Etiologic factors

The cause of this pigmentation most likely results from a combination of both postinflammatory hyperpigmentation (incontinence of melanin pigment) and hemosiderin deposition.^18–20 However, histologic examination has demonstrated 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).^21–24 Defects in iron storage and/or transport mechanisms have also been found in a significant number of patients who have developed pigmentation after sclerotherapy.²⁵

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.

(From Goldman MP, Kaplan RP, Duffy DM: J Dermatol Surg Oncol 13:547, 1987.)

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.²⁶ Erythrocyte diapedesis also may occur after inflammation of the vessel and is commonly seen after thrombophlebitis. Perivascular inflammation is presumed to promote degranulation of perivascular mast cells. Released histamine leads to endothelial cell contraction, which results in widening of endothelial gaps through which extravasation of RBCs can occur.^27–31 Thus, injecting a 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.^32,33 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%.³⁵ Iron hydroxide contained in hemosiderin occurs in different forms, with differing amounts of ferritin.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.³⁷ 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 RBCs.^38–40 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.

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.

Technique

Optimal technique consists of limiting pressure into damaged (sclerosed) veins to prevent extravasation of RBCs. To limit 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).

Figure 8.4 Pressure and syringe. Small syringes increase the risk of extravasation and necrosis (micro arteriovenous fistulas, backflow injections).

Gravitational and Other Intravascular Pressures

Postsclerotherapy pigmentation appears most commonly in vessels treated below the knee²⁰ but can occur anywhere on 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.

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.¹⁸ This may be caused by an increased incidence of postinflammatory hyperpigmentation in patients with these colorings However, Chatard²⁰ 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 post-sclerotherapy 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.⁵⁵ A preliminary study of 16 patients with age-matched controls disclosed that pigmentation developed in patients who had higher serum ferritin levels. Serum ferritin levels correlate with total body iron stores.⁶¹ To clarify the relationship between serum ferritin and postsclerotherapy pigmentation, a prospective study of 233 consecutive patients was conducted.⁶² A linear relationship between the occurrence of pigmentation and pretreatment serum ferritin levels was found at each post-treatment assessment date. This supports the hypothesis that high total body iron stores increase the susceptibility toward hyperpigmentation. However, serum ferritin levels are not an absolute predictor for the development of hyperpigmentation. In a patient with hemochromatosis having a serum ferritin level of 1200 ng/mL, pigmentation did not develop after sclerotherapy of telangiectasia 0.6 mm in diameter with 0.2% STS.⁶³ The explanation may be that this patient’s physician probably used outstanding technique to avoid extravasation of RBCs.

Therefore, serum ferritin levels may be used to identify patients at risk for this complication. These patients may require special attention with meticulous microthrombectomy, and an increase in time and extent of post-treatment compression is advocated.

If histamine-induced endothelial contraction promotes extravasation of RBCs or hemosiderin, or both, histamine antagonists should prevent or limit its occurrence. The catecholamines norepinephrine (noradrenaline) and isoproterenol antagonize histamine-induced edema in canine brachial artery preparations.⁶⁴ Similarly, corticosteroids decrease the size of histamine-induced endothelial gap junctions.⁶⁵ Terbutaline also inhibits macromolecular leakage from postcapillary venules in hamster femoral veins.⁶⁶ Cimetidine blocks histamine-induced widening of endothelial gaps in rat femoral veins.⁶⁷ Therefore, patients who have developed postsclerotherapy pigmentation in past treatments may be pretreated with one or a combination of these medications to block or limit histamine effects.

Vessel fragility may also result in an innate predisposition toward pigmentation. Capillary strength is related to both menstrual cycles and circulating estrogen.⁶⁸ Decreased capillary strength occurs 3 to 5 days before and 2 days after menses and during ovulation. Fragility has been found to improve with intravenous (IV) and oral administration of conjugated equine estrogen (Premarin) in postmenopausal women.

Patients taking minocycline may have an increased risk for postsclerotherapy pigmentation.^69,70 This propensity may be related to the inflammatory effects of sclerotherapy. Unlike the golden to deep brown color characteristic of typical sclerotherapy-induced pigmentation, pigmentation associated with minocycline use is most commonly blue–gray (Fig. 8.6). Minocycline, known to have increased tissue distribution due to its lipophilicity, produces pigmentation in a variety of organs and structures.^71,72 The most common form of minocycline-related pigmentation appears as bluish-black or bluish-gray macules within acne scars or at other sites of inflammation.^10,73–77 Other forms of minocycline-related pigmentation have been described on the skin of the lower legs, including that associated with sites of UV-exposure,⁷⁸ as well as with sites of pre-existing capillaritis.⁷⁹ The pigment involved in minocycline hyperpigmentation is most likely a drug metabolite–protein complex chelated with calcium, or an insoluble minocycline–melanin complex.^75,78–83 It is hypothesized that minocycline or a metabolite interferes with degradation of hemosiderin through lysosomal disruption, leading to macrophage death and deposition of pigment.⁷⁷ Recently, four cases of minocycline-related hyperpigmentation involving the subcutaneous fat were reported.⁸⁴ Histopathologically, tissue exhibited the previously well-described deposition of brown/black, Fontana-Masson and Perls’ positive granules along elastic fibers in the papillary dermis as well as within dermal macrophages located near vessels and eccrine glands. In addition to these dermal findings, tissue from the four patients also showed green–gray, nonrefractile, flocculent globules within macrophages in the subcutaneous tissue. Also, two of the four patients demonstrated the distinctive finding of pigment-related lipomembranous changes. Although further studies are needed to establish a direct relationship, it may be prudent to withhold minocycline therapy in sclerotherapy patients. Of note, successful lightening of minocycline-induced, post-traumatic pigmentary deposition has been described with successive Q-switched Nd:YAG laser treatments.⁸⁵ Often discontinuation of minocycline will result in spontaneous clearing of minocycline pigmentation within 6 to 12 months.

Figure 8.6 32-year-old woman who underwent sclerotherapy to telangiectasia on the thigh with sodium tetradecyl sulfate 0.25% 6 months previously. She presented with a bluish discoloration overlying the treated area which was devoid of telangiectasia. History disclosed that she was taking minocycline 100 mg b.i.d. for an acne eruption prescribed by her dermatologist 3 months earlier. Discontinuation of the minocycline resulted in resolution of the pigmentation. No biopsy was taken to confirm the diagnosis of minocycline pigmentation, but the clinical course and history supported the diagnosis.

Postsclerotherapy Coagula

Removal of postsclerotherapy coagula may decrease the incidence of pigmentation. Thrombi to some degree are thought to occur after sclerotherapy of all veins, regardless of size, because of the inability to occlude the vascular lumen completely with external pressure. The persistence of a small vascular lumen, even with maximal external pressure, has been predicted with experimental models of vein wall.⁸⁶ This has also been directly observed with fiberoptic varicography (Muntlak H, personal communication, 1989).

Persistent thrombi are thought to produce a subacute ‘perivenulitis’ that can persist for months.^87–89 The perivenulitis favors extravasation of RBCs through a damaged endothelium or by an increase of the permeability of treated endothelium. In addition, intratissue fixation of hemosiderin may occur.²⁰ This provides a rationale for drainage of all foci of trapped blood 2 to 4 weeks after sclerotherapy. Sometimes blood can be released even 2 months after sclerotherapy.

Thrombi are best removed by gentle expression of the liquefied clot through a small incision made with a 21-gauge needle (Figs 8.7 and 8.8). A no. 11 blade or lancet or 18 gauge no core needle have also been recommended by some, but, since this results in a larger incision and often requires pretreatment with a local anesthetic, we favor the more conservative 21-gauge needle approach.

Figure 8.7 Method for evacuation of a thrombosis in a 1-mm diameter reticular varicose vein 2 weeks after sclerotherapy. A, Small incision. B, Expelling clot (see text for details).

Figure 8.8 Trochard thrombectomy 10 days after injection of a bulging varix of the calf. The content of the vein (‘sclerus’) is liquid and little lateral pressure is necessary to empty the vein.

The expression of coagula is accomplished through a rocking action applied around the clot to aid in its expulsion. This should be continued until all dark blood is removed. The art of this procedure is to find the right place to puncture, which is best perceived as a hard, subcutaneous nodule. If the thrombosis is in the deep dermis, the area should be marked, and lidocaine 1% can be infiltrated around the area to facilitate a less painful removal. Compression pads or stockings are then worn for an additional day or two to prevent further thrombosis formation and to aid in adherence of the opposing endothelial walls to establish effective endosclerosis.

In a multicentered, randomized, controlled study, 101 patients with varicose veins were treated at 1–3 weeks with microthrombectomy in one half of the treated veins.⁹⁰ Photographs of the sclerotherapy-treated areas were evaluated at 16 weeks. Veins ≤1 mm in diameter had less pigmentation when drained, but veins ≤3 mm did not show any benefit from microthrombectomy.

Perchuk⁹¹ raised the possibility of infection occurring from stab incisions. This danger was presumed to be caused by the presence of bacteria in varicose veins – a belief commonly held by physicians 40 to 50 years ago.^92,93 However, there have been no reports in the modern medical literature of infections occurring in patients treated with stab incisions into postsclerotherapy clots. This problem has not occurred in our practice, in which this procedure is used routinely.

Duration

Despite therapeutic attempts, pigmentation often lasts from 6 to 12 months.²³ Rarely, pigmentation may last more than 1 year. Georgiev² estimates that 1% of his patients, and Duffy⁶ that up to 10% of his patients, have pigmentation lasting more than 1 year. Izzo¹ reports a 2% incidence after 1 year. Our experience parallels that of Georgiev.

Persistent telangiectasia may be caused by factors other than sclerotherapy itself. In certain patients, pigmentation may be present over superficial varicosities and telangiectasias before sclerotherapy is performed.^2,20 Hyperpigmentation as a result of ‘physiologic’ diapedesis of RBCs through fragile vessels is common in patients with venous stasis, or over varicose veins. Therefore, preoperative documentation, including photographs, may be beneficial during follow-up patient visits.

Prevention and minimization

To minimize the risks of development of pigmentation, sclerotherapy should produce limited endothelial necrosis and not total destruction with its resulting diapedesis of RBCs. This may be achieved by using meticulous technique, avoiding excessive injection pressures, selecting the appropriate solution concentration, and treating areas of venous reflux in a proximal-to-distal manner.

Thibault and Wlodarczyk⁶² recommend that patients avoid taking all iron supplements during the course of treatment and for 1 month after treatment. This presumably decreases serum ferritin levels. Alternatively, patients’ serum ferritin levels may be assessed before sclerotherapy to determine if iron chelation therapy is warranted. Obviously, this latter recommendation awaits further study. We think it is prudent to ask our patients who have developed pigmentation if they are taking iron supplementation, and, if so, discontinue it before future treatments.

Preventing formation of postsclerotherapy-related ecchymoses would theoretically prevent postinflammatory hyperpigmentation through avoidance of dermal hemosiderin deposition. Although Arnica montana is routinely used by many surgeons to prevent perioperative bruising, the efficacy of this homeopathic product has not been scientifically proven. A recent randomized, prospective, double-blind study evaluated the perioperative use of A. montana (SinEcch) in 29 patients undergoing face-lifts.⁹⁴ Interestingly, the amount, duration, and degree of bruising did not differ between those treated with 10 days of A. montana and those in the placebo group. Although further procedure-specific studies would be necessary, it is likely that this lack of efficacy would be similar if A. montana was used in conjunction with sclerotherapy.

While laser treatment of telangiectatic leg veins is said not to be associated with pigmentation, we have documented numerous patients treated with a variety of lasers who developed prolonged pigmentation (Fig. 8.9).

Figure 8.9 A, Telangiectasia treated by a nurse not under physician supervision with a DioLite 532 laser at 13 J/cm², 3 W, 1000 µm spot size at 5 Hz with a total of 5856 pulses to the leg veins. Note extensive hyperpigmentation over the treated veins 2 months post-treatment. B, This pigment failed to resolve over 9 months of topical application of Triiluma cream after which the patient was lost to follow-up.

Treatment

Treatment of pigmentation, once it occurs, is often unsuccessful unless one has access to a Q-switched laser. Because this pigmentation is caused primarily by hemosiderin deposition and not melanin incontinence, bleaching agents that affect melanocytic function are usually ineffective. Exfoliants (trichloroacetic acid) may hasten the apparent resolution of this pigmentation by decreasing the overlying cutaneous pigmentation or promoting the exfoliation of hemosiderin, but they carry a risk of scarring, permanent hypopigmentation, and postinflammatory hyperpigmentation. However, some physicians have reported apparent success with this therapeutic method.^1,95 The combination of 20% trichloroacetic acid with retinoic acid and hydroxyquinoline has also been reported to totally fade pigmentation in 76% of patients whose pigmentation persisted from 6 months to 5 years.¹ Pigmentation decreased in the remaining patients. Treatments were given every 7 to 10 days from 4 to 12 weeks.

Chatard²⁰ has found that using light cryotherapy to exfoliate the epidermis and ‘evict the pigment’ is helpful. We have not found cryotherapy useful in our practice.

Terezakis (personal communication, 1989) has found the use of topical retinoic acid to enhance resolution of the pigmentation. She speculates that retinoids enhance fibroblastic removal of hemosiderin. We have treated patients who have had pigmentation for more than 3 months with topical tretinoin (Retin-A 0.1% cream). Although formal placebo-control studies have not been completed, it appears this therapy may be effective. It does not seem to have any adverse sequelae and has the advantage of bringing the patient into active therapy.

A seemingly logical form of treatment would be chelation of the subcutaneous iron deposition. Myers⁹⁶ reported the use of a 150 mg/ mL ointment of disodium ethylenediamine tetraacetic acid (EDTA) in the treatment of 10 patients with pigmentation after sclerotherapy or vein stripping or with pigmentation in chronic postphlebitic legs. He reported a consistent reduction in the shade of the pigmentation in every patient treated. Unfortunately, this was an uncontrolled study, and there have been no further reports of this form of treatment since its presentation in 1965. In our experience, intradermal injections of deferoxamine in an attempt to cause chelation of the hemosiderin appear to be somewhat effective but are painful and expensive. The timing of injections and the concentration and quantity of deferoxamine injected have not been systematically studied.

The topical iron chelator 2-furildioxime (FDO) has been found to provide a level of photoprotection and theoretically may also be useful to treat cutaneous hemosiderin pigmentation.⁹⁷ However, at the time of that research proposal, Proctor and Gamble had no interest in providing this agent for clinical testing of postsclerotherapy pigmentation (personal correspondence, Oct 1994).

Graduated elastic compression with coadministration of the anabolic steroid stanozolol decreases pigmentation in patients with lipodermatosclerosis who also have varicose veins.⁹⁸ Skin pigmentation did not change when patients used graduated compression stockings alone. Stanozolol may exert its effect through reduction in perivascular fibrin from fibrinolytic enhancement. In addition, compression alone improves lipodermatosclerotic skin changes, including hyperpigmentation (Partsch H, personal communication, 1992). Although it seems reasonable to promote the wearing of graduated support stockings after treatment, further studies are needed before recommending systemic stanozolol therapy.

