1. Polidocanol vs STS for Spider Veins
Saturday: Nov 5, 2016
Presentation: PL55E-4 - Polidocanol vs. STS for Telangiectasias/Spider Veins 
Type: Concurrent Session
Time: 2:30 PM - 2:50 PM
Presented During: Clinical Dilemmas
Presented During Time: 1:30 PM - 3:30 PM
Location: Anaheim Marriott, Platinum 5 - 6
Role: Speaker
Presentation: PL55E-6 - Question & Answer 
Time: 3:10 PM - 3:30 PM
Steven E. Zimmet, MD RPVI RVT FACPh

2. Disclosures/COI
No COI
Off-label use

3. Lipid bilayer with membrane proteins
Lipid bilayers are the basic structures that make up cell membranes.
membrane phospholipids are amphiphilic and contain a hydrophilic polar head group and a hydrophobic tail group.
Detergents are also amphiphilic- possessing both hydrophilic (water-loving, polar) and lipophilic (fat-loving) properties.
All sclerosants work by interfering with normal functioning of cell membrane proteins. Mechanisms of interference may be through ionic or osmotic distruption (hypertonic solutions), by chemical bonding (cell toxins) or by amphiphilic interactions (fatty alcohol detergents)
Proteins vital- transport for nutrients and metabolic products and for signaling
• Lipid bilayers are the basic structures that make up cell membranes.
• Membrane phospholipids are amphiphilic and contain a hydrophilic polar head group and a hydrophobic tail group.

4. Mechanism of Action
Detergent sclerosants produce endothelial damage via interference with cell surface lipids
Strong detergents, such as STS, produce maceration of the endothelium within 1 second of exposure.
The intercellular ‘cement’ is disrupted
Detergent destructive action on endothelial cells is enhanced when they act as aggregates rather than monomers.
FIND REFERENCE]
Strong detergents, such as STS and SM, produce maceration of the endothelium within 1 second of exposure.20 The intercellular ‘cement’ is disrupted
At high enough concentrations, surfactants solubilise cell membranes resulting in cell lysis.

5. Bioactive Aggregates Critical Micellar Concentration
Concentration dependent
CMC of STS to be % in normal saline and 0.200% in water1
CMC of POL to be % in both normal saline and water1
Reach threshold, critical micellar concentration, tipping point- molecules aggregate into micelles
After diffusion, dilutes to below critical micellar concentration, forming monomers and becoming inactive
Concentration dependent,
1. Wong K, Chen T, Connor D, et al. Basic physiochemical
and rheological properties of detergent sclerosants.
Phlebology. Epub ahead of print 26 March
2014.
Other factors- temperature, see Feied below
I'm kind of out there all alone on this -- when I first developed the early materials on sclerosants, nobody before me had ever recognized that the detergents were threshold-mediated in their sclerosing potency and that the explanation for this was the threshold implicit in micellar formation above the CMC -- I was probably the first person with a serious chemistry and biophysics background who ever bothered to think about it :)
At that time I could find no published experimental data for these specific substances. I did BOTEC thermodynamic calculations to estimate the CMC at STP for STS and polidocanol -- I don't have those notes here in Hawaii, but if I remember correctly I came up with something like 0.1% for STS and something like 0.05% for POLI, but I knew those could only be rough estimates because the mobility constants are not well established. And of course CMC is exquisitely sensitive to chain length, iconicity, and the stabilizing buffer solution in which a detergent is suspended (saline vs plasma) -- as well as temperature.
It's very easy to establish this experimentally -- truly accurate results take about an hour in a lab with an electron paramagnetic (spin) resonance spectrometer -- though sadly, I haven't had access to a lab with ESR since I left San Diego in The measurement can also be done by many other techniques (e.g., dye dilution or by tensiometry) but in my mind these results are always going to be less accurate because they measure bulk-phase attributes rather than single-molecule sampling the way ESR does.
The micellar concentration curve necessarily steepens rapidly at the CMC, so in a real-world setting we find experimentally that when we are very near the CMC we may observe from 0% to perhaps 5% of the total dissolved detergent in micellar form, with the amount of detergent found in micelles rising almost 1:1 as further detergent is added above the CMC.  5% is a pretty small amount of absolute micellar agent, and it's easy to believe that an effective denaturant or emulsifier would require some concentration significantly above the CMC in order to have enough micelles to matter.
For that reason, I believe the CMC for polidocanol must be somewhere well below 0.5% and the CMC for STS must be well below 0.1%, as these concentrations have been shown to induce endothelial injury patterns consistent with protein denaturation (or protein theft).
With that said, here's the actual data of which I'm aware.
The critical micellar concentration for sodium lauryl sulfate in water is known to be 0.045% and that of sodium dodecyl sulfate is 0.23% -- these are "well-known" values  because the substances are used commercially as denaturants and emulsifiers & people care because you have to remain above the CMC for there to be any effect on the solubility of whatever it is you're trying to emulsify or denature...
There are now a few published experimental reports of CMC for both POLI and AETHOX. I'd take them with a grain of salt.
One gives 1.0 x 10^-4 as the experimental molar concentration of poli at CMC => this would be about % w/v (poli has a molecular weight of about 230).
Another gives 0.86 x 10^-3 as the molar concentration of STS at CMC => with a MW of 316 this would be about 0.27 % w/v, which I think cannot be quite correct based on my experience with the agent at low concentrations. This measurement was done with fluorescent dye, which may over or under-estimate the true CMC.
In terms of temperature effects: most of these substances exhibit a U-shaped dependence of CMC on temperature starting just above the melting point of water, with the lowest CMC (largest amount of material in micellar form) found near room temperature and a monatonically increasing CMC with temperature above that point. The U-shaped dependence and an observation that ionic detergents are differently affected than nonionic ones suggests that this probably has more to do with the thermodynamics of water and the entropy changes when hydrogen bonds experience a different environment than it has to do with the detergent molecules themselves.
I have no data on the magnitude of the effect for these specific agents, but it could be a doubling effect based on what we see for some other agents. Here's a graph showing an example where the CMC changes by 1 millimol/liter over this temperature range (that magnitude of change would halve or double the CMC for our sclerosing agents):
Well, that's all I have to offer -- sorry I can't be more specific. This would be a good research project for somebody  :)
Best,
-- Craig

