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Chapter
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7
Table 7.7 Volume in cm3 of a vein segment according to venous diameter and venous length
Length (cm)
Vein Diameter (cm)
1.00 3.93 7.85 11.78 15.71 19.63 23.56
0.90 3.18 6.36 9.54 12.72 15.90 19.08
0.80 2.51 5.03 7.54 10.05 12.57 15.08
0.70 1.92 3.85 5.77 7.70 9.62 11.55
0.60 1.41 2.83 4.24 5.65 7.07 8.48
0.50 0.98 1.96 2.95 3.93 4.91 5.89
0.40 0.63 1.26 1.88 2.51 3.14 3.77
Mechanism of Action of Sclerotherapy
From Guex J-J: Semin Vasc Surg 18:25, 2005.
cm
Diameter Length
1.4
0.8
0.5
0.2
0.1
0.32
1.00
2.55
15.92
63.69
5.00 10.00 15.00 20.00 25.00 30.00
Figure 7.27
Figure 7.28 How much to inject? (theoretical)
Proportional representation of a 0.5 cm3 injection volume.
Diameter cm Length cm
1.2
1
0.8
0.5
1.2
1
0.8
0.5
1.2
1
0.8
0.5
30
30
30
30
25
25
25
25
15
15
15
15
Volume ml cm
3
33.9
23.9
15.1
5.9
28.3
19.6
12.6
4.9
17.0
11.8
7.5
2.9
volume V of a vein segment is: V = L × π × (D/2)
the length, and D the inner diameter. It is very simple to calculate that – for example – a length of 10 cm of a vein of
0.7 cm inner diameter has an inner volume of 3.85 cm3.
Other examples are computed in Table 7.7 (Fig. 7.26). It is
interesting to note that since volumes are proportional to the
square of the radius, it is possible to inject a very long vein of
small diameter with a small volume of liquid. Figure 7.27
emphasizes the fact that the injection of 0.5 cm3 has very different diffusions in veins of different diameters. This leads us
to understand that when deciding the injected volume, the
most important reference is the venous diameter (Fig. 7.28).
174
Diameter is
more
important
than length!
2
, where L is
Parietal
damage
Transparietal burn latrogenic reaction
Sclerosis Therapeutic efficacy
Absence of lesion No therapeutic effect
0
Figure 7.29 Effects of concentration.
Concentration of sclerosant in contact with endothelium
For all these reasons, we presented a theoretical model that
is useful for predicting subsequent sclerosing reactions from
a given dilution (Fig. 7.29).
138
The concentration of sclerosing
agent decreases progressively when drifting away from the
point of injection (Fig. 7.30A). Practically, when the liquid
sclerosing agent is injected at a single point, the injected concentration is usually too high (in order to obtain a sufficiently
long sclerosed zone, despite some dilution), and can induce
side effects. To some extent, the problem can be addressed by
injecting a greater volume of a milder solution (Fig. 7.30B) or
by injecting small volumes in multiple points close to each
other (Fig. 7.30C). If a venous spasm occurs, or if some means
allows a reduction in the vein diameter, the laminar flow will
Ci
https://t.me/med1917
One injection site,
high concentration,
low volume.
Cs
0
Injection site
Ci = concentration in the vein
Cs = concentration in the syringe
X = length of vein segment
Aggressive concentration
Effective concentration
Ineffective concentration
Sclerosis
Varicose vein
Ci
One injection site,
low concentration,
high volume.
Aggressive concentration
Cs
Injection site
x
0
Effective concentration
Ineffective concentration
Sclerosis
x
Varicose vein
A
Ci
Three injection sites,
low concentration,
low volume (per site).
Cs
Injection site
0
C
Ci
One injection site
of foam
s
Inflammatory reaction
Injection site
Sclerosis
Injection site
Aggressive concentration
Effective concentration
Ineffective concentration
Injection site
Aggressive concentration
Effective concentration
Ineffective concentration
B
Ci
Three injection sites,
low concentration,
low volume (per site)
venous spasm
Cs
Injection site
x
0
D
Injection site Injection site
Aggressive concentration
Effective concentration
Ineffective concentration
x
Sclerosis
Clinical Use of Sclerosing Agents
0
E
Figure 7.30 A–E, Theoretical modeling of dilution of sclerosing agents in several conditions.
further improve the phenomenon (Fig. 7.30D). The ultimate
evolution of this thinking is the use of foam, as described
below.
