Guidelines for the diagnosis and therapy of diseases of the veins and lymphatic vessels

Evidence-based report by the Italian College of Phlebology

INTERNATIONAL ANGIOLOGY  vol. 20 - suppl.2 to issue 2 - JUNE 2001

 

TASK FORCE:

G.B. Agus, C. Allegra, G. Arpaia, G. Botta, A Cataldi, V. Gasbarro, S. Mancini

 

in collaboration with:

M. Bartolo jr., G Belcaro, P. Bonadeo, S. Camilli, M. Georgiev, A. Orsini, F. Stillo, P. Zamboni

 

CONTENTS 

1.    Definition

2.    Epidemiology

3.    Classification and categories (CEAP)

4.    Non-invasive diagnosis

5.    Surgical treatment

6.    Sclerotherapy

7.    Compression

8.    Drug therapy

9.    Physiotherapy

10.  Mineral water therapy

11.  Treatment of venous ulcers

12.  Venous malformations

13.  Quality of life (QOL)

14.   References

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GUIDELINES FOR THE  PREVENTION AND TREATMENT OF THROMBOEMBOLIC DISEASE

Prophylaxis of venous thromboembolism.

Treatment of deep venous thrombosis (DVT): methods and recommendations

References

 

GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF THE LYMPHATIC DISEASE

Lymphatic vessel diseases

Malformations of the lymphatic vessels

Quality of life

References

 

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PRESENTATION OF THE CLAUDIO ALLEGRA

President of the Italian College of Phlebology

I have real pleasure in writing this introduction to the Italian College of Phlebology’s guidelines on venous and lymphatic diseases planned and drafted at the start of my presidency. For those of us with a “Latin” culture, this is the answer to the equation ‘clinical approach/controlled feasibility checks’. It provides us with a means of sharing with our Colleagues the best, proven information available in the field today. It is not the “Gospel” for sure, but only a set of recommendations based on  our own and international research.

While apparently ‘recommendations’ implies the positive aspects of evidence-based medicine, in reality it shows how much still remains unproven and subjective in the field of venous and lymphatic pathology.  To this summary of the state of the art we must add the incentive for future rigorous, reliable and reproducible research.

A comparison of these guidelines and those drawn up by respected international groups shows that we are not too far from the proven opinions of our foreign Colleagues – so we are entitled to the satisfaction of being the professional authors of a universally agreed text.

However, what distinguishes these guidelines is the discussion of difficult subjects such as compression and sclerotherapy. Again, the “Latin” peoples have long traditions on these subjects, which are now set in an appropriate context using Anglo-Saxon methods which bring everything back to controlled evidence.

Intuition, tradition, trade, and craft, all characteristics of the Mediterranean peoples, become signposts along the path of diagnosis and treatment, obeying international regulations.

It is exciting that this summary comes from the Italian College of Phlebology which a few years ago recognised the need to unite the main Italian phlebology societies within the College.

Recommendation: What really holds scientific associations together is the cultural message borne in the seed of continuity beyond personal and group claims and ambitions.

 

METHODS AND DEFINITIONS OF THE RECOMMENDATIONS

 In Spring 1998, the Italian College of Phlebology set up task forces to prepare guidelines for diagnosis and treatment in phlebology and lymphangiology. The basic method drew on evidence-based medicine (1-3), applying the rules of evidence to the medical literature to produce recommendations for clinical management. Particular consideration was given to the evidence set out in Consensus Statements in this field (4-11) and the meta-analyses and available randomised trials were used.

We set out to adapt the findings to the working methods and approach taken by the Italian National Health Service, taking account of the extensive experience of European phlebology, using recent Anglo- Saxon scientific models.

Therefore, the different levels of recommendations have been classified as A, B and C:

 

-       Grade A, recommendations based on large, randomised clinical trials, or meta-analyses with no heterogeneity.

 -       Grade B, recommendations based on randomised clinical trials with small populations, and meta-analyses including non-randomised clinical trials, with some possible heterogeneity.

 -       Grade C, recommendations based on observational studies and on consensus reached by the authors of the present guidelines.

 

REFERENCES

1. Sackett GL et al. Evidence-based medicine: how to practice and teach EBM. London: Churchill Livingstone, 1996.

2. Greenhalgh T.  How to read a paper.  The basics of evidence-based medicine.  B. M. J. publishing group, 1997 (Ediz. Italiana; Infomedica. Pianezza – TO, 1998).

3. Liberati A. (Ed.), La medicina delle prove di efficacia. Potenzialità e limiti della evidence-based medicine. Roma: Il Pensiero Scientifico. Ed., 1997

4. Porter JM, Moneta GL and International Consensus Committee on Chronic Venous Disease: reporting standards in venous disease.  J Vasc Surg 1995; 21: 635-45

5. Consensus paper on venous leg ulcers.  Phlebology 1991: 7:48-58.

6. Sclerotherapy for varicose veins: practical guidelines and sclerotherapy procedures.  Handbook of Venous Disorders. London: Chapman & Hall.  1996: 337-54

7. Consensus Conference on sclerotherapy on varicose veins of the lower limbs. Phlebology 1997;12: 2 -16.

8. Consensus statement - The investigation of chronic venous insufficiency.  Circulation 2000. 

9. International Task Force.  The management of chronic venous disorders of the leg: an evidence-based report. Phlebology 1999; 14 (Supplement 1).