6. Thus, the concentration of the sclerosing solution in the vessel is
Detergent sclerosants produce endothelial damage through interference with cell surface lipids
Strong detergents, such as STS and SM, produce maceration of the endothelium within 1 second of exposure.20 The intercellular ‘cement’ is disrupted, causing desquamation of endothelial cells in plaques. Because the hydrophilic and hydrophobic poles of the detergent molecule orient themselves so that the polar hydrophilic part is within the water and the hydrophobic part is away from the water, they appear as aggregates in solution (micelles) or fixed onto the endothelial surface
Detergents act as micelles when injected into a nondetergent environment (blood). Their destructive action on endothelial cells is enhanced when they act as aggregates rather than monomers. Thus, the concentration of the sclerosing solution in the vessel is an important factor regarding endothelial destruction and activity (Fig. 7.5
They have been found to aggregate to a significant extent at lower temperatures as opposed to room temperatures
Therefore, this study confirms that effective endosclerosis occurs through damage to endothelium and not through thrombosis induced by destruction or damage to red and/or white blood cells.
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.b
The capacity of POL to cross the placental barrier was investigated in rats.123 Of radioactivity from labeled POL, 15% to 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.
Thus, the concentration of the sclerosing solution in the vessel is
an important factor regarding endothelial destruction and activity

7. STS and POL are clinically used to induce endovascular fibrosis and vessel occlusion.
They achieve this by lysing the endothelial lining of target vessels. These agents are surface active (surfactant) molecules that interfere with cell membranes.
The ionic charge of the surfactant molecule can influence the effect on plasma proteins and the protein contents of cell membranes. STS, an anionic detergent, denatures the tertiary complex of most proteins and in particular the clinically relevant clotting factors. By contrast, POL has no effect on proteins due to its non- ionic structure. These agents therefore exhibit remarkable differences in their interaction with lipid membranes, target cells and circulating proteins with potential implications in a range of clinical applications
Both STS and POL are biochemically classified as surfactant
detergents.
Surfactants are amphiphilic compounds and in general
contain a hydrophobic (non-polar) hydrocarbon
tail and a hydrophilic (polar) head group (Figure
1(a)). Therefore, surfactants are soluble in both oils
(via the hydrophobic tail) and water (via the hydrophilic
head). Surfactants reduce the surface tension by
adsorbing at the interface between the two substances.
Normally oil fragments suspended in water form large
droplets. The presence of a surfactant would decrease
the surface tension between oil and water surfaces. This
allows more mixing with water and prevents the coalescence
of oil droplets into a bigger mass. Therefore, the
surfactant allows the break-up of oil into multiple
minute droplets that can be washed away.
By contrast to the effects observed at low concentrations,
both agents lyse endothelial cells, platelets and
other circulating blood cells at high concentrations.17
Furthermore, high concentration STS denatures and
inactivates proteins and in particular clotting factors.
19,20 This is due to the anionic nature of these
detergents and interference with the tertiary structure
of target proteins. Consequently, this agent prolongs
most clotting tests and prevents clot formation at
high concentrations.17,19 POL, a non-ionic detergent,
can lyse platelets at high concentrations but has no
destructive effect on plasma clotting factors.
See PAPER
Interaction of detergent sclerosants with cell membranes
Kurosh Parsi
Abstract
Phlebology 2015, Vol. 30(5) 306–315 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: / phl.sagepub.com
Commonly used detergent sclerosants including sodium tetradecyl sulphate (STS) and polidocanol (POL) are clinically used to induce endovascular fibrosis and vessel occlusion. They achieve this by lysing the endothelial lining of target vessels. These agents are surface active (surfactant) molecules that interfere with cell membranes. Surfactants have a striking similarity to the phospholipid molecules of the membrane lipid bilayer. By adsorbing at the cell membrane, surfactants disrupt the normal architecture of the lipid bilayer and reduce the surface tension. The outcome of this interaction is concentration dependent. At high enough concentrations, surfactants solubilise cell membranes resulting in cell lysis. At lower concentrations, these agents can induce a procoagulant negatively charged surface on the external aspect of the cell membrane. The interaction is also influenced by the ionic charge, molecular structure, pH and the chemical nature of the diluent (e.g. saline vs. water). The ionic charge of the surfactant molecule can influence the effect on plasma proteins and the protein contents of cell membranes. STS, an anionic detergent, denatures the tertiary complex of most proteins and in particular the clinically relevant clotting factors. By contrast, POL has no effect on proteins due to its non-ionic structure. These agents therefore exhibit remarkable differences in their interaction with lipid membranes, target cells and circulating proteins with potential implications in a range of clinical applications.