A study on the use of 20- to 30-mmHg compression stockings after sclerotherapy treatment of telangiectasia and reticular veins 0.4 to 3 mm in diameter found a decreased incidence of pigmentation when compression was used. Compression for 3 days resulted in a 20% decrease in pigmentation; compression for 1 week produced a 60% decrease in pigmentation compared with no compression; and compression for 3 weeks resulted in limited pigmentation in only 2 of 10 patients.⁹⁹ This follows the logic of compression reducing vessel lumen size, resulting coagula, and hydrostatic pressure. However, Guex found an even lower incidence of residual pigmentation in a prospective study on reticular and spider veins without compression.¹⁰⁰

Finally, laser treatment has been efficacious in 45%²⁴ to 69%¹⁰¹ of patients with pigmentation of 12 or 6 months’ duration, respectively. Hemosiderin has an absorption spectrum that peaks at 410 to 415 nm, followed by a gradually sloping curve throughout the visible spectrum (Fig. 8.10)^102,103 The copper vapor laser (CVL) at 511 nm in a continuous airbrush technique and the flashlamp-excited pulsed dye laser (PDL) at 510 nm should interact relatively specifically with the hemosiderin absorption spectrum. Competition from oxygenated hemoglobin (peak absorption at 577 nm) should be low, but interaction with epidermal melanin, which has a higher absorption rate at these wavelengths, may be significant. These lasers are thought to result in physical fragmentation of pigment granules, which are later removed by phagocytosis. However, penetration of laser energy at 510 and 511 nm is limited to 1 mm below the granular layer. Since hemosiderin may occur up to 2.8 mm below the granular layer, nonthermal effects may result in clinical resolution. An inflammatory reaction from thermal or photoacoustic effects may stimulate hemosiderin absorption. Although CVL-treated pigmentation responded better than that treated with PDL therapy, thermal relaxation times used by the latter laser system should be more selective.

Figure 8.10 Absorption spectra for hemosiderin (freshly frozen, average of two determinations).

(From Wells CI, Wolken JJ: Nature 193:977, 1962.)

The Q-switched ruby laser (694 nm) is also effective in removing recalcitrant pigmentation. Hemosiderin has a peak at 694 nm, and the Q-switching impulse at 20 to 30 nanoseconds is effective in removing tattoo granules. In addition, 694 nm is not absorbed to a significant extent by epidermal melanin or hemoglobin and thus has a relative specificity for dermal hemosiderin. An older ruby laser (Laseaway, England) was been found to effectively remove or minimize pigmentation in a number of patients (Fig. 8.11)¹⁰⁴ In a study of eight patients with pigmentation still present 1 to 2 years after sclerotherapy, 92% of the lesions lightened with treatment; 58% of lesions demonstrated significant (75–100%) resolution after one to three (average 1.7) treatments. The Laseaway ruby laser was used with a 4-mm beam size and a fluence range of 5.6 to 10.5 J/cm². Weiss and Weiss¹⁰⁵ could achieve 90% resolution of pigmentation that had been present for an average duration of 18 months with 3.2 treatments using a Q-switched ruby laser as well (Ruby Star, Aesclepion-Meditec AG, Jena, Germany) at 5 to 10 J/cm² with a 2-nsecond pulse and a 4- to 5-mm diameter spot. We now use a Q-switched ruby laser (Sinon) from WaveLight Laser Technologies (Erlangen, Germany) at 4 to 7 J/cm² with a 20-nsecond pulse and a 4- to 5-mm diameter spot size. Treatments are performed every 4 weeks until resolution. Care is taken to use the minimal fluence required to produce a whitening of the skin without causing bleeding. Our patients require one to two treatments for complete resolution.

Figure 8.11 A, Pigmentation from sclerotherapy lasting over 1 year. B, Resolution 2 months after the second of two treatments with the Q-switched ruby laser at 8.0 J/cm².

(Courtesy David Duffy, MD; from Goldman MP, Weiss RA, Bergan JJ, editors: Varicose veins and telangiectasias: diagnosis and treatment, St Louis, 1999, Quality Medical Publishing.)

Interestingly, we have not found satisfactory results using a variety of Alexandrite lasers either in long-pulse or Q-switched mode. This may be due to the decreased interaction of the 755-nm wavelength with hemosiderin.

Weiss¹⁰⁶ has reported successful clearing with the use of intense pulsed light (IPL; Photoderm PL, Lumenis, Santa Clara, Calif.) in 10 patients with pigmentation persisting after 1 to 2 months. He used the IPL at 30 to 40 J/cm² given in a single 4-msec pulse with a 590-nm cut-off filter. Significant lightening occurred in 6 of the 10 patients.

The most recent Q-switched laser used to treat postsclerotherapy pigmentation was a novel 532/1064-nm Nd:YAG laser (Palomar Med Tech, Burlington, Mass.). Ten patients who had had persistent pigmentation for an average of 18 months were treated at 2-nsecond pulse with 75% 1064 nm and 25% 532 nm simultaneously with a 6-mm diameter spot at 2 J/cm². There was a 75% resolution in an average of 2.8 treatments.¹⁰⁷

The simplest treatment is ‘flashbulb therapy’ or ‘chronotherapy’. Since pigmentation usually resolves within 1 year in the majority of patients, time and photographic documentation to demonstrate resolution are usually all that is necessary for the understanding patient. Persistence of pigmentation beyond 1 year usually indicates untreated reflux from above and should be investigated by Duplex ultrasound.

Etiologic factors

Multiple factors are responsible for swelling of a treated area. These factors include changes in the pressure differential between the intravascular and perivascular space and changes in endothelial permeability. Edema is most common after treatment of varicose veins or telangiectasias below the ankle, because of the increase in gravitational intravascular pressure in this area and the relative scarcity of perivascular fascia at the ankle. Riddock¹⁰⁸ speculates that edema is caused by an unduly prolonged reflex spasm spreading to some of the subfascial (deep) veins.

The extent of edema appears to be related to the strength of the sclerosing solution. This result apparently correlates with the degree of perivascular inflammation produced by the sclerosing solution. The byproducts of inflammation, including release of histamine and various mediators, increase endothelial permeability. In addition to the degree of inflammation induced by sclerotherapy itself, the innate sensitivity of a patient’s perivascular mast cells (possibly related to their atopic or asthma history), concomitant medications that may promote or inhibit mast cell degranulation (e.g. corticosteroids, antihistamines, nonsteroidal anti-inflammatory agents), and previous exposure sensitivity to the sclerosing agent may all contribute to edema. Duffy⁸ and Goldman¹³ estimate that the occurrence of pedal edema ranges from 2% to 5%.

Edema may also occur if compression is not applied gradually. Edema may be produced when localized pressure on the thigh is applied over an injected vein and with the addition of a tape dressing over or under a graduated compression stocking. If patients are informed of the possibility of a tourniquet effect by the extra compression, they can be advised to remove the dressing at the first sign of edema distal to the dressing.

Prevention and treatment

Two techniques may decrease temporary swelling. First, perivascular inflammation must be limited, as previously described (see the sections ‘Recommended sclerosing solution amounts and concentrations’ and ‘Postsclerotherapy compression’ in Chapter 9). Ankle edema occurs much less frequently if the quantity of sclerosing solution is limited to 1 mL per ankle.

One method that we have found helpful is topical application of a strong-potency corticosteroid cream, lotion, or gel. Methylprednisolone acts both to stabilize mast cell membranes, preventing histamine release, and to exert part of its anti-inflammatory action directly on the endothelial cell, rendering it less responsive to various mediators.¹⁰⁹ Ruscus extract inhibits macromolecular permeability, increasing the effect of histamine in the hamster cheek pouch model.¹¹⁰ This effect is due to stabilization of endothelial pore size. Beta-receptor agonists such as terbutaline and theophylline counteract histamine-induced venular permeability. This effect also occurs with verapamil and glucocorticoids.¹¹¹

A second method for limiting the degree of pedal or ankle edema is application of a graduated pressure stocking routinely after injections in this area.¹¹² One study compared the use of postsclerotherapy graduated compression for 3 days to 3 weeks and reported that none of 10 patients complained of edema when stockings were worn for 3 weeks; 40% of patients who did not wear post-treatment compression stockings had edema, with 30% having edema if stockings were worn for only 3 days and 20% complaining of ankle/pedal edema if stockings were worn for 1 week.⁹⁹

Etiologic factors

Postsclerosis TM was first described in the 1960s by Ouvry and Davy.¹²¹ They observed that the incidence of matting was proportional to the degree of inflammation and thrombus formation. The etiology of TM is probably related either to angiogenesis^8,122 and/or to a dilation of existing subclinical blood vessels by the promotion of collateral flow through arteriovenous anastomoses.^122,123

Probable risk factors for the development of TM in patients with leg telangiectasia include obesity, use of estrogen-containing hormones, pregnancy, and a family history of telangiectatic veins. Excessive standing does not appear to influence the incidence of TM.¹¹⁵ Excessive postsclerotherapy inflammation also may predispose toward development of TM.

After sclerotherapy, the development of TM occurs rapidly; often patients report the development over a few days at 3 to 6 weeks after treatment. Normally, the more than one trillion endothelial cells that line blood vessels have a turnover time of more than 1000 days.¹²⁴ However, under appropriate conditions, new vessels can develop in 2 to 3 days. Observations of mammalian systems have demonstrated the development of a vein from a capillary, an artery from a vein, a vein from an artery, or from either back to a capillary.^125,126 In coronary vessels, the number of arterioles and capillaries increases within 1 week after injury.¹²⁷

Angiogenesis

Angiogenesis is a complex process in which capillary blood vessels grow in an ordered sequence of events. Angiogenic factors act either directly on the endothelium to stimulate locomotion and mitosis or indirectly by mobilization of host helper cells (mast cells and macrophages) with release of endothelial growth factors (see below). When a new capillary sprout grows from the side of a venule, endothelial cells degrade basement membrane, migrate toward an angiogenic source, proliferate, form a lumen, join the tips of two sprouts to generate a capillary loop, and manufacture new basement membrane.¹²⁸ Obstruction of outflow from a vessel (which is the end result of successful sclerotherapy) is one of the most important factors contributing to angiogenesis.¹²⁹ Initiation of angiogenesis also follows disruption of endothelial continuity or intercellular contact. This contact results in endothelial cell sprouting and migration.¹³⁰

Hypoxia with a decrease in the partial pressure of cellular oxygen also is a potent stimulator of neovascularization. With ischemia, one of the first genes upregulated is the gene encoding hypoxia-inducible factor-1 (HIF-1).¹³¹ This factor activates genes involved in angiogenesis, glycolysis, modulation of vascular tone, and erythropoiesis.^131–133

In addition, endothelial damage leads to the release of heparin and other mast cell factors that both promote the dilation of existing blood vessels and stimulate angiogenesis.^134–137 Finally, neovascularization may be promoted by numerous other angiogenic factors, including, but not limited to, heparin-binding fibroblast growth factor (FGF),^2,138,139 tumor necrosis factor (TNF),^135,140,141 platelet-derived endothelial mitogen,¹⁴² endothelial cell growth factor (ECGF),¹⁴³ and other macrophage-derived growth factors.^144,145 These factors and many others are released from perivascular mast cells.¹⁴⁶ FGF is released at cell death and is essential for the stimulation of angiogenesis and wound repair.^147,148 Thus, sclerotherapy, through endothelial damage, promotes the release of both endothelial angiogenic factors and perivascular mast cell angiogenic factors that provide multiple mechanisms for the formation of new blood vessels. Indeed, it is remarkable that postsclerosis TM does not occur more frequently.

Sclerotherapy-induced perivascular inflammation also may promote TM.²⁶ Inflammation may be considered a hypermetabolic state, with new vessel growth occurring as a result of increased metabolic demand.¹⁴⁹ In addition, mast cells are found in increased numbers in inflammatory states, such as allergic contact dermatitis or delayed hypersensitivity reactions.¹⁵⁰ Since mast cell heparin is one factor responsible for capillary endothelial cell migration,¹²⁴ the degree of inflammation should be limited as much as possible to decrease angiogenic stimuli. This is achieved by choosing an appropriate solution concentration for each type of vessel treated, limiting the quantity of solution to the amount that will not produce excessive endothelial damage, and limiting the size of postsclerotherapy thrombosis. This was confirmed by Weiss and Weiss,⁴² who found that in a random sample of 113 sclerotherapy patients, TM developed in 10 with injection of POL 1% into vessels less than 1 mm in diameter. When POL 0.5% was used for subsequent treatments in these patients, further areas of TM did not develop. The use of low concentrations of POL was found in a multicenter report of 16,804 legs to have an incidence of TM of 0.04%.¹⁵¹ However, it is unclear how closely patients in this large prospective clinical trial were followed. A comparison of POL 1% with HS 20% in treating leg telangiectasia showed that the incidence of TM was higher with the more caustic POL (36%) than with HS (31%) (Fig. 8.14).⁴⁴

Figure 8.14 A, Before treatment. Note reticular vein feeding into telangiectasia on the superior lateral thigh. B, 6 weeks after sclerotherapy treatment. Note resolution of superior lateral thigh telangiectasia with appearance of ‘new’ telangiectasia distal to point of injection.

Another group of investigators reported TM in 12% of patients treated with Sclerodine 0.25%, in 17% treated with Sclerodex, and in 15% treated with 0.25% POL.¹² These agents should all be comparatively similar in their sclerosing power despite their different mechanism of action on endothelial cells. Interestingly, although their effectiveness in eliminating telangiectasia varied from 73% for POL to 44% for Sclerodine and Sclerodex, the incidence of TM was relatively similar.

A study comparing different times of postsclerotherapy compression in treating leg telangiectasia also demonstrated a decrease in TM when compression was maintained for 1 to 3 weeks (5%) versus 3 days (30%) or no compression (40%).¹⁵² This is most likely a reflection of a decrease in intravascular thrombosis with prolonged graduated compression, which results in a decreased phlebitic effect with decreased inflammation.

As noted previously, assuming a role for the perivascular mast cell in the etiology of TM is intriguing. With aging, cutaneous mast cells decrease by 50%, associated with a 35% decrease in subepidermal venules.⁶⁰ Thus, if TM develops predominantly from mast cell factors, its incidence should be decreased in the elderly; however, this has not been observed in two studies.^113,115 Cutaneous mast cells usually occur perivascularly, with a distribution ranging from 7000/mm to 20,000/mm.^{7,8,153–156} This represents 0.2% to 0.7% of normal skin. In telangiectatic macules associated with mastocytosis, mast cells account for 3.5% (±1.8 SEM) of cells, whereas telangiectasia not associated with mastocytosis has a mast cell volume of 0.4% (±0.1 SEM).¹⁵⁷ An analysis of mast cell content in TM lesions is needed.