10. Consensus Statement.  Prevention of venous thromboembolism. Int Angiol 1997 ; 16: 3-38.

11. Consensus Document.  The diagnosis and treatment of peripheral lymphedema.  Lymphology 1995: 28: 113-7.

 

1.    DEFINITION

      Chronic venous insufficiency (CVI) is caused by inadequate function of the peripheral veins. The equilibrium between tissue requirements and the amount of blood returning to the heart is not guaranteed, either in an orthostatic position or lying down. However, CVI does not simply involve the patency of the veins and the condition of their walls and valves (vascular factor) but includes any other cause that might affect venous return, such as muscle pump action in the feet, calves and thighs or changes in joint mobility and connective tissue (extravascular factors). A distinction must also be made between insufficiency of the superficial venous system and insufficiency of the deep venous system, or of both.

The key to recognising the subjective and objective signs of CVI is local or diffuse venous hypertension with rheologic repercussions on the macrocirculation and microcirculation, leading to the characteristic edema.   These signs are valid at both the physiopathological and clinical levels.

The acquired or congenital pathological process causing CVI (angiodysplasia, valvular insufficiency or agenesis) can be functional or organic, the latter being more common but usually less severe. 

 

2.     EPIDEMIOLOGY

 CVI is a serious clinical condition affecting large numbers of people, and is important both from an epidemiological point of view and on account of its socio-economic repercussions. In the western world the consequences of the high prevalence of CVI are well known, the costs of diagnostic procedures and treatment programmes, the significant amount of work hours lost and the repercussions on quality of life (1-3).

The current prevalence of CVI in the lower limbs is from 10-50% of the adult male population and 50-55% of the adult female population. Clinical signs of varicosis are present in 10-33% of women and 10-20% adult men (1, 4-6).

To give pure data on the incidence of these diseases, prospective epidemiological studies are most interesting from our point of view, although in actual fact very few of these focus solely on CVI.  The most widely cited is the Framingham study, which found the incidence of varicose veins (new cases appearing in each unit of time) was 2.6% in women and 1.9% in men per year; at two years varicose veins affect 39/1000 men and 52/1000 women (7). The prevalence of varicose veins in epidemiological studies covering different geographical areas varies widely (6).

The correlation between the prevalence of varicose veins and age is almost linear: 7-35% and 20-60% respectively in men and women between the ages of 35 and 40 years up to 15-55% in men and 40-78% in women over the age of 60. Venous diseases and varicose veins are rarely seen in children and adolescents, although children with a family history of varicose veins can develop venous ectasia and incompetence in their teens (1, 6, 8).

It is still debated whether the transmission of venous disorders is hereditary.  The incidence of varicose veins in people with or without transmissible hereditary factors varies between 44 and 65% in the presence of these factors as opposed to 27-53% when these factors are absent (6).  Familial predisposition is found in 85% of people with varicose veins but only 22% of those with no family history (9).  Although many studies demonstrate "vertical inheritance" none have yet shown a “horizontal inheritance” which could be attributed to a genetic model.

CVI mainly affects women in their fifties and sixties. After this age there is no real difference between the sexes.  Overall, epidemiological studies give evidence of a male/female ratio of 1:2-3, although Widmer’s large Basel trial (10) found a ratio of 1:1.  This is probably due to the different trial methods (6).

Numerous epidemiological studies correlate the incidence of varicose veins with pregnancies and with the number of births.  This varies between 10 and 63% in women with children as opposed to 4-26% in nulliparous women. Women who have had 1-5 pregnancies have an incidence of venous disease of between 11 and 42%, the proportion rising linearly with the number of births.  This correlation is even more striking if the woman already has venous disorders. However, there is no shortage of studies disagreeing with this conclusion, which find no relationship between the incidence of varicose veins and the number of births (6).

The relationship between varicose veins and body weight has been widely examined. People who are overweight, especially women living in developed countries, suffer more from CVI and varicose diseases than people of normal weight:  from 25% to over 70% (both sexes) as opposed to 16-45% (6).  Varicose veins appear in both legs in 39-76% of cases (6). 

Hypertension, cigarette smoking and constipation have not been shown to be correlated to CVI nor to be statistically significant risk factors for CVI.

It is widely recognised that certain occupations, particularly those that involve standing for long periods, are associated with an increased prevalence of varicose veins; however, it is extremely difficult to demonstrate a statistical correlation (4,11).  Studies have focused on the incidence of varicose veins among people in a variety of jobs, particularly industrial and several authors have confirmed the association between the upright posture and varicose veins (6,12).  The temperature of the workplace also has an influence (11).

Edema and trophic lesions, eczema and hyperpigmentation, all expressions of CVI CEAP categories 4-6, are reported in 3-11% of the population. The development of new symptoms/year is about 1% for edema and 0.8% for mild skin disorders (1). Active venous ulcers (VU) are found in about 0.3% of the adult population in the West and the overall prevalence of active and healed ulcers has been put at 1%, rising to 3% in the over-70 age bracket.

VU seems to be less likely or slower to heal among patients in the middle-lower social classes. The prognosis for VU is anyway not good, as they take a long time to heal and recur easily;  50-75% take 4-6 months to heal while 20% are still open at 24 months and 8% at five years.

Among patients of working age 12.5% apply for early retirement (1,,  2, 13-15). CVI is thus not only a serious burden on the health care services but also a considerable cost to society (16,17).

The number of working hours lost through CVI each year in England and Wales is around 500,000, whilst in the United States (where 25,000,000 people have varicose veins, 2,500,000 suffer from CVI and 500,000 from active venous ulcers) it reaches 2,000,000. The Brazilian public health figures show that, of the fifty illnesses most often cited as the reason for absenteeism and normally acknowledged in compensation schemes, CVI is placed 14th as it is the 32nd most frequent cause of permanent invalidity (1).