8. Cell lysis reached almost 100 % with STS at 0. 3 % and with POL at 0
Both sclerosants induced endothelial cell (EC) apoptosis at sub-lytic concentrations through a caspase-dependant pathway. Both agents induced EC oncosis.
Apoptosis Jul;21(7): doi: /s
Detergent sclerosants at sub-lytic concentrations induce endothelial cell apoptosis through a caspase dependent pathway.
Cooley-Andrade O1,2, Cheung K2, Chew AN2, Connor DE1,2, Parsi K3,4.
Abstract
To investigate the apoptotic effects of detergent sclerosants sodium tetradecylsulphate (STS) and polidocanol (POL) on endothelial cells at sub-lytic concentrations. Human umbilical vein endothelial cells (HUVECs) were isolated and labelled with antibodies to assess for apoptosis and examined with confocal microscopy and flow cytometry. Isolated HUVECs viability was assessed using propidium iodide staining. Early apoptosis was determined by increased phosphatidylserine exposure by lactadherin binding. Caspase 3, 8, 9 and Bax activation as well as inhibitory assays with Pan Caspase (Z-VAD-FMK) and Bax (BI-6C9) were assessed to identify apoptotic pathways. Porimin activation was used to assess cell membrane permeability. Cell lysis reached almost 100 % with STS at 0.3 % and with POL at 0.6 %. Apoptosis was seen with both STS and POL at concentrations ranging from to 0.15 %. PS exposure increased with both STS and POL and exhibited a dose-dependent trend. Active Caspase 3, 8 and 9 but not Bax were increased in HUVECs stimulated with low concentrations of both STS and POL. Inhibitory assays demonstrated Caspase 3, 8, 9 inhibition at low concentrations (0.075 to 0.6 %) with both STS and POL. Both agents increased the activation of porimin at all concentrations. Both sclerosants induced endothelial cell (EC) apoptosis at sub-lytic concentrations through a caspase-dependant pathway. Both agents induced EC oncosis.
Cooley-Andrade et al. Apoptosis Jul;21(7):

9. The lytic effect of sclerosants is not limited to EC.
Our group demonstrated lysis of erythrocytes, leukocytes, and platelets at concentrations specific to cell types
Both sclerosants induced leukocyte apoptosis at sublytic concentrations. STS activated both extrinsic and intrinsic pathways of apoptosis, while POL stimulated the intrinsic pathway of apoptosis only. Both agents induced oncosis. Based on these results, STS appears to have a greater effect than POL.
The lytic effect of sclerosants is not limited to EC.
Our group demonstrated lysis of erythrocytes, leukocytes,
and platelets at concentrations specific to cell
types and dependent on the diluting media.1,2 Plasma
proteins and membrane lipids deactivate the sclerosants
resulting in a massive drop in the active concentration
and a reduced lytic effect on ECs.2
Eur J Vasc Endovasc Surg Jun;51(6): doi: /j.ejvs Epub 2016 Apr 8.
Detergent Sclerosants Stimulate Leukocyte Apoptosis and Oncosis.
Cooley-Andrade O1, Goh WX2, Connor DE3, Ma DD4, Parsi K5.
Abstract
OBJECTIVE/BACKGROUND:
The objective was to investigate the effects of the detergent sclerosants sodium tetradecyl sulfate (STS) and polidocanol (POL) on human leukocytes at sublytic concentrations.
METHODS:
Leukocytes were isolated and labelled with antibodies to assess for apoptosis and examined with confocal microscopy and flow cytometry. Isolated leukocyte count and viability was assessed using trypan blue, and propidium iodide staining. Phosphatidylserine (PS) exposure, a universal hallmark to measure cell apoptosis, was identified by flow cytometry using lactadherin. Caspases 3, 8, and 9, and Bax activation, as well as inhibitory assays with pan-caspase (Z-VAD-FMK) and Bax (BI-6C9) were assessed to determine apoptotic pathways. Porimin activation was used to assess cell permeability.
RESULTS:
Up to 40% of leukocytes maintained membrane integrity at sublytic concentrations (≤0.15%) of sclerosants. The remaining 60% did not maintain membrane integrity but were not completely lysed. PS exposure was increased with both STS and POL exhibiting a dose- and time-dependant trend. While activation of caspases 3, 8, and 9, as well as Bax activation, were increased in leukocytes stimulated with low concentrations of STS, only caspases 3 and 9 and Bax were increased with POL. Inhibitory assays demonstrated caspases 3, 8, and 9, and Bax inhibition at low concentrations with both STS and POL. Both agents increased the leukocyte activation of porimin at all concentrations. On confocal microscopy, stains for caspases 3, 8, and 9, and Bax were increased for both STS and POL. Porimin stain was markedly positive for both STS and POL.
CONCLUSION:
Both sclerosants induced leukocyte apoptosis at sublytic concentrations. STS activated both extrinsic and intrinsic pathways of apoptosis, while POL stimulated the intrinsic pathway of apoptosis only. Both agents induced oncosis. Based on these results, STS appears to have a greater effect than POL.
Cooley-Andrade et al. Eur J Vasc Endovasc Surg Jun;51(6):846-56

10. Histological Study
40 patients after spider vein ( mm diameter) treatment
Punch biopsies obtained 15 minutes after treatment
H&E stains
Pre- and post-tx photos compared by authors regarding amount of intraluminal thrombus and hyperpigmentation
Histological findings
Level 1: endothelial cell destruction
Level 2: subintimal disruption
Level 3: fibrin replacement of vessel wall
Level 4: disruption of vessel wall
Bush et al. Evaluation of sodium tetradecyl sulfate and polidocanol as sclerosants for legtelangiectasia based on histological evaluation with clinical correlation. Accepted for publication in Phlebology

11. Histological Study

12. Histological Study
Based on the histological determinations in this study, STS 0.15% and POL 0.31% appear to be equivalent in cellular alterations.
The clinical effects after treatment with these two sclerosants are also similar with minimal staining and mild intraluminal thrombosis.
Using concentrations less than the STS 0.15% or POL 0.31% is not as effective in producing the desired level of cellular damage.
Using concentrations above these levels may produce thrombosis of vessel with resultant inflammatory changes and hyperpigmentation.

