History of sclerotherapy

One of the cornerstones of varicose vein treatment is sclerotherapy, which literally means “hard therapy”. The diseased vein is injected with a sclerosant that causes the vein to plug up, harden, and eventually disappear. Sclerotherapy can be compared to and contrasted with thermal venous ablation, which accomplishes the same thing by using a heated catheter in the vein instead of a chemical.

The primary effect of a sclerosant is to damage the inner lining of the affected veins. Within a few minutes of injection of the medication, a thrombosis develops in the vein which adheres to the lining of the vein and stops blood flow through the vein. Over the course of the next few weeks and months, the thrombosis is replaced with fibrotic tissue and the vein eventually becomes a small strand of scar tissue.

The thrombosis that develops with sclerotherapy adheres quite tightly to the vein lining and very rarely breaks loose to travel to other organs such as the lungs. Any sclerosant that escapes from the target vein is immediately diluted by blood and neutralized so that it has no effect on other vessels in the body.

Sclerotherapy was first described in an 1840 animal study involving arterial abnormalities. By the 1850’s a variety of different chemicals, such as alcohol, ferric chloride, iodine, and tannin were being used in an attempt to treat varicose veins, generally with very poor results. Many of the compounds were successful in treating the varicose veins, but frequently caused blood clots elsewhere in the body that resulted in pulmonary emboli and some deaths.

Over the next several decades a variety of different injectable medications including arsenic, phenol, potassium iodide, sodium salicylate, sodium bicarbonate, quinine sulfate, hypertonic saline, grape sugar, sodium citrate, sodium morrhuate, chromated glycerin, and ethanolamine oleate were used for sclerotherapy. These compounds for the most part proved to be neither effective nor safe.

The sequence of events that led to their use for the treatment of varicose veins is interesting. Many were used in the treatment of other diseases. For example, salvarsan, was used to treat neurosyphilis during World War I. A French physician named Jean Athanase Sicard noticed that this substance caused the veins in which it was injected to thrombose and eventually disappear. Consequently, he investigated the use of salvarsan and other medications for the treatment of varicose veins.

In the early 1900’s mercuric chloride used in the treatment of syphilis was also noticed to thrombose veins. It was used for sclerotherapy in a series of 90 patients, and found to be reasonably effective but not very safe with patients developing mercury toxicity. Quinine, which was given intravenously for the treatment of malaria, was also noted to sclerose veins. One physician routinely injected quinine into the varicose veins of patients with malaria in an attempt to treat both diseases at the same time.

Sodium bicarbonate

There was tremendous progress in the understanding and treatment of diabetes in the first few decades of the twentieth century, culminating in the discovery and widespread adaption of insulin in the 1920’s. It was discovered that intravenous sodium bicarbonate was useful in the treatment of diabetic coma. Dr. Sicard noted that highly concentrated injections of the substance resulted in sclerosis of the veins in the arms of the patients. Sicard determined that sodium bicarbonate was also the agent in salvarsan that caused sclerosis, and adapted its use for the treatment of varicose veins. He found it worked extremely well as long as none of the chemical escaped (extravasated) from the vein. If there was extravasation, extreme pain and necrosis of the overlying skin could result.

Sodium salicylate

In an attempt to avoid the problems associated with sodium bicarbonate, Sicard investigated a chemical that has become one of the most widely used drugs in medical history. It was used in the treatment of the symptoms of malaria and was derived from the bark of the willow tree, which had been used since time immemorial for relief of pain, inflammation, and fever. This class of drugs was known as salicylates, and achieved widespread use for the treatment of various inflammatory conditions in the 19th century. Acetylsalicylic acid, better known as aspirin, continues to be one of the most widely used medications in the world.

Intravenous sodium salicylate was used in the 1920’s for treatment of advanced cases of rheumatism, and was one of the medications that Sicard adapted for use in the treatment of varicosities. In 1928 he published a paper detailing the results of his treatments, which included over 325,000 injections in patients. While the treatment appeared to be reasonably effective, it commonly caused severe cramping. In addition, injections of the medication into the subcutaneous tissue frequently resulted in large ulcerations. Although not approved for use in the United States for this purpose, it continues to be used in other countries under brand names such as Saliject.

