein-theft denaturization.
Detergent sclerosing solutions
Sodium morrhuate
Sodium morrhuate (Palisades Pharmaceuticals, Tenafly, NJ;
American Regent Laboratories, Shirley, NY) is a mixture of
sodium salts of the saturated and unsaturated fatty acids
present in cod-liver oil (Table 7.3). It is prepared by the saponi-
fication of selected cod-liver oils. Each milliliter contains
morrhuate sodium, 50mg; benzyl alcohol, 2% (as a local
anesthetic); water for injection (as much as will suffice); and
hydrochloric acid and/or sodium hydroxide to adjust the pH
to approximately 9.5. It is available as a 5% concentration that
can be diluted with normal saline (to the appropriate concentration) for the vessel to be treated.
This sclerosing agent was first prepared for injection by
98
Ghosh
United States by Biegeleisen
cutaneous necrosis occurs when SM is inadvertently injected
perivascularly. Many cases of anaphylactic reactions within a
few minutes after injection have been reported. More commonly, these reactions occur when therapy is reinstituted after
a few weeks. Anaphylaxis has resulted in fatalities, albeit rarely
(see Chapter 8). The FDA has approved the usage of SM for
sclerosis of varicose veins. However, because of its extremely
caustic nature, it is not recommended for use as a sclerosing
agent for telangiectasias, although Gallagher
use diluted to a 0.25% to 0.5% concentration.
with an occasional tenderness at the injected site for a few
days.
treated with SM is notably free of significant adverse sequelae,
with only one episode of ‘full anaphylactoid reaction’. He
describes more than 20 patients who had immediate postinjection ‘early anaphylactoid reactions’ manifesting as chest
pain, shortness of breath, tachycardia, and hypotension, who
responded to intravenous dexamethasone and intramuscular
Benadryl. Gallagher states that STS has a higher incidence of
adverse reactions than SM, so he prefers the latter for
telangiectasia.
or Cutting99 and was met with enthusiasm in the
54
and others. However, extensive
89
advocates its
Most patients have minimal discomfort after injection,
100
Gallagher’s 25-year experience with 20,000 patients
Table 7.3 Fatty acid composition of sodium morrhuate
Component Percentage
Linoleic acid 28.2
Unknown 20.8
Eicosadienoic acid 15.5
Palmitoleic acid 12.1
Arachidonic acid 8.2
Palmitic acid 8.1
Myristic acid 4.2
Oleic acid 1.8
Stearic acid 1.1
From Monroe P et al: Gastroenterology 85:693, 1983.
Ethanolamine oleate
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Marketed under the name of Ethamolin (QOL Medical, USA),
ethanolamine oleate (EO) is a synthetic mixture of ethanolamine and oleic acid with an empiric formula of
C
20H41NO3
. It is available as a 5% aqueous solution containing approximately 50 mg of EO per milliliter. Benzyl alcohol,
2% by volume, is used as a preservative. The pH ranges from
8.0 to 9.0. The minimum lethal intravenous dose in rabbits is
130 mg/kg.
101
The oleic acid component is responsible for the inflammatory action. Oleic acid may also activate coagulation in vitro
by release of tissue factors and Hageman factor XII. It is not
known whether EO is secreted into breast milk, so its use
during lactation cannot be recommended. A 5% concentration used in gross varicose veins (diameter not specified) completely destroyed the veins 8 weeks after injection.
102
Advantages
Ethanolamine oleate was first reported to be an ideal sclerosing agent by Biegeleisen
No toxic effects were noted in 500 injections and it is thought
to be less likely to cause allergic reactions than either SM or
104
STS.
However, pulmonary toxicity has been associated with
this sclerosing agent (see Chapter 8).
The sclerosing action is thought to occur as a dosedependent, extravascular inflammatory reaction caused by diffusion of EO through the venous wall.
regarding its use in esophageal varix injection demonstrated
that variceal obliteration occurred as a result of mural necrosis, followed by fibrosis, and that thrombosis was a transient
phenomenon.
105,106
103
in the medical literature in 1937.
a
Autopsy findings
Disadvantages
Ethanolamine oleate is a viscous solution that can be injected
only through a 30-gauge needle with dilution. Some degree
of nonspecific RBC hemolysis may occur with its use. A hemolytic reaction occurred in 5 of 900 patients with injection of
over 12 mL of EO 0.5% per patient per treatment session.