13. Sodium Tetradecyl Sulfate (STS)
Anionic surfactant
Nonmutagenic when tested in a mouse lymphoma assay, but no long-term animal carcinogenicity studies have been performed
FDA-approved 1946
Commercially available preparations as1% or 3% solutions
Indicated in the treatment of small uncomplicated varicose veins of the lower extremities that show simple dilation with competent valves
Sotradecol should be given to a pregnant woman only if clearly needed and the benefits outweigh the risks
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sotradecol is administered to a nursing woman.
Maximum single treatment should not exceed 10 mL.
Can be readily made into foam (physician-compounded)
When tested in the L5178YTK +/- mouse lymphoma assay, sodium tetradecyl sulfate did not
induce a dose-related increase in the frequency of thymidine kinase-deficient mutants and,
therefore, was judged to be nonmutagenic in this system. However, no long-term animal
carcinogenicity studies with sodium tetradecyl sulfate have been performed.
POL- non-ionic
STS- anionic (negatively charged)
Nonionic- foam less, less denaturing

14. Polidocanol (POL)
Non-ionic detergent, consisting of two components, a polar hydrophilic (dodecyl alcohol) and an apolar hydrophobic (polyethylene oxide) chain.
FDA-approved 2010
Asclera (polidocanol) indicated to treat uncomplicated spider veins (varicose veins ≤1 mm in diameter) and uncomplicated reticular veins (varicose veins 1 to 3 mm in diameter) in the lower extremity. It has not been studied in larger varicose veins > 3 mm in diameter.
Maximum 10 mL/session
Severe allergic reactions have been reported following polidocanol use, including anaphylactic reactions, some of them fatal.
Severe reactions are more frequent with use of larger volumes (> 3 mL). The dose of polidocanol should therefore be minimized. Be prepared to treat anaphylaxis appropriately.
It is not known whether polidocanol is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, avoid administering to a nursing woman.
Can readily made into foam (physician-compounded), commericially available as Varithena (GSV)
Per article by Sadick- it is contraindicated in
patients receiving disulfiram due to the fact that it contains a small amount of ethyl alcohol
in its solution.

15. Clinical Pharmacology
Mechanism of Action
Damages endothelium
Dense network of platelets, cellular debris and fibrin occludes the vein
Pharmacodynamics
Concentration and volume-dependent
Pharmacokinetics
The mean plasma half life (4 subjects) who received 4.5 to 18.0 mg polidocanol was 1.5 hours. These are far greater mg dosages than would be reached in a typical clinical setting.
Maximum recommended volume per treatment session of 10 mL.
The active ingredient in Asclera® is polidocanol, a non-ionic detergent consisting of a polar hydrophilic and an apolar hydrophobic chain.
In the Phase III study blood samples were taken on some subjects for pharmacokinetic analysis. These showed low levels of polidocanol present. The mean plasma half life in 4 subjects who received 4.5 to 18.0 mg polidocanol was 1.5 hours. These are far greater mg dosages than would be reached in a typical clinical setting. It is recommended to use 0.1 to 0.3 mL of either 0.5% or 1.0% Asclera® per vein with a maximum recommended volume per treatment session of 10 mL.
Reference
1. Asclera® (polidocanol) Injection Prescribing Information.

16. Polidocanol has been shown to have an embryocidal effect in rabbits when given in doses approximately equal (on the basis of body surface area) to the human dose. This effect may have been secondary to maternal toxicity. There are no adequate and well- controlled studies in pregnant women. Asclera should not be used during pregnancy.

17. STS & POL are deactivated by blood proteins1,2
Conner et al3 found detergent sclerosants are also deactivated by circulating blood cells. This deactivating effect is above and beyond the neutralizing effects of plasma proteins and contributes to the overall neutralizing effect of blood.
At high enough concentrations, surfactants solubilise cell membranes resulting in cell lysis.
In Vitro study: endothelial cell lysis at STS .25% and POL 0.4%2
At high enough concentrations, surfactants solubilise cell membranes resulting in cell lysis.
Results
The method was reproducible and increasing volumes of blood protein lowered the STS concentration in a linear fashion.
Approximately 2 ml of a 4% blood protein solution deactivates 1 ml of 3% STS, which means approximately 0.5 ml of whole blood
will deactivate 1 ml of 3% STS.
Watkns. European Journal of Vascular & Endovascular Surgery 2011;41(4):
Parsi et al. Eur J Vasc Endovasc Surg (2008) 36, 216e223.
Connor et al. Eur J Vasc Endovasc Surg (2015) 49, 426e431.