The annual cost of CVI management – almost certainly underestimated - is put at GB£290 million, 14.7 billion French francs, 2,420 million German marks, 1,638 billion Italian lira and 17,240 million Spanish pesetas. In addition, the European Community allocates  1.5 – 2% of its entire health budget – 418-1135 million ECU in 1992  – for the principal countries in Europe, over and above the indirect costs due to disability (2,17).

The annual cost of treating VU in the UK reaches £400-600,000,000 (£40,000,000 for medications alone), more than one billion dollars in the United States  ($300,000,000 for domiciliary treatment), 400,000,000 DM in Germany and 300,000,000 Swedish krona, whilst in France ulcer treatments cost an average of 240,000 francs a year (1).  In Italy around 291,000 doctor’s visits/year are made for ulcers, with prescriptions in 95% of cases, giving a financial burden of 243 billion lira (18). In total, the direct and indirect cost of CVI is around one billion dollars for each European state for which recent figures are available (UK, France, Germany) (1).

 

3.    CLASSIFICATION AND CATEGORIES (CEAP)

 The CEAP classifications were drawn up by an international group of specialists in 1994,  the aim being to produce a new, standard method for the evaluation of chronic venous diseases which encompassed all the signs and symptoms of the disease (19). At the World Conference of Phlebology, in London in 1996, these classifications were reviewed and validated internationally. Since then, they have been translated into a number of languages and the international literature offers many papers that use these classifications (20-26).

CEAP CLASSIFICATIONS

 

Clinical

CO      no signs of venous disease

C1       teleangectasia or reticular veins

C2       varicose veins

C3       edema without skin changes

C4       skin changes (pigmentation, venous eczema, lipodermatosclerosis)

C5       skin changes with healed ulceration

C6       skin changes with active ulceration

Etiologic

Primary

Secondary

Congenital

Anatomic

Superficial

Deep

Perforator

Pathophysiological

Reflux

Obstruction

Both

 

Examples:

 1)      Cs2 – Ep – As4 – Pr

Patient with primary varicose veins of the small saphenous vein with reflux.

Anatomic scoring:             1

Disability scoring:             1

Clinical scoring:                2

 

2)      Cs6 – Es – As2 – 3 – 5, p11-13, Pr,o

 Patient with post-phlebitis syndrome with active trophic lesions and obstruction of the deep femoral circulation with incontinence along the whole great saphenous vein.

 Anatomic scoring:         5

Disability scoring:           3

Clinical scoring:            7

 

CEAP Classifications

 -         Clinical

-         Etiologic

-         Anatomic

-         Pathophysiological

 

C = clinical signs (C0-6)

        a = asymptomatic

       s = symptomatic

E = etiology (Ec, Ep, Es)

A = anatomic findings (As, d, p)

P = physiopathology (Pr, o)

 

Clinical classifications (C 0-6)

class 0: no visible or palpable clinical signs of venous disease

class 1: telangiectasia or reticular veins

class 2: varicose veins

class 3: edema

class 4: skin changes of venous origin (pigmentation, eczema, subcutaneous inflammation)

class 5: as class 4 with healed ulceration

class 6: as class 4 with active ulceration

 

Etiologic classifications (Ec, Ep, Es)

Ec = congenital (from birth)

Ep = primary (non-identifiable cause)

Es = secondary (post-thrombotic, post-traumatic, other)

 

Anatomic classifications (As,d,p)

 As = involving the superficial veins

Ad = involving the deep veins

Ap = involving the perforating veins

 

Superficial veins: As

 1)      telangiectasias, reticular veins on the  small vena saphena

2)      above the knee

3)      below the knee

4)      small saphenous vein

5)      non-saphenous venous districts

 

Deep veins: Ad

 6)   inferior vena cava/iliac vein

7)   common iliac

8)   internal iliac

9)   external iliac

10) pelvic veins: gonadal, broad ligament, femoral vein, other

11) common femoral

12) deep femoral

13) superficial femoral

14) popliteal vein

15) crural, and leg veins: anterior and posterior tibial, peroneal

16) muscle veins: gastrocnemius, soleus, etc.

 

Perforating veins

 17) Thigh

18) Calf

 

Scoring venous malfunction by severity

*anatomic scoring: number of parts affected: 1 point for each part affected

*clinical scoring: objective symptoms and signs

pain                             0 none

                                   1 moderate, not requiring treatment

                                    2 severe, requiring pain killers

 

edema                         0 none

                                   1 moderate, not requiring treatment

                                   2 extensive

 

venous claudication      0 none

                                   1 moderate, not requiring treatment

                                   2 disabling

 

pigmentation                 0 none

                                    1 localised

                                    2 extensive

 

subcutaneous               0 none

inflammation                 1 localised

                                     2 extensive

 

ulcer (size)                    0 none

                                    1 less than 2 cm

                                    2 more than 2 cm

 ulcer (duration)            0 none

                                    1 less than 3 months

                                     2 more than 3  months

 ulcer (recurrences)        0 not recurrent

                                     1 only one ulcer

                                      2 recurs after healing

 ulcer (number)              0 none

                                      1 one

                                      2 more than one

 disability score               0 asymptomatic

                                      1 symptoms, but  can lead a normal  life without support hose

                                       2 able to work an eight-hour day only with support hose

                                       3 unable to work even with  support hose

 

4.    NON-INVASIVE DIAGNOSIS

Non-invasive diagnostic methods for venous disease were developed for screening, for quantifying lesions, and for hemodynamic studies. Centers for non-invasive diagnosis have grown up mainly in the last few decades.