Estrogen may play a role in the development of TM. It appears that the incidence of persistent TM may be increased in patients taking systemic estrogen preparations.^8,42,115 Weiss and Weiss⁴² found a relative risk of 3.17 (P < 0.003) for development of TM while patients were receiving exogenous estrogen. Sadick also found an increased incidence of TM (10% vs 4%) in patients on oral contraceptive agents or hormone replacement therapy.¹⁵⁸ The mechanism for promotion of TM by estrogen is speculative but may be the result of its effect on modulating mast cell responses.¹⁵⁹

Estrogen receptors have been found in a number of tumors, including angioma of the nose, soft tissue sarcoma, breast carcinoma, endometrial carcinoma, and unilateral nevoid telangiectasia syndrome. Estrogens also play a role in the development of vascular tissues. In vitro, estrogen and estradiol have promoted endothelial cell migration and proliferation.^160,161 Spider angiomas develop during pregnancy and resolve after delivery.^162,163 Spider nevi also occur in patients with hepatic cirrhosis associated with elevated serum estradiol levels.¹⁶⁴ In addition, Davis and Duffy¹⁰⁵ have reported on the virtual disappearance of leg telangiectasia and TM in a 51-year-old woman with estrogen-receptor-positive breast carcinoma after initiation of antiestrogen therapy with tamoxifen citrate (nolvadex). This may be due to the inhibition of angiogenesis by tamoxifen.^165,166 However, although it seems logical that estrogen plays a role in the development of TM, estrogen receptors could not be demonstrated in biopsy specimens from leg telangiectasia.¹⁶⁷ An evaluation of estrogen receptors in 10 patients with TM lesions did not demonstrate estrogen/progesterone receptors as assayed by ERICA/PRICA technique.¹⁶⁸ The limiting factor of this study as stated by the authors was the small size of the study group, as well as the possibility that the immunocytochemical and radioligand assays may not have been sensitive enough to document a small number of estrogen or progesterone receptors. In addition, a selective estrogen-receptor modulator that is specific for blood vessels has yet to be identified.¹⁶⁹ Further, circulating endothelial progenitor cells are also elevated with estrogen therapy and may lead to neoangiogenesis.¹¹⁶ Since estrogen receptors have been implicated in the promotion of angiogenesis,¹⁷⁰ it may be prudent, albeit premature, to withhold estrogen therapy during sclerotherapy treatment until double-blind controlled studies have been performed.

Prevention and treatment

Regardless of the cause of TM, since patients seek treatment to eliminate leg telangiectasia, it is disconcerting for the sclerotherapist to produce new areas of telangiectasia. Unfortunately, even in the most expert hands, TM occurs in a significant percentage of patients. Fortunately, TM usually resolves spontaneously over 3 to 12 months.^8,42 It has been estimated that 10% to 20% of patients will have persistent TM.^115,171 Our experience is that less than 1% of patients will have TM persisting for 1 year.

Treatment methods for TM are limited. Reinjection with hypertonic solutions or glycerin may be helpful. Because of the extremely small diameter of these vessels, use of a 31- to 33-gauge needle is helpful. Injection of any feeding reticular veins or venulectases into the TM area should also occur.

Various vascular-specific lasers and IPL sources may be useful in treating these vessels.^172–176 In our practice, at least 75% of patients with persistent TM partially or completely improve after laser or IPL treatment. Interestingly, individual TM lesions may respond better to one laser or IPL than another. Reasons for the variable response are speculative. The 532-nm long-pulse Nd:YAG laser set at the highest fluence and pulse durations available has been found to be most effective on the most recalcitrant lesions. However, persistent and, rarely, permanent hypopigmentation may occur. The use of the PDL may also be effective but result in long-term hyperpigmentation. Glaich et al recently reported successful treatment of postsclerotherapy matted telangiectasias using fractional photothermolysis.¹⁷⁷ Specifically, marked improvement was noted in these telangiectasias, which had been present for longer than a year, after five successive treatments with a 1550 nm fractional photothermolysis laser at 4 week intervals. The reason for this reported success is questioned as in this study resolution required 6 months, which is the time course of spontaneous resolution of TM. In addition, this was a single case report. We therefore can not recommend fractional photothermolysis as effective at this time. (A complete discussion of laser treatment is found in Chapter 13.) Unfortunately, even with the aformentioned therapeutic approaches, rare TM may remain resistant to treatment, possibly because in certain cases TM may have a feeding arteriolar network that prevents persistent vessel elimination.

In patients who demonstrate a propensity for the development of TM, additives to the sclerosing solutions or topical agents may minimize this complication. Protamine blocks the ability of mast cells and heparin to stimulate migration of capillary endothelial cells.¹⁷⁸ Protamine also prevents the neovascularization induced by an inflammatory agent when it is applied locally or given systemically.¹⁷⁹ It has no effect on established capillaries that are not proliferating.¹⁸⁰ In addition, beta-cyclodextrin tetradecasulfate administered with cortexolone is a potent inhibitor of angiogenesis.¹⁸¹

Systemic treatment before or during sclerotherapy also may be helpful in limiting TM. Through suppression of TNF synthesis, pentoxifylline (Trental) may minimize angiogenesis.^182,183 Inhibition of mast cell mediators with the cell wall-stabilizing medication ketotifen also may help prevent TM, edema, and localized urticaria. Ketotifen, a benzocycloheptathiophene derivative, has H₁ antihistaminic properties in addition to decreasing mast cell mediator release.^184,185 Ketotifen may also exert its effect by depleting mediators in cutaneous mast cells and so requires multiple doses over a few days for maximal effect.¹⁸⁶ Its clinical beneficial effect in patients with chronic idiopathic urticaria, cutaneous mastocytosis, and urticaria pigmentosa has been established.^186–190

Prevention

Since most patients who seek treatment of leg telangiectasia require multiple treatment sessions, each consisting of numerous injections, an attempt should be made to minimize the unpleasantness of the procedure. Certain areas are slightly more painful, especially the ankles, feet, upper medial thighs, and medial knees. The authors have not found it necessary to utilize topical anesthetic creams and indeed a commonly used anesthetic cream, EMLA (eutectic mixture of lidocaine and prilocaine) has been found to produce vessel contraction, making it more difficult to perform treatment (Fig. 8.15). Two variables that can be adjusted to minimize pain are the type and size of the needle and the type of sclerosing solution.

Figure 8.15 EMLA (eutectic mixture of lidocaine and prilocaine ) applied to the proposed treatment area after 45 minutes of occlusion. Note blanching of target blood vessels.

Treatment

In our experience, localized urticaria and itching can be diminished by applying topical steroids immediately after injection and by limiting the injection quantity per injection site. This is particularly helpful in patients who will wear a graduated support stocking after treatment. High-potency topical corticosteroids, such as clobetasol propionate, have been shown to rapidly decrease histamine-induced pruritus.¹⁹⁵ Therefore we recommend application of a non-greasy, fast-absorbing, high-potency corticosteroid to all treated areas after sclerotherapy. A secondary effect of the topical corticosteroid is vasoconstriction, which also may help with vessel resolution, reduction of TM and minimize post-treatment thrombosis with its sequelae.

Prevention

If compression pads will be used under graduated stockings in a patient susceptible to blistering, a tubular support bandage can be used over the pad to hold it in place while the stocking is being applied. Although somewhat costly, this dressing (similar to a net dressing used in burn patients) helps prevent blister formation. (It also can be used in patients with allergies to tape.)

Treatment

Resolution of the blister occurs within 1 or 2 weeks without any adverse sequelae. To aid healing and prevent infection of the denuded skin, the use of an occlusive hydroactive dressing is helpful. Occlusive dressings may also help alleviate any pain associated with the blister.

Treatment

Treatment consists of removal of the occlusive dressing and application of topical treatment with an antibacterial soap such as chlorhexidine gluconate or a topical antibiotic gel such as erythromycin 2% or clindamycin phosphate topical solution 1%. The folliculitis usually resolves within a few days. Systemic antibiotics are rarely necessary.

Morpheas

Presenting like morphea observed in scleroderma, this can appear after injection of subcutaneous varicose veins. The etiology is unknown and the incidence is rare. Some patients suffering from scleroderma have been treated by sclerotherapy without presenting morphea; conversely, patients without scleroderma have developed morphea (Fig. 8.21).

Figure 8.21 Morpheas: subcutaneous and cutaneous retraction following sclerotherapy of subcutaneous varices. The patient (a 67-year-old female) was not suffering from scleroderma (neither clinical nor biological). A type of localized scleroderma can be suspected.

Treatment

Tournay²⁰¹ was the first physician to stress the importance of postinjection removal of blood clots, in 1938. The importance of draining these postsclerotherapy thrombi has since been emphasized by Sigg,²⁰² Pratt,²⁰³ Hobbs,²⁰⁴ and Orbach.¹⁹⁸

With proper technique, varicose veins only rarely recur. A biopsy study of six patients with ‘recurrence’ of previously treated veins demonstrated that the veins thought to have recurred were in reality new varicose veins.²⁰⁵ Raymond-Martimbeau and Dupuis¹⁹⁷ have reported a 3.6% recurrence rate with 2-year follow-up of 884 sites of telangiectasia in 525 patients. When high recurrence rates are reported, the patients have usually been treated with minimal compression.¹⁹⁸ For example, in one recent study of 310 patients, 83% required reinjection of a treated varicosity. These patients received only 48 hours of compression with elastic bandages.¹⁹²

Unlike recanalization through a varicose vein cord, recanalization is not common through a sclerosed telangiectasia. Post-treatment histologic studies have demonstrated only fibrosis in an area treated with sclerotherapy.⁷ One study of telangiectasia found a ‘recurrence rate’ of 56% when patients were evaluated 5 years after sclerotherapy. In 48% of patients affected by a recurrence, the additional telangiectasias were of minimal extent, requiring little if any treatment.²⁰⁶ Examination of telangiectasia present 1 year after treatment most likely indicated either untreated telangiectasia or new telangiectasia, and not recurrent veins. Our experience in observing before and after images on thousands of patients with multiple treatments over two decades confirms that telangiectasias are typically not recurrent but new.

Vasovagal reflex

The vasovagal reflex (neurocardiogenic syncope) is a common adverse sequela of any surgical or invasive procedure. A survey conducted in an ambulatory care center revealed an incidence of 10.6% during vein cannulation in 1500 patients.²⁰⁷ It has been estimated to occur in 1% of patients during sclerotherapy²⁰⁸ and is more frequent when using the technique of Fegan or Sigg, which requires patients to stand on insertion of needles.²⁰⁹ Duffy,⁸ who performs sclerotherapy with 30-gauge needles in reclining patients, estimates the incidence of vasovagal reactions as 0.001%. Interestingly, the percentage of men who have this response far exceeds the percentage of women. We (MPG, RAW) have seen a patient with a vasovagal reaction only twice in over 20 years of performing sclerotherapy in reclining patients, and, interestingly, have seen vasovagal reactions many times in male patients just being examined with duplex ultrasound or hearing the Doppler flow sound.

Vasovagal reactions have typical clinical findings. The usual symptoms include light-headedness, nausea, and sweating. The patient also may have shortness of breath and palpitations. Syncope may occur and usually provokes the most concern in the physician and staff. With progression of the reaction, a seizure may occur, as well as cardiac arrhythmia with a rapid decrease in cardiac output and even cardiac arrest.²¹⁰ Vasovagal reactions most often are preceded by painful injection but may even occur from the patient seeing the needle or smelling the topical isopropyl alcohol or sclerosing solution.

Underlying medical disease

More serious stress-induced problems include exacerbation of certain underlying medical diseases. Patients with a history of asthma may start wheezing, which can be treated with bronchodilator therapy such as metaproterenol sulfate (Alupent, Proventil) or over-the-counter epinephrine bitartrate or metered-dose inhalers (Primatene).

Angina may develop in patients with cardiovascular disease and can be treated with sublingual nitroglycerin (NTG) tablets. As discussed in detail later, POL is a negative inotropic agent and slows cardiac contractility in a dose-dependent manner. Chest pain has also been reported with the use of STS, but this is not cardiac in nature. In our practice, one 65-year-old patient without a history of cardiac disease and treated with STS had acute chest pain on two separate occasions when using 2–4 mL of 0.5% STS. An electrocardiogram taken immediately while the patient was having chest pain was normal, and sublingual NTG was ineffective in resolving the pain, which lasted approximately 5 minutes. This may have been an idiosyncratic reaction.

Etiology

Cutaneous necrosis may occur with the injection of any sclerosing agent, even under ideal circumstances, and does not necessarily represent physician error (Fig. 8.30) Fortunately, its occurrence is both rare and usually of limited sequelae. Its cause may be the result of:

Figure 8.30 Cutaneous necrosis after injection with polidocanol 0.5% into telangiectasia. A, Preinjection. B, Early atrophie blanche 10 days after injection. C, Superficial ulceration is present 5 weeks after injection. D, Clinical appearance 24 weeks after injection; complete resolution had occurred in 12 weeks.

Extravasation

Extravasation of caustic sclerosing solutions may directly destroy tissue. The extent of tissue injury is directly related to both the concentration of the sclerosing solution and the quantity extravasated. As discussed below, different sclerosing solutions have a greater or lesser ability to destroy tissue. Since the final clinical appearance of the skin may not be apparent for several days, therapeutic intervention must be undertaken as soon as possible in all cases.

Clinically, bright erythema is present in the skin overlying the extravasated solution (Fig. 8.31). With certain extravasation injuries, the formation of epidermal blistering may occur but does not predict a partial-thickness injury, although it may precede eventual full-thickness necrosis.²²⁵

Figure 8.31 Erythema overlying an area of extravasation from injection of a telangiectasia with sodium tetradecyl sulfate 0.25%.

During injection of an abnormal vein or telangiectasia, even the most adept physician may inadvertently inject a small quantity of sclerosing solution into the perivascular tissue (Fig. 8.32). A tiny amount of sclerosing solution may be left in the tissue when the needle is withdrawn, and sclerosing solution may leak out of the injected vessel, which has been traumatized by multiple or through-and-through needle punctures. Rarely, the injection of a strong sclerosing solution into a fragile vessel may lead to endothelial necrosis and rupture producing a ‘blow-out’ of the vessel and perivascular extravasation of sclerosing solution (Fig. 8.33). Therefore, injection technique is an important but not foolproof factor in avoiding this complication, even under optimal circumstances.

Figure 8.32 Mechanism for extravasation of sclerosing solution. A, Extravasation through multiple needle puncture holes. B, Extravasation from injection of sclerosing solution after slight withdrawal of the needle. C, Extravasation of sclerosing solution along needle shaft. D, Extravasation from injection with needle bevel partially in the vein. E, Extravasation through excessive destruction of the vein wall.

(Redrawn from Biegeleisen HI: Varicose veins, related diseases, and sclerotherapy: a guide for practitioners, Montreal, 1984, Eden Press.)

Figure 8.33 Cutaneous necrosis after injection of sodium tetradecyl sulfate 0.5%. A, Immediately after injection. Note ‘hyperemic burn reaction’. B, Necrotic epidermis 2 weeks after injection.

Sclerosing solutions vary in the degree of cellular necrosis they produce. If minimal tissue necrosis is caused by a sclerosing agent, it may perhaps be suitable for perivascular injection in the treatment of telangiectatic mats whose vessels cannot be cannulated even with a 33-gauge needle.

With an osmolality greater than that of serum (281–289 mOsm/L), hyperosmotic agents can cause tissue damage as a result of the osmotic gradient. Epidermal necrosis has even occurred from extravasation of solutions containing 10% dextrose.²²⁶ Hypertonic saline 23.4% is a caustic sclerosing agent, as demonstrated in intradermal injection experiments. Clinically, small punctate spots of superficial epidermal damage occur at points of injection, especially when a small bleb of the solution escapes from the vein. However, subcutaneous injection of up to 1 mL of HS 23.4% (by mistake) in lieu of lidocaine into the neck or cheek has been reported to result in no adverse sequelae.²²⁷ In this situation, cutaneous necrosis was most likely avoided by rapid physiologic dilution of the HS. Alternatively, dermal tissue may be more resistant to the caustic effects of hypertonic solutions. However, the increasing frequency of cutaneous necrosis occurring after extravasation of inadvertent subcutaneous injection of HS has moved the US Department of Health and Human Services and the product manufacturer (American Regent Laboratories, Inc.) to recommend that HS be stored only in pharmacies where all dilutions would be performed before dispensing. This would eliminate the possibility of an iatrogenic medication error outside the pharmacy (Mary Helenek, American Regent Laboratories, Inc., written communication, May 1990). It is recommended that HS be stored in a location separate from other injectable solutions to prevent this potential complication.