18. Samples of whole blood, platelet-rich plasma, and isolated leukocytes were incubated with various concentrations of STS or POL and added to human umbilical vein endothelial cells
Detergent sclerosant activity was decreased in WB when compared with plasma and saline controls
Detergent sclerosants are consumed and deactivated by circulating blood cells. This deactivating effect is above and beyond the neutralizing effects of plasma proteins and contributes to the overall neutralizing effect of blood.
Eur J Vasc Endovasc Surg (2015) 49, 426e431
Detergent Sclerosants are Deactivated and Consumed by Circulating Blood Cells
D.E. Connor a,b,c, O. Cooley-Andrade a,b, W.X. Goh a,b, D.D.F. Ma b,c, K. Parsi a,b,*
See PAPER
Objective: To investigate the deactivating effects of circulating blood cells on the lytic activity of detergent sclerosants. Methods: Samples of whole blood (WB), platelet-rich plasma (PRP), and isolated leukocytes were incubated with various concentrations of sodium tetradecyl sulfate (STS) or polidocanol (POL) and added to human umbilical vein endothelial cells (HUVECs), which were then counted using a fluorescent plate reader. Full blood counting was performed using a hematology analyzer. Platelet lysis and microparticle formation was assessed using lactadherin binding in flow cytometry.
Results: Detergent sclerosant activity was decreased in WB when compared with plasma and saline controls. The sclerosant lytic activity on endothelial cells was increased 23-fold for STS and 59-fold for POL in saline controls compared with WB. At high concentrations, sclerosants lysed erythrocytes, leukocytes, and platelets. Platelets were more sensitive to the lytic activity of sclerosants than other cell types. Neutrophils were the most susceptible of all leukocytes to the lytic activity of sclerosants. The presence of erythrocytes and leukocytes in samples decreased the lytic activity of sclerosants. Sclerosants at all concentrations induced erythrocyte-derived microparticle formation.
Conclusions: Detergent sclerosants are consumed and deactivated by circulating blood cells. This deactivating effect is above and beyond the neutralizing effects of plasma proteins and contributes to the overall neutralizing effect of blood. Different blood cell types exhibited varying levels of vulnerability to the lytic activity of sclerosants with platelets being the most and erythrocytes the least vulnerable
Connor et al. Eur J Vasc Endovasc Surg (2015) 49, 426e431

19. Liquid Detergent Sclerosants & Endothelial Cell Death
Cell cultures of bovine aortic endothelial cells
Continuous exposure to varying concentrations of Pol ( %) and STS ( %)
Fluorescence imaging every 2-6 seconds for up to 60 minutes to assess:
Intracellular calcium
Nitric oxide
Cell death
Kobayashi et. al. Derm Surg 2006;32(12):

20. Liquid Detergent Sclerosants & Endothelial Cell Death
Time to response for all markers was inversely related to sclerosant concentration
STS 0.5% 15 seconds to cell death
STS 0.1% 3.5 minutes to cell death
STS 0.02% 15 minutes to cell death
STS 0.005% no cell death
Appeared to be sequential activation of
Calcium-dependent pathways
Nitric oxide production
Followed by rapid progression to cell death
Inc Intracellular Calcium activates phosphorylation of proteins, which activates nitric oxide snythase.
Pol: Degree of cellular toxicity was non-linearly related to exposure times
STS: degree of cell toxicity can be approximated by simple inverse linear relationship between concentration and exposure times

21. French POL Study
12 physicians- Data on 1,605 patients included in the French registry were reviewed with a maximum followup of 60 months, covering 3,357 patient years.
Most of the sessions were performed with sclerosants in foamed formulation (n = 4,403); the rest (n = 2,041) was performed with liquid sclerosants.
we recommend
the use of liquid polidocanol for treatment of
spider, reticular, and small varicose veins
The five reactions observed after injection with
polidocanol liquid were one cramp, two inflammatory
reactions, one pigmentation, and one visual
disturbance. The total rate of adverse events with
liquid polidocanol was 0.25%.
Most common adverse reactions directly related
to polidocanol foam were 13 visual disturbances.
Only one such event could be seen after treatment
with the liquid. There were seven cases of headaches
(including migraines), and eight muscular
vein thrombosis were noticed with polidocanol
foam.
One deep vein thrombosis (DVT) occurred at
mid-term after administration of polidocanol foam.

22. French Study

23. Australian POL study 98 physicians, 16804 limbs, results at 2 years
65 Investigators utilized polidocanol and compared it to their previous use of other sclerosants
% for spider veins
85% felt POL superior to STS
90% felt fewer complications
Stated double blind RCT required- planned to do it, but apparently never published
Conrad et al. Derm Surg 1995;25:334-6.

24. Goldman RCT 129 pts w/o related underlying reflux
Spider veins, reticular veins, varicose veins
Spiders: .25% STS or .5% POL
3 Independent blinded photo reviewers at 4 and 16 wks
Both groups average 70% improvement
Similar side effect rate