Interestingly enough, Sicard achieved more fame as a neurologist and radiologist than he did in treating varicose veins. There are several syndromes named after him, and he is credited with the development of several radiological examinations of the central nervous system.

Hypertonic saline

At about the same time that Sicard was experimenting with the use of sodium bicarbonate and sodium salicylate for sclerosing purposes, another physician familiar with the use of mercuric chloride for syphilis and varicose vein treatment adapted sodium chloride for sclerosing purposes. The concentration of sodium chloride used was about twenty times the concentration of sodium chloride in blood. Since sodium chloride is a vital substance in the body, it has no allergic potential, in contrast to many other medications. However, it was found to only be effective in the treatment of veins less than about four millimeters in diameter. Like sodium salicylate, injections that extravasate can be extremely painful and can cause necrosis of the overlying skin. It continues to be used today mainly for treatment of spider veins. It is approved by the FDA, but for the induction of abortions, and not for sclerotherapy, although many physicians do use it for this off-label purpose.

Hypertonic glucose

Medical literature of a century ago contains references to what sounds like some rather bizarre treatments—such as the use of intravenous grape sugar for the treatment of heart disease. The rationale for such treatments becomes a bit more understandable when it is realized that another name for grape sugar is glucose—the exact same sugar found in the blood stream. Yet another name used to describe a solution of this sugar intended for intravenous use is dextro-glucose—or dextrose. Although quite common now, the use of intravenous solutions was just beginning to gain acceptance ninety years ago. For example, the paper describing the use of grape sugar for cardiac patients was published in 1923.

The first use of intravenous hypertonic salt solutions was in 1909. The use of hypertonic glucose for various conditions was described in papers published in 1917, 1918 and 1920. In 1921 there was a report describing the use of hypertonic grape sugar to increase the effectiveness of arsenic treatment for neurosyphilis.

Just like hypertonic sodium bicarbonate and hypertonic saline, hypertonic glucose is quite an effective vein sclerosant whether it is used for that purpose or not. It should be no surprise that it was also adopted for the treatment of varicose veins. Two surgeons from John Hopkins University, Kern and Angle, conducted some reasonably elegant animal experiments and developed a mixture of 50% dextrose and 30% saline for sclerosant purposes. Although not approved for use in the US by the FDA, a similar solution is still commercially available under the name Sclerodex in other countries. It is about half the concentration of the solution developed by Kern and Angle—25% dextrose and 10% sodium chloride.

Sodium morrhuate

Medications used in the treatment of tuberculosis were also found to be useful in the treatment of varicose veins. As strange as it might seem, one such treatment involved the intravenous injection of cod liver oil, which was noted to cause sclerosis of the injected veins. It was also noted to cause a high incidence of allergic reactions. This was felt to be due to the proteins in cod liver oil. In an attempt to remove proteins from the cod liver oil, a compound consisting of fatty acids derived from cod liver oil was developed. It was derived from cod liver oil by saponification—the very same process used in the production of soap. This compound also sclerosed veins, and sodium morrhuate was adopted for use in the treatment of varicosities. In essence, as described by one of its developers, it was cod liver oil soap, and continues to be used to this day with FDA approval.

While sodium morrhuate was less allergenic than cod liver oil for intravenous injection, it still triggered severe allergic reactions in some patients. Subsequent studies have shown an allergic response in 3% of patients, including some fatal anaphylactic reactions. It was felt this was due to the persistence of some cod liver proteins in spite of the steps taken to just use the fatty acids.

Ethanolamine

In 1933 an analysis of sodium morrhuate revealed that one of the chief fatty acids of this compound was oleic acid, which was a known constituent of olive oil and from which it took its name. It is the most common fatty acid found in the human body, and is a principal component of many varieties of margarine. The sodium salt of the substance is the principal component of many types of soaps. A number of compounds intended for medical use were synthesized at that time, including oleate quinine and monoethanolamine oleate. The latter compound is still in use and marketed under the brand name Ethamolin. It’s used predominantly for the treatment of esophageal varicose veins, and is rarely used presently for treatment of varicose veins of the legs.

