An Investigation into the Influence of Various Gases and
Concentrations of Sclerosants on Foam Stability
JENNIFER D. PETERSON, MD,
AND
MITCHEL P. GOLDMAN, MD
BACKGROUND Foam sclerotherapy is an increasingly popular modality in varicose vein treatment. Our
previous work showed that the half-life of room air foam varied according to the percentage and type of
sclerosant solution.
MATERIALS AND METHODS A plastic connector was used to create foam made from a combination of
0.25%, 0.50%, and 1% sodium tetradecyl sulfate (STS) and room air, carbon dioxide (CO 2), oxygen (O2),
or a mixture of CO2 and O2. To measure foam stability, the foam half-life was defined as the time it took
for half the original volume of sclerosing solution to settle.
RESULTS Half-life varied according to sclerosant concentration when room air, O2, or a mixture of CO2
and O2 was used for foam creation but not when CO 2 was used. Room air foam is more than 3 times as
stable as CO2 foam and 1.5 times as stable as a mixture of CO 2 and O2.
CONCLUSIONS CO2 foam half-life did not vary according to sclerosant solution concentration, though
room air, O 2, and CO2/O 2 did. The half-life of room air foam is more than 3 times as long as that of CO2
and 1.5 times as long as that of a mixture of CO 2 and O2. Foam half-life for room air and O2 are similar at
low concentrations of STS but differ at higher concentrations.
Portable Medical Devices, Inc., North Fort Myers, Florida, provided CO2 mmander for testing.
I
nitially, sclerotherapy was performed using solutions (liquids) to promote sclerosis of the vein wall
through a controlled phlebitic reaction. In the past
few decades, foam sclerotherapy, created from mixing room air with the sclerosant solution, has
become increasingly popular. Foam sclerotherapy
has the advantage of higher efficacy rates because
of longer contact time between the sclerosant and
the vein wall. There are no statistically different
rates of adverse events between foam and liquid
sclerotherapy. Foam-specific side effects occur
at distant sites, are rare, and include cough,
chest tightness, dizziness, and visual disturbances.1
Although the majority of phlebologists use room air
for foam preparation, carbon dioxide (CO2)2 or a
70% CO2/30% oxygen (O2) mixture can also be
employed.3 Our previous work showed that the halflife of room air foam varied according to the
concentration of sclerosant solution.4 We sought to
investigate whether the half-lives of foams made
with CO2, O2, and CO2/O2 varied according to the
concentration of sclerosant solution and to compare
the half-lives of foam made from room air, CO2,
O2, and CO2/O2.
Methods
Foam half-life was measured using a BD Safety
Lok 3-mL syringe, a BD 5-mL syringe (Becton,
Dickinson and Company, Franklin Lakes, NJ), and a
B. Braun Adapter W/W connector (Melsungen,
Germany). Room air, composed of 78% nitrogen,
21% O2, and 1% of trace gases (CO2, argon, neon,
methane, helium, krypton, hydrogen, and xenon),
was used as a control. Medical grade CO2 and a
nonmedical grade 77% CO2/23% O2 mixture, were
obtained using a CO2mmander portable medicalgrade CO2 delivery system (Portable Medical
Devices, Inc., North Fort Myers, FL). Medical
grade O2 was obtained from an O2 cylinder
tank (Western Medica, Westlake, OH). Sodium
Dermatology Cosmetic Laser Associates of La Jolla, La Jolla, California
& 2010 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2011;37:12–18 DOI: 10.1111/j.1524-4725.2010.01832.x
12
PETERSON AND GOLDMAN
tetradecyl sulfate (STS; Sotradecol, Bioniche
Pharma, Belleville, ON, Canada) was selected
because it is the only sclerosant that the Food and
Drug Administration has approved for sclerotherapy.
New sterile syringes and connectors were used
for each trial so that decreasing silicone content
in the syringe would not occur with subsequent
trials.
Foam Creation with Room Air
The following standardized technique was employed
throughout the study to create foam and determine
exact foam half-lives. A sterile 3-mL syringe was
used to draw up 1.0 mL of 0.25%, 0.5%, or 1% STS
sclerosant and was connected to the end of a B.
Braun Adapter W/W connector. Next, the syringe
plunger was advanced forward until all air had been
displaced from the syringe and adapter (Figure 1).
A sterile 5-mL syringe with 4 mL of predrawn air
was attached to the other end of the connector.