Both the general practitioner and the specialist must, with varying degrees of competence, know the significance of the various vascular tests,  their indications and limitations, so they can avoid having to prescribe unnecessarily invasive and costly tests (27-29).

Venous disease is more difficult to evaluate than arterial disease and requires experience and closer evaluation. This means venous tests are much more operator- dependent and require specific clinical skills, particularly in the evaluation of CVI. CVI can be the result of obstruction to venous outflow or return, or to a combination of the two.  Clinical examination and diagnostic techniques therefore aim to establish which conditions are present.  The anatomical location of the alterations must be found and the reflux and/or obstruction must be identified. 

There are many simple, rapid and efficient tests available which are cost-effective.  Just three types of examinations give the basic information usually needed to evaluate and quantify venous problems:

-      continuous-wave  (CW) Doppler

-      duplex scan/colour Doppler ultrasound

-          plethysmography

adding, as necessary:

-         investigation of the microcirculation.

 

EVALUATION OF VENOUS REFLUX

Reflux is usually assessed with the patient standing, with the limb under examination relaxed and the knee slightly bent.  After the clinical and physical examination the screening can be completed with a directional pocket Doppler scanner which gives information about the presence or absence of reverse flow at the sapheno-femoral and sapheno-popliteal junctions.  Manual compression of the calf produces an upward flow in the limb and reverse flow can be seen when the pressure is released.  Compression must be applied for at least three seconds, not more than 10-20 cm distally from the site of examination.   If the reverse flow disappears on compressing the superficial vein distal to the junction it is limited to the superficial system. 

The CW Doppler gives information on the presence or absence of reflux at the venous junctions in 50-90% of patients (Consensus).  Anatomical anomalies in the popliteal cavity can cause various errors; for example, reverse flow in the gastrocnemius veins may be interpreted as incontinence of the popliteal vein.  The CW Doppler is not useful for locating incompetent perforating veins.

Screening with the CW Doppler can be completed with a duplex/color flow map (CFM), giving information on the site of the reflux;    for example, the femoral vein, the popliteal or the perforating veins can all be studied individually. Color testing (CFM) means a faster assessment can be made.  Using a 7.5 MHz probe the vein under examination can be visualised with the patient upright. The compression test can then show whether there is reverse flow.  A high-resolution probe serves to document the competence of the valve.   CFM is particularly useful for locating reverse flow in patients with recurrent varicose veins after surgery or sclerotherapy, or with anatomical anomalies. CFM also confirms the competence of the deep venous system and the extent and the site of any deep reflux. Reverse flow in a single vein can be quantified but this takes longer. 

Some plethysmographic techniques give accurate and reproducible results.

 

VENOUS PLETHYSMOGRAPHY

 Venous plethysmography measures changes in venous blood volume in the legs, to evaluate overall venous function. Three plethysmography techniques are currently in use: photoplethysmography/light reflection rheography (PPG/LRR), strain gauge plethysmography (extensimetric, SGP), and air plethysmography (APG) (30, 1, 31).

     PPG/LLR uses photo sensors attached to the skin to measure filling of the cutaneous vein network (27).   SGP uses extensimetric sensors (elastic sensor straps) to measure changes in the circumference of the leg at the point where they are applied (28). The APG sensors are inflatable leg cuffs which measure changes in the total venous volume of the leg (29).

By taking measurements in various positions and during various maneuvres it is possible to evaluate the following:

- venous outflow (slowed if there is occlusion)

- total venous reflux (degree of valvular incontinence)

- the efficiency of the muscle pump in the calf (venous drainage during exercise and the speed of refilling after exercise).

These measurements can be done as baseline values, as a basis for assessing overall venous function or, using a tourniquet to exclude the superficial veins, to give separate evaluations of the superficial and deep veins.

Venous plethysmography has the following applications in clinical practice:

- to measure and document the degree of impairment of the various venous functions (obstruction, reverse flow) and follow them over time;

- to measure the involvement of the superficial and deep veins and predict the hemodynamic effects of superficial vein surgery;

- to study and document the hemodynamic effects of different surgical options and validate new technics.

 

METHODS FOR INVESTIGATING THE MICROCIRCULATION

        -  Laser-Doppler

-  Capillaroscopy

-  Microlymphography

-  Interstitial pressure

-  O2 and CO2 partial pressure

Recommendations:

 

-       After clinical  examination, the main screening method for CVI should be the CW Doppler.   Grade B

-       Echo-Doppler and colour echo-Doppler should be used to establish the location and the morphology of the problem. Grade A

-       Phlebography is only needed for a small number of patients who have anatomical anomalies, or malformations, or when surgery on the deep venous system is indicated.  Grade B

-       Plethysmography should be considered as an additional quantitative test.  Grade B

-       Investigations of the microcirculation are only indicated in selected patients, mainly for research  purposes.  Grade C

 

5.    SURGICAL TREATMENT

 Surgical treatment for superficial venous insufficiency

 

BACKGROUND AND INDICATIONS

 

Surgical treatment of varicose veins in the lower limbs started virtually a century ago, with the work of Mayo and Babcock (32, 33), and is still a current procedure.  Many thousands of operations and studies have confirmed its value (34-36). Essentially, three relative innovations have improved the results of the standard surgical technique:  the stripping technique itself has been improved, in the light of new anatomical and physiopathological knowledge; simplified surgical procedures are now used, such as microsurgical phlebectomy (37,38) and stripping by invagination (39); and pre-operative mapping is done using colour echo-Doppler tests (40-43).