Foam sclerosants (foamed sclerosing
agents, sclerofoam)
The first foam sclerosants were described 60 years ago, and
Wollmann
really invented the technique. However, it remains obvious
that two authors – Cabrera in Spain
France
The first advantage of foam is that it does not mix much
with blood, and, therefore, little dilution occurs in the body.
Provided the diameter is not too large, the foam ‘pushes’ the
blood like liquid does, ensuring an even effect on the endothe-
139
has demonstrated well that it is hard to tell who
141
– have boosted its use in the past 15 years.
Sclerosis
Varicose vein
140
x
and Monfreux in
lium (Fig. 7.30E). However, when diameters are too high, the
foam floats and only the upper wall is in contact. In these
cases, additional maneuvers should be undertaken in order to
ensure a full contact (alternative massages, compression, elevation, creation of spasm).
Dilution of foam occurs anyway through two distinct
phenomena: dilution of the sclerosing agent bound to the
microbubbles – leaving plain gas bubbles – and dispersion
of microbubbles after coalescence into larger bubbles.
Many different types of foam have been used and presented, using different sclerosing agents (only detergent solutions like STS, POL and morrhuate can foam), different gases
(room air, sterile air, CO
, O2, CO2 + O2, N2O), different gas/
2
liquid ratios, different preparation tools, etc. At present,
two techniques are predominant: the Provensis, which has
been manufactured and standardized, and the double-syringe
175
Chapter
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7
Mechanism of Action of Sclerotherapy
Figure 7.31 Turbofoam. (Courtesy i2m-labs, Caen, France.)
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been mechanized by use of an automated device: Turbofoam
(Kreussler France, Paris) (Fig. 7.31).
Foam sclerosants also offer the advantage of being an excellent contrast medium for B-mode echography since ultrasounds are scattered by the multiple air/liquid interfaces and
foam is recognized by its white cloud aspect and dark shade
cone. Thanks to this property, control of diffusion within the
desired vein is simple and accurate.
142
In veins smaller than
3 mm, theoretical advantages of foam sclerosants are less
obvious, since experiments have demonstrated that a laminar
flow ensures replacement of blood by injected liquid sclerosants. The increased sclerosing power must be taken into
account with care, and adverse reactions caused by transparietal burn are common. Chapter 9 details the use and Chapter
8 describes side effects related to the use of foam for the treatment of varicose, spider, and reticular veins.
A complete discussion on the use of foam in sclerotherapy
treatment of varicose veins is found in Chapter 9.
176
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sulfate for sclerotherapy treatment of
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solution safe? Dermatol Surg
2004;30:1454.
117. Almeida JI, Raines JK. FDA-approved
sodium tetradecyl sulfate (STS) versus
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118. Sadick NS, Farber B. A microbiologic
study of diluted sclerotherapy
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1993;19:450.
119. Blenkinsopp WK. Choice of
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120. Schulz KH. Uber die verwendung von
alkyl-polathylenoxyd-derivaten als
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121. Soehring K, et al. Beitrage zur
pharmakologie der
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subchronische Toxizitat bein
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122. Siems KJ, Soehring K. Die ausschaltug
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Meerschweinchen.
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123. Olesch B. Neuere Erkenntisse zur
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124. Soehring K, Frahm M. Studies on the
pharmacology of alkylpolyethyleneoxide
derivatives. Arzneimittelforschung
1955;5:655.
125. Carlin MC, Ratz JL. Treatment of
telangiectasia: comparison of
sclerosing agents. J Dermatol Surg
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126. Grubb TC, Dick LC, Oser M. Studies
on the toxicity of polyoxyethylene
dodecanol. Toxicol Appl Pharmacol
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127. Larkin V De P. Polyethylene
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128. Conrad P, Malouf GM. The Australian
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129. Goldman MP. Treatment of varicose
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130. Belcaro G, Cesarone MR, Dugal M,
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131. Satokawa H, Hoshino S, Sakaguchi S,
Yamada C. The Japanese polidocanol
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ultrasound and evaluation of
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December 11, 1991.