Using the double-syringe system (DSS) technique,
the 5-mL syringe was pushed to empty the 4 mL
of air as much as possible through the connector to
the 3-mL syringe with the sclerosant. This action
was counted as one pump. Immediately thereafter,
the room air–sclerosant mixture in the 3-mL syringe
was emptied through the connector to the 5-mL
syringe. This action was counted as two pumps. The
to-and-fro cycle was repeated for a total of 10
pumps. At completion of the 10 pumps, a homogeneous white foam was created (Figure 2) and filled
the 5-mL syringe.
Figure 1. Syringe plunger advanced forward until all air was
displaced from the syringe and adapter.
the other end of the B. Braun Adapter W/W
connector. Using the DSS technique, a homogeneous
white foam was created using the same technique
as above.
Foam Creation with CO2
A sterile 3-mL syringe was used to draw up
1.0 mL of 0.25%, 0.5%, or 1% STS sclerosant
and was connected to the end of a B. Braun Adapter
W/W connector. Next, the syringe plunger was
advanced forward until all air had been displaced
from the syringe and adapter. A sterile 5-mL syringe
was connected to the CO2mmander system, and
4 mL of CO2 was withdrawn under 10 pounds/inch2
(Figure 3). This syringe was then connected to
Figure 2. At completion of the 10 pumps, homogenous white
foam was created.
3 7 : 1 : J A N U A RY 2 0 1 1
13
F O A M S TA B I L I T Y W I T H G A S E S
white foam was created using the same technique as
above.
Measuring Foam Stability
Figure 3. Sterile 5-mL syringe connected to the CO2mmander
connector.
Foam Creation with O2
For the sake of completeness, the effect of O2 on
foam stability was also investigated. A sterile 3-mL
syringe was used to draw up 1.0 mL of 0.25%,
0.5%, or 1% STS sclerosant and was connected to
the end of a B. Braun Adapter W/W connector. Next,
the syringe plunger was advanced forward until all
air had been displaced from the syringe and adapter.
A sterile 5-mL syringe was connected to the O2 tank
and 4 mL of O2 was withdrawn. This syringe was
then connected to the other end of the B. Braun
Adapter W/W connector. Using the DSS technique, a
homogeneous white foam was created using the
same technique as above.
The foam-filled 5-mL syringe was placed exactly
vertical to the rubber stopcock of the 5-ml syringe on
the bottom. The timer was started. Over the course
of time, as the foam degenerated back into its
constituents, the sclerosing solution was found to
gradually re-form at the bottom of the syringe. When
the bottom of the solution’s meniscus attained a
volume of exactly 0.5 mL (half of the original
sclerosing volume of 1.0 mL), as measured according
to the graduations on the side of the syringe, the
timer was stopped, and the time was recorded in
seconds (Figure 4). Three sets of recordings were
obtained and were averaged for each concentration
Foam Creation with 77% CO2/23% O2 Mixture
A sterile 3-mL syringe was used to draw up 1.0 mL
of 0.25%, 0.5%, or 1% STS sclerosant and was
connected to the end of a B. Braun Adapter W/W
connector. Next, the syringe plunger was advanced
forward until all air had been displaced from the
syringe and adapter. A sterile 5-mL syringe was
connected to the CO2mmander system, and 4 mL of
CO2/O2 was withdrawn under 10 pounds/inch2
(Figure 3). This syringe was then connected to
the other end of the B. Braun Adapter W/W
connector. Using the DSS technique, a homogeneous
14
D E R M AT O L O G I C S U R G E RY
Figure 4. Foam half-life measurement occurred as the bottom of the solution’s meniscus attained a volume of 0.5 mL
(half of the original sclerosing volume of 1.0 mL).
PETERSON AND GOLDMAN
of STS sclerosant used. All recordings were performed at an ambient room temperature of 201C.
Discussion
Results
The results are summarized in Table 1. The mean
time for foam stability using room air was 85.7, 89,
and 90.7 seconds with 0.25%, 0.5%, and 1% STS,
respectively. The mean time for foam stability using
CO2 was 25.3, 25.7, and 28.3 seconds; using O2 was
85.7, 79, and 73 seconds; and using a mixture of
CO2 and O2 was 54.3, 58, and 49.7 seconds, at
0.25%, 0.5%, and 1% STS, respectively.
After three sets of recordings for each STS concentration in the four arms of the study, it was found that
the foam half-life was 3 times as great with room air
as with CO2 group and 1.5 times as great with room
air as with the mixture of CO2 and O2. There were no
differences in room air and O2 foam half-lives with
0.25% STS, but differences were seen at 0.5% and
1% STS. Although there was a significant increase in
room air foam stability, with increasing concentrations
of STS, this relationship did not occur with the CO2 or
CO2/O2 foam. O2 foam half-life decreased with increasing concentrations of STS.