107
Acute renal failure with spontaneous recovery followed injection of 15 to 20 mL of Ethamolin in two women.b The patients
were described as ‘feeling generally unwell and shivery, with
aching in the loins and passage of red-brown urine. All rapidly
recovered with bed-rest and were perfectly normal the next
day.’ One hundred and four injections of less than 12 mL per
treatment session did not result in this reaction.
In addition, even a 0.5% solution produces an unacceptable incidence of eschar, ulceration, or pigmentation when
injecting telangiectasias of less than 1 mm in diameter.
102
Sodium tetradecyl sulfate
Sodium tetradecyl sulfate (Sotradecol, Bioniche Pharma
Group, Inverin, Co. Galway, Ireland; Thromboject, Omega
Laboratories, Montreal, Canada; Trombovar, Laboratoires
Innothéra, Arcueil, France) is a synthetic, surface-active substance first described by Reiner
composed of sodium 1-isobutyl-4-ethyloctyl sulfate plus
benzoyl alcohol 2% (as an anesthetic agent) and phosphate
buffered to a pH of 7.6. It is recommended that solutions be
protected from light. It is a long-chain fatty acid salt of an
alkali metal with the properties of soap. The solution is clear,
non-viscous, has a low surface tension and is readily miscible
with blood, leading to a uniform distribution after injec-
108
tion.
It primarily acts on the endothelium of the vein,
because, if diluted with blood, the molecules attach to the
a
Product information from Glaxo Pharmaceuticals, Research Triangle
Park, N.C. (1989).
b
Ethamolin injection, 5%; product information from Glaxo Pharma-
ceuticals Inc. (December 1988).
45
in 1946 (Fig. 7.24). It is
CH
CH(CH3)
2
2
O
CH3(CH2)3CH(CH2)2CHOSONa
C2H
5
Figure 7.24 Structural formula of sodium tetradecyl sulfate.
surface of RBCs, causing hemolysis. The recommended
maximum dosage suggested by STD Pharmaceutical Products
in a treatment session is 4 mL of a 3% solution or up to 10 mL
of lower concentrations (e.g. 1%).a The recommended
maximum dosage from Bioniche Pharma Group and Omega
Laboratories is 10 mL of a 3% solution, with intervals between
treatments of 5 to 7 days.
b,c
The solution just mentioned should not be mixed with
other anesthetic solutions because it will become turbid and
form a new compound.
109
In addition, heparin should not be
included in the same syringe as STS because the two are
incompatible (product insert, rev. October 1988). Yet, a paired
comparison study of STS with and without heparin disclosed
no difference in the therapeutic effect between the two
solutions.
36
In the United States, STS is available as a 1% or 3% solution
that can be diluted with sterile water or normal saline to
achieve an appropriate therapeutic concentration. It is also
available – with the same pH and preservative – as Fibro-Vein
(STD Pharmaceutical Products, Hereford, England), in 5-ml
multiuse vials in concentrations of 0.2% and 3% and in 2-ml
ampules in concentrations of 0.5%, 1%, and 3%. The Canadian manufacturer recommends dilution with phosphatebuffered saline to preserve the original pH level.
prevents pain from injection.) It is limpid and does not stick
to the syringe cylinder when blood is withdrawn to ensure
accurate needle placement. Concentrations of 0.1% to 0.3%
are commonly used for the treatment of telangiectatic veins
0.2 to 1.0 mm in diameter; 0.5% to 1% for treatment of
uncomplicated varicose veins 2 to 4 mm in diameter; and
1.5% to 3% for the treatment of larger varicose veins, incompetent perforating veins, or an incompetent SFJ.
Advantages
Sodium tetradecyl sulfate became widely used in the 1950s
after its introduction in 1946 by Reiner.
first reported the injection of a 1% solution into spider angiomata. He noted excellent results in virtually all 144 patients
treated. He also noted an unspecified number of episodes of
epidermal necrosis without significant sequelae and a 30%
incidence of postsclerosis pigmentation that resolved within
a few months.
Shields and Jansen
microsclerosis of telangiectasias with STS in the dermatologic
literature. They injected STS 1% into 105 patients and reported
only one episode of necrosis in more than 600 treatments of
vessels less than 5 mm in diameter. There were no systemic
a
STD injection product data sheet from STD Pharmaceutical Products,
Hereford, England (1977).
b
Sotradecol, Bioniche Pharma Group, Casla, Co. Galway, Ireland.
c
Thromboject product information from Omega, Montreal, Canada
(rev 10/87).