26. EASI Study Double blind, randomized prospective study
Spider veins (n=160)
0.5% Pol
1% STS
placebo
Reticular veins (n=156)
1% Pol
Phlebology Jun;25(3): doi: /phleb
Sclerotherapy of telangiectases and reticular veins: a double-blind, randomized, comparative clinical trial of polidocanol, sodium tetradecyl sulphate (Sotradecol- my note) and isotonic saline (EASI study).
Rabe E, Schliephake D, Otto J, Breu FX, Pannier F.
Source
Department of Dermatology, University of Bonn, Sigmund-Freud-Str. 25, Bonn, Germany.
Abstract
OBJECTIVES:
To assess the efficacy and safety of polidocanol (POL) in comparison to sodium tetradecyl sulphate (STS) and isotonic saline (placebo) for sclerotherapy of telangiectases or reticular veins by means of standardized digital imaging system, independent medical observers and detailed monitoring.
METHODS:
Of 316 randomized patients, 160 with telangiectases were randomly assigned to 0.5% POL, 1% STS or placebo, and 156 with reticular veins received 1% POL, 1% STS or placebo. Veins selected for injection were clearly visible telangiectases or reticular veins in a predefined treatment area (10x10 cm). Exact retrieval of the location was guaranteed by a newly established digital imaging system. Images were taken before first injection and 12 and 26 weeks after the last of three possible injection visits, and evaluated by the investigator and two blinded independent observers. The detailed safety monitoring included ultrasound screening for 'silent' deep vein thrombosis, electrocardiograms and clinical laboratory tests.
RESULTS:
POL demonstrated a statistically significant superiority versus placebo (P < ) for the primary criterion 'improvement of veins'. Significantly more patients were satisfied with POL at 12 or 26 weeks (84%, 88%) compared to STS (64%, 63%; P < ) and placebo (14%, 11%; P < ). POL was safe and well tolerated apart from expected local symptoms at the injection site.
CONCLUSION:
Sclerotherapy of telangiectases and reticular veins with detergent-like sclerosants such as polidocanol (POL) or sodium tetradecyl sulphate (STS) is a well-established technique. However, evidence from clinical trials comparing these substances with a non-active solution is sparse and does not live up to expectations of modern clinical trial concepts necessary for authorisation purposes. The presented multicentre EASI study fulfils these requirements and clearly demonstrates that Sclerotherapy of C1 veins with POL is highly effective and deserves the adjunct 'gold standard'.
Rabe et al. Phlebology Jun;25(3):124-31s

27. Treatment Success Rates
Rated by blinded panel
Defined as grade 4 0r 5 (good or complete success)
No difference between Pol and STS
In terms of objective treatment success, treatment with Asclera® was statistically significant to placebo (P<0.0001) for the primary efficacy criterion “improvement of veins”.
Treatment success was predefined as subjects scoring 4 (good improvement) or 5 (complete treatment success); subjects scoring 1, 2, or 3 (worse, same as before, or moderate improvement) were considered treatment failures.
95% of subjects treated with Asclera® showed treatment success at 12 and 26 weeks, which was statistically significantly higher than subjects treated with placebo, 8% and 6%, respectively.
Subjects treated with STS scored slightly lower than those treated with Asclera® ( 92% at 12 weeks and 91% at 26 weeks) but were also statistically significantly higher than placebo.
References
1. Asclera® (polidocanol) Injection Prescribing Information.
*Treatment success was rated on a 5-point scale:
1 = worse than before
2 = same as before
3 = moderate improvement
4 = good improvement
5 = complete treatment success 27

28. Patient Satisfaction Patient Satisfaction rated on 1-5 scale
(% reflects patients satisfied or very satisfied)
Asclera® (0.5% or 1%)
STS (1%)
Placebo (0.9% isotonic saline)
87%
84%
64%
63%
NEED TO ADD REFERENCE- AND COMMENTS ABOUT THE EASL STUDY
At 12 and 26 weeks, subjects received the digital images of their treatment area taken at baseline and were asked to rate their satisfaction with their treatment using a verbal rating scale, where 1 = very unsatisfied, 2 = somewhat unsatisfied, 3 = slightly satisfied, 4 = satisfied, and 5 = very satisfied.
87% of subjects treated with Asclera® were satisfied with their treatment at 12 weeks and 84% were satisfied at 26 weeks. The numbers of subjects who were satisfied with treatment was statistically significantly lower for STS (64% at 12 weeks and 63% at 26 weeks) and saline (14% and 16%).
References
1. Asclera® (polidocanol) Injection Prescribing Information.
16%
14%
P< for all comparisons 28

29. Complications Actually, POL concentration (0.5/1.0 %) also too high
Could argue Pol dose too high
POL 1% for spider veins and reticular veins
Actually, POL concentration (0.5/1.0 %) also too high
Too high a concentration of STS (1%)

30. Complications Used too high a concentration of STS
Could argue Pol dose too high
Increased endothelial damage- increased rbc extravasation- increased pigmentation- also increased inflammation
High injection pressure- could lead to vessel rupture
Incidence pigmentation probably not related to skin type
Intravasular pressure may play a role- uncommon in hand veins, but common as proceed distally on legs
Rabe et al. Phlebology Jun;25(3):124-31

31. Spider vein: HS vs POL
Non-randomized study in 113 consecutive patients HS
POL .5 %
POL 1 %
Pigmentation
10.8%
20%
30.7%
Matting
13 %
10%
33%
Weiss and Weis. Derm Surg 1990, 16(9):800-4.
POL concentration probably too high
Weiss and Weiss. Derm Surg 1990, 16(9):800-4.

32. Spider Veins: HS vs POL 81 spider vein patients
Blinded assessment 0-3 scale by non-treating physician
Equal improvement
POL
Significantly higher pigmentation score (p=.003)
Significantly higher matting score (p=.04)
McCoy et al. Derm Surg 1999;25(5):381-5.

33. Glycerin Prospective, randomized blinded studies
More painful, more effective than Polidocanol 0.25% solution and 0.25% foam (Monfreux)1
Decreased pigmentation, better clearance vs STS 0.25% (13 patients)2
Monfreux- generation of negative pressure by drawing back plunger of glass syringe whose tip is tightly closed- yields large bubbled fluidy foam
Another study: CG: xylocaine (2:1) had less pain/same efficacy vs. CG 1
This has not been my experience with regards to efficacy
Kern et al. Dermatol Surg Mar;30(3):
Leach & Goldman Dermatol Surg Jun;29(6):612-4.