Experimentally, POL apparently is minimally toxic to subcutaneous tissue. Duffy^228,229 has reported injecting 0.5 mL of a 3% solution of POL directly into his own forearm skin without the development of an ulceration. Although some physicians advocate the use of intradermal POL 0.5% to treat tiny telangiectatic leg veins,^230,231 POL in sufficient concentration causes cutaneous necrosis. Solutions of POL greater than 1.0% may produce superficial necrosis with intradermal injection.²³⁰ This unfortunately occurred with the mistaken injection of 0.1 mL POL 5% solution into a leg telangiectasia 0.2 mm in diameter in our practice. This injection resulted in extensive overlying cutaneous necrosis that took 8 weeks to heal. Therefore, POL is not without the risk of cutaneous necrosis if a strong enough concentration is injected.

Although STS is more toxic to tissue than is POL, with extravasation, concentrations above 0.25% usually are necessary to produce ulceration. Banning reported on the development of ulcerations in 5 of 4860 consecutive patients after telangiectasias were injected with STS 0.1%. (Presentation at the Eighth Annual Meeting of the North American Society of Phlebology, Fort Lauderdale, Fla., February 28, 1995.) As discussed below, this probably represents injection into an arteriole.

Of note, several cases of Nicolau’s livedoid dermatitis (NLD) following sclerotherapy have been reported.^232–235 Although most commonly seen after intramuscular injections, NLD manifests as pain at the injection site followed by the development of a livedoid plaque, often progressing to cutaneous necrosis. One case of delayed NLD following ultrasound-guided sclerotherapy with POL 2% foam was described recently.²³⁵ This particular case was unique in that, not only did it follow an intravenous injection but it also did not manifest until 4 days after the procedure, when the patient first experienced acute pain followed by subsequent cutaneous ischemia. Interestingly, in each reported case of NLD following sclerotherapy, duplex scans failed to show evidence of thromboses in major arteries or deep veins. The author hypothesized that NLD most likely occurred via perivascular spreading of the sclerosant, after leakage from a site of intravenous injection. Subsequently, POL probably acted as a local irritant, inducing arterial or arteriolar vasospasm. Concentrations of POL associated with sclerotherapy-induced NLD ranged from 0.5% to 3%, disfavoring a concentration-dependent phenomenon. One unifying theme among these isolated cases of NLD is that each occurred after injection into veins known to be in close proximity to rich arterial or arteriolar networks. Examples of these at-risk sites include the inguinal fold, medial knee, and medial ankle. Although the limited number of cases of NLD following sclerotherapy reflects its rarity, the clinician is encouraged to remain aware of this potential complication.

Glycerin or CG solutions have not been reported to produce cutaneous necrosis with extravasation. Duffy (personal communication, 1992) has shown that injection of ‘full-strength’ CG will not produce cutaneous necrosis when it is injected into the mid-dermis. Histologic examination of his patient showed no evidence of dermal or epidermal damage.

Even when sclerotherapy is performed with expert technique, using the safest sclerosing solutions and concentrations, cutaneous ulceration may occur (Figs 8.30, 8.34, and 8.35). Therefore, it appears that extravasation of caustic sclerosing solutions alone is not totally responsible for this complication.

Figure 8.34 Cutaneous necrosis 6 weeks after sclerotherapy with polidocanol 0.25%. Note that 2 mL of solution was injected into a feeder vein approximately 10 cm distal to the necrotic area.

Figure 8.35 A 38-year-old woman who had undergone numerous sclerotherapy treatments with and without ultrasound guidance. The last ultrasound-guided sclerotherapy treatment with sodium tetradecyl sulfate 2% into a perforating vein resulted in immediate blanching of the overlying skin. Nitroglycerin paste was rubbed into the affected area. A 7 × 5cm dusky blue patch developed 1 week later when the compression stocking was removed, with 2 × 5 mm diameter areas of superficial skin necrosis. In this instance the injection was clearly intravenous even though the effects were those of arterial ischemia.

(From Bergan JJ, Weiss RA, Goldman MP: Dermatol Surg 26:535, 2000.)

Arteriolar Injection

De Faria and Moraes²³⁶ have observed that 1 in 26 leg telangiectasias is associated with a dermal arteriole. Bihari and Magyar²³⁷ have found pulsatile flow in 68.9% of patients in 16 of 18 biopsies (2.5 × 1.5 cm) taken from the pulse-positive telangiectasia in patients demonstrating arteriovenous (AV) microshunts. This gives a 61% incidence of AV microshunts in patients with leg telangiectasia. An expanded study of 155 patients with leg telangiectasia by the same group demonstrated a 72.2% incidence of pulsatile flow.²³⁸ We believe that the incidence seen in our patients is considerably lower and may represent only 10% or less and might be attributed to a different age or subset of patients, or perhaps to the more physiologic conditions seen with Duplex ultrasound rather than biopsy. The higher incidence found in the later two studies is probably caused by the larger biopsy specimens taken. Of the 22 Doppler-positive telangiectasias, 19 demonstrated AV microshunts on biopsy. Thus, it is likely that rapid injection or large-volume injection into leg telangiectasias that are associated with microshunts will force the sclerosing solution into the arterial circulation. It is our opinion that inadvertent injection into or near this communication is the most common cause of cutaneous ulcerations.

It has been shown by Duffy and by our experience that when POL is injected intradermally to effect sclerosis of TM, cutaneous ulceration does not occur, even with the injection of 0.5 mL of a 0.75% solution. However, we have noted the development of 3- to 6-mm diameter ulcerations in approximately 0.0001% of injections with POL 0.5%. Five consecutive ulcerations that appeared over the course of 12 months were excised. In these patients, each cutaneous ulceration developed as the result of the occlusion of the feeding dermal arteriole. This produced a classic wedge-shaped arterial ulceration (Fig. 8.36). The Australian Polidocanol Open Clinical Trial at 2 years reported 43 ulcers on 32 legs after sclerotherapy treatment of varicose and telangiectatic leg veins on 12,544 legs, for an incidence of 0.23%.²³⁹ Therefore, it appears that rare cases of small ulcerations may be unavoidable to some extent, especially in the pretibial and malleolar areas.

Figure 8.36 A, Low-power view showing skin ulceration and focal inflammation extending into the subcutaneous fat. A thrombosed vessel, most likely an artery, is present directly under the area of necrosis (hematoxylin–eosin; ×25). B, Higher magnification of the same area as in A, showing a thrombosed artery that caused the infarct. The arterial lumen is completely occluded by fresh thrombus (hematoxylin–eosin; ×200).

Interestingly, since we have been using glycerin solution in a 72% concentration mixed 2 : 1 with lidocaine 1% with or without epinephrine 1 : 100,000 we have not seen ulcerations at all. The safety of glycerin may be its high viscosity, which prevents the solution from flowing into arteriole connections. Alternatively, the epinephrine mixed into the solution may put the arteriolar portion of the AV anastomosis into spasm and/or the lidocaine portion may vasodilate and protect the arteriolar portion of the AV anastomosis. Or the actual incidence of AV anastomosis is much lower than previously estimated.

Vasospasm

Rarely, after injection of the sclerosing solution, an immediate porcelain-white appearance is noted at the site of injection (Fig. 8.37). A hemorrhagic bulla usually forms over this area within 2 to 48 hours (Fig. 8.38) and progresses to an ulcer.⁸⁷ This cutaneous reaction might represent an arterial spasm. Duffy²²⁹ reported this effect when injecting facial telangiectasia.

Figure 8.37 Porcelain-white cutaneous reaction immediately after injection with polidocanol 0.25%. This area progressed into a punctate cutaneous ulceration.

Figure 8.38 A, Hemorrhagic macular reaction 1 week after injection with polidocanol 0.5%. B, Appearance after 2 months. This area healed without any complication.

Vasospastic reactions of arteries occur in predisposed individuals for unknown reasons.^240–242 This may occur even with puncture of the artery without injection of sclerosing solution.²⁴² Thus, small vessels, when irritated in susceptible patients, may spasm.

In an attempt to reverse the spasm, vigorous massage when the white macule appears usually prevents the development of ulceration. However, prevention of the ulceration with massage alone is not always successful. Massaging in a nitroglycerin ointment 2% is more likely to prevent the development of ulcerations in this setting.

The major systemic action of nitrates is a direct reduction in venous smooth muscle tone.²⁴³ Nitrates also relieve spasm of angiographically normal and diseased arteries.²⁴⁴ Topical nitroglycerin ointment has been reported as beneficial in treating both dopamine extravasation and vasoconstriction necrosis.^245,246 Although more experience from other investigators needs to be reported, it seems prudent to use this technique.

Another technique that may help in reversing vasospasm is the topical application of nitric-oxide-generating gel. This gel has been found to increase baseline blood flow in the fingers of patients with Raynaud’s syndrome.²⁴⁷ Since patients with Raynaud’s syndrome have abnormal digital vasoconstriction, the improvement found in application of this gel may crossover to potential improvement in sclerotherapy-induced vasospasm. The gel is prepared by mixing a solution of KY jelly and sodium nitrate (5% weight per volume (w/v)) with a solution of KY jelly and ascorbic acid (55% w/v).

Arterial spasm also may explain the development of cutaneous ulceration upstream from the injection site (see Fig. 8.34). In this latter case, 2 mL of POL 0.25% was injected into a feeding reticular vein (arrow Fig. 8.34). That was the only injection given to the patient in that sclerotherapy session. This has also been reported by Rabe and termed embolia cutis medicamentosa.²⁴⁸

Subcutaneous Injection

Parmentier observed a case of necrotizing panniculitis after an accidental, large volume, subcutaneous injection of 0.5% POL.²³⁵ We have seen a similar patient develop a small necrotizing panniculitis after injection with HS (Fig. 8.39).

Figure 8.39 A, 55-year-old woman who developed a nonhealing ulceration 6 months after treatment by a non-supervised cardio-cath nurse with hypertonic saline for leg telangiectasia. There is a necrotic debris within the ulceration. B, Removal of the necrotic debris shows extrusion of adipose tissue. C, Excision of the necrotic area with a 4 mm surgical punch closed with a 5/0 nylon suture resulted in rapid healing over 2 weeks with minimal scarring. Pathologic examination was remarkable only for necrotic adipose tissue with a mixed inflammatory infiltrate.

Excessive Localized Compression

Excessive compression of the skin overlying the treated vein may produce tissue anoxia with the development of localized cutaneous ulceration (Fig. 8.40). Subcutaneous tissue flow in the leg is decreased when cutaneous pressure exceeds 20 mmHg.²⁵⁰ In addition, external pressure greater than 30 mmHg reduces muscle blood flow in some patients.²⁵¹ Therefore, excessive compression may produce tissue ischemia. However, both these studies used indirect measurements of subcutaneous tissue flow and calf muscle blood flow and thus must be viewed with caution. A more physiologic method for measuring the effect of compression on blood flow was recently performed through determination of femoral blood flow.²⁵² These authors demonstrated that in the recumbent patient, static, graduated external compression of approximately 20 mmHg at the ankle, reduced to approximately 10 mmHg in the upper thigh, produces an increase in femoral flow of up to 75%. However, if calf pressures exceed 30 mmHg when the patient is recumbent, a progressive fall in subcutaneous tissue flow and deep venous velocity occurs. Therefore it is recommended that patients not wear a graduated compression stocking of greater than 30 to 40 mmHg when lying down for prolonged periods.

Figure 8.40 Cutaneous ulceration developed 2 days after application of a compression bandage in a nongraduated manner.

One method for applying compression to treated veins that could be varied with patient position consists of a double layer of graduated compression stockings. This would ensure that maximal pressure over the vein is maintained while the patient is ambulatory. When the patient is recumbent, the outer stocking is removed, thereby decreasing the cutaneous pressure to 20 to 30 mmHg at the ankle, which should prevent a reduction in cutaneous and subcutaneous blood flow. Another method described in Chapter 6 is to use foam or rolled cotton wool directly over the treated varicose vein, which increases the pressure applied by the foam by over 50%.

Prevention

If extravasation of sclerosing solution occurs, the solution must be diluted as soon as possible. Hypertonic solutions should be diluted with copious amounts of normal saline solution. At least 10 times the volume of extravasated solution should be injected to limit osmotic damage.

Detergent sclerosing solutions of adequate strength also may be toxic to tissues. Dilution is again of paramount importance. Dilution with hyaluronidase in normal saline solution limits the extent and prevents development of cutaneous necrosis from STS 3%.²⁵⁶ Hyaluronidase (Wydase, lyophilized, 150 USP U/mL) enzymatically breaks down hyaluronic acid in connective tissue. This is hypothesized to disrupt the normal interstitial fluid barrier to allow rapid diffusion of solution through tissues, thereby increasing the effective absorption.^257,258 This beneficial effect has been demonstrated in limited IV extravasation injuries from 10% dextrose, calcium and potassium salts, contrast media, sodium bicarbonate, aminophylline, hyperalimentation solution, and doxorubicin.^{257,259–262} In addition to its enhanced dilutional ability, hyaluronidase may have an independent cellular preservation function.

Hyaluronidase injection improves skin flap survival²⁶³ and reduces myocardial infarction.²⁶⁴ This has been postulated to occur through enhanced nutritive flow. Enhanced healing with resolution of painful induration was observed when 250 U of hyaluronidase was injected in an area where neoarsphenamine and oxophenarsine (mapharsen) were extravasated subcutaneously.²⁶⁵ Finally, hyaluronidase promotes wound repair in fetal skin, contributing to scarless repair of wounds by as of yet unclear mechanisms.²⁶⁶ In summary, accelerated dilution, cellular stabilization, and wound repair properties of hyaluronidase appear useful in preventing cutaneous necrosis from inadvertent sclerosing solution extravasation.

Side effects from hyaluronidase use are rare and generally of the urticarial type.^267,268 Because of its limited stability, it should be reconstituted with 0.9% sodium chloride solution immediately before use. The ideal concentration and quantity to inject after extravasation has been reported to be 75 U in a volume of 3 mL. Higher doses did not appear to improve clinical outcome after intradermal infiltration of 0.25 mL of HS 23.4%.²⁶⁹ For maximum effectiveness, we recommend injecting the diluted solution into multiple sites around the extravasated area. Studies have demonstrated that hyaluronidase solution must be injected within 60 minutes of extravasation to be effective.²⁷⁰

Treatment

Whatever the cause of the ulceration, it must be dealt with when it occurs. Fortunately, ulcerations, when they do occur, are usually fairly small, averaging 4 mm in diameter in our practice. At this size, primary healing usually leaves an acceptable scar (Fig. 8.41). In addition to various topical therapies directly applied to the ulcer, elevation of the affected extremity and systemic pentoxifylline may be helpful in minimizing the ulcer size. In a series of 26 extravasation sloughs, less tissue damage occurred when limbs were elevated.²⁷¹

Figure 8.41 Cutaneous ulceration on the posterolateral thigh. A, 3 weeks after treatment with polidocanol 0.5%. B, After 6 months. Treatment consisted of a duoderm dressing that was changed every 4 days until complete healing occurred in 5 weeks. Note the cosmetically acceptable stellate scar.

Pentoxifylline may decrease tissue injury of ischemia–reperfusion by inhibiting the production of platelet-activating factor during reperfusion.²⁷² Pentoxifylline should improve microcirculatory dysfunction observed during reperfusion of ischemic tissues. Pentoxifylline causes increased deformability of RBCs and lowers blood viscosity.^273–275 From experimental studies in the canine gracilis muscle model, the optimal dose for protective effects appears to be 25 mg/kg. However, the dose that produces maximal protective effects in humans is unknown.

Bodian,¹¹⁷ who uses HS 23.4%, notes that ulceration usually takes months to heal, even when judicious wound care is provided. He advocates treatment with a daily application of 20% benzoyl peroxide powder (Vanoxide Acne Lotion) under moist dressings cut to fit snugly over the ulcer. However, benzoyl peroxide is cytotoxic for newly growing epidermis and therefore cannot be recommended by us. We have found that the use of occlusive or hydrocolloid dressings results in an apparent decrease in wound healing time. Occlusive dressings do not speed healing of full-thickness ulcers until granulation tissue has formed. Hydrocolloid gel dressings enhance debridement of wounds, possibly through their pectin–gelatin base. Non-gelatin, non-pectin hydrocolloid dressings only act to stimulate fibrin lysis. Thus, its enhanced efficacy may be related to wound debridement, which should always be used either medically or surgically to promote granulation tissue formation. More important, the use of occlusive dressings decreases the pain associated with an open ulcer. Dressings must be changed every 3 to 4 days, and necrotic tissue should be sharply debrided every week or two, as needed, to promote granulation tissue.

However, because an ulcer may take 4 to 6 weeks to heal completely, even under ideal conditions, if possible, excision and closure of these lesions are recommended at the earliest possible time. This affords the patient the fastest healing and an acceptable scar.

Minor reactions

Minor reactions such as urticaria are easily treated with an oral antihistamine such as diphenhydramine (Benadryl), 25 to 50 mg by mouth, or hydroxyzine (Atarax), 10 to 25 mg by mouth. Rarely, the addition of corticosteroids is needed if the reaction does not subside readily. A short course of prednisone, 40 to 60 mg per day for 1 week, in conjunction with systemic antihistamine every 6 to 8 hours is helpful. Suppression of the adrenal axis is not a problem with this short course, so a tapering schedule is not necessary.

Because of the possibility of angioedema or bronchospasm, each patient with evidence of an allergic reaction should be examined for stridor and wheezing by auscultating over the neck and chest while the patient breathes normally. Supine and sitting blood pressure and pulse should be checked to rule out orthostatic changes, hypotension, or tachycardia that might result from the vasodilation that precedes anaphylactic shock.

Minor degrees of angioedema can be treated with oral antihistamines; however, if stridor is present, an IM injection of diphenhydramine and IV corticosteroids should be administered, and a laryngoscope and endotracheal tube should be available.

Bronchospasm has been estimated to occur after sclerotherapy in 0.001% of patients.⁸ It usually responds to the addition of an inhaled bronchodilator or IV aminophylline, 6 mg/kg over 20 minutes, or to the antihistamine–corticosteroid regimen already noted.

Wheezing has been reported to occur in up to 5% of patients treated with HS solution (Michael Coverman, personal communication, 1991). Coverman has reported wheezing that occurs 15 minutes after the completion of sclerotherapy and resolves spontaneously. He has found that wheezing ceases if treatment sessions are performed with the patient sitting at a 45-degree angle. This probably is not an allergic reaction but an irritant phenomenon on the airways. Alternatively, it may be related to rapid infusion of histamine from perivascular mast cell degranulation with damage from the hyperosmotic solution.

Major reactions

Four types of potentially serious systemic reactions specific to the type of sclerosing agent have been noted: anaphylaxis, pulmonary toxicity, cardiac toxicity, and renal toxicity. These reactions are discussed both in general and separately for each sclerosing solution.

Anaphylaxis is a systemic hypersensitivity response caused by exposure or, more commonly, re-exposure to a sensitizing substance. Anaphylaxis is usually an IgE-mediated, mast cell-activated reaction that occurs most often within minutes of antigen exposure. Other classes of immunoglobulin such as IgG may also produce anaphylaxis.²⁷⁶ Since the risk of anaphylaxis increases with repeated exposures to the antigen, one should always be prepared for this reaction in every patient.²⁷⁷

The principal manifestations of anaphylaxis occur in areas where mast cell concentrations are highest: skin, lungs, and gastrointestinal (GI) tract. Histamine release is responsible for the clinical manifestations of this reaction. Although urticaria and abdominal pain are common, the three principal manifestations of anaphylaxis are airway edema, bronchospasm, and vascular collapse. Urticaria alone does not constitute anaphylaxis and should not be treated as such because of the potential side effects of treatment with epinephrine, especially in older patients.

The signs and symptoms of anaphylaxis initially may be subtle and often include anxiety, itching, sneezing, coughing, urticaria, and angioedema. Wheezing may be accompanied by hoarseness of the voice and vomiting. Shortly after these presenting signs, breathing becomes more difficult, and the patient usually collapses from cardiovascular failure resulting from systemic vasodilation. One helpful clue in distinguishing between anaphylaxis and vasovagal reactions is heart rate. Sinus tachycardia is almost always present in a patient with anaphylaxis, whereas bradycardia or cardiac rhythm disturbances are commonplace in vasovagal reactions.

The recommended treatment is epinephrine (adrenaline), 0.2 to 0.5 mL 1 : 1000 subcutaneously. This can be repeated three or four times at 5- to 15-minute intervals to maintain a systolic blood pressure above 90 to 100 mmHg. This should be followed with establishment of an IV line of 0.9% sodium chloride solution. Diphenhydramine hydrochloride, 50 mg, is given next, along with cimetidine, 300 mg; both the IV solution and oxygen are given at 4 to 6 L/min. An endotracheal tube or tracheotomy is necessary for laryngeal obstruction. For asthma or wheezing, IV theophylline, 4 to 6 mg/kg, is infused over 15 minutes. At this point it is appropriate to transfer the patient to the hospital. Methylprednisolone sodium succinate, 60 mg, is given IV and repeated every 6 hours for four doses. Corticosteroids are not an emergency medication because their effect appears only after 1 to 3 hours. They are given to prevent the recurrence of symptoms 3 to 8 hours after the initial event. The patient should be hospitalized overnight for observation.

Sodium morrhuate

Although promoted by the manufacturer as ‘the natural sclerosing agent’, sodium morrhuate causes a variety of allergic reactions, ranging from mild erythema with pruritus^278–280 to generalized urticaria^280–282 to GI disturbances with abdominal pain and diarrhea^278,279 to anaphylaxis. It has been estimated that ‘unfavorable reactions’ from the treatment of varicose leg veins occur in 3% of patients.²⁸³ The incidence of allergic reactions in the treatment of esophageal varices ranges from 11% to 48%.²⁸⁴ The reason for the high number of allergic reactions with this product may be related to the inability to remove all the fish proteins present in sodium morrhuate. In fact, 20.8% of the fatty acid composition of the solution is unknown.²⁸⁵

Many cases of anaphylaxis have occurred within a few minutes after injection or, more commonly, when therapy is reinstituted after a few weeks.^{280,286–288} Most of these cases occurred before 1950. Rarely, anaphylaxis has resulted in fatalities,^282,283,289 many of which have not been reported in the medical literature.²⁷⁸

Bronchospasm developed in one patient while being treated with the twelfth injection under anesthesia. This responded readily to antihistamine and epinephrine. The patient was subsequently treated with STS without an adverse reaction.²⁹⁰

Pleural effusions with pulmonary edema and acute respiratory failure appearing as adult respiratory distress syndrome (ARDS) are common with esophageal injection.²⁸⁵ It has been estimated that pleural effusions occur in 46% of patients with an esophageal injection.²⁹¹ With injection into esophageal varices, the sclerosing solution rapidly enters the pulmonary circulation, causing increased permeability of the pulmonary microvasculature.²⁸⁵ There have been no reports of pleural effusions with injection into varicose veins of the legs.

Prolonged dysrhythmia requiring placement of a permanent pacemaker has been reported in two cases.²⁹² This complication has been attributed to a direct cardiotoxic effect of sodium morrhuate.

Ethanolamine oleate

Ethanolamine oleate (Ethamolin; EO) is a synthetic mixture of ethanolamine and oleic acid with an empirical formula of C₂₀H₄₁NO₃. It is a salt of an unsaturated fatty acid that acts as a sclerosant when administered intravenously.²⁹³ The minimal lethal IV dose in rabbits is 130 mg/kg.²⁸¹ The oleic acid component is responsible for the inflammatory action. Oleic acid may also activate coagulation in vitro by release of tissue factor and Hageman factor. Biegeleisen²⁹⁴ observed no toxic effects in 500 injections, and EO is thought to have a lesser risk of causing allergic reactions compared with sodium morrhuate or STS.²⁹⁵ However, pulmonary toxicity and allergic reactions have been associated with this sclerosing agent.

Pleural effusion, edema, and infiltration and pneumonitis have been demonstrated in human trials with the injection of esophageal varices. Pleural effusion or infiltration has been estimated by the product manufacturer to occur in 2.1% of patients and pneumonia in 1.2% of patients. One study of 75 patients treated for esophageal varices disclosed abnormal chest X-ray films showing infiltration or effusion in 45 patients, for an incidence of 60%.²⁹⁶ These conditions usually resolve spontaneously within 48 hours.²⁹⁶

The product manufacturer has reported anaphylactic shock after injection in three cases (product information (1989) from Glaxo Pharmaceuticals, Research Triangle Park, N.C.). Another case of a nearly fatal anaphylactic reaction during the fourth treatment of varicose leg veins with 1 mL of solution has also been reported.²⁹⁷ In one additional case, a fatal reaction occurred in a man with a known allergic disposition (product information (1989), Glaxo Pharmaceuticals). Another episode of a fatal anaphylactic reaction occurred in a woman having her third series of injections.²⁷⁸ This represented one reaction in 200 patients from that author’s practice. Generalized urticaria occurred in approximately 1 in 400 patients; this symptom responded rapidly to an antihistamine.²⁹⁸

Acute renal failure with spontaneous recovery occurred after injection of 15 to 20 mL of EO in two women.²⁹⁹ A hemolytic reaction occurred in five patients in a series of over 900 patients, with injection of over 12 mL of 0.5% EO per patient per treatment session.²⁹⁸ The patients were described as ‘having pain in the loins and passing red–brown urine. All rapidly recovered with bed rest and were perfectly normal the next day.’ Injections of less than 12 mL per treatment session have not caused this reaction.

Transient chest pain also has been reported in 13 of 23 patients treated for esophageal varices.³⁰⁰ However, pyrexia and substernal chest pain are considered common sequelae of esophageal varices injection with any sclerosing agent.²⁹⁵

The EO mixture has also been tested for carcinogenic activity in the albino rat by intradermal injection without induction of tumors.³⁰¹ Recently, EO was found to be a successful sclerosing agent in 21 patients treated for reactive vascular lesions.³⁰² Interestingly, the authors of this study found that pain developed when the sclerosant permeated the normal dermis before leaking out through the epidermis and thus stopped the injections at the first sign of pain development.

Sodium tetradecyl sulfate

A synthetic detergent developed in the 1940s, STS has been used throughout the world as a sclerosing solution. A comprehensive review of the medical literature (in multiple specialties and languages) until 1987 disclosed a total of 47 cases of nonfatal allergic reactions in a review of 14,404 treated patients; this included six case reports.³⁰³ A separate review of treatment in 187 patients with 2249 injections disclosed no evidence of allergic or systemic reactions.³⁰⁴ An additional report of 5341 injections given to an unknown number of patients found ‘no unfavorable reaction’.³⁰⁵ Fegan³⁰⁶ has reviewed his experience with STS in 16,000 patients. He reported 15 cases of ‘serum sickness, with hot, stinging pain in the skin, and an erythematous rash developing 30 to 90 minutes after injection’. These patients subsequently underwent additional uneventful treatment with STS after premedication with antihistamines. In 10 additional patients, ‘mild anaphylaxis’ developed that required treatment with an injection of epinephrine. If one were to combine only those reviews of over 1000 patients, the incidence of nonfatal allergic reactions would be approximately 0.3%.^{9,298,307–309}

Bioniche Pharma Group, the manufacturer of Sotradecol, notes at least six fatalities associated with the use of Sotradecol, two from the sclerotherapy procedure itself and not specifically related to STS. One fatality occurred in a patient who was receiving an antiovulatory agent. Another death (fatal pulmonary embolism) was reported in a 36-year-old woman who was not taking oral contraceptives. Bioniche Pharma Group was also required through a warning letter by the FDA to disseminate information to providers regarding four of the six fatalities related to Sotradecol administration, which resulted from anaphylactic shock after sclerotherapy treatment with STS.³¹⁰ One of the four patients had an underlying history of asthma, which is a contraindication to the administration of Sotradecol. Similarly, four deaths attributed to anaphylactoid reactions were reported to the Committee on Safety of Medicines for the United Kingdom between 1963 and 1988, with 22 nonfatal allergic reactions such as urticaria noted over the same period.³¹¹

A fatality has been reported after a test dose of 0.5 mL of STS 0.5% was given to a 64-year-old woman.³¹² An autopsy performed by the Hennipin County, Minnesota, Coroner’s Office revealed no obvious cause of death. Subsequently, mast cell tryptase studies were performed on blood collected approximately 1 hour after the reaction while the patient was receiving life support. A normal tryptase level is less than 5 ng/mL; in experimental anaphylactic reactions induced in the laboratory, levels up to 80 ng/mL have been observed. In this patient, the levels were extremely high at 6000 ng/mL, suggesting that an anaphylactoid reaction had caused her death. Since all reported cases of allergic reactions are of the IgE-mediated immediate hypersensitivity type, it is recommended that patients remain in or near the office for 30 minutes after sclerotherapy when STS is used. However, allergic reactions also may develop hours or days after the procedure.^309,313 For example, urticaria occurred 8 hours after treatment in one patient³¹³ and 2 weeks after treatment in two other patients.³⁰⁹ Therefore, patients should be warned about the possibility of allergic reactions and how to obtain care should a reaction occur. In a review of 2300 patients treated over 16 years, four cases of allergic reactions were reported (0.17% incidence).³¹⁴ Reactions in this study were described as periorbital swelling in one patient and urticaria in three. All reactions were easily treated with oral antihistamines. It is of interest that French phlebologists have advocated a 3-days-before and 3-days-after treatment course with an antihistamine. P. Flurie noted no episodes of allergic reactions in 500 patients treated in this manner.³¹⁵

In a 2-year prospective study of 2665 patients treated with STS by Paul Thibault,³¹⁶ there were four cases of anaphylactoid reactions (0.15%). These occurred 10 to 30 minutes after injection of 3% solution, with patients having facial flushing, urticaria, dizziness, tachycardia, shortness of breath, and, finally, GI symptoms of nausea, vomiting, and abdominal pain. All four patients responded well to a subcutaneous injection of 0.5 mL of 1 : 1000 epinephrine followed by promethazine HCl 25 to 50 mg IM. Urticaria occurred in an additional two patients (0.07%).

Between August 1985 and January 1990, 37 reports of adverse reactions to STS, including five cases of suspected anaphylaxis and two cases of asthma induced by injection, were reported to the Drug Experience Monitoring Program of the Food and Drug Administration (FDA). One of the cases of anaphylaxis resulted in a death previously discussed. After a detailed review, it is unclear to us whether anaphylaxis indeed occurred in every reported case.

The reports of the Clinical Drug Safety Surveillance Group of Wyeth-Ayerst Laboratories, the prior manufacturer of Sotradecol are compiled from voluntary reporting to the manufacturer or the FDA, or both. The following are summaries of those reports. January to July 1991 disclosed one episode of erythema multiforme, one episode of ARDS, one episode of fever, lymphadenopathy, and rash, and three episodes of abdominal pain, nausea, vomiting, and diarrhea. The case report of erythema multiforme was reported in a woman after her thirteenth sclerotherapy treatment.³¹⁷ Pruritus developed the morning after the last injection, with a generalized eruption beginning on the legs 4 days later. This was followed by fever the following day. A rapid tapering course of oral prednisone was given, with complete resolution of the rash in 2 weeks. From September 1991 to November 1992 there were five reports of urticaria and one episode of ARDS. From December 1992 to September 1993 there was only one case of a maculopapular rash. From September 1993 through October 1994 there was one case of angioedema, and generalized weakness was reported in one patient after receiving 10 mL of 3% STS. From November 1994 through January 1996 there was one case of anaphylaxis. From January 1996 through December 1996, there was one case of allergic vasculitis. From November 1997 through October 1999 there were three cases of urticaria and four cases of nonspecific hypersensitivity reactions. These reactions voluntarily reported to Wyeth-Ayerst occurred with approximately 500,000 2-mL ampules of 1% and 3% being sold yearly within the United States. Thus, the incidence of adverse reactions is rare. (Most information regarding adverse reactions from Sotradecol was provided by Paul Minicozzi, Ph.D., Wyeth-Ayerst Laboratories, through yearly correspondence.)

A similar low experience with adverse reactions was reported by STD Pharmaceuticals, the manufacturer of Fibro-Vein (correspondence from Robert Gardiner, Hereford, UK, March 1995, and the Adverse Drug Reaction Information Tracking Product Analysis from the Medicines Control Agency of Great Britain). The adverse drug reactions reported in the United Kingdom between 1963 and 1993 were one nonspecific allergic reaction, two cases of anaphylactic shock, six cases of gastrointestinal disorder, two cases of bronchospasm, four patients with a nonspecific cutaneous eruption, and two patients with urticaria. This summary comprised 30 years, during which time an estimated 7,200,000 mL of STD 1% and 3% was sold within the United Kingdom.

In the French registry of 12,173 sessions of sclerotherapy, no allergic reaction has been reported.²²⁴ In France, sclerosing agents are STS, POL, and CG.

The most common systemic reaction consists of transient low-grade fever and chills lasting up to 24 hours after treatment.³¹⁸ This has also been seen in one of our patients. Of note is that three patients with allergic systemic reactions to monoethanolamine oleate had no evidence of allergy to STS.³¹⁸

An interesting dilemma arises with patients who have a history of allergy to sulfa medication. STS contains a sulfate; therefore one can assume that these patients would be at increased risk for an allergic reaction. However, a review of all reported cases of allergic reactions to STS has not disclosed an independent allergic history to sulfa-containing medications (correspondence from Tom Udicious, R.Ph., Wyeth-Ayerst Laboratories, November 1993). We have used STS to treat many patients with a history of sulfa allergy and have observed no adverse sequelae. This experience is shared by Drs. Robert and Margaret Weiss as well (personal communication, 1998).

Reactions can occur with any sclerosing solution; they are not allergic in nature but represent the effect of the sclerosing solution on the vascular system. One such reaction is hemolysis that occurs through lysis of RBCs that are present in the treated vein. A hemolytic reaction occurred in five patients in a series of more than 900 patients with injection of more than 8 mL of STS 3%.²⁹⁸ Like a similar reaction that occurred with EO, patients were described as ‘…feeling generally unwell and shivery, with aching in the loins and passage of red-brown urine. All rapidly recovered with bed rest and were perfectly normal the next day.’ Injections of less than 8 mL per treatment session did not result in this reaction. Intravascular hemolysis was also reported to the FDA after injection of STS into a hepatic artery feeding a hepatic tumor.

Although the lethal dose in humans has never been reported, the IV median lethal dose (LD₅₀) in mice is 90 mg/kg.³¹⁹ The lethal volume after IV injection in the rat is approximately four to six times as high for STS as for POL in equivalent concentrations.³²⁰ In our practice, it is not uncommon for patients to be treated with up to 30 mL of 0.5% STS. We have not observed an adverse reaction from this dose of STS.

The experience of two of the authors (MPG, RAW) over 20 years in an estimated 40,000 patients is that no patient has developed a serious allergic reaction from the use of STS. Since STS from various sources may have a variable purity (see Chapter 7) it appears possible that allergic reactions may occur from the impurities, such as carbitol, and not STS itself.³²¹ This may explain the decreased reported incidence of allergic reactions with the use of Fibro-Vein (STD Pharmaceuticals) as compared with Sotradecol (Bioniche Pharma Group) and/or Trombovar (Laboratoires Innothéra, Arcueil, France).

Polidocanol

Kreussler Pharma has sold over 250,000,000 mL of polidocanol (Aethoxysklerol) for sclerotherapy from 1987 to 2010 and estimates that this translates to between 40 and 45,000,000 treatments (personal communication Christian Freyberg, International Sales and Marketing Director, January 2010). Allergic reactions to POL are quite rare and had been reported in only four patients in a review of the world’s literature up to 1987, with an estimated incidence of 0.01%.³⁰³ Amblard³²² reported no allergic reactions in over 250 patients, including no allergic reactions in two patients who were intolerant to STS. Hoffer²³¹ reported no allergic reactions in over 19,000 cases. In addition, patients who are allergic to STS or iodine have no allergic manifestations to injections of POL.^322–324 However, rare allergic reactions have been reported, including a case of nonfatal anaphylactic shock to 1 mL of POL 2% injected into a varicose vein during the fourth treatment session.^{314,325–327} Also, Ouvry et al³²⁸ reported generalized urticaria with cough and dyspnea in a patient after receiving 2 mL of POL 2%; the condition resolved in 30 minutes with IV corticosteroid therapy.

Since the previous review, additional cases of allergic reaction have been reported. Guex⁵⁸ reported seven cases of minor general urticaria in nearly 11,000 patients treated over 12 years. These patients cleared completely in 1 to 2 days with antihistamine and topical corticosteroid therapy, with one patient requiring systemic corticosteroids. He has more recently reported only one possible case of benign allergy and no cases of anaphylaxis in 3357 patients treated.³²⁹

Kreussler & Co. GmbH, the product manufacturer in Germany, has documented 35 cases of suspected sensitivity from 1987 to 1993 (personal correspondence, January 1994). Of these reports, most were either vasovagal events or unproved allergic reactions. Nine patients were given repeat challenges with POL, with only three demonstrating an allergic reaction (urticaria or erythematous dermatitis). One patient died of anaphylactic shock 5 minutes after injection with 1 mL, despite maximal intervention. In 1994, Kreussler reported two patients with urticaria. In 1995, two additional patients were reported with urticaria, two with bronchospasm, and one with angioedema. In 1996, there were four reports of urticaria, two of anaphylactoid reactions, one with angioedema, one with pruritus, and one with contact allergy. Therefore, POL is not free from allergy and, as with all sclerosing solutions, physicians must be prepared to evaluate and treat patients who have an allergic reaction to the sclerosing solution.

A detailed account of three serious cases of anaphylaxis was reported from the Netherlands.³³⁰ These patients were anaphylactic within 15 minutes after injection of POL. Two of them had received the drug for the first time. One patient, a 70-year-old woman with a complicated medical history of two heart operations, two cerebrovascular accidents, and hyperthyroidism, was successfully resuscitated after cardiac arrest. She was receiving multiple medications, including digoxin, carbimazole, captopril, furosemide, mebeverine, and acenocoumarol. She had been treated with POL without complications on four previous occasions. The second patient showed signs of ARDS after being treated with epinephrine and systemic methylprednisolone for ‘shock’. The third patient developed urticaria, dyspnea, paresthesia, headache, and chest pain with electrocardiographic (ECG) findings of cardiac ischemia. No further studies were performed on these patients.

The Australian Polidocanol Open Clinical Trial at 2 years, with over 8000 treated patients, reported nine local urticarial reactions and three generalized reactions, with two patients developing a rash, for an incidence of approximately 0.2%. There were no cases of anaphylaxis.²³⁹ After a further 8804 patients were evaluated, an additional three patients developed urticaria, again without any additional significant adverse sequelae.¹⁵¹ A 5-year experience in 500 patients treated with POL 3% reported five cases of allergic reaction (1% incidence); one patient had nonfatal anaphylactic shock, with the other patients experiencing urticaria.³³¹

Two of 689 sequential patients were reported who developed an immediate-type hypersensitivity reaction with systemic pruritus and urticaria.³³² This represented an incidence of 0.3% in their patient population and 0.91% for the ‘true’ population. These two reactions occurred without prior exposure to POL as a sclerosing agent. Since POL is used as an emulsifying agent in preprocessed foods, patients may have been exposed previously through ingestion. Both patients responded easily to either a single dose of oral diphenhydramine, 50 mg, or 0.3 mL of subcutaneous epinephrine plus 50 mg of diphenhydramine IM.

Jaquier and Loretan²³⁰ believe that the decrease in antigenicity is the result of the absence of a benzene nucleus and a paramine group and the presence of a lone free alcohol group. Dexo SA Pharmaceuticals, the product manufacturer in France, recommends that this substance not be used in patients with an allergic diathesis (e.g. asthma) (product description of hydroxypolyethoxydodecane (May 1985) received with correspondence from Dexo SA Pharmaceuticals, France). Thus, allergic reactions to POL are similar to those reported with STS.

An interesting adverse effect may be noticed in patients in whom a near maximal dosage of POL is used. These patients report paresthesia or tingling of the tongue or a strange sensation in taste that resolves within 5 minutes. This effect was reported to Kreussler five times between 1986 to 1993 (correspondence, January 1994) and has been noted in our practice as well. Particular effects of the anesthetic properties of POL may explain this sensation.

Other unusual reactions reported to Kreussler (correspondence, January 1994) include rare episodes of short convulsive coughing, acute pressure sensation in the chest, acute difficulty with breathing, and one case of stabbing chest pain without demonstrable ECG changes or myoglobin band creatine phosphokinase fluctuations. One specific case report describes a 30-year-old woman who underwent four separate sclerotherapy sessions with POL. On the fourth session, 3 mL of POL 1.5% and 12 mL of POL 0.5% were administered. The patient complained of chest heaviness and constriction, which had also appeared after two of her other sessions but had not been brought to the attention of the medical staff. During the fourth episode, she lost consciousness and was found without a pulse or blood pressure, with dilated pupils. Spontaneous respiration occurred after 2 to 3 minutes; she began to vomit and complained of headache and earache. She recovered and was discharged after 10 hours well, but returned the next day with dysosmia which lasted 6 weeks. Although a brain CT scan was normal, the presumed cause was cerebral.³³³

Like EO and sodium morrhuate, POL has demonstrated a dose-dependent cardiac toxicity when injected into esophageal varices. POL has a negative inotropic, chronotropic, and dromotropic effect, reducing atrioventricular and intraventricular conduction, as well as lowering blood pressure. Animal studies have demonstrated a reversible, dose-dependent decrease in myocardial contractility, blood pressure and pulse rate, and a prolongation of the PQ interval.³³⁴ This effect may explain the cause of heart failure in three elderly patients with severe liver failure who were given massive quantities of POL during esophageal sclerotherapy (760 mg in a 74-year-old woman, 600 mg in a 70-year-old woman, and 750 mg in a 76-year-old woman).^335,336 In addition, a case of sinus bradycardia with eventual asystolic cardiac arrest occurred after administration of 4 mL of 1% POL into a 5-year-old girl under general anesthesia with sevoflurane 2% with Klippel-Trénauny syndrome. After appropriate emergency care, cardiac function was restored without adverse sequelae.³³⁷

Polidocanol, being a local anesthetic, demonstrates a systemic toxicity level similar to that of lidocaine and procaine; when combined with other anesthetics, an additive risk to the cardiovascular system occurs.^338,339 Specifically, when administered concomitantly with other local anesthetics, additional proarrhythmic effects were observed. The LD₅₀ in rabbits at 2 hours is 0.2g/kg, which is three to six times greater than the LD₅₀ for procaine hydrochloride.³⁴⁰ The LD₅₀ in mice is 110 mg/kg.³⁴¹ Finally, the teratogenicity was evaluated by Fournier in rabbits and rats.³⁴² The pregnant animals received 2.7 to 4.5 mg/kg per day and did not demonstrate a significant increase in the number of abnormal fetuses.³⁴³ One severe malformation was seen in a rat pup out of 530 normal pups (0.08%) whose mother received 4.5 mg/kg per day. This is far in excess of the recommended doses of POL in humans. Kreussler has reported that POL does cross the placental barrier in rats, but that perinatal and postnatal development and behavior were not impaired in rats whose mothers received intravenous POL every other day during late gestation as well as in the lactation period.³³⁹ However, no formal studies in pregnant women have been reported. Sigg³⁴⁴ has reported treating 3600 pregnant women with 34,000 injections without fetal injury or abortion.

Chromated glycerin/glycerin

Chromated glycerin 72% (Sclérémo) is a sclerosing solution with a very low incidence of side effects (Sclérémo product information (1987)).^21,86,345 Hypersensitivity is a very rare complication.^346,347 Contact sensitivity to chromium occurs in approximately 5% of the population.³⁴⁸ Intravenous potassium dichromate leads to complete desensitization in chromium-sensitized guinea pigs. This effect occurs because chromium needs to bind to skin proteins to become an effective antigen.³⁴⁹ This may be related to the necessity for epidermal Langerhans’ cells to produce an allergic response, whereas T lymphocyte accessory cooperation is not optimal with IV injection and its resulting endothelial necrosis. Thus it is more common for a sclerotherapist to develop an allergic contact dermatitis to CG than it is for a patient to have an allergic reaction to IV use of CG. Indeed, Ouvry (personal communication, 1995) has developed an allergic contact dermatitis from CG injected without the use of protective gloves.

Ramelet et al³⁵⁰ have reported seven patients who developed an allergic reaction to CG. One patient had a vasculitis, and six patients had an eczematous reaction. All allergic patients demonstrated a sensitivity to topically applied chromium.

One case of fatal allergic reaction has been described recently.³⁵¹ The patient, a 51-year-old female, developed a laryngeal edema immediately after the end of the first sclerotherapy session with undiluted Sclérémo, and died after 2 hours of appropriate resuscitation. The patient had declared a past history of asthma, but no cutaneous allergy. One patient, treated with 72% glycerin with lidocaine and epinephrine for spider veins, developed leg swelling with 3–4+ pitting edema several days following sclerotherapy (personal email communication with Joseph Ang, October 2007). In this case, 18 mL of non-foam sclerosant was used in the treatment of one leg, the patient wore compression stockings following treatment, and there was no evidence of an underlying DVT. The etiology of this lower extremity edema is unclear. Regardless, due to the potential for hemolysis, we recommend limiting the total volume of glycerin per treatment session to 10 mL.

Hematuria accompanied by ureteral colic has been reported to occur transiently after injection of large doses of CG. Ocular manifestations, including blurred vision and a partial visual field loss, have been reported by a single author, with resolution in less than 2 hours.³⁵² Glycerin (or any sclerotherapy) induced hemolysis may not be a benign event. Hemoglobin can exert direct cytotoxic, inflammatory and pro-oxidant effects that adversely affect endothelial function.³⁵³ Hemoglobin from destroyed RBCs dimerizes and is rapidly bound by the serum protein haptoglobin. The haptoglobin–hemoglobin complex causes endocytosis and degradation, which can lead to a variety of adverse effects.³⁵⁴

Although transient hemoglobinuria is common in athletes and is without known long-term adverse effects, hemoglobulinemia can cause renal failure.³⁵⁵ More commonly, hemoglobulinemia can cause a dose-related gastrointestinal dystonia and pain including esophageal spasm and dysphagia.³⁵⁴ The reader is referred to an excellent recent review which details more clinical manifestations of hemoglobinemia.³⁵⁶

An additional case was reported of transient hypertension and visual disturbance after the injection of 12 mL of 50% CG into spider and ‘feeder’ leg veins in a fourth treatment session.³⁵⁷ These symptoms occurred hours after treatment and lasted more than 3 hours without treatment. This may have represented a retinal spasm or an ophthalmic migraine. Since we have been using glycerin alone without chromium but mixed 2 : 1 with lidocaine 1% with or without 1 : 100,000 epinephrine, we have yet to see an allergic reaction. We have also yet to see hemoglobinuria or adverse effects with the use of up to 12 mL of this glycerin mixture, except for a minute or two of epinephrine-induced ‘rush’ which can occur in rare patients who have a sensitivity to epinephrine.

Polyiodinated iodine

Polyiodinated iodine (Varigloban, Variglobin, Sclerodine 6) is a stabilized water solution of iodide ions, sodium iodine, and benzyl alcohol. Sigg et al³⁵⁸ reported on their experience with over 400,000 injections with Variglobin. Paravenous injections readily produced tissue necrosis. In 1975, Sigg and Zelikovski³⁵⁹ reported an incidence of 0.13 allergic cutaneous reactions per 1000. No systemic allergic reactions were observed. Obvious contraindications to the use of polyiodinated iodine are hyperthyroidism and allergies to iodine and benzyl alcohol.

High concentrations of iodine solutions may also produce bronchiomucosal lesions. Therefore, Wenner³⁶⁰ recommends that a maximum of 5 mL of 12% solution be used in a single sclerosing session.

Sodium salicylate

The proprietary product, Saliject, has not been reported in a literature review to cause allergic reactions. Dr. Beverly Kemsley has reported 1 of 6000 patients who developed an anaphylactic reaction after the use of Saliject. Thirty patients developed localized erythema and urticaria that responded to the oral antihistamine terfenadine 120 mg (personal communication, 1996).

Hypertonic saline

Alone, HS solution shows no evidence of allergenicity or toxicity. Complications that may arise from its specific use include hypertension, which may be exacerbated in predisposed patients when an excessive sodium load is given, sudden hypernatremia, central nervous system disorders, extensive hemolysis, and cortical necrosis of the kidneys (Mary Helenek, written correspondence, American Regent Laboratories, May 1990). These complications among others have led that manufacturer to add to its label the warning ‘For IV or SC use after dilution’ in bold red ink.

As discussed previously, hematuria can occur with any sclerosing agent. Dodd³⁶¹ has reported painless hematuria in five patients injected with HS. Sometimes blood appears in the urine after one or two acts of micturition and occasionally at other times throughout the day. Usually there are no other ill effects, and the hematuria resolves spontaneously. Hematuria probably occurs because of hemolysis of RBCs during sclerotherapy.

Coverman (personal communication, 1989) described two patients injected with up to 6 mL of HS 23.4% who developed ‘peculiar visual symptoms in just one eye’. This was described as either blurred vision or an aura. There were no other symptoms, and each incident passed quickly and spontaneously. Coverman speculates that this may have been caused by the addition of lidocaine to the HS solution.

Heparin in hypertonic saline

Whereas unadulterated HS solutions in concentrations from 15% to 30% are used for the treatment of varicose and telangiectatic leg veins, adding heparin to the solution to prevent the theoretic risk of embolization associated with sclerotherapy has been advocated.²² Although the necessity for heparin has been discounted in a well-controlled 800-patient randomized study,²⁴ Foley’s solution, Heparsal, consisting of HS 20% with heparin, 100 U/mL, and procaine 1%, is commonly used in the treatment of telangiectatic leg veins. Therefore, the risk of adverse reactions to heparin should be mentioned.

Commercial preparations of heparin consist of straight-chain anionic polysaccharides of variable molecular weight (usually 7000 to 40,000). Heparin prepared from different tissues also appears to vary: more protamine is required to neutralize a unit of beef lung heparin than porcine mucosal heparin. Plasma lipolytic activity, antifactor Xa activity, and activated partial thromboplastin time ratios are significantly different.³⁶²

Fever, urticaria, and anaphylaxis occur occasionally after administration of heparin.^362–366 Necrosis has been reported in patients receiving subcutaneous heparin,^{358,367–370} and has usually occurred 3 to 10 days after multiple subcutaneous injections. Pruritus, local tenderness, and burning sensations associated with large, indurated, erythematous plaques have also been reported to occur in six patients 10 to 20 days after beginning prophylactic doses of heparin.³⁷¹ Thus, there is a measurable risk of toxicity to heparin.

Although heparin is not a totally benign substance, those who use Heparsal have not reported any adverse reactions that could be attributed to the heparin component.^8,22,24,192 The absence of side effects has been reported in one series of 310 patients when volumes of 10 to 20 mL have been injected into varicose veins.¹⁹² In the doses used, heparin in Heparsal may be without significant side effects, but one must be aware of the potential dangers associated with its use.

Lidocaine in hypertonic saline or glycerin

Alderman⁹ and Duffy⁸ advocate the addition of lidocaine (to achieve a 0.4% final concentration) to minimize patient discomfort during injection of HS. This addition introduces a potentially allergenic sclerosing mixture. Although the most common cause of patient-reported ‘allergic reactions’ to lidocaine is psychogenic or vasovagal phenomena,³⁷² allergic reactions may occur. Vasovagal reactions are due to emotional or physical stimuli and are not directly due to the local anesthetic. Besides vasovagal reactions, the majority of side effects to lidocaine are localized and include bruising and edema at the injection site.³⁷³ A report on 28 patients who had a variety of adverse reactions to lidocaine, including skin reactions, loss of consciousness, and vasovagal symptoms, were evaluated with skin testing and found not to be allergic to lidocaine. Nineteen of these patients were subsequently treated with lidocaine without an adverse reaction.³⁷⁴ In a more recent study, 183 patients with a reported allergy to lidocaine were patch tested and those patients who tested positive received a 0.1 mL intradermal challenge with lidocaine 1%. Of the 183 patients tested, four had positive reactions to lidocaine, two of whom had sensitivity to local injections of lidocaine manifested by dermatitis.³⁷⁵ Impending anaphylaxis must be distinguished from vasovagal reactions, which occur more commonly. One important distinction is that in vasovagal reactions the patient demonstrates bradycardia, whereas a patient with anaphylaxis exhibits tachycardia.³⁷⁶ As described previously in this chapter, vasovagal reactions also commonly include lightheadedness, hypotension, and diaphoresis.

Unlike the ester class of anesthetics, which are much more commonly shown to cause allergic reactions, members of the amide class of anesthetics, to which lidocaine belongs, have a very low risk of allergic reaction.^377–382 There are two types of allergic reaction to local anesthetics: a type I immediate hypersensitivity or anaphylactic reaction and a type IV delayed hypersensitivity reaction. The former is mediated by antibodies and the latter by cell-mediated immunity. Allergy is most likely caused by the methylparabens or sodium metabisulfite that is used as a preservative in anesthetic solutions.^{377,378,383–385} To keep the allergic risk as low as possible, single-dose vials of lidocaine without preservatives should be used.

Despite the low risk of allergenicity to lidocaine, a few true allergic reactions, including anaphylaxis, have been reported.^386–393 The prevalence of anaphylactic reactions to anesthetics is approximately 1 : 3500 to 1 : 20,000, with a mortality of between 3% and 6%.³⁹⁴ One patient demonstrated a type I hypersensitivity reaction to lidocaine after undergoing intralesional injections to his keloids with a total of 0.5 mL of Kenalog diluted to 10 mg/mL with lidocaine 1% and epinephrine 1 : 100,000.³⁷³ He was fine when leaving the office, but approximately 15 minutes later began to experience wheezing, lightheadedness, and periorbital edema. Symptoms resolved several hours after treatment in the emergency room with an albuterol nebulizer and oral famotidine. Interestingly, this patient subsequently had a positive wheal and flare response to intradermal lidocaine 1% at a dilution of 1 : 10,000 during allergy testing. Thus, HS or glycerin, when adulterated with lidocaine, may place the patient at risk for allergic reactions.

Etiology

Superficial thrombophlebitis appears 1 to 3 weeks after injection as a tender erythematous induration over the injected vein (Fig. 8.42). Duffy⁸ estimates that it occurs in 0.5% of his patients who have primarily small-vessel varicose veins and telangiectasia. Mantse³⁰⁹ reported an incidence of 1% in the treatment of varicose (nontelangiectatic) veins despite the use of a tensor bandage for 6 weeks. Mantse notes that the patients who developed superficial thrombophlebitis found the bandage was too tight and reapplied it too loosely at home. In our recent 5-year retrospective, this complication occurred to some degree in approximately 1.7% of patients (6 of 351). Most patients have minimal phlebitis and require either no treatment or simple drainage of an associated coagulum with a 22-gauge needle.¹⁷ Rarely, in symptomatic patients, treatment with graduated compression and anti-inflammatory agents is given (0.001% of patients totaling more than 10,000 separate injections).

Figure 8.42 A, This 45-year-old woman had incompetence of the saphenofemoral junction and refused surgical ligation and stripping of the great saphenous vein. Therefore, all reticular, accessory, and tributary veins were treated with polidocanol 0.75% for a total of 20 mL to the entire right leg. Localized compression, with STD foam pads and a short stretch bandage, was applied to the medial thigh only. She did not apply the graduated 30- to 40-mmHg compression stocking until 30 to 45 minutes after leaving the office. B, Acute thrombophlebitis developed 3 days after sclerotherapy. Note ecchymosis from compression padding.

In certain cases it presents as an extensive pigmented cord along the superficial venous pathway (Fig. 8.43). The content of the venous lumen can vary according to the etiology, emphasizing the need to distinguish between ‘phlebitis’ and ‘thrombosis’. The presented case represents obviously a pure ‘phlebitis’ (Fig. 8.44).

Figure 8.43 Extensive superficial phlebitis with very little/no thrombotic material within the vein lumen. The picture was taken 15 days after injection of 2.5 mL polidocanol 0.5% in multiple reticular and spider veins of the same limb. The great saphenous vein had not been injected. The patient was treated with tamoxifen (for 3 years after breast cancer treatment); no evidence of cancer recurrence has been observed. Evolution of pigmentation is unknown. Clinically, this phenomenon is very similar to Mondor’s disease.

Figure 8.44 A 55-year-old woman, 1 year after diagnosis of breast cancer treated with bilateral mastectomy, presented with reticular and telangiectatic leg veins. She was treated with 1 mL of sodium tetradecyl sulfate (STS) 0.5% mixed 1 : 4 with room air to veins 3–5 mm in diameter, 1 mL of STS 0.25% mixed 1 : 4 with room air to veins 1–3 mm in diameter and 4 mL of 72% glycerin/1% lidocaine 2 : 1 with epinephrine followed by 7 days/24 hours a day 30–40 mmHg graduated compression stockings. 6 weeks after treatment she presented with a tender erythematous streak over the proximal portion of the treated vein. Coagula were drained with a 22G needle and ibuprofen was prescribed 400 mg po t.i.d. with reapplication of the graduated compression stocking while ambulatory. She returned for additional draining of coagula at 4, 6 and 8 weeks with gradual resolution of erythema and tenderness. A complete onocologic work-up did not disclose recurrent breast carcinoma. The patient was seen 2 years later for treatment of minor telangiectasia with glycerin and was in excellent health.

Sometimes confused with superficial thrombophlebitis, patients may, although rarely, develop a chemical lymphangitis. It typically appears within 24 hours after treatment but resolves spontaneously within 72 hours. It is not associated with pain or tenderness. Shown in Figure 8.45, this occurred after treatment with 1% STS liquid.

Figure 8.45 A, Appearance at 24 hours after STS 1% injection. B, Spontaneous resolution after 72 hours post-injection.

Prevention

The cause of thrombophlebitis is related in part to treatment technique as well as to lack of adequate post-treatment compression. In our experience, a decreased incidence of superficial thrombophlebitis may result from a greater degree and length of compression used after sclerotherapy is performed. An inadequate degree or length of compression results in excessive intravascular thrombosis. Sigg⁴⁰¹ notes that perivenous inflammation is observed only at those parts of the limb not covered by a compression dressing. Thus, to avoid this complication, one should prevent or minimize the development of postsclerosis thrombosis by using compression pads and hosiery over the entire leg and not just over the treated veins.

However, even when appropriate compression is used, thrombosis and perivascular inflammation may still occur (Fig. 8.46). Ascending phlebitis in the small saphenous vein (SSV) or its long tributaries, starting at the upper edge of the compression stocking, is relatively common. Here, the sclerosing action continues up the abnormal vessel (even beyond what apparently is the extent of the abnormality). It is thought that the sclerosing solution destroys damaged endothelium to a greater extent than normal endothelium (product description on polidocanol received with correspondence, May 1985). Therefore, the placement of a foam pad extending above the compression stocking or bandage to create a gradual transition of pressure from compressed to noncompressed vein may provide a safety margin, as well as prevent damage to the vein by the otherwise abrupt cut-off of the pressure stocking.

Figure 8.46 A, Clinical appearance of the vein over the anterior tibia before injection. B, Acute thrombophlebitis developed 10 days after sclerotherapy with polidocanol 0.5%.

Thrombophlebitis is a complication that should not be taken lightly. If untreated, the inflammation and clot may spread through perforating veins to the deep venous system. This extension may lead to valvular damage and possible pulmonary embolic events.^402–407 A study of a group of 145 patients with superficial thrombophlebitis found that 23% of affected limbs had proximal extent into the SFJ.⁴⁰⁸ Pulmonary embolism (PE) was found in 7 of 21 patients (33.3%) with thrombophlebitis of the GSV above the knee;⁴⁰⁹ 17 of the 21 patients had varicose veins. Interestingly, in this study, clinical symptoms suggestive of PE were present in only one of the seven patients. The occurrence of DVT in patients with below-knee superficial vein thrombosis (SVT) was 32% in one study of 78 patients.⁴¹⁰

Treatment

In addition to adequate compression, drainage of thrombi after liquefaction (approximately 2 weeks after sclerotherapy) hastens resolution of the otherwise slow, painful resorption process.⁴⁰¹ Adequate compression and frequent ambulation should be maintained until the pain and inflammation resolve. Aspirin or other nonsteroidal anti-inflammatory agents may be helpful in limiting both the inflammation and pain.