111
in 1982 were the first to describe
O
c
(This also
45
Tretbar
110
in 1978
Clinical Use of Sclerosing Agents
169
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7
Mechanism of Action of Sclerotherapy
170
reactions, and the majority of postsclerosis pigmentary
changes resolved in 3 to 4 months. However, as more experience with its use in the treatment of leg telangiectasias
occurred, even further dilutions (0.1% to 0.3%) were recommended, both to achieve clinical efficacy and to limit adverse
sequelae (see Chapter 12).
Disadvantages
Approved for use by the FDA for vein sclerosis, STS nevertheless has a number of disadvantages. Epidermal necrosis frequently occurs with extravasation of concentrations higher
than 1%; however, telangiectasias and spider veins are usually
treated with 0.1% to 0.2% and extravasation at this concentration rarely causes a problem. Allergic reactions occur rarely.
Postsclerotherapy hyperpigmentation occurs in proportion to
its concentration (see Chapter 8), therefore its dilution is critical. The previously mentioned percentages per diameter of
treated vein provide only a preliminary guide for effective
treatment. In addition, the Canadian and US manufacturers
recommend that as a precaution against anaphylactic shock,
0.3 mL of a 1% solution should be injected into the varicosity,
and then the patient should be observed for several hours
before proceeding with further injections.
a
The reason for this
recommendation is unclear, impractical, and potentially hazardous; it is discussed further in Chapter 8.
The intravenous lethal dose in 50% of the population
(LD
) is 90 ± 5 mg/kg in mice and between 72 and 108 mg/kg
50
in rats. When tested in the L5178YTK mouse lymphoma
assay, STS did not induce a dose-related increase in the
frequency of thymidine kinase-deficient mutants. However,
long-term animal carcinogenicity studies have not been
reported (product insert rev. October 1988).
Historical Manufacturing of STS Injections
Historically, the commercial STS injections were made from a
compound manufactured as a high-grade detergent used to
clean optical surfaces by Niacet (Niagara Falls, N.Y.). The
product is manufactured in an industrial plant and is called
NIAPROOF Anionic Surfactant 4, also known as NAS 4 and
NIAPROOF 4. It is manufactured to have between 26% and
28% by weight STS with 20% by weight maximum of diethylene glycol ethyl ether (carbitol) and 1% to 2% by weight
sodium chloride. During the manufacture, carbitol is added
so that the final product is three parts STS to two parts carbitol.
This 27% parent compound is the same compound provided
to each manufacturer of STS for injection. Each manufacturer
then purifies the active ingredient STS to remove the carbitol.
tory shows that the four major companies that manufacture
STS have different levels of impurities, including carbitol.
Fibro-Vein contains 0.02% w/v of carbitol; Sotradecol produced by Elkins Sinn until 2000 contains 0.6% w/v of carbitol,
and Trombovar contains 2.6% w/v of carbitol. (Analysis performed 4 January 1989, 20 June 1989, and 8 May 1990 by
Butterworth Laboratories Ltd, Great Britain. Leberco Testing,
Roselle Park, N.J., and County of Avon Scientific Services,
Bristol, Great Britain, confirmed these percentages of carbitol
content.) Sotradecol produced by Bioniche Pharma USA since
2007 contains no carbitol or any other impurities (analysis
performed by ChemCon, Freiburg, Germany, 19 Nov 2007.)
What effect the carbitol impurity has on efficacy or toxicity is
unknown.
Carbitol has about the same toxicity as ethylene glycol
when ingested, which has a mean lethal dose in humans of
3 to 4 oz (90–120 mL).
tol was 5.39 mL/kg in both rats and mice. The Ames test was
a
Thromboject product information from Omega, Montreal, Canada
(rev 10/87).
112
The LD50 for intraperitoneal carbi-
Table 7.4 Analysis of sodium tetradecyl sulfate (STS) from four sources
Batch pH STS (%) Carbitol Content (%)
Fibro-Vein 7.5 3.0 0.045
CAP 7.89 2.59 1.79
McGuff 8.01 3.39 4.18
Kronos 7.99 3.21 0.33
From Goldman MP: Dermatol Surg 30:1454, 2004.
very weakly mutagenic for Salmonella typhimurium and Saccharomyces cerevisiae. Carbitol is reported to be teratogenic in
rats and mice.
produce a dermatitis with both immediate and delayed
hypersensitivity.