Many new surgical approaches have been proposed, some only used by the proponent. These may give good clinical results, but controlled multicenter trials are needed to assess them.  For the time being, therefore, they cannot be considered substitutes for the standard techniques; at best they can be considered alternatives.

The importance of varicose vein surgery in Western health services is shown by the frequency of demand. Generally, the requirements are calculated at 70 interventions per 100,000 inhabitants in the United Kingdom (44), 200 per 100,000 inhabitants in Finland (45), and a much larger number in France (more than 150,000/year (46) and Italy (more than 100,000/year in 1997 according to an estimate by the DGR, including - but probably underestimating - the private sector. Therefore, the surgical indications must be discussed in depth.

The aim of surgery is total removal of all varicose veins, and this itself must be viewed within the context of the underlying pathology - CVI - and the troublesome problem of varicose veins recurring and new ones appearing after surgery.

The main aim of treating patients with CVI is to cure or improve the symptoms and to prevent or treat complications. The standard treatment for varicose veins is elevation of the lower limb to a drainage position and elastic compression hosiery to control edema, with local medication for ulcers. However, this does not treat the underlying hemodynamic disorder causing the venous disease. 

Significant progress has been made in the surgical treatment of severe forms of CVI which can now be diagnosed non-invasively with imaging and velocimetry methods.  It is possible to distinguish between situations in which obstruction prevails, and others – either primary or secondary – in which reverse flow is dominant.  The surgical strategy chosen will depend on the different clinical, anatomical and pathological presentations. A wide range of strategies is available, no longer restricted to extensive and indiscriminate ablation, but aimed at correcting, where possible, the venous and microcirculatory hemodynamic abnormalities in the limb (47,48).

Indications for surgery in CVI depend on the symptoms, and on the objective findings of varices or their complications. The symptoms and pathologies that motivate the surgical choices are:

-       clinical presentation and appearance

-       pain

-       heaviness of the leg

-       fatigue in the limb

-       superficial venous thrombosis

-       bleeding varices

-       pigmentation at the ankle

-       lipodermatosclerosis

-       white atrophy

-       ulcers.

However, as the patient himself may not attribute several of these signs and symptoms to CVI, a thorough, specific case history should be taken.   Fifty percent of patients with telangiectasia and varices suffer from some of the disorders listed and with suitable treatment these problems will be eliminated in 85% of cases (49).

Heaviness of the legs is the most common reason for an examination by a venous specialist, especially among younger women. Recent studies indicate that it may not be caused by a varicose state, nor is it necessarily a pre-varicose syndrome.  It is more likely to be the result of a combination of constitutional venous stasis, venous hypertension and lipedema (50,51).

Numerous other diseases give the same symptoms of fatigue and easy functional exhaustion: joint, neurological and peripheral arterial diseases are the most frequently cited. Similarly, edema of the lower legs is not obligatorily correlated with CVI, and a differential diagnosis must be made taking account of congestive cardiopathy, blood dyscrasia, metabolic disorders, etc. Finally, patients who have an unhealthy lifestyle, are overweight, do little exercise, have bad posture and are excessively sedentary may also have CVI, or actually become predisposed to CVI because of these factors. In these cases, surgery may even be contraindicated, and corrective measures may be sufficient to obviate the need for surgical intervention.  Recent studies suggest that many symptoms may not be caused by venous factors and the venous disorder is simply concomitant with the underlying problem; in cases such as these surgical intervention is unlikely to relieve the symptoms (52,53).

Surgery of the superficial venous system accounts for a substantial portion of the workload of a general and vascular surgical unit and is one of the main reasons why waiting lists tend to be long. There is also the suggestion that “inadequate” venous surgery is responsible for many cases of recurrent varicose veins, even if the surgical technique was error-free (54) although it is not clear what exactly was meant by adequate (or appropriate) or inadequate (or inappropriate) surgery (55).

 

 Recommendations:

 -       The aim of varicose vein surgery is to relieve the symptoms, and prevent or treat any complications while recognising that the varicose disorder is likely to be progressive. Grade A

 -       The surgical patient will require regular follow-up. Grade A

-       There are valid medical alternatives, and sclerotherapy, for collateral veins, which therefore do not necessarily call for a surgical approach. Grade B 

 

SURGICAL TECHNIQUES FOR VARICOSE VEINS

        Nowadays any surgical intervention for superficial venous insufficiency should be preceded by hemodynamic studies using colour echo-Doppler mapping of the area.

        The surgical techniques can be classified in four main groups:

-       ablative surgery

-       symptomatic ablative surgery

-       conservative surgery, without excision of the saphenous trunks

-       endovascular treatment

 

Ablative surgery

 This includes stripping along the whole length of the greater saphenous vein (from the sapheno-femoral junction to the medial malleolus), restricted stripping of the greater saphenous vein (from the sapheno-femoral junction as far as the upper third of the leg), stripping the small saphenous vein (from the saphenous-popliteal junction to the lateral malleolus or the mid-calf).

Ablation of the saphenous veins is usually completed by varicectomy and by section and ligature of the incompetent perforating veins so as to achieve the required hemodynamic result by excising the refluxing vessels.