Sodium tetradecyl sulfate

In an attempt to take advantage of sclerosing properties of the fatty acids, while avoiding the allergic potential of cod liver oil proteins, pharmacologists developed a synthetic fatty acid chemically similar to sodium oleate—sodium tetradecyl sulfate. In 1946 sodium tetradecyl sulfate, or STS (brand names Sotradecol, Fibro-vein, and Tromboject) was introduced and rapidly found widespread use. It continues to be used worldwide for vein sclerosing. The drug has been used in millions of patients with an extraordinarily low incidence of allergic reactions. It is approved by the FDA for use in the US.

Polidocanol

Besides medications originally developed for the treatment of syphilis, malaria, and tuberculosis that have been used in the treatment of varicose veins, there was one other type of medication that was found to be effective as a sclerosing agent. In 1884 the first effective local anesthetic agent, cocaine, was described by Sigmund Freud and an ophthalmologist associate. Within about ten years this agent found widespread use. While the drug was quite effective, it also had numerous side effects. Hence, the search continued for an effective and safer local anesthetic.

Armed with the knowledge of cocaine’s molecular structure, in 1903 Alfred Einhorn synthesized procaine hydrochloride which was marketed as Novocain. When used in combination with adrenalin (epinephrine), this drug was found to be considerably less dangerous than cocaine, and so found widespread use. In the next several decades a number of other synthetic local anesthetic agents were developed, such as Topicaine, Stovaine, Eucaine, Borocaine, Butyn, and polidocanol.

In 1936 the German chemical/pharmaceutical company, BASF, introduced polidocanol for use as a local anesthetic agent. Similar to the experiences with sodium morrhuate and quinine, one of the side effects of the new drug was localized clotting in veins in the injection area. In fact, this proved to be such a problem that its use as an anesthetic agent was abandoned. But this observation led to the investigation of polidocanol for use as a sclerosing agent.

Polidocanol (brand names Asclera and Aethoxysklerol) was introduced for the treatment of varicose veins in Europe in 1966, and has a safety and effectiveness profile similar to that of sodium tetradecyl sulfate. It was approved for use in the United States in 2010 under the brand name Asclera.

Iodine

One of the 19th and early 20th century treatments for an overactive thyroid gland was a combination of elemental iodine and potassium iodide. In 1906 this compound was investigated for use as a sclerosant and did find limited acceptance outside of the United States. One European group reported on their experience with the drug in 6000 patients in the 1980’s. While it does appear to be effective and reasonably safe, injection outside the vein is quite painful and produces ulcers. A compound of iodine and sodium iodide is available outside the US under the brand names Sclerodine and Varigloban.

Glycerine

Fats are a combination of glycerin (also known as glycerol) and fatty acids. Glycerin was first discovered in 1783 in olive oil. It has a sweet taste and oily texture, and is a by-product from the manufacture of soap. It was first mentioned as a remedy for skin diseases in the eighth edition of the USA Dispensatory published in 1849. By 1858 glycerin was reported to possess extensive powers as a solvent, and supposedly was superior to cod liver oil in the treatment of tuberculosis. However, by 1899 the use of glycerin as a treatment for tuberculosis and diabetes had completely fallen out of favor.

Given the extensive use of glycerin as a solvent for various medications, it’s not surprising that the intravenous use of glycerin was also investigated for various conditions. In 1931 a French dermatologist by the name of Jausion reported on the use of intravenous glycerin in the treatment of varicose veins. Jausion felt that glycerin worked well as a sclerosant; but was concerned with one side effect, hematuria (blood in the urine), that occurred with the chemical. To avoid this complication, glycerin was treated with a chemical normally used in tanning processes, chromium potassium sulfate, to form chromated glycerin. This drug is not approved by the FDA, but has found widespread use in Europe, where it is marketed under the name Scleremo. It is typically used for the treatment of telangiectasias, or spider veins.