113
Cutaneous contact with carbitol also can
114,115
Many compounding pharmacies supply STS. Various loopholes in Federal and State regulations allow pharmacies to
compound a variety of medications for use in humans. The
FDA has no regulatory power over this ‘branch’ of the pharmaceutical industry. Although the compounding pharmacy
industry has voluntary standards, no organization exists to test
the quality and accuracy of medications provided by the compounding pharmacies. Our analysis found both a discrepancy
between the stated concentration and the actual concentration
of STS in bottles from all three compounding pharmacies. The
concentration of the sclerosing solution should be matched
to the size and type of vein treated to produce the minimal
sclerosing effect.
116
The reason for the difference in concentration may be
related to the variability of the percentage of the bulk STS
industrial solution. At temperatures below 15°C, the product
fractionates so that the concentration of STS is greater than
27% at the bottom of the drum and below 27% at the top of
the drum. An analysis of this 27% STS solution by the Professional Compounding Centers of America (PCCA; Houston,
Tex) performed in July 2003 found that the 27% STS contained 27.94% of STS. No analysis of the carbitol component
or any other component in the industrial solution was performed. The presence of impurities in any intravenous injection is worrisome (Table 7.4).
Compounding pharmacies manufacture STS from industrial source material. Carbitol is a known contaminant of
industrial STS. If a company is going to use an industrial
chemical to prepare a pharmaceutical injectable product, then
it is duty bound to disclose other chemical compounds present
too. However, by far the most important consideration in our
opinion is that carbitol, like STS, is a high-molecular-weight
organic molecule. The presence of both molecules in an injectable product will increase the risk of unwanted side effects
relating to sensitivity and anaphylaxis. It is not a coincidence
that Fibro-Vein has displayed a very low incidence of such side
effects, but rather that it is due to the very low levels of carbitol
that have been present in Fibro-Vein for the last 25 years. We
find it very difficult to justify the deliberate administration by
intravenous injection of two large-molecule organic compounds when physicians are being led to believe that they are
only injecting the one compound, namely STS. In fact, Alemeida and Raines have compared the therapeutic effect of
compounded STS with Sotradecol and found that compounded STS was less effective in sclerosing varicose veins.
117
Current Manufacturing of STS Injections
In recent years the FDA has made it a requirement that all
active ingredients in pharmaceutical products are manufactured according to current good manufacturing practices
(CGMP). The same ruling came into effect in Europe on 30
October 2005. The legislation means that a pharmaceutical
Table 7.5 Analysis of impurities in Sotradecol* 3%
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Individual
Impurities 1 month 2 months 3 months
7-Ethyl-2-methylundec-3-ene/7Ethyl-2-methylundec-4-ene
Benzaldehyde None detected None detected None detected
7-Ethyl-2-methyl4-undecanol
Single largest
unknown
*Bioniche Pharma Group, Inverin, Co. Galway, Ireland
None detected None detected None detected
None detected None detected None detected
None detected 0.085% None detected
product manufactured and sold in either the United States or
the European Union must have the active ingredient manufactured under CGMP conditions. It is no longer acceptable
to purify and dilute an industrial-grade concentrate.
To our knowledge, only two brands of STS injection are
currently made using an active ingredient manufactured under
the rigorous conditions required by the US and EU pharmaceutical regulations: they are Fibro-Vein and Sotradecol.
Fibro-Vein has the active ingredient manufactured in
Europe using the same process as the original Niacet molecule
but now manufactured in a pharmaceutical plant.
Sotradecol is manufactured by Bioniche Pharma Group in
an FDA-approved facility at Inverin, County Galway, Ireland.
The formulation involves preparation of a solution of the
active ingredient, STS, and the inactive ingredients, benzyl
alcohol, dibasic sodium phosphate, and water for injection.
After sampling, testing, and approval of the sample, the
product is sterile filtered. Aseptic filling occurs in a class 100
clean room with a class 1000 background.
The Bioniche active pharmaceutical ingredient (API) was
tested for the presence of carbitol by gas chromatography
analysis.
a
A carbitol reference standard was sourced from
Sigma Aldrich Inc., St Louis, Mo. USA. The test results revealed
that no carbitol was detected.
Accelerated stability studies of Sotradecol 3% and 1% manufactured by Bioniche were performed at 40°C and analyzed
for impurities. The results for Sotradecol 3% are shown in
Table 7.5.