This is the standard surgical treatment. It has been extensively studied over the years and comparative studies have been made with sclerotherapy and with crossectomy alone or combined with sclerotherapy, but there have been no comparative studies with the alternative surgical treatments. However, ablative surgery was more effective than the other two methods (34, 35, 56-62).  Several techniques have been described: Babcock’s intravenous stripping; Mayo’s external stripping – and its derivations; stripping by invagination as done by Van der Strict, Ouvry, Oesch.

 

 Recommendations:

 Before any decision on which of these techniques is indicated, a detailed echo-Doppler study should be done to avoid or reduce the risk of technical errors.  With the appropriate indications and pre-operative studies - Grade A

 

Symptomatic ablative surgery

 Nowadays this is a phlebectomy with or without incisions, according to Muller, and may be either used to cure varicose veins or complementary to other techniques.

The Muller method is technically preferable as it gives less trauma and a better esthetic and functional result.  An incision of few millimeters is made and the incompetent branches of the superficial circulation, with the exclusion of the saphenous junction, are removed through this incision using special instruments (37,38).

Another technique for treating the symptoms is to incise the thrombosed varicose branches to ablate them or, in the case of superficial venous thrombosis, simply squeeze out the thrombotic material.

 

Recommendations:

The patient should be informed that the aim of the intervention is to treat the symptoms; when limited to the specified indications this is currently rated as Grade B.

 

Conservative surgery without excision of the saphenous trunk

 The aim is to treat the varicose veins, maintaining the saphenous drainage but not the reflux. Saphenous flow can be directed physiologically (sapheno-femoral external valvuloplasty and first step of the CHIVA 2 strategy - see below) or reversed and directed towards the re-entering perforating vein (CHIVA 1).

        These techniques can be complemented by phlebectomy but an echo-Doppler examination must be done beforehand.

 

Sapheno-femoral external valvuloplasty

 The rationale for this treatment is based on the histological finding that in the initial stages the valve cusps are still healthy but are incompetent because of dilation of the vessels walls (63,64).

The aim of the intervention is to bring the valve leaflets back together, closing the dilated vessel walls. This can be done by either suturing the wall directly or by “banding” the vessel with some sort of external prosthetic belt. An ultrasound examination must be made to check that the valve is mobile and not atrophied at the terminal or subterminal level of the greater saphenous vein. Competence can be tested during the operation using the milking maneuver and/or  a Doppler scan.

 

CHIVA type 1 hemodynamic correction

 This is done when the perforating re-entry vein of a refluxing saphenous system is on the saphenous trunk. The sapheno-femoral vein is disconnected and the saphenous vein is freed of any incompetent branches, with or without a phlebectomy. The perforating re-entry vein should be treated by tying it off or sectioning the saphenous vein downstream of its entry point (terminalization) (40,65).

 

CHIVA type 2 hemodynamic correction

        This is done when the penetrating re-entry vein of a refluxing saphenous system is on a tributary of the saphenous vein. The tributary/ies are disconnected flush from the saphenous wall by clipping and a phlebectomy may be carried out (66). In 60% of cases, after 18 months, this is the only intervention required.  In the remaining cases the treatment will need to be completed by a CHIVA 1 hemodynamic correction or by repeating this procedure depending on the hemodynamic outcome.

 

Crossectomy with or without phlebectomy.

         A simple crossectomy gives functional results in the treatment of varicose veins, but is less effective than stripping. (67,68). Crossectomy with phlebectomy gives results comparable to stripping only when it is based on thorough preoperative radiological or ultrasound examination  (69-71).

 

Endovascular treatment

         This heading includes positioning Van Cleef type clips under radiological guidance, and treating the walls at the height of the terminal valves with a heat-transmitting radio probe.

 

 Recommendations:

As yet,  there are not enough studies of an adequate level to validate any of the interventions which aim to preserve the saphenous trunk, although for some of them phase II trials have been completed or are in progress. Grade C.

 

 SURGERY OF THE PERFORATING VEINS

         The perforating veins supply blood through the muscular aponeurosis to the superficial and deep venous systems. These veins are numerous, from 80 to 140 per leg, the diameters not exceeding two millimeters. The valves are normally located in the sub-aponeurotic area.

       Venous examination must assess the anatomical and morphological criteria in parallel with the hemodynamic criteria.  A reflux is defined as pathological if it fulfils the following criteria:

-       duration more than one second

-       caliber of the perforating vein more than 2 mm, calculated from the ultrasound findings.

        The severity of the CVI in relation to incontinent perforating veins is based on the number of perforating veins involved and, in particular, whether more than one system (superficial/deep/perforating) is involved (72,73); there may be a venous–venous shunt starting in the deep venous system and involving the saphenous vein, the perforating veins or even the pelvic veins, or a venous-venous shunt established in the superficial system (74).

       However, there is some controversy over the identification of incontinent perforating veins in the leg. Doppler ultrasound appears to be the most reliable investigation, but there is still debate about the best method (75,76).

       Elimination of the incontinent perforating veins in combination with drainage of the varicose veins and restoration of the saphenous return in patients with severe chronic venous insufficiency is one therapeutic approach for trophic disorders of the skin (77).

 

    Surgical treatment

         There are two main procedures for surgical treatment of perforating veins: the traditional method (of Linton, Cockett, Felder, De Palma) for the suprafascial and subfascial veins (78) or endoscopic treatment of the subfascial veins.   Indications for traditional surgical and endoscopy are incompetent perforating veins of the leg and active or healed ulcers (CEAP classes C5- C6);  this mainly involves post-thrombotic syndromes.   Treatment of perforating veins due to superficial vein inadequacies is reserved for symptomatic cases. Some studies suggest the surgical approach for patients with symptomatic cutaneous dystrophy (CEAP class C4) (79,80).