Mihael Georgiev, a European phlebologist of some renown, revisited the use of glycerin by itself for the treatment of telangiectasias (spider veins) in 1994. It was reported to be just as effective as the chromate substance for these small veins. Two San Diego physicians, Brian Leach and Mitchel Goldman, did a study comparing a mixture of glycerin and lidocaine with sodium tetradecyl sulfate in the treatment of spider veins; and concluded that it was just as safe as STS and gave superior cosmetic results. The amount of glycerin used to treat telangiectasias is much less than that required for treatment of larger varicose veins; and hence, hematuria does not tend to be a problem. Glycerin is approved by the FDA for intravenous use, but in much larger amounts for the treatment of swelling of the brain. It is also used in the emergency treatment of glaucoma. Many phlebologists in the United States do use glycerin “off-label” because they feel it gives superior cosmetic results for spider veins.

Gas

In 1939 a Liverpool physician, Stuart McAusland, who specialized in the treatment of varicose veins and hemorrhoids, described a technique in which he injected varicosities with a froth produced by shaking up a vial of sodium morrhuate. He apparently was not completely pleased with his results, as two years later his preferred sclerosants were lithium salicylate and quinine. In 1944 another British physician, Robert Rowden Foote, recommended the use of foamed sodium morrhuate for the treatment of spider veins. In 1950 a Swiss phlebologist by the name of Sigg noted that sclerosant foam injected into a vein seemed to persist in the vein longer than liquid sclerosant did. In the 1950s and 60s a Connecticut physician, Egmont Orbach, advocated the use of an “air-block” technique which involved injecting both air and a foam made from air and sodium tetradecyl sulfate. He reported that the sclerosant foam was 3.5 to 4 times as effective as just the liquid sclerosant. A Norwegian physician, Arve Ree, reported excellent results just with the use of a foam made with ethanolamine oleate—and without the use of the air-block technique.

From 1955 to 1995 no less than eight other physicians from various countries reported on the use of foam sclerosant in the treatment of varicose vein disease. Despite these reports, foam sclerotherapy was not used other than by a handful of practitioners. In 1995 an Italian physician, Cabrera Garrido, reported on a series of patients with venous disease treated with foam produced by a high speed rotating brush. This report led physicians in France, Spain, and Italy to again investigate foam sclerotherapy. In 1999 an Italian phlebologist, Lorenzo Tessari, described a quick and inexpensive method to produce high quality foam.

Ultrasound guided sclerotherapy

In a 2000 report by Garrido described the results of using foam sclerotherapy in a series of 500 patients. The study also incorporated another new technology—that of using ultrasonic imaging to allow precise injections of diseased subcutaneous veins that are not normally visible. Known as ultrasound guided sclerotherapy (USGS), the technique had first been described in France in 1989. This technique did not replace the century practice of injecting veins under direct vision, but expanded sclerotherapy to incorporate diseased veins that previously could not be seen.

Garrido’s study reported excellent results. Several other confirming studies followed in close succession. By 2003 the practice had been adapted by physicians around the world, and was the subject of a European Consensus conference that concluded that foam sclerosant was a “powerful tool in the hands of an expert who has sufficient experience in sclerotherapy.” The conference recommended the use of ultrasound guidance for sclerotherapy involving larger varicose veins and recurrent varicose veins, and noted that it was also useful in the treatment of smaller diseased veins.

Air was the gas first use to produce foam sclerosants. Recently there has been a great deal of interest in the use of carbon dioxide rather than room air for the production of foam. Carbon dioxide is cleared from the blood stream much more readily than air, and at least theoretically is less likely to cause side effects.

Conclusion

Sclerotherapy is an excellent example of both the science and art of medicine. It is based upon a firm scientific foundation constructed with both laboratory and clinical studies. Its practice, though, is very much an art. Today’s phlebologists are medical artists who choose from a pallet of proven medications and techniques to achieve the best results for an individual patient.

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