Foam sclerotherapy is more efficacious in sclerotherapy because of longer contact time of the
sclerosant with the endothelial cells. The majority of
phlebologists use readily available room air for foam
creation in sclerotherapy, although CO22 and physiologic mixtures of 70% CO2/30% O23 are becoming increasingly popular. Foam bubbles produced via
turbulent flow using the Tessari technique and the
double syringe system are smaller than the bubbles
produced using the Monfreux technique. This
smaller bubble size is associated with greater surface
area of sclerosant, so a greater amount of sclerosant
can be delivered to the endothelial cells.5 Bubble size
is inversely related to the difference in density between a liquid and gas, as represented in the below
equation.6
1
6dos 3
dp ¼
Drg
dp is bubble diameter, do is orifice diameter, s is
surface tension, and Dr is the difference in density
between a liquid and gas. CO2 and O2 are 1.5 times
and 1.14 times as dense, respectively, as room air.
Therefore foam bubbles prepared from CO2, O2, or
TABLE 1. Foam Stability with Gases
Seconds
Percentage of Sodium
Tetradecyl Sulfate
0.25
First recording
Second recording
Third recording
Mean
0.5
First recording
Second recording
Third recording
Mean
1
First recording
Second recording
Third recording
Mean
Room Air
Stability
Carbon
Dioxide Stability
Oxygen Stability
77% Carbon
Dioxide/23%
Oxygen Stability
87
84
86
85.7
24
27
25
25.3
84
85
88
85.7
52
55
56
54.3
89
91
87
89.0
26
27
24
25.7
75
80
82
79
58
59
57
58
91
89
92
90.7
29
27
29
28.3
72
74
73
73
50
50
49
49.7
3 7 : 1 : J A N U A RY 2 0 1 1
15
F O A M S TA B I L I T Y W I T H G A S E S
a combination of CO2 and O2 are smaller than those
from air.
Laplace’s law states the pressure difference between
the inside and outside of a bubble is inversely proportional to the bubble radius.
DP ¼ Pi Po ¼
2g
r
Pi is pressure inside the bubble, Po is pressure outside the bubble, g is surface tension, and r is the
radius of the bubble.
Therefore smaller bubbles, such as CO2, disintegrate
more quickly than larger bubbles because of a greater
pressure gradient. Nitrogen is less dense than air and
would therefore result in larger bubbles, and we hypothesize a longer foam half-life than with room air.
Foam composition, foam volume, and injection
technique affect foam stability.7 Liquid sclerosant to
gas ratios of 1:4 (1 part liquid to 4 parts gas) or 1:5
(1 part liquid to 5 parts gas) have been found to
produce the most stable foams.8 CO2 foam bubbles
disintegrate quickly, and this effect is more pronounced as the ratio of sclerosant to gas is increased.9 The following equation describes foam
stability in vivo.
TP ¼
r2 d
2DSf
TP is time of bubble persistence, r is radius, d is air
density inside the bubble, D is the gas diffusibility
through the bubble, and Sf is the saturation factor of
gas in blood.
CO2 has much greater diffusibility into blood than
nitrogen (the dominant gas in room air), and, as a
result, the half-life foam is shorter for CO2.10 The
diffusibility of CO2 into blood is 19 times as high as
that of O2, as Graham’s Law, which states that
diffusion rate of a gas through a liquid is proportional to gas solubility in a liquid and inversely
proportional to the square root of the density of the
gas, expresses.11
16
D E R M AT O L O G I C S U R G E RY
Silicone coating is present in syringes and syringe connectors to provide lubrication, but silicone is an antifoaming agent. Prior studies by Rao and Goldman4
and Lai and Goldman12 have shown that the amount
of silicone in syringe connectors does not affect foam
stability, although foam stability varies between syringe
manufacturers because of differences in the silicone
content of syringes between manufacturers.
Our previous work showed that the half-life of room
air foam varied according to the percentage of
sclerosant solution. In our current study, we showed
that the half-life of CO2 foam did not vary according
to the concentration of sclerosant solution, although
room air, O2, and a combination of CO2 and O2 did.
Although the half-lives of room air and CO2/O2 increased with increasing concentrations of sclerosant,
we were surprised to find that the half-life of O2
foam decreased with increasing concentrations of
STS. We also found that the half-life of room air
foam is more than 3 times as long as that of CO2 and
1.5 times as long as that of CO2/O2. There were no
differences in the half-lives of room air and O2 foam
with 0.25% STS, although differences were seen
with 0.5% and 1% STS.