 

Traditional surgery

        The various traditional treatment methods give broadly similar results, with 9-16.7% of patients having recurring ulcers when followed up for 5-10 years (78, 81, 82). The percentage of recurring ulcers in patients with post-thrombotic syndrome is higher (>16%) with a five-year follow-up.

       Some authors have combined these methods with venous bypass (83), valve grafts and endoscopy (78), but the outcomes cannot be compared.

       Considerations: No substantial differences have been observed between the traditional techniques and there are as yet no multicenter trials to compare the results of the different traditional approaches alone or in association with other methods.

 

Endoscopic surgery

 Endoscopy, a recent concept in this field, uses single access (one trocar) or double access (operating trocar and optic). A number of studies report recurrent ulcers at five-year follow-up in 0-10% of cases (80, 84-87).

Many authors have associated surgical endoscopic treatment with drainage of the incontinent superficial venous system, reporting similar proportions of recurrent ulcer at five years of follow-up. One multicenter trial, however, which compared endoscopic surgery alone with endoscopy plus drainage of the superficial system, found a smaller percentage of recurring ulcers in the second group at two years of follow-up (86).

Considerations – Multicenter trials are currently in progress to evaluate endoscopy compared with traditional treatment and whether it is appropriate to combine this with plastic surgery for the ulcers. Regardless of the methods used, the worst results have been seen in patients with post- thrombotic syndrome.

At present, endoscopic surgery is preferred to traditional techniques as it is less invasive, causes fewer post-operative complications and, under endoscopic guidance, it is possible to work at a distance from the site of ulceration.

 

Recommendations:  

In patients with post-thrombotic syndrome treatment of incontinent perforating veins, whether with sclerotherapy, traditional surgical techniques or endoscopy, has a pivotal role. Grade B

For varicose veins it is essential to distinguish the hemodynamic role of the perforating veins of the thigh (Dodd and Hunter perforating veins) and the Boyd communication perforating veins.  When these are incontinent they must always be closed or removed.  For any other perforating veins, the clinical aspects and the radiological findings must be taken into account. Grade C.

 

 

RECURRENT VARICOSE VEINS

         These are varicose veins that appear after surgical treatment, not the remains of the treated veins (88-92).  Although surgery for varicose veins in the lower limbs appears to be a simple procedure, there are a number of traps. The high percentages of recurrences reported in the international literature confirm this (88-93).  However, it is difficult to interpret these findings, as the patient populations differ and the diagnostic and therapeutic protocols vary.

       The most frequent causes of recurrences are:

-       errors in the diagnostic strategy and inappropriate treatment

-       technical errors.

 

        Errors of diagnostic strategy and treatment

         The long-term results of surgical treatment of varicose veins depends on correct diagnosis. If the hemodynamic causes of the varicose veins are properly identified an appropriate treatment plan can be chosen (94). “Radical surgery”, defined as physical extraction of the saphenous vein with all its collaterals and all the enlarged varices, which has been the surgical procedure of choice for varicose veins for almost a century, is increasingly being replaced by “radical hemodynamics”, meaning elimination of all the hemodynamic defects which are at the root of the formation of the varices (the reflux).

       Mapping was started a decade ago to ensure reproducibility over time (40). A sort of “geographical” map of the varicose veins and circulation defects of the lower limbs is used in both CHIVA interventions and “traditional” surgical procedures. Incorrect application of these concepts can leave the way open to recurrences.

 

        Technical errors

        Numerous papers have given incontrovertible evidence of a high number of errors, frequently serious, made during operation (93, 95-98).

       Haeger in an autopsy study reported 158 (15.1%) residual saphenous veins in 837 lower limbs that had been operated on for varicose veins.

       Crane described 57% crossectomy ligatures that were incorrectly executed.

Marques reported 54.5% of incorrect ligatures in cases of re-operations for recurring varicose veins.

Tong found 168 (68.9%).saphenous vein residues in 244 lower limbs studied

       Of all the causes of error during surgery for varicose veins in the lower limbs, the main one is the wide range of anatomical variation at the junction of the saphenous-femoral veins which may cause the surgeon to leave some collaterals in place.

 

Treatment

         Surgery: The most suitable seems to be the lateral subfascial approach where the technical difficulty of dealing with cicatricial sclerosis is not encountered (99, 100);   this is reserved for cases where there is a residual stump of the saphenous vein with collaterals. Where indicated, varicectomies using Muller micro-incisions and hemodynamic correction of the incompetent perforating veins is performed.

       Pharmacological and compression treatment or sclerosing therapy: Used in all cases in which surgical treatment is not indicated or as an alternative.

       Mixed: A combination of the two approaches.

 

 

Recommendations:

The likelihood of varicose veins recurring as the disease progresses remains. To limit the risk correct diagnosis is essential.   This is routinely done by ultrasound (Levels I and II), leaving selective phlebography for special cases (Level III) in order to minimize the risk of error. Grade C

 

NATIONAL HEALTH INSURANCE (ITALIAN) CLASSIFICATIONS

         A proposal for regulations (101) has been made to cover clinical, organisational and administrative possibilities for surgical interventions, invasive and semi-invasive diagnostic and/or therapeutic procedures without hospital admission and without the need for post-operative observation; such procedures can be done in the consulting room, in out-patient or other supervised centers, using local and/or local-regional anesthetics. Three possible regimens for surgical treatment of varicose veins are given: walk-in, day surgery or standard admission.