Pharmaceutical-grade STS is sourced by Bioniche under an
exclusivity agreement from a supplier who holds a Drug
Master File (DMF) for the API. The API is a white to off-white
solid and meets the following specifications for chromatographic purity:
7-Ethyl-2-methyl-undec-3-ene/
NMT 0.15%
7-Ethyl-2-methyl-undec-4-ene
7-Ethyl-2-methyl-4-undecanol NMT 0.10%
Individual unknown NMT 0.10%
Total impurities NMT 1.0%
Assay 96.0% to 100.0%
Forced degradation of the API at 80°C for 2 hours increased
the impurities:
7-Ethyl-2-methyl-4-undecanol 5.0%
7-Ethyl-2-methyl-undec-4-ene 2.1%
7-Ethyl-2-methyl-undec-3-ene 0.4%
a
Analyses were performed at the Bioniche Pharma Group Limited
Quality Control Laboratory, Inverin, County Galway, Ireland.
If a temperature of 80°C was required to distill out carbitol
(which is not the case with the Bioniche product), then there
is an increased likelihood that the above-mentioned impurities would appear. A full discussion on the toxicity of carbitol
is found in Chapter 9.
Polidocanol
Polidocanol, manufactured by Kreussler & Co., GMBH
(Wiesbaden-Biebrich, Germany) and sold under the names of
Aethoxysklerol and Asclera, distributed by Bioform Medical
(San Mateo, Calif. in the US), is composed of a mixture of
hydroxypolyethoxydodecane dissolved in distilled water, to
which 96% ethyl alcohol is added to a concentration of 5%
to ensure emulsification of POL micelles (which provides a
clear solution) and to decrease foaming during the production
process. Thus, 1 mL of POL contains 40.5 mg of ethanol, and
patients taking disulfiram (Antabuse; Wyeth-Ayerst Laboratories, New York, NY) should be warned about a possible
alcohol–disulfiram reaction.
Varying from one country to another, POL is available in
2-ml ampules in concentrations of 0.25%, 0.5%, 1%, 2%, 3%,
and 4%, as well as multiuse 30-ml vials in 0.5% and 1% concentrations. In the US, it is available as 2 mL ampules of 0.5%
and 1.0%. The other ingredients are disodium hydrogen
orthophosphate dihydrate and potassium dihydrogen orthophosphate. Sclerovein (Globopharm, Switzerland) contains
chlorobutanolum as a preservative, 0.5g/100 mL. Its pH varies
from 4.8 to 6.1. The manufacturer has no stability data on
POL when it is diluted with bacteriostatic water or normal
saline, but Sadick and Farber
remains sterile for at least 3 months following dilution. The
sterility is confirmed even when used daily through a multiuse
vial. Manufactured by Craveri (Buenos Aires, Argentina), AET
is diluted in absolute alcohol and is available in 2-ml ampules
of 0.25%, 0.5%, 1%, 1.5%, 2%, 3%, and 4%, as well as in
2-ml syringes at concentrations of 0.25%, 0.5%, and 1%.
POL was synthesized by BASF and introduced in 1936 as a
local and topical anesthetic under the tradename Sch 600.
Unlike the two main groups of local anesthetics – esters (procaine, benzocaine, and tetracaine) and the amides (lidocaine,
prilocaine, mepivacaine, procainamide, and dibucaine) – POL
has a noncyclic chemical structure. The anesthetic effect is not
a direct function of its concentration but is optimum at a
concentration between 3% and 4%.
as a local anesthetic demonstrated the occurrence of obliteration of vessels as a side effect.
Henschel, the former Medical Director of Kreussler Pharma,
first started clinical trials of several concentrations of POL to
treat varicose veins (correspondence from B. Olesch, 1992).
The maximum daily dose recommended by Kreussler Pharma
is found in Table 7.6. Blenkinsopp
maximum daily dosage of 10 mL of a POL 6% solution for
an average person based on toxicity experiments extrapolated
from rats. However, rats are much less sensitive to POL. Since
the LD
in rabbits is approximately 11.7 mg/kg, Blenkin-
50
sopp’s minimum dose may be toxic (Pfahler B, Kreussler:
Personal communication, 29 March 1990).
POL is unique among local anesthetics in its lack of an aromatic ring. As an aliphatic molecule, it is composed of a
hydrophilic chain of polyethylene glycolic ether and a liposoluble radical of dodecylic alcohol. It is used as a topical
anesthetic agent in ointments and lotions for mucous membranes, including hemorrhoidal treatment.
as a local anesthetic for skin irritation, burns, and insect bites
and as an epidural anesthetic.
thetic effect of a 0.4% solution is equal to a 2% solution of
a
Henschel O: Sclerosing of varicose veins sclerotherapy with
Aethoxysklerol-Kreussler (product booklet), Kreussler & Co GmbH,
Wiesbaden-Biebrich, Germany.
118
have determined that it
a
Animal trials on its use
119
recommended a higher
120
It is also used
121–123
The subcutaneous anes-
Clinical Use of Sclerosing Agents
171
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7
Table 7.6 Maximum daily dose of polidocanol (POL)
Dose (mL) According to Body
Concentration
of POL (%)
0.5% 20 24 28 32 36
1.0% 10 12 14 16 18
2.0% 5 6 7 8 9
3.0% 3.3 4 4.6 5.3 6
From Kreussler & Co., GMBH: Product insert for Aethoxysklerol, Wiesbaden-Biebrich,
Germany, 1985.
50 kg 60 kg 70 kg 80 kg 90 kg
Weight of Patient
Figure 7.25
Structural formula of polidocanol.
Mechanism of Action of Sclerotherapy
novocaine.
121
The LD50 in rabbits at 2 hours is 0.2 g/kg, which
is three to six times greater than the LD50 for novocaine.
The LD
(personal correspondence from Kreussler Pharma, 1992) and
1.2 g/kg.
and lidocaine.
in mice has been found to vary between 110 mg/kg
50
121
The systemic toxicity is similar to that of procaine
124
Thus, POL was considered an ideal local anesthetic. However, it soon became apparent that intravascular and
intradermal instillation produced sclerosis of small-diameter
blood vessels and ‘moderate, clinically unimportant reversible
damage to healthy tissue’.
a
Therefore, compound Sch 600 was
considered for use as a sclerosing agent. The polidocanol preparation Aethoxysklerol was registered at the German health
authority, the Bundesgesundheitsamt (BGA), in 1967.
Experimental evaluation of absorption, distribution, metabolism, and excretion of POL has been studied in dogs, rats,
and humans.
within minutes of injection.
123
It is rapidly distributed throughout the body
123
The compound is rapidly
metabolized and eliminated, having a terminal elimination
half-life of 1.4 to 1.7 hours in dogs. After 72 hours, 97% of
the administered compound is excreted (61% in urine, 37%
in feces).
In humans, the elimination half-life is 4 hours, with 89%
of the dose eliminated from the blood within 12 hours.
Amounts excreted in the urine and feces are equal, and almost
80% of the injected compound is excreted via respiration
through a breakdown into low-molecular-weight products.
Polidocanol is completely eliminated from body organs
whether the patient receives one dose or repeated doses.
Therefore, no accumulation takes place, nor does POL cross
the blood–brain barrier.
123
Sixty-four percent of POL is bound
to protein, with a volume of distribution of 24.5 L/hour. The
total clearance is 11.7 L/hour, with renal clearance of 2.01 L/
hour and biliary clearance of 3.08 L/hour.
The capacity of POL to cross the placental barrier was inves-
tigated in rats.
123
Of radioactivity from labeled POL, 15% to
b
87% was recovered from fetal tissue after 13 days. The striking
variations in an earlier differentiation phase may come from
weight differences between fetuses. The fetus of day 19 accumulated less activity per gram of tissue than those of day 13
and showed only 18% to 19% of the maternal blood values.
From the data obtained, the placenta is evidently only a partial
barrier for POL, and its penetration capacity declines on
increasing differentiation of the fetus.
Polidocanol belongs to the class of detergent sclerosing
solutions that are nonionic compounds. It consists of an
apolar hydrophobic part (dodecyl alcohol) and a polar
hydrophilic part (polyethylene-oxide chain) that is esterified
(Fig. 7.25). In solution, POL is associated as macromolecules
through electrostatic hydrogen bonding between the H
a
Henschel O: Sclerosing of varicose veins sclerotherapy with
Aethoxysklerol-Kreussler (product booklet), Kreussler & Co GmbH,
Wiesbaden-Biebrich, Germany.
b
172
Kreussler Pharma: ‘Expert Information on Aethoxysklerol’, July 1993.
123
+
atom
of the OH– group in one molecule, and the free electron-pair
of an oxygen atom of a second molecule. This bonding results
122
in the formation of a network (see Fig. 7.4). The sclerotherapeutic activity results from this double hydrophobic and
hydrophilic action, and thus POL is a ‘detergent’. The optimal
efficacy of the compound coincides with the highest concentration that still permits the existence of nonaggregated molecules, 3%.a However, Kreussler Pharma states that POL 4% is
also optimal and soluble (personal correspondence, 1992).
Telangiectasias are treated with concentrations of 0.25% to
0.75%. A randomized study determined that a 0.5% concentration may be ideal for sclerosis of leg telangiectasias.
cose veins are treated with concentrations of 1% to 4%. Small
vessels and telangiectasias respond well. Efficacy is decreased
in the treatment of large or medium-sized varicose veins.
Kreussler Pharma
b
recommends the use of POL 4% for treatment of varicosities greater than 8 mm in diameter. A 3%
solution is recommended for varicose veins 4 to 8 mm in
diameter, 2% is recommended for varicose veins 2 to 4 mm
in diameter, and 1% for veins 1 to 2 mm in diameter. The
practitioner should take care not to exceed the maximum dose
of POL, which is 2 mg/kg per day.
Advantages
The safety and efficacy of this agent is such that in the 1950s the
Vick Chemical Company developed a derivative of POL, polyoxyethylene dodecanol, as a mucolytic wetting agent for use in
vaporizers.
sensitization to cutaneous application and no toxicity with oral
ingestion or with exposure to steaming electric vaporizers. A
clinical study carried out on 168 infants and children treated
with this compound in vaporizers showed no harmful effects.
Henschelc stated that the selective activity on damaged
endothelium results from the steric structure of POL: ‘The
macromolecules retard the individual molecules and thus
shield the tissue from their uninhibited action.’ This damage
is therefore said to be reversible in normal tissue. Henschel
goes on to claim that since the surface-active-induced absorption on the varix wall is greatest at the point of injection and
falls off rapidly with increasing distance, large quantities can
be injected without danger of damage to the deep venous
system. He recommends the injection of a maximum of 2 mL
of POL 3% at each site, with a maximum of 6 mL of POL 3%
injected in one sclerotherapy session. However, Goldman
et al43 have demonstrated that POL scleroses normal vessels
(rabbit ear vein) and that the concentration injected is critical
to the final outcome of vein sclerosis. Polidocanol is a weaker
a
Dexo SA Pharmaceuticals, France: product description on hydroxy-
polyethoxydodecane. Received with correspondence, May 1985.
b
Product information (July 1993) from Kreussler Pharma, Wiesbaden,
D-65203, Germany.
c
Henschel O: Sclerosing of varicose veins sclerotherapy with
Aethoxysklerol-Kreussler (product booklet), Kreussler & Co GmbH,
Wiesbaden-Biebrich, D-6202, Postfach 9105, Germany.
126
Toxicity studies on rats demonstrated a lack of
125
Vari-
127
detergent-type of sclerosing solution than STS. These experi-
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mental studies indicate that its sclerosing power is approximately 50% of the strength of STS.
Polidocanol is unique among sclerosing agents in that it is
both painless to inject and does not produce cutaneous ulcerations, even with intradermal injection of concentrations less
than 1.0% (see Chapter 8). Allergic reactions rarely have been
reported. The degree of pigmentation produced may be less
than that of other detergent sclerosing agents (see Chapter 8).
An open clinical trial comparing POL with STS and HS
was conducted in Australia by 120 physicians.
128
The results
at 2 years showed that 55 of 65 physicians considered that
POL had a better efficacy than STS, with two claiming decreased
efficacy and eight seeing no difference. When compared with
HS, 49 of 58 claimed better efficacy for POL, with one physician reporting decreased efficacy and eight physicians finding
no difference. Pain on injection with POL was less than with
STS in the experience of 54 of 65 physicians, and was less than
with HS as reported by 56 of 58 physicians. Finally, 58 of 65
physicians considered that, overall, POL caused fewer complications (pigmentation, ulceration, phlebitis, telangiectatic
matting) than STS, and 43 of 58 considered that it caused
fewer complications overall when compared with HS.
A double-blind prospective comparative trial between POL
and STS in 129 patients found no therapeutic difference
between the two agents.
129
Concentrations of POL were twice
that of STS for comparable-sized veins. Adverse effects were
also not statistically different. All patients had an average 70%
improvement with one treatment. An Italian study which did
not mention exact numbers of patients treated or concentrations of solutions also compared POL with STS.
130
This study
found an increase in closure from 66% to 89% in favor of
POL. The adverse reaction of skin inflammation was also
increased with STS compared to with POL. Thus, POL may
have better efficacy than STS as well as fewer adverse effects.
In Japan, a 6-year study of 261 patients treated in 21 centers
found a 70% to 100% efficacy of POL in treating variably sized
leg veins.
131
No subject developed any treatment-related sys-
temic adverse effect.
Sclerosing solution combinations
As mentioned in the introduction and previously in this
chapter, almost any caustic substance can be or has been used
to sclerose blood vessels. Although this chapter has detailed
those commonly used commercially available solutions, it is
by no means complete.
Another method for sclerosing varicose veins is to combine
solutions either together or in a sequential manner. Certainly,
diluting PII with HS or SX increases the potency and localizes
the sclerosing effect to the point of injection. This technique
may be useful when sclerosing junctions between the superficial and deep systems (saphenofemoral-saphenopopliteal
junctions and/or perforating veins).
Stemmer (personal communication, 1993) found that a
mixture of 0.30 mg of sodium salicylate and 1.80 mg of glycerin in 5 mL of distilled water, giving a final concentration of
6% sodium salicylate and 26% glycerin, is an excellent sclerosing solution for telangiectasias of less than 1 mm in diameter.
The author’s limited experience with this solution in humans
confirms Stemmer’s observation. According to the rabbit ear
model, this solution has an equivalent clinical and histologic
effect to undiluted CG 72% (Goldman MP, unpublished
observations, 1994).
Adding 66% glucose as a diluent can modify the viscosity
of POL. This increases the sclerosant endothelium contact
time, which in turn increases the surfactant action of the
detergent. Making the solution thicker lowers the force of
injection and minimizes the diffusion of the sclerosing solution. A mixture of one-third POL 0.5% with one-third glucose
66% and one-third sterile water has been found to decrease
132
thrombosis and telangiectatic matting in the treatment of
telangiectasias.
133
Sequential injections of different
sclerosing solutions
Sequential injections may be useful to enhance the efficacy of
a milder sclerosing solution, either by increasing its potency
or by the act of sequentially damaging endothelium. After
mechanical trauma, endothelial cells are unable to generate
various substances or to respond to circulating or locally
produced substances.
134
In this damaged state, further injury
may produce irreparable damage. In addition, combining a
solution with another may produce an additive effect on its
potency.
Sodium tetradecyl sulfate 3% is currently the strongest sclerosant approved by the FDA. When treatment with this alone
may prove ineffective, such as in patients with a large varicose
vein or an area of high reflux, sequential use of HS produces
a stronger, synergistic effect. This technique has been reported
recently using ultrasound guidance to sclerose the SFJ.
135
Oneyear follow-up of 66 patients treated with STS 3% alone under
ultrasound guidance at the SFJ demonstrated a recanalization
rate of 25%. When a second group of 70 patients with similar
pathology were treated with STS 3% immediately followed by
HS 23.4%, only 12% demonstrated recanalization at 1-year
follow-up. Thus, the sclerosing effect was enhanced. A second
report of the identical technique performed on 100 patients
reported that a ‘small number’ of treatment failures have
occurred.
1- to 2-year follow-up in a response to a ‘letter to the editor’,
136
Unfortunately, when the author reported on the
137
he noted that gradual recanalization was the rule on duplex
evaluation, even though the clinical outcome was good.
Volumes, concentrations, and progressive
dilution of sclerosing agents
A sclerosing reaction is induced by the contact of a sufficiently
concentrated agent with the venous wall for a sufficient period
of time. This adequate/effective concentration remains theoretical and ranges between a too strong, ‘aggressive’ concentration (responsible for transparietal burn and adverse reactions)
and a too low, ineffective concentration (not inducing a sclerosing reaction). Contact should be even and homogeneous
along the whole length of the vein being treated, and around
the complete circumference of the vein. However, injection of
liquid in a vein which is full of blood leads to some dilution,
and in situ adequate concentrations are difficult to obtain. In
veins smaller than 3 mm, a laminar flow of sclerosing agent
replaces blood in the vein and no dilution occurs, but in
bigger veins, a turbulence occurs and is responsible for dilution of the sclerosant.
The following is a method to compute theoretically how
much sclerosing agent is necessary to fill up a vein. The inner
V = L × S, therefore:
L = V/π(D/2)
0.5 cm3 represents a length of approximately
3 mm in a 14 mm Var. Vein
10 mm 8 mm Var. Vein
25 mm 5 mm Var. Vein
160 mm 2 mm Retic. Vein
630 mm 1 mm Telangiect.
Figure 7.26 Volume and injected length.
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Clinical Use of Sclerosing Agents
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