A 42-year-old man with a venous malformation of the hand, before the start of treatment (A) and at 9 months after 12 sessions of polidocanol microfoam sclerotherapy (B). A 28-year-old man with a superficial venous malformation of the foot treated with 13 sclerotherapy sessions for 7 months, before the start of treatment (C) and at 3 years after the end of treatment (D).
A 26-year-old woman with Klippel-Trénaunay syndrome, with repeat ulcers in her ankle and abundant phlebectasias in her leg, before the start of treatment (A) and at 5 months after 6 sclerotherapy sessions, with disappearance of all phlebectasias, closure of ulcers, and persistence of a telangiectatic nevus (B and C).
A 16-year-old female adolescent with a giant venous malformation of the buttock and thigh, with muscle infiltration, before treatment (A) and at 13 months after 23 sclerotherapy sessions (75% reduction in size) (B). The magnetic resonance image shows how the venous malformation at the subcutaneous tissue level has been replaced by residual fibroadipose tissue, with persistence of the untreated muscle involvement (C). After a 6-year follow-up, there have been no significant recurrences. L indicates left side.
Cabrera J, Cabrera J, García-Olmedo MA, Redondo P. Treatment of Venous Malformations With Sclerosant in Microfoam Form. Arch Dermatol. 2003;139(11):1409-1416. doi:10.1001/archderm.139.11.1409
Copyright 2003 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2003
Treatment of congenital venous malformations poses a major clinical challenge. Surgery is difficult and frequently unsuccessful, radiological intervention with embolization has an ill-defined role, and conventional sclerotherapy has little to offer.
To evaluate the efficacy and safety of sclerosant in microfoam form in treating congenital venous malformations.
A retrospective study of medical records, pretreatment and posttreatment color photographs, echo-Doppler ultrasonographic results, and/or magnetic resonance imaging in patients with congenital vascular malformations of venous predominance. Follow-up ranged from 6 to 103 months (mean, 30 months).
Private vascular surgery clinic in Granada, Spain, and dermatology department at a university hospital in Pamplona.
The study population comprised 50 patients, 19 with limited venous malformations, 16 with infiltrating venous malformations, and 15 with Klippel-Trénaunay syndrome.
Percutaneous sclerotherapy by direct injection of 0.25% to 4% polidocanol microfoam under du-plex ultrasonographic guidance. The number of sessions varied between 1 and 46 (mean, 12 sessions).
Main Outcome Measure
The primary efficacy end point was defined as a reduction in size after completion of the treatment.
Sclerosis therapy with polidocanol microfoam was judged beneficial in 46 (92%) of the 50 patients. Among the 46 responders, 18 showed disappearance of treated malformations, 15 showed a reduction in malformation size of more than 50%, and 13 showed a reduction in malformation size of 50% or less. Of the 39 patients who presented with pain, the pain disappeared in 25 and was reduced in 14. No major adverse effects were reported by any patient. There were 4 cases of transient skin pigmentation and 3 cases of skin necrosis.
Color echo-Doppler ultrasonography–guided sclerotherapy with polidocanol microfoam was effective in 46 (92%) of the patients. The technique is delivered on a strictly ambulatory basis and has proved simple and innocuous. The quality and durability of the outcome make this novel procedure the treatment of choice in the care of patients with congenital venous malformations.
ACCORDING TO the classification of Mulliken and Glowacki,1 congenital vascular anomalies are catalogued as hemangiomas or vascular malformations. Vascular malformations are localized or diffuse errors of embryonic development,2 and are subdivided anatomically and rheologically into slow-flow lesions (eg, capillary, lymphatic, and venous malformations) and fast-flow lesions (eg, arterial malformations, such as aneurysms, ectasia, stenosis, fistulas, and arteriovenous malformations).3,4
Venous malformations occur in a wide dysmorphic spectrum, including varicosities and ectasias, localized spongy masses, and complex lesions that can permeate any organ system, particularly muscle. They are present from birth and, unlike hemangiomas, they do not have a cycle of growth and subsequent spontaneous regression. They grow proportionately during infancy and childhood, and to a lesser degree during adulthood. Most venous malformations are asymptomatic and should be treated conservatively, although swelling and pain are common; extensive venous malformations can cause a localized intravascular coagulopathy. Doppler ultrasonography should be the initial imaging modality, and demonstrates the absence of flow or low-velocity venous flow. Magnetic resonance imaging is the most informative radiological technique for venous malformations, which are typically seen as T2-hyperintense lesions.