        Day surgery is probably suitable for the majority of surgical interventions for varicose veins as long as specific selection criteria are used:

- procedures carried out as day surgery should preferably last less than one hour

- patients scheduled for this treatment must be very carefully selected and should be informed prior to the procedure about the type of intervention and/or treatment.  They should signed a personalised informed consent form;

- the lines between the interventions feasible under the various regimens are blurred. Therefore, the medical team will decide which type of regimen is best suited to each patient, after having carefully selected and informed them individually about the choice of regimens available;

- selection must take into account the  patient’s general condition and any pertinent family and logistic factors;

- patients who are entered in walk-in and day surgery programmes must be in good general health. The ideal candidates are classified as ASA classes 1 and 2. Emergencies cannot be dealt with on this basis;

- age and weight selection criteria apply. With few exceptions, the upper age limit is 75 years. Obesity is a very important risk factor and must be very carefully evaluated.

- as regards logistics, the patient’s home should not be too far from the place where the operation will be done. The patient should be reachable in a short time, if necessary. Therefore the travelling time should be less than one hour.  Another requirement is that phone contact with the center should be possible;

- patients must have a family member or reliable person with them during the recovery period, particularly during the first 24 hours after surgery.  This person should be given detailed instructions and should be able to accompany the patient home and give any assistance the patient might require, particularly in the first 24 hours;

- the decision to enroll a patient in a particular regimen is the exclusive responsibility of the doctor, who, after obtaining the patient’s informed consent, must be at liberty to select the most suitable regimen, on the grounds of the sound scientific and ethical principles always underlying health care;

- the choice of the most suitable regimen will be guided by the patient’s clinical and psychological condition. Many of the pathologies that would normally lend themselves to treatment under a walk-in regimen should, if they are more extensive or complicated, be treated in the day surgery or actually in hospital.

- finally, even if a pathology or surgical procedure appears on the official list of services available in day surgery, this does not oblige a doctor necessarily to carry out the treatment under that regimen.

         However, various difficulties are still encountered in Italy due to the very high demand for these procedures, and there is no          obligation for a patient to be enrolled in any particular regimen without a specialist’s evaluation and without giving informed         consent (102)

       Certain clear observations justify hospital admission.  In such cases, regardless of the doctor’s opinion whether day surgery is possible or not, the patient must agree to being operated in hospital.  If a patient, for whatever logistic or psychological reason, does not want to be operated in day surgery but insists on hospital admission, this is a valid reason for the NHS covering the whole cost, provided it is clearly documented in the clinical records and on the informed consent form.

       Logistic and family factors are particularly important in Italy and they can be justification for admitting a patient the day before the procedure, provided there are also valid health care reasons.  The period after discharge must be carefully organised: the patient must be properly accompanied after discharge, s/he must be able to contact the center easily for advice or help and must be able to return there easily if complications arise. Any logistic situation which does not comply with these requirements must be described in the patient’s records and may justify a longer stay.

       Current DRG data for varicose vein surgery (101)  show an average stay in hospital of 3.7 days; 54.3% of these patients stay in hospital 2-3 days; under-use of day surgery is limited to 8.3% of cases.

 

Surgical treatment of deep venous reflux

      Candidates for deep venous surgery suffer from severe CVI, with significant venous reflux and ambulatory venous hypertension. Conservative therapy has failed for these patients and the venous disease reduces their quality of life.  When the deep vein reflux is slight, stripping of the saphenous vein can bring considerable benefit and eradicate the reflux in the femoral vein (103).
However, if there is severe, fast reflux, the deep venous system will require direct surgery, considering the high percentage of recurring ulcers after conservative treatment and the excellent, lasting results obtained in centers that opt for the direct approach.

Reconstructive valvular surgery includes direct methods, which aim to restore the competence of the valve, and indirect methods, which aim to improve the venous hemodynamics of the limb (104-107).  Direct surgical methods are indicated in PPVI when the valve cusps are dilated or prolapsed but still present and functioning.  In STP or valvular agenesis when the valves are damaged or absent an indirect technique is the better therapeutic choice.

CVI is a complex pathology as the venous circulation involves so many levels and systems. Rapid healing of stasis ulcers can be achieved by correcting all the points of reflux and maintaining or setting up venous return channels.  Depending on the site and extent of the valvular lesion a variety of surgical techniques can be used. 

In a review of 423 valve reconstructions Raju (108) listed the duration of success of the surgical methods, monitored with Doppler ultrasound, in the following order:

- internal valvoplasty;

-external valvoplasty with prosthetic cuff

- external valvoplasty with direct sutures;

- venous graft.

There were no significant differences in the recurrence of ulcers with these various methods.

The time is ripe for standardisation of pathology reports, clinical reports and hemodynamic parameters so that the different surgical techniques can be compared in randomised prospective trials.

 

 Recommendations:

 These surgical approaches are not recommended for routine use;  they should be reserved for cases with specific indications, and done by surgeons with the necessary skills, in well-equipped facilities Grade C. 

 

 

6.    SCLEROTHERAPY

 

Definition

Sclerotherapy is the chemical obliteration of varicose veins. The veins are injected with a histo-lesive substance (sclerosing liquid) which damages the endothelium, producing spasm, thrombosis and an inflammatory reaction which are intended to produce stenosis, fibrosis and the permanent obliteration of the vein (Table I).

 

Table I – The most widely used sclerosing substances: indications and concentrations

Substance                  

Glycerin chromate

Sodium salicylate

Polydocanol

Sodium tetradecyl sulphate

Sodium