Patients with extensive involvement of leg varices should receive anticoagulation, particularly if the thrombosis extends into the proximal part of the SFJ. In addition to propagation of the thrombus through the SFJ, 11% to 40% of patients with SVT at the SFJ have evidence of concurrent DVT.^409–412 In these patients, anticoagulation for 6 months achieved resolution of the DVT/SVT while preventing PE. This success occurred despite duplex evidence of progression of SVT to DVT in 2 of 20 patients.⁴¹¹ Of interest is the fact that the incidence of coincidental DVT with SVT was greater in patients without varicose veins (60% versus 20%), thus indicating that other innate factors place patients with SVT at additional risk for DVT.

In addition, the use of low-dose low-molecular weight heparin (LMWH) in patients with SVT may decrease perivascular inflammation. LMWH has been demonstrated to limit neutrophil extravasation.⁴¹³ Thus, LMWH has anti-inflammatory properties in addition to anticoagulant properties.

Other methods for enhancing thrombolysis may be considered for SVT as well as for DVT. Ultrasound-enhanced systemic thrombolysis has recently been found to augment arterial recanalization.⁴¹⁴ This procedure utilizes a 2-MHz Doppler ultrasound in conjunction with systemic tissue-type plasminogen activator (t-PA). Ultrasound increases enzymatic fibrinolysis through mechanisms that include improving drug transport, altering the fibrin structure, and increasing the binding of t-PA to fibrin.⁴¹⁵

Recently, a liposomal heparin spray (Lipohep Forte Spraygel) applied after the onset of SVT has been found to improve symptoms as well as hasten resolution of the SVT.⁴¹⁶ This spray was as effective as LMWH injections. Finally, distinguishing between hypereosinophilic syndrome-related and idiopathic superficial venous thrombophlebitis is important, since anticoagulant therapy is probably indicated in the former, which carries an increased thrombotic risk.³⁹⁹

Etiology

Arterial injection occurs most commonly in the posterior or medial malleolar region, particularly when an effort is made to inject the internal ankle perforator vein, specifically in the posterior tibial artery.^{398,419,421,428} Other areas predisposed to inadvertent arterial injection include the groin and the back of the knee, but any injected area can be prone to arterial injection.⁴²⁹ The patient will usually, but not always, note immediate pain (it can be supposed that since it has a local anesthetic effect, intra-arterial injection of POL could be painless during the first days – see Fig. 8.49). Evidence is still lacking and the decrease in incidence of these complications with the use of ultrasound guidance and foam will probably (and fortunately) not allow one to draw more precise conclusions. Pain then typically slowly propagates down into the foot and outer toes over the following 2 to 6 hours post-injection. During this time, arterial pedal pulses are palpable. At 10 to 12 hours later, the four outer toes are white, with the sole of the foot becoming painful. Cutaneous blanching of the injected area usually occurs in an arterial pattern associated with a loss of pulse and progressive cyanosis of the injected area.

Figure 8.49 Postsclerotherapy necrosis at an early stage: 8 days after injection of 3 × 0.5 cm³ of polidocanol 0.5% in medial leg postsurgical residual varicose veins (38-year-old male). Extreme pain appeared only 3–4 days after the injections. Limited surgical excising was carried out after 30 days, leaving small scars and no other sequelae. This complication is rare in this area. Despite the pejorative initial aspect of the leg and the extreme pain, necrosis was limited to three zones smaller than 1 cm² each. The injection of an aberrant superficial skin artery was suspected; the alternative explanation being embolia cutis medicamentosa.²⁴⁸

Natali and Farman⁴²⁹ reported 40 cases of arterial injection in their 20-year experience and review of the French medicolegal system. They found that injection of the SSV was the most common preceding event. Seven patients required amputations (two above the knee and five below the knee), six required peripheral amputations of one or more toes, and 27 had abnormalities of the triceps and/or sural muscles. Muscle abnormalities consisted of infarction with subsequent fibrosis and retraction of the affected area, with or without limb atrophy. In one case, POL 0.5% was injected into the SSV in the popliteal fossa. An arteriogram showed thrombosis of the peroneal artery with clinical symptoms of a pale, numb foot with muscular necrosis.⁴³⁰

Another area in which the artery and veins are in close proximity is the junction of the femoral vein and GSV. A review of one sclerotherapy practice spanning more than 20 years disclosed two cases of accidental arterial injection in this area, requiring thigh amputations.⁴³¹ This also has been the experience of Biegeleisen et al,⁴²² who reported seven cases of arterial injection during attempts to inject the GSV or SSV at the groin or popliteal areas, even under color-flow ultrasound control. In this location, the external pudendal artery bifurcates and may surround the GSV shortly after the location of its connection with the femoral vein. In addition, the junction of the GSV with the popliteal vein has been demonstrated to have a tortuous and variably located satellite arteriole.⁴³² Because these collateral arteries vary anatomically in these locations, duplex scanning may be useful before sclerosing these vessels but does not guarantee absolute safety, as detailed in a series of case reports.⁴²⁴

With the onset of duplex-assisted sclerotherapy, small arteries in the superficial and deep aspects of the thigh and calf have been inadvertently injected (Fig. 8.50).⁴²⁴ As described previously, the usual sequelae are both loss of tissue (cutaneous and subcutaneous) and nerve damage, which may result in muscle atrophy or necrosis, or both. Color-flow duplex scanning and the use of open needles or a long catheter when sclerosing these very tricky areas are recommended but still do not guarantee a completely risk-free procedure. While the development of solid-state high-resolution duplex has allowed for more precise anatomic visualization, Duplex-guided injection should be performed only by experts with experience of thousands of sclerotherapy procedures. A physician should be present at all times to give immediate treatment if needed.

Figure 8.50 A, 2 days after duplex-assisted sclerotherapy with STS 1.0% into the gastrocnemial area to treat cutaneous telangiectasia. Note mottled skin. Treatment consisted of pain medication and local infiltration with lidocaine. B, 3 weeks after treatment, a well-circumscribed necrotic area is apparent. C, Intraoperative debridement of all necrotic tissue to fascia.

Reports cited in the previous discussion assume direct arterial injection as the cause of extensive tissue necrosis. However, another explanation may be valid. De Takats⁴³³ described and illustrated preferential arterial and venous connections in the precapillary circulation by stating: ‘These shunts permit more direct transmission of pressure from the arterial to the venous system. They offer less resistance to flow than the capillaries and help maintain venous pressure and flow.’ In patients with prolonged chronic venous hypertension who develop dilated and elongated varicose and subcutaneous veins, free flow of blood from the venous to the arterial system may occur in this manner. Thus, injection into a varicose vein near these shunts may allow the sclerosing solution direct access to the arterial circulation (Fig. 8.51).

Figure 8.51 Late aspect of a skin necrosis after sclerotherapy (undocumented). The color of the scar suggests that the necrosis was deep.

Prevention and treatment

Arterial injection is a true sclerotherapy emergency. The extent of cutaneous necrosis is usually related to the amount of solution injected. Therapeutic efforts to treat this complication are usually unsatisfactory but should be attempted.⁴¹⁹ Because its occurrence is extremely rare, we recommend that an emergency flow sheet be readily accessible (Box 8.1). Hobbs (personal communication, 1989) recommends that, on realization of arterial injection, blood and sclerosing solution should be aspirated back into the syringe to empty the needle of solution. In addition, aspiration of the injected artery as rapidly and completely as possible, if performed immediately, may help remove the injected sclerosing solution. The needle should not be withdrawn, but the syringe should be replaced with one containing 10,000 U of heparin, which should be injected slowly into the artery. Unfortunately, this maneuver is difficult to accomplish because the patient usually is in considerable pain and may find it difficult to hold still (Hobbs, personal communication, 1991) and it also assumes that arterial injection has typical manifestations which make it recognizable while the vein is still cannulated.

Rarely, patients have no complaints of pain and demonstrate only a mild, sharply demarcated erythema that becomes dusky and cyanotic after a few hours.⁴²² More practical treatments include periarterial infiltration with procaine 3%, 1 mL, which will form a complex with STS and render it inactive.^398,428 The foot should be cooled with ice packs to minimize tissue anoxia. Immediate heparinization (continued for 6 days) and administration of IV dextran 10%, 500 mL per dose, for 3 days is recommended. Use of IV streptokinase or another thrombolytic agent may also be considered if there are no contraindications for its use. Finally, use of oral prazosin, hydralazine, or nifedipine for 30 days should be considered. Cockett⁴²¹ has found that treatment that is delayed for more than an hour has no effect in limiting damage to the foot.

Use of IV heparin followed by subcutaneous heparin has been found to avert skin necrosis.⁴²² It was observed that warfarin (Coumadin) did not appear as effective as subcutaneous heparin in these patients. The protective effect of heparin may be unrelated to its anticoagulant activity.⁴³⁴ Postischemic endothelial cell dysfunction was prevented with heparin perfusion in the rat hind limb model.⁴³⁵ Heparin infusion at 0.5 U/mL resulted in endothelial-dependent vasodilation. Serum levels less than 0.5 U/mL (the average serum heparin level in a patient undergoing therapeutic anticoagulation) were less effective. It is postulated that direct interactions of heparin with the endothelium, inducing maintenance of a strong luminal charge, may produce beneficial membrane-stabilizing effects. Heparin may also modulate TNF activity, contributing to this effect.⁴³⁶ In addition, a favorable resolution of arterial injection occurred in one patient with injection of t-PA.⁴³⁷ In this patient, promazine was injected into an artery. Use of heparin, axillary plexus blockade, and IV sodium nitroprusside was not successful. Brachial artery injection of t-PA (Actilyse, 50 mg over 8 hours) resulted in therapeutic efficacy. Thus, local fibrinolytic therapy should be considered if conservative treatments prove ineffective.

Given the known relationship of injection site to the development of this problem, one must consider the necessity for injecting vessels in the vicinity of the medial malleolus. The British Medical Journal published an interesting report of a legal case brought against a physician for performing such an injection, which resulted in a transmetatarsal amputation.⁴¹⁷ The case was found in favor of the physician after several renowned sclerotherapists stated that the injection should be attempted if the patient would benefit, since the risks are infrequent and the benefits significant.

Prevention of this dreaded complication is best accomplished by visualization of the blood emanating from the needle. If it is pulsatile and continues to flow after the leg is horizontal, injection should not be attempted at this site. Mantse³⁰⁹ advises that when the medial malleolar area is treated, placement of the sclerosing needle should be performed while the patient is standing, so that the varix is bulged and the distance between the artery and vein is increased.

Theoretically, visualization of arteries and veins with duplex-assisted sclerotherapy should negate this risk. Indeed, newer color-flow duplex imagery allows visualization of minute arteries and veins. However, a number of arterial ulcerations have occurred with this technique, even when injecting posterior calf, gastrocnemius, and SFJ varicose veins. Thus, no technique is completely free from this complication.

Cause

The cause of DVT, with or without PE, after sclerotherapy is unclear. The three major factors responsible for DVT were first elucidated more than 100 years ago by Virchow:⁴⁷³

Sclerotherapy treatment always produces the first two causes in the triad, with coagulability changes related to endothelial damage, as well as to the coagulability properties of sclerosing solutions and predisposing hypercoagulability factors in the patient. Chemical endophlebitis produced by sclerotherapy should anchor the thrombus to the site of injection. Histologic examination of treated varicose veins has demonstrated that firm thrombosis occurs only on the damaged endothelium. Nonadherent thrombosis occurs on normal endothelium.⁴⁷⁴ Therefore, the most logical explanation for the development of emboli is damage to the deep venous system by migration of sclerosing solution or a partly attached thrombosis into deep veins from treated superficial veins. This may occur as a result of either injection of excessive volumes of sclerosing solution or physical inactivity after injection.⁴⁷⁵

An additional possibility concerns injection of tributary perforator veins, which may directly communicate with the deep venous system. In this situation, inadequate compression or injection of even 0.5 mL of sclerosing solution may force nonadherent thrombi into the deep circulation with muscle contraction. Ascending venography and digital subtraction phlebography in women with leg telangiectasia found that 0.7 mL of contrast medium injected into telangiectatic branches spread into the saphenous system in 8 of 15 patients.⁴⁷⁶ Two of the eight patients had telangiectasia as the only clinically perceptible abnormality. Therefore it is possible that up to 13% of patients with telangiectatic veins are at risk for the spread of sclerosing solution directly into the deep venous system. This further emphasizes the importance of limiting injection volumes.

Amount of Injection per Site

The circulation and direction of blood flow in varicose veins have been determined radiographically as stagnant or reversed (away from the heart), so the chemically induced thrombus is forced distally toward the smaller branching veins.⁴⁷⁷ However, cinematographic studies documented that a small amount of sclerosing solution entered the deep circulation after injection of 0.5 to 1.0 mL of solution into a superficial varicosity during 7 of 15 injections in nine subjects (Figs 8.53 and 8.54).⁴⁷⁸ No adverse effects were noted in these patients treated with POL 2%, probably because of rapid compression and ambulation of treated individuals and the resulting rapid dilution of the sclerosing agent within the deep venous system.

Figure 8.53 Injected contrast media, 1.5 mL, shown seconds after injection into a varicose vein with the patient supine.

(From Goldman MP, Weiss RA, Bergan JJ, editors: Varicose veins and telangiectasias: diagnosis and treatment, St Louis, 1999, Quality Medical Publishing.)

Figure 8.54 Injected contrast media, 1.5 mL, shown seconds after injection into a varicose vein with the patient standing.

(From Goldman MP, Weiss RA, Bergan JJ, editors: Varicose veins and telangiectasias: diagnosis and treatment, St Louis, 1999, Quality Medical Publishing.)

Although studies demonstrating the rarity of DVT after sclerotherapy are reassuring, DVT and embolic episodes usually occur 4 to 28 days after the sclerotherapy treatment session,⁴⁶⁰ and therefore longer follow-up is necessary. In addition, nearly 40% of patients with DVT have symptomatic PE.⁴⁷⁹

Both DVT and PE have been reported to occur with injection of large quantities of sclerosing solution (12 mL) in a single site.⁴⁸⁰ Two separate case reports of this complication, occurring with injection of less than 0.5 mL of POL 1% in two patients in each report, have been published.^239,481 In both reports, the injected veins were leg telangiectasia. In addition, the injection of 0.5 to 1 mL of sclerosing solution above the midthigh resulted in a presumed thrombus at the SFJ with resulting PE.²⁹⁸ This prompted Reid and Rothnie²⁹⁸ to recommend that injections not be given above the midthigh.

Thus, the quantity of sclerosing solution per injection site must be limited to ensure that the agent remains within the superficial system, and blood flow in the deep venous system must be rapidly stimulated by compression and muscle movement after sclerotherapy.

Finally, sclerotherapy of pedal veins may be hazardous, since the lack of valves or reversal of valves allows inward flow from superficial to deep veins,⁴⁸² which may produce DVT. Therefore, when treatment of pedal veins is necessary, phlebectomy may be preferable to sclerotherapy.