Klippel-Trénaunay syndrome (KTS) is a well-known eponym for a capillary-lymphatic-venous malformation, which is associated with soft tissue and skeletal hypertrophy, usually of one or more limbs.5,6 Anomalous lateral veins become prominent because of incompetent valves and deep venous anomalies.
The treatment of venous malformations is complicated. A surgical approach is indicated in well-circumscribed malformations of moderate size, in which the possibilities of anatomical and functional restoration are maximal. However, the surgical treatment of more extensive lesions can often lead to loss of motor function, nerve damage, and massive bleeding. Sclerotherapy is an alternative method of treatment for venous malformations,7 and is used to reduce the size of the lesion, preoperatively as a support to surgery or as a postoperative complement. Sclerosants destroy the vascular endothelium through different mechanisms: chemical agents (iodine or alcohol8), osmotic agents (salicylates or hypertonic saline), and detergents (morrhuate sodium,9 sodium tetradecyl sulfate,10 polidocanol,11 and diatrizoate sodium12), which change the surface tension of the cell, producing tissue maceration. There is no safe sclerosant, and all are associated with complications of different degrees of severity.13
To our knowledge, we present the first description of the improvements in action obtained after administering conventional sclerosant in the form of microfoam to patients with venous malformations.14,15 This novel approach may widen the indications of sclerotherapy and overcome the limitations of sclerosants in liquid form.
Between July 1, 1993, and January 31, 2002, 50 patients with congenital vascular malformations of venous predominance were treated with sclerotherapy using polidocanol microfoam. There were 18 male and 32 female patients, ranging in age from 8 to 62 years. All had been diagnosed as having a venous malformation by the referring center, and had been offered no therapeutic alternative. Investigations to assess the extent of the lesions were made clinically, and by invasive and noninvasive techniques with one or more diagnostic methods: ultrasonography with Doppler scanning (N = 50), magnetic resonance imaging (n = 15), contrast phlebography (n = 8), and arteriography (n = 4). Thirteen patients had undergone previous surgery elsewhere and had experienced recurrences; 3 had undergone embolization, with scant improvements. Most patients came from Spain; 4 patients were referred from Italy, and 1 was referred from England. The baseline characteristics of the patients, the number of treatment sessions, and the outcomes are shown in Table 1 and Table 2. Only patients who were followed up for more than 6 months after treatment were included in the study.
All the assessments were performed by at least one investigator (J.C.) who had also examined each patient before treatment and at each of the initial posttherapy visits. All 50 patients were examined at 6 months after therapy, 10 were examined at 12 to 24 months after therapy, 11 were examined at 25 to 48 months after therapy, and 13 were examined at more than 48 months after therapy. All the patients gave written informed consent.
All patients were evaluated by physical examination and color duplex Doppler ultrasonography, used to establish the anatomical features of the deep veins and to determine whether a clinically significant arteriovenous malformation was present.
Following the Hamburg classification,16 we divided all patients into 3 categories: those with localized or extensive subcutaneous lesions (limited venous malformations [n = 19]), those with intramuscular infiltrations (infiltrating venous malformations [n = 16]), and those with complex-combined vascular malformations (such as KTS [n = 15]).
Polidocanol sclerosant in microfoam form was administered by direct ultrasonographic-guided percutaneous injections. The polidocanol microfoam is composed of carbon dioxide (CO2) microbubbles with a small diameter, with sufficient stability to be injected into the vessels. The combination with gas greatly increases the volume and creates an enormous increase in surface area compared with the liquid. At each session, 20 to 80 mL of microfoam was injected, corresponding to a moderate dose (3-6 mL) of the original liquid solution.14 The maximum recommended dose in the treatment of varicose veins is 6 mL of 3% polidocanol.15,17
Polidocanol was injected at concentrations of 0.25% to 4%, depending on the size of the malformation and the hemodynamic characteristics of the area treated. Intramuscular (infiltrating) malformations always required higher concentrations (3%-4%). The peripheral remains of giant malformations and the superficial phlebectasias of patients with KTS were treated at lower concentrations (0.25%-0.5%). The remainder were treated with a 1% to 2% concentration.