A recent study in incompetent great saphenous veins
treated with ultrasound-guided foam sclerotherapy
created from CO2 versus room air demonstrated
fewer incidences of foam bubble–related side effects,
including visual disturbances, chest tightness, cough,
and dizziness, with CO2-generated foam.13 One can
speculate that the decreased upstream foam-related
side effects are attributable to the short half-life of
CO2 foam. Further randomized controlled studies
are needed to investigate whether efficacy varies
between room air, CO2, and a combination of CO2
and O2 in foam sclerotherapy.
References
1. Jia X, Mowat G, Burr JM, et al. Systematic review of foam
sclerotherapy for varicose veins. Br J Surg 2007;94:925–36.
2. Breu FX, Guggenbichler S, Wollmann JC. 2nd European Consensus Meeting on Foam Sclerotherapy 2006, Tegernsee,
Germany. VASA 2008;37(Suppl 71):1–29.
PETERSON AND GOLDMAN
3. Wright D, Gobin JP, Bradbury AW, et al. Varisolves
polidocanol microfoam compared with surgery or sclerotherapy
in the management of moderate to severe varicose veins:
European randomized controlled trial. Phlebology 2006;21:
180–90.
9. Wollmann JC. The history of sclerosing foams. Dermatol Surg
2004;30:694–703.
10. Cavezzi A, Tessari L. Foam sclerotherapy techniques: different
gases methods and methods of preparation, catheter versus direct
injection. Phlebology 2009;24:247–51.
4. Rao J, Goldman MP. Stability of foam in sclerotherapy: differences between sodium tetradecyl sulfate and polidocanol and the
type of connector used in the double-syringe system technique.
Dermatol Surg 2005;31:19–22.
11. Nehrenz GM. Altitude and oxygenation. Internet J Aeromed
Transport 2000;1 Available at www.ispub.com (accessed
November 26, 2010).
5. Frullini A, Cavezzi A. Sclerosing foam in the treatment of varicose
veins and telangiectases: history and analysis of safety and
complications. Dermatol Surg 2002;28:11–5.
12. Lai SW, Goldman MP. Does the relative silicone content of
different syringes affect the stability of foam in sclerotherapy?
J Drugs Dermatol 2008;7:399–400.
6. Hu WS. Oxygen transfer in cell culture bioreactors. Cell Biopress
Technol 2004;1–14.
13. Morrison N, Neuhardt DL, Rogers CR, et al. Comparisons of
side effects using air and carbon dioxide foam for endovenous
chemical ablation. J Vasc Surg 2008;47:830–6.
7. Hill D, Hamilton R, Fung T. Assessment of techniques to
reduce sclerosant foam migration during ultrasound-guided
sclerotherapy of the great saphenous vein. J Vasc Surg 2008;
48:934–9.
8. Kendler M, Wetzig T, Simon JC. Foam sclerotherapyFa possible
option in therapy of varicose veins. J Dtsch Dermatol Ges
2007;5:648–54.
Address correspondence and reprint requests to: Mitchel P.
Goldman, MD, Dermatology Cosmetic Laser Associates of
La Jolla, 9339 Genesee Ave, Ste 300, La Jolla, CA 92121,
or e-mail: [email protected]
COMMENTARY
An Investigation into the Influence of Various Gases and
Concentrations of Sclerosants on Foam Stability
ALESSANDRO FRULLINI, MD
Alessandro Frullini, MD, has indicated no significant interest with commercial supporters.
T
he article from Peterson and Goldman1 is
valuable for the clear demonstration of the
differences between different types of foam. This
is an important point because the comparison of
different experiences is often made notwithstanding
the evident differences between techniques of
treatment.
In addition, the problem of bubbles and gases used
for foam generation has been greatly overempha-
sized. My recent studies on high endothelin levels
after foam sclerotherapy (Proceedings of ‘‘Sclerotherapy 2010,’’ Bologna, Italy, March 26–27) clearly
demonstrate that the cause of visual and neurological disturbances may be related to a different
pathogenesis. It has been demonstrated that
endothelin provokes vasospasm in the cerebral and
retinal vessel, and the very high peak concentration
after foam sclerotherapy may be the cause of such
side effects.
Studio Medico Flebologico, Florence, Italy
& 2011 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2011;37:17–18 DOI: 10.1111/j.1524-4725.2010.01839.x
17