133. Zuccarelli F. Combination of
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134. Vanhoutte PM. The endotheliummodulator of vascular smooth-muscle
tone. N Engl J Med 1988;319:512.
135. Mauriello J, Zygmunt J Jr: Synergistic
effect of sclerosing agents. Presented
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136. Miller D, Biegeleisen K. Sequential
injection of 3% sodium tetradecyl
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Dermatol Surg 1994;20:329.
137. Biegeleisen K. Response to sequential
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sulfate and 20% sodium chloride in
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138. Guex J-J. Indications for the sclerosing
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139. Wollmann JC. The history of
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8
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C H A P T E R
Complications and Adverse
Sequelae of Sclerotherapy
When analyzing side effects and complications of sclerotherapy treatment, one should remember that sclerosing agents
are not drugs that are injected in veins to cure them, but to
obliterate them. In terms of safety of use and results, sclerosing
agents are more comparable to a surgical tool than to an
intravenous drug. However, their toxicity, and allergenicity
must be known. Bad results from using these methods
are usually the consequences of an inappropriate use or
indication.
As with any therapeutic technique, sclerotherapy is associated with a number of potential adverse sequelae and complications. Fairly common, and often self-limiting, side effects
include cutaneous pigmentation, edema of the injected
extremity, a flare of new telangiectasia, pain with injection,
localized urticaria overlying injected sites, blisters or folliculitis caused by postsclerosis compression, and recurrence of
previously treated vessels. Relatively rare complications
include localized cutaneous necrosis, nerve damage, systemic
allergic reactions, thrombophlebitis of the injected vessel,
arterial injection with resultant distal necrosis, and deep vein
thrombosis (DVT). The latter may result in chronic venous
insufficiency or pulmonary emboli. This chapter addresses the
pathophysiology of these reactions, methods for decreasing
their incidence, and treatment methodology should they
occur.
Adverse Sequelae
Postsclerotherapy hyperpigmentation
The reported incidence of hyperpigmentation is variable and
depends on many factors, including sclerosing solution type
and concentration, and treatment technique, as well as how
‘pigmentation’ is defined. We believe that the definition of
post-treatment related pigmentation should be ‘any brownblack staining of the skin occurring after sclerotherapy’, with
a subcategory of persistent pigmentation further delineated by
those patients whose brown staining is still present after 1
year. As discussed later, it is our hypothesis that pigmentation
develops due to the extravasation of red blood cells (RBCs)
through damaged vessels with consequential inflammation
contributing to ineffective digestion of hemosiderin. This
results in a hemosiderin tattoo.
Pigmentation is usually temporary. Physicians report a 1%
to 2% incidence of pigmentation persisting after 1 year.
Pigmentation is usually linear along the course of the treated
blood vessel. We use the term ghost of the blood vessel to explain
to patients that it represents a resolving and not functioning
vessel. However, in addition to linear lines of pigmentation,
osmotic sclerosing solutions may produce punctate pigmentation at points of injection, which may be related to their
mechanism of action through an osmotic gradient that pro-
1,2
duces maximal osmolality and resultant endothelial destruction at the injection site. In contrast, detergent-type sclerosing
solutions destroy the treated vessel for a few centimeters along
its length, producing a more linear golden brown color (Figs
8.1 and 8.2). Cutaneous pigmentation is to some degree a rela-
tively common occurrence after sclerotherapy with any sclerosing solution.
3
It has been reported in 11% to 80%
patients treated with sodium tetradecyl sulfate (STS). One
study found that a 0.1% concentration of STS resulted in
pigmentation in 11% of patients. The incidence of pigmentation with hypertonic saline (HS) has been reported to range
from 10% to 30%.
have a reported incidence of pigmentation from 6.7%
8,13,14
31%.
treated with POL, ethanolamine oleate, or iodine-iodide solution.
incidence of 15.7% with Sclerodex (dextrose with sodium
chloride),
iodide).