Sclerotherapy was performed in a treatment room, without anesthesia. Sedation was deemed necessary for 2 pediatric patients to ensure adequate compliance. The microfoam was injected into the patient using a 20-G × 40-mm needle or a 20-G × 51-mm catheter (Abbott, Madrid, Spain). After the injection of 20 to 25 mL of microfoam guided by echo-Doppler ultrasonography, subsequent aspiration with a syringe revealed the degree of dilution of the microfoam; if the aspirate was red, indicating a great dilution, the limb was elevated or the area was manually compressed to reduce the volume of blood, and, in some cases, the afferent arterial trunk was compressed. The aim was to achieve a pink or white aspirate (lesser degree of dilution or no dilution) after the repeat injection of a similar volume. Occasionally, the second volume was injected faster, increasing the flow rate of the microfoam, to obtain a greater mechanical action to displace the blood. These simple maneuvers improved the response to the sclerotherapy. The outcome of each session was evaluated by ultrasonography at the beginning of the next session, taking account of the endovascular hyperechogenicity and noncompressibility of the injected zones. The number of sessions varied between 1 and 46 (mean, 12 sessions). Twenty-one patients underwent more than 10 sessions.
The primary efficacy end point was defined as a reduction in size after completion of the treatment. The primary end point was determined by the investigators' (J.C. and A.G.-O.) physical examination of the patient, including magnetic resonance imaging results in 15 patients and medical photographs and echo-Doppler studies in all patients. Secondary measures of efficacy included objective aspects, such as correction of coagulation abnormalities, closure of skin ulcers, and a reduction in the episodes of hemorrhage, together with subjective aspects, including decrease of pain and functional limitation and the patients' opinion (about color, size, swelling, and aesthetic outcome). The patients or their parents were asked to report the end result as excellent (completely cured), good (much better), moderate improvement, unchanged, or worse.
Table 1 shows the patients' clinical characteristics. We treated 15 patients with KTS; they presented with large and ectatic varicose veins. Eight of these patients had infiltration of the muscles by the venous malformation, and 5 had deep venous anomalies (1 had aplasia, 2 had hypoplasia, 1 had avalvulia, and 1 had an aneurysm). Sixteen patients had infiltrating venous malformations, 15 (94%) of which were located principally in the extremities. In the 19 patients with limited venous malformations, the most frequent location was also in the extremities (64%). Taking the 3 groups of patients into account, the most frequent location of the vascular malformations was the lower extremities.
Table 2 shows the outcome and results of microfoam treatment in the 50 patients. The number of sessions varied between 1 and 46 (mean, 12 sessions). Of the patients with infiltrating venous malformations, 50% needed more than 20 sessions, while only 16% of the patients with limited venous malformations needed more than 10 sessions and none needed more than 20 sessions. Of the patients with KTS, 66% underwent between 6 and 20 sessions. Sessions took place at 15- to 30-day intervals. In the patients with infiltrating venous malformations, the interval was every 7 to 15 days. Greater response within this group was observed in patients treated weekly compared with patients treated every 15 days. In most patients with KTS and in all of the patients with infiltrating venous malformations, the most significant symptom was the pain. There was no attempt at correlating the extent of pain with treatment efficacy.
In 46 (92%) of the patients, there was an improvement on physical examination and using noninvasive techniques (Figure 1, Figure 2, and Figure 3). Only 2 patients (4%) did not respond. Two other patients (4%), both with an associated arteriovenous fistula, had a relapse after the initial response. Among the 46 responders, 18 (39%) showed a total disappearance of treated malformations, 15 (33%) showed a reduction in malformation size of greater than 50%, and 13 (28%) showed a reduction in malformation size of 50% or less. Of the 39 patients who presented with pain, 31 had mild or moderate pain and 8 had severe pain. This disappeared in 25 patients and was reduced in 14. Of the 10 patients who presented with a functional limitation, function was restored in 7. Chronic ulcers healed in all 5 patients with this condition. In 9 patients with episodes of hemorrhage, these decreased (n = 1) or disappeared (n = 8). No significant recurrences were found, even in patients followed up for more than 4 years. Most patients reported the overall outcome as excellent, good, or a moderate improvement (Table 2). Sixteen patients had been previously treated: 13 had undergone surgery (20 operations), with subsequent recurrences, and 3 had undergone embolization (5 procedures), with scant improvements. All these patients significantly improved after our treatment, and their satisfaction level after sclerosis with microfoam was much higher than after previous treatments.