34. Liquid vs Foam
Spider veins: Higher incidence pigmentation, ulceration1
French POL Study2: “We recommend the use of liquid polidocanol for treatment of spider, reticular, and small varicose veins”
Liquid treatment of choice in C1 patients3
Dermatol Surg Mar;30(3):367-72; discussion 372.
Single-blind, randomized study comparing chromated glycerin, polidocanol solution, and polidocanol foam for treatment of telangiectatic leg veins.
Kern P1, Ramelet AA, Wutschert R, Bounameaux H, Hayoz D.
Author information
Abstract
BACKGROUND:
A single-blind, randomized, comparative study was performed to evaluate the efficacy of pure chromated glycerin (CG), polidocanol (POL) 0.25% solution, and POL 0.25% foam (Monfreux technique) for treatment of telangiectasias and reticular leg veins.
OBJECTIVE:
To determine the relative efficacy and safety of two sclerosing agents and foam.
METHOD:
Of 150 randomized patients presenting comparable areas (lateral face of thigh) of telangiectasias and reticular leg veins, 147 could be evaluated by photographic assessment, patients' satisfaction score, and pain at injection sites. Internal and external agreement for the photographic assessment was good for two independent blinded experts.
RESULTS:
CG cleared vessels significantly better than POL solution or foam (p<0.002). The patients' satisfaction score was also higher in the CG group, although the difference did not reach statistical significance. CG was significantly more painful at injection sites. Other side effects were very few, precluding any statistical comparison. Foam was associated with more side effects (microthrombi, matting) than CG or POL solution. Three patients treated with POL foam experienced a transient visual disturbance.
CONCLUSION:
This study shows that CG is superior to POL solution and foam for sclerotherapy of leg telangiectasias.
Dermatol Surg Jan;28(1):11-5.
Sclerosing foam in the treatment of varicose veins and telangiectases: history and analysis of safety and complications.
Frullini A1, Cavezzi A.
To review the use of sclerosing foam in the treatment of varicose veins, to describe the different techniques of foam preparation, and to report the complications of our 3-year experience with this treatment.
From November 1997 to the end of October 2000, 453 patients were treated with a sclerosing foam for large, medium, and minor varicosities with sodium tetradecylsulfate (STS) or polidocanol (POL). A first group of 257 patients (90 for minor varicosities and 167 for medium to large veins) received a sclerosing foam according to the Monfreux technique. From December 1999 to October 2000, 196 patients were treated with a sclerosing foam prepared according to Tessari's method (36 for minor size veins or teleangectasias and 170 for medium-large veins). Every patient was studied with (color-flow) duplex scanning before and after the treatment and large vein injections were administered under duplex guide.
The immediate success rate was 88.1% in the first group for the medium-large veins. In the same districts we registered an early success rate in 93.3% for the patients treated with the Tessari's method. The complication rate (mostly minor complications) was 8.5% in the first group and 7.1% in the second group.
The use of sclerosing foam may become an established therapy in the treatment of varicose veins with a high success rate, low cost, and low major complication rate. According to our actual experience and knowledge, the safe amount of foam should not exceed the 3-ml limit, but further advancements could come from standardization of the foam preparation technique.
European guidelines for sclerotherapy in chronic venous disorders
E Rabe1, FX Breu2, A Cavezzi3, P Coleridge Smith4, A Frullini5, JL Gillet6, JJ Guex7, C Hamel-Desnos8, P Kern9, B Partsch10, AA Ramelet11, L Tessari12 and F Pannier13; for the Guideline Group
Phlebology 0(0) 1–17 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: / phl.sagepub.com
Kern et al. Derm Surg Mar;30(3):367-72
Guex et al. Derm Surg 2010;36:S2:
Rabe et al. European guidelines. Phlebology, 2013.

35. Sclerosant: Liquid vs Foam
RCT: 75 pts (69 women) served as their own control
Reticular or post-op varices
1 session: POL liquid or foam
Concentration adjusted based on vein size
[Foam] 50% lower than liquid
Eur J Vasc Endovasc Surg Jan;31(1): Epub 2005 Oct 14.
Efficacy and safety of sclerotherapy using polidocanol foam: a controlled clinical trial.
Alòs J1, Carreño P, López JA, Estadella B, Serra-Prat M, Marinel-Lo J.
Author information
Abstract
OBJECTIVE:
To assess the efficacy and safety of sclerotherapy performed with polidocanol foam compared to liquid polidocanol.
METHODS:
Controlled clinical trial with 1 year follow up in which each patient acted as his/her own control. A total of 75 patients (six men and 69 women) with reticular or postoperative varices were enrolled and sclerotherapy was performed with liquid and with foam (Tessari method) using the same quantity of sclerosant for homogeneous varicose regions, to a total of 150 procedures. The sclerosant concentration was adjusted according to the vein diameter as assess by ultrasonography. The foam group was given 50% lower concentrations of sclerosant than liquid sclerosant group. Clinical assessment (pain, inflammation, pigmentation) and ultrasound examination (diameter of the lumen and length of sclerosed vein) were carried out at 15, 30, 90, and 365 days.
RESULTS:
Foam allowed complete sclerosis at 90 days in 94.4% of patients compared with 53% for liquid (p<.001) and also allowed a more extensive venous sclerosis (10.1cm compared with 7.2 cm; p<.001). Pain, signs of inflammation, and pigmentation appeared more often with foam sclerosis, with significant difference. The degree of satisfaction was similar for both techniques.
CONCLUSIONS:
Efficacy of venous sclerosis with foam seems to be greater than with liquid although there is a higher risk of minor secondary effects.
Eur J Vasc Endovasc Surg Jan;31(1):101-7.