A 35% incidence has been reported in 7200 patients
15
Post-sclerotherapy hyperpigmentation has a reported
12
12
A 2% incidence of hyperpigmentation was reported
from one series of patients treated with POL, chromated
glycerin (CG), and sodium salicylate.
was reported from another series of 102 patients treated
with either STS, POL, or CG.
6–10
Patients treated with polidocanol (POL)
and 32% with Sclerodine (iodine and sodium
1
A 2%–4% incidence
16
Between 2003 and 2008, 1187 of our patients underwent
sclerotherapy treatment. Of this group, 351 had been treated
with foam or liquid STS and were available for follow-up.
Thirty-five percent of these patients experienced hyperpigmentation following sclerotherapy. However, hyperpigmentation
was graded as minimal to mild. Furthermore, no hyperpigmentation was evident in any patient 1 year after treatment.
Of note, the ‘hyperpigmentation’ reported by many patients
was actually a post-treatment coagulum.
17
Etiologic factors
The cause of this pigmentation most likely results from a
combination of both postinflammatory hyperpigmentation
(incontinence of melanin pigment) and hemosiderin
deposition.
strated that this pigmentation is caused only by hemosiderin
staining of the dermis, irrespective of the type of sclerosing
solution used, pigmentation of the patient, or length of time
after injection (Fig. 8.3, Table 8.1).
and/or transport mechanisms have also been found in a significant number of patients who have developed pigmentation after sclerotherapy.
Hemosiderin deposition occurs predominantly in the
superficial dermis, although it may be present in periadnexal
and mid-dermal locations, particularly near the ankle. This
phenomenon probably occurs when RBCs extravasate into the
dermis after the rupture of treated vessels.
pedesis also may occur after inflammation of the vessel and
is commonly seen after thrombophlebitis. Perivascular inflammation is presumed to promote degranulation of perivascular
18–20
However, histologic examination has demon-
21–24
Defects in iron storage
25
26
Erythrocyte dia-
4–6
11,12
of
to
Rights were not granted to include this figure
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in electronic media.
Please refer to the printed publication.
Adverse Sequelae
A C
Figure 8.1 Linear pigmentation along the course of a treated blood vessel. A, Before treatment. B, Eight weeks after treatment with Polidocanol 0.5%.
C, Punctate pigmentation 8 weeks after treatment with Sclerodex.
In Bergan JJ, Goldman MP, editors: Varicose veins: diagnosis and treatment, St Louis, 1993, Quality Medical Publishing.)
Figure 8.2 Linear pigmentation, no compression, 6 weeks after 0.25%
sodium tetradecyl sulfate liquid sclerotherapy.
B
(C from Goldman MP: Adverse sequelae of sclerotherapy treatment of varicose and telangiectatic leg veins.
Table 8.1 Postsclerotherapy hyperpigmentation: treatment
characteristics
Patient’s
Agent
POL 0.25% White 6 weeks Heme
POL 0.75% White 6 weeks Heme
POL 0.75% Hispanic 6 months Heme
POL 0.75% White 2 months Heme
SM ? White 7 years Heme
HS 18% White 8 months Heme
HS 20% White 2 months Heme
STS 0.5% White 5 months Heme
STS 0.25% Hispanic 3 months Heme
POL, Polidocanol; SM, sodium morrhuate; HS, hypertonic saline; STS, sodium
tetradecyl sulfate; Heme, hemosiderin.
Race
Time of Biopsy (Period
after Injection Result
mast cells. Released histamine leads to endothelial cell contraction, which results in widening of endothelial gaps through
which extravasation of RBCs can occur.
sclerosing solution dilates the vessel both directly through
pressure generated by the syringe and indirectly through
histamine-induced endothelial cell contraction.
Perivascular phagocytosis of RBCs occurs either by intact
cells or piecemeal after fragmentation by macrophages.
The intracellular fragments in the macrophage cytoplasm are
further compartmentalized into hemoglobin-containing globules. They are referred to as secondary lysosomes. Since hemosiderin is an indigestible residue of hemoglobin degradation,
it may appear as aggregates up to 100 µm in diameter.34
Hemosiderin has a variable concentration of these aggregates.
Iron concentrations vary from 24% to 36%.
contained in hemosiderin occurs in different forms, with differing amounts of ferritin.
27–31
Thus, injecting a
35
Iron hydroxide
36
On unstained tissue it appears
golden and is 30% iron by weight. Its elimination from the
area through phagocytosis may take years, if it ever occurs.
In addition to being insoluble, hemosiderin may directly
affect cellular function. Histologic examination with X-ray
fluorescence analysis of patients with varicose ulceration disclosed an elevation of mean iron levels in periulcerated skin.
32,33
The authors speculate that free radical formation resulting
from local iron accumulation may cause melanocytic stimulation, thereby augmenting brown pigmentation. Indeed,
multiple authors have demonstrated melanin incontinence in
the presence of venous stasis, complicated by extravascular
38–40
RBCs.
Whether melanocytic stimulation plays a role in
the early appearance of postsclerotherapy pigmentation is
unlikely, but it may contribute to the persistence of pigmentation in certain patients, especially in Fitzpatrick skin types V
and VI.
37
181
Chapter
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8
Complications and Adverse Sequelae of Sclerotherapy
C D
Figure 8.3 Section stained with hematoxylin–eosin taken 6 months after injection with polidocanol 0.75%. Note scattered foci of golden brown pigment.
A, Original magnification ×50. B, Perls-stained section from the same patient as in Figure 8.1. Note scattered foci of green-blue granules within siderophages.
Original magnification ×200. C, Original magnification ×350. D, Original magnification ×3200.
1987.)
A
Regardless of its cause, the incidence of pigmentation is
apparently related to multiple factors, including: (1) sclerosing solution type and concentration; (2) sclerotherapy technique; (3) gravitational and other intravascular pressures; (4)
innate tendency toward cutaneous pigmentation (total body
iron stores and/or altered iron transport and storage mechanisms, innate enhanced histamine release or hypersensitivity,
and vessel fragility); (5) postsclerotherapy treatment (graduated compression); (6) susceptibility to post-inflammatory
hyperpigmentation; (7) vessel diameter; and (8) concomitant
medication.
Solution Type and Concentration
The type and concentration of the sclerosing solution affect
the degree of endothelial destruction. The extent of endothelial destruction with resulting inflammation and extravasation
of RBCs is thought to influence the development of postsclerotherapy hyperpigmentation. The increased incidence of pigmentation with certain concentrations of STS and HS, which
produce a greater reaction than POL, confirms this hypothe-
4,41–43
sis.
used to treat telangiectasias (1%), the pigmentation rate is
even higher than with 20% HS.
that sclerosing solutions reported to have the lowest incidence
182
In fact, when excessive concentrations of POL are
44
It is therefore not surprising
B
(From Goldman MP, Kaplan RP, Duffy DM: J Dermatol Surg Oncol 13:547,
of postsclerotherapy pigmentation – CG,
alone,
50
and sodium salicylate
1,20
– also produce minimal
1,41,45–49
inflammation.
A higher concentration of the same sclerosing solution
produces increased inflammation.
51
Thus, the inflammatory
response after treatment should be kept to a minimum, and
sclerosing solutions and concentrations should be altered for
each treatment session so that the minimal effective sclerosant
concentration is used.
Foam sclerosants are stronger than liquids for an identical
concentration. Therefore, when foam is used, special attention
should be directed towards reducing the strength or concentration of the agent. This is especially true for treatment of
reticular and spider veins.
52
Recently published analyses of
large numbers of patients treated with foam sclerotherapy
estimate the incidence of post-inflammatory hyperpigmentation to be between 10% and 30%.
53–55
Furthermore, Alos et al
noted that – although the overall incidence of pain with sclerotherapy using 0.5% POL is rare – foam is more often associated with pain than is liquid.
56
Technique
Optimal technique consists of limiting pressure into damaged
(sclerosed) veins to prevent extravasation of RBCs. To limit
glycerin
Pressure Diameter Applied force
https://t.me/med1917
> 300 mmHg
5 mm
250 gF
Insulin syringe (1 ml) cm
180 mmHg
Figure 8.4 Pressure and syringe. Small syringes increase the risk of
extravasation and necrosis (micro arteriovenous fistulas, backflow
injections).
2.5 ml
8 mm
syringe syringe
3
)
250 gF
the degree of intravascular pressure, larger feeding varices,
incompetent varices, and points of high pressure reflux should
be treated first. A greater incidence of pigmentation occurs if
vessels distal to the saphenofemoral junction (SFJ) are treated
before successful closure of the junction, with a decreased
incidence of pigmentation when treatment is from proximal
to distal.
57
The degree of injection pressure is also important. Because
telangiectasias and small venules are composed essentially of
endothelial cells with a thin (if any) muscular coat and basement membrane, excessive intravascular pressure from injection may cause vessel rupture. In addition, endothelial pores
and spaces between cells in the vascular wall dilate in response
to pressure, leading to extravasation of RBCs. It is therefore
important to inject intravascularly with minimal pressure.
Since injection pressure is inversely proportional to the square
of the piston radius, a syringe with a larger radius causes less
pressure and theoretically may reduce risks of pigmentation.
The average piston radius is 8 mm for a 2-mL syringe
and 5 mm for a 1-mL syringe. The calculated pressure with
an implied force of 250 g is 180 mmHg for a 2-mL syringe
and more than 300 mmHg for a 1-mL syringe.58 This is one
reason we recommend using a 3-mL syringe for sclerotherapy
(Fig. 8.4).
Gravitational and Other Intravascular Pressures
Postsclerotherapy pigmentation appears most commonly in
vessels treated below the knee
the leg, probably as a result of a combination of increased
capillary fragility and increased intravascular pressure by
gravitational effects in this location. Pigmentation has been
observed once in our practice after sclerotherapy treatment of
hand veins (Fig. 8.5)
. Duffy et al59 note that pigmentation did
not develop after treating 100 patients with dilated hand veins
with either 0.5% STS, 1.5% POL, or 3% POL.
20
but can occur anywhere on
Vessel Diameter
It is commonly observed that telangiectasias that have the
maximal incidence of pigmentation are between 0.6 and
1.2 mm in diameter. This could be related to an increased
incidence of microthrombi in these vessels. Chatard20 also has
observed an increased incidence of pigmentation in the treatment of blue venulectases as opposed to the treatment of red
telangiectasias. The reason behind this latter observation
is unknown but may be related to vessel diameter, since
blue telangiectasias are usually of larger diameter than red
telangiectasias. An evaluation of 113 patients treated with
sclerotherapy demonstrated pigmentation only rarely in
vessels less than 1 mm in diameter.
60
A
B
Figure 8.5 A, Appearance of dorsal hand veins, upper 2 weeks after
treatment with 1 mL of sodium tetradecyl sulfate 0.5% foam mixed 1 : 4 with
room air. Note total resolution of the vein as compared with the untreated
hand veins below and development of minor coagula in the treated dorsal
hand vein. B, 6 months post treatment there is pigmentation on the dorsal
distal arm from the sclerosing effect of the proximal dorsal hand vein.
Predisposition to Pigmentation
Certain individuals appear to be predisposed to the development of pigmentation through a variety of genetic mechanisms. Pigmentation has been reported as more common and
pronounced in patients with dark hair and ‘dark-toned’ skin.
This may be caused by an increased incidence of postinflammatory hyperpigmentation in patients with these colorings
However, Chatard
20
reported that pigmentation is unrelated
to skin or hair color. We are not aware of the number of Type
V and Type VI patients Chartard has treated, but in our experience (RAW, MPG) it is clear that patients with darker skin
coloring and Asians do have an increased incidence of postsclerotherapy pigmentation.
Pigmentation resolves from a gradual resorption of ferritin
particles from macrophage digestion. It is hypothesized that
the patient’s iron storage and transport mechanisms may
influence the rate of clearance of dermal hemosiderin.
preliminary study of 16 patients with age-matched controls
disclosed that pigmentation developed in patients who had
18
55
A
Adverse Sequelae
183
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