The best response to our treatment was among the patients with KTS (Figure 2), with 12 (80%) of them showing a reduction in malformation size of more than 50%. Most of these patients (87%) reported the overall outcome as excellent or good. Owing to the complexity and extension of the malformations, the group with infiltrating venous malformations was the most resistant to the treatment, with only a 50% reduction in size in 9 (57%) of the patients. Of these patients, 50% reported the overall outcome as excellent or good. In 4 patients with malformations in their hands, and 5 in their feet, many small arteriovenous communications were observed. A color echo-Doppler examination was essential in these patients to avoid direct arterial injection. The microfoam was injected in the postfistula venous dilatations, with compression of the efferent artery, forcing the advance of the foam to the communication. Moreover, the early occlusion of the dilated drainage veins (where sclerosis without previous blocking of the arteriovenous fistulas would induce a return deficit and exacerbate the symptoms) was avoided. These veins were sclerosed later, after the occlusion of the nidus of the malformation. The treatment of these malformations poses greater technical problems compared with those of venous predominance (Figure 1).
Six patients with giant malformations (Figure 3) (3 with KTS and 3 with infiltrating venous malformations) underwent a hematological examination (including determination of plasma fibrinogen level, platelet count, and prothrombin time) before sclerotherapy. The examination was repeated 24 to 48 hours after each session, until the lesion reduced in size. No patient showed any worsening of the hematological variables analyzed, and no thrombotic sequelae were found. The abnormal coagulation finding, in one patient with localized intravascular coagulopathy, progressively normalized with treatment (data not shown).
Four patients developed skin pigmentation that spontaneously disappeared. A small skin necrosis appeared in 2 patients during superficial sclerosis with 0.5% polidocanol microfoam. Another patient had more extensive necrosis of the thigh after the inadvertent injection of a small arterial branch (Table 3).
The unintentional intra-arterial injection of 3% polidocanol microfoam into the cubital artery of one patient caused intense pain in the forearm and hand and subsequent weakness of the fifth digit. The immediate appearance of irregular violaceous areas indicated capillary thrombosis. The patient recovered the function of the digit within a few weeks, with resolution of skin lesions. The injected artery was occluded at a subsequent checkup. Temporary interdigital necrosis in the foot was produced in another patient.
After the sclerosis, there were some cases of moderate local pain, which generally required no analgesic treatment and progressively disappeared. In some patients with giant malformations, oral prednisone, 0.5 mg/kg per day for 3 days, was administered to reduce inflammation. No patient had thrombosis of the deep venous system, a pulmonary embolism, or neurological lesions. There were no cases of hemoglobinuria due to hemolysis, perhaps because of the selective action of the sclerosant on the endothelium and the moderate doses administered.
Two thirds of all vascular malformations are predominantly venous. Most venous malformations are asymptomatic, and should be treated conservatively. It is usually impossible to remove the lesion surgically without causing severe scarring or other complications.
Sclerotherapy with fluoroscopic monitoring is the mainstay of treatment for venous malformations. The common sclerosants (alcohol8 and sodium tetradecyl sulfate10) are potentially dangerous and require the use of tourniquets and compression to minimize the passage of sclerosing agent into the systemic circulation. Each session of multistaged alcohol sclerotherapy has to be performed with the patient under general anesthesia, with careful monitoring of cardiovascular status intraoperatively. Local complications include blistering, full-thickness cutaneous necrosis, and damage to local nerves. Systemic complications include hemolysis and a potential for renal toxicity and cardiac arrest. Liquid polidocanol (Ethoxysclerol) has been used for nearly 20 years in the treatment of varices.18
It is difficult to control the dosage of sclerosing liquids because of the progressive dilution and irregular distribution in the vessels. It is also impossible to control the distribution of sclerosant after injection, and its spread cannot be visualized on ultrasonography. Sclerosant microfoam is composed of microbubbles of CO2. The combination with CO2 greatly increases the volume and creates an enormous increase in surface area compared with the liquid. Polidocanol in microfoam form displaces the blood from the lesion, permitting homogeneous contact between the sclerosant and the endothelium, facilitating endothelial destruction, and can be visualized on ultrasonography. Since the 1950s, the intravenous injection of 50 to 100 mL of CO2 has been used as a contrast for radiological and hemopericardiac diagnosis and in echocardiography.19,20 Several researchers21- 23 reported the injection of CO2 in the right side of the heart without complications, and described its use as a contrast in aortoarteriography, even after administering up to 450 mL in one procedure. Carbon dioxide is sufficiently fluid to allow fine catheters to be used. It is nontoxic, and large amounts can be administered. Other conventional foams, obtained with different methods, are formed with atmospheric air that is rich in nitrogen, whose low solubility coefficient and low diffusibility in body fluids hamper its elimination and, therefore, limit the total volume that can be injected.
When the gas is mixed into the surfactant liquid sclerosant with the appropriate coadjuvants, microbubbles of a reduced diameter can be obtained; these microbubbles have sufficient stability to be injected into the vessels.24- 26 The liquid on their surface gains an enormous increase in surface area,24 which grows exponentially in inverse proportion to the diameter of the bubble. Alongside the high solubility of the gas used, this increased surface area facilitates its metabolism by blood solubility and pulmonary diffusibility.24 The reduced volume of micronized gas in the microfoam and the low rate of flow during its administration are important safety elements.
The present review of our experience using this new form of sclerotherapy on patients with venous malformations shows a high degree of success. Among the patients whose treatment was completed, almost half (42%) of the limited malformations disappeared. More than half (69%) of the infiltrating malformations were considerably reduced, and some disappeared. The best response to the sclerosis was in the patients with KTS, in 80% of whom most of the malformation was eliminated. Some minimal varicosities (<20% of the original lesion) recurred in 10 patients. The therapeutic efficacy of polidocanol in microfoam form depends on its mechanical action, because the microfoam exerts its effect when it totally displaces the blood in the vessel. If the blood flow is increased, dilution occurs, reducing this effect. Patients with KTS present large ectatic and incompetent vessels in which the desired intravascular concentration of the sclerosant microfoam is easier to achieve. In patients with KTS, surgical treatment is known to initially decrease symptoms, but recurrence is common. With our approach, although limited recurrence is frequent, clinical improvement is substantial and further microfoam sclerotherapy can be performed when required.
The response to microfoam in patients with venous malformations depends on the size of the incompetent veins and the muscle involvement. In many patients with muscle involvement, there are small arteriovenous communications that can increase the flow within the malformation, hampering its filling with the microfoam. Our outcomes are excellent in limited malformations of small and moderate size, whereas we can control the progression and growth of malformations of greater size with muscle involvement, but their eradication is difficult to achieve.
Large venous malformations are an incurable disease, and the medical community has observed their natural evolution with impotence. Sclerotherapy with microfoam allows moderation of their progression and the reduction in size of those with lower flow rates. We emphasize the great increase in action of the sclerosing agents in this new pharmaceutical, its selective effect on endothelium, its visibility on ultrasonography, and the predictability of outcome. The technique is tolerated well locally and generally, without major complications.
To our best knowledge, we present the first series of patients with vascular malformations of venous predominance treated with sclerosant in microfoam form. The simplicity, speed, low cost, strictly ambulatory nature, and safety of sclerotherapy, combined with the quality and stability of outcome achieved with our novel procedure, may make sclerotherapy with microfoam the approach of choice for the anatomical and functional elimination of congenital vascular malformations of venous predominance.
Corresponding author and reprints: Pedro Redondo, MD, PhD, Department of Dermatology, University Clinic of Navarra, Pio XII, 36, 31080 Pamplona, Spain (e-mail: email@example.com).
Accepted for publication March 4, 2003.
This study was presented in poster and videotape form at the 20th World Congress of Dermatology; July 1, 2002, Paris, France; and at the 16th Annual Congress of the American College of Phlebology; November 7, 2002; Fort Lauderdale, Fla.