36. Sclerosant Concentration
The key is to deliver a minimum sclerosant volume & concentration to irreversibly damage the endothelium &
cause complete sclerosis, without collateral damage.
Spider Veins
Reticular Veins
Varicose Veins HS
11.7 – 23.4%
n/a
D/S
FS (25%/10%) G
72%
Pol
.25-.5%
.5 - 1%
1 - 3%
STS % %
.33 – 3%
Spider: Bent or straight needle, Bevel up, No aspiration, Low pressure, Small area and volume
Reticular: 26 gauge needle, bevel up, aspirate, Volume mL/site, Injection spacing: 5-10 cm

37. Telangiectatic Matting
Group of fine telangiectasias
Usually develops after sclerotherapy
Can be seen after thermal ablation/surgery
Can occur spontaneously

38. Telangiectatic Matting
Patient factors 1,2
Obesity
Estrogens
Angiogenic factors 3
Inflammation
Obstruction of blood flow
Mast cell release of heparin, endothelial cell growth factor and other growth factors
Incidence 15-24% (see Weiss, Weiss, Feied)
Most common- medial knee
Often clears spontaneously- but need inform patients could be long-standing
Inflammation- hypermetabolic state- increase vessels due to increased metabolic demand
Enothelial damage- release mast cell factors (see slide)-
1. Davis LT, Duffy DM. J Dermatol Surg Onc. 1990;16:
2. Vin F et. al. J Dermatol Surg Onc. 1992;18:
3. Weiss RA, Feied CF, Weiss MA. Vein Diagnosis and Treatment

39. Prevention of Matting Evaluate for and treat underlying reflux
Avoid excessive treatment- can result in inflammation or obstruction with subsequent angiogenesis
Use minimal
Concentration
Volume
Injection pressure
Foam more likely to cause matting
High initial concentrations or large volumes of sclerosant can also result in inflammation or excessive vein obstruction with subsequent angiogenesis.

40. Cutaneous Necrosis Most common cause of sclerotherapy-related lawsuits
More often with inexperienced practitioners

41. Mechanism of Necrosis Extravasation Artery Compression
Extravascular injection
Vessel rupture
Artery
Intra-arteriolar/arteriole
Diffusion into arterial circulation via AV anastomoses
Vessel spasm
Compression
1. Zimmet SE. Derm Surg 1993;19(7):641-6.
2. deFaria JL, et. al.. Dermatologica 1963;127:321-9
3. Goldman MP et. al. Varicose veins and telangiectasias: diagnosis and treatment. 1999

42. Latex and STD Allergy Theory
Latex protein from multidose vial stopper and/or rubber syringe plunger gets solubilized by detergent sclerosant
Allergic reactions to STD due to latex senstivity

43. Latex and STD Allergy
Culled allergic reactions to STS from practitioners from around the US.
4 patients total over 1 year
Latex RAST test done
Test for IgE antibody directed towards latex.
Negative on 3 patients <0.35 ku/L
Weakly + in 1 patient ku/L
Ku/L = Kunitz units

44. Assays performed Guthrie Research Institute, Sayre, Pennsylvania
Total Protein Assay
STS stored in a:
Syringe
Multi-dose vial
Glass ampule
Total protein assay (modified Lowry)
Measures the level of extractable proteins in latex products
No protein detected in any solution
Mean 440 ug/g- exam gloves
Inhibition ELISA for Latex Antigen
This assay uses an Inhibition ELISA to quantitate antigenic latex protein in product extracts.
All STD samples strongly inhibitory
Most likely reflects surfactant blocking antibody antigen recognition
STD in glass had same reactivity
Inhibition curve different from the latex standard
This is nonspecific inhibition due to the surfactant rather than latex
Assays performed Guthrie Research Institute, Sayre, Pennsylvania

45. Cost of FDA-Approved Agents
Sotradecol
Cost/mL
Asclera 1%
$57
.5%
$10 3%
$63
$11
.15%
$3.13
.25%
$3.33

46. Image of two good choices

47. Compounded Sclerosants
1% Polidocanol concentrations ranged 1-3%, and impurities found1
STS 3% concentrations ranged 2.59%-3.39% and carbitol present in samples from all three sources (0.33%-4.18%)2
Study funded by Merz aesthetics
Weiss et al. Dermatol Surg Jun;37(6):812-5.
Goldman. Dermatol Surg Dec;30(12 Pt 1):

48. Compounding: Ask Yourself
Is an FDA-approved version available?
Do you inform your patients you’re using a compounded version as a substitute for an FDA-approved medication?
Why are you using a compounded product when an FDA-approved version exists?
If compounded drug determined to be the cause of a negative, preventable outcome, the physician may be liable for selecting the compounded drug
The Money Question: Did the physician benefit financiallly by using a compounded drug could expose you to punitive damages. jury may punish- allowed in many states.
Think New England Compounding Center

49. The Money Question
Did the physician benefit financially by using a compounded drug?
This could expose you to punitive damages
The Money Question: Did the physician benefit financiallly by using a compounded drug could expose you to punitive damages. jury may punish- allowed in many states.
Kenneth McKenna, Esq, 2007 ACP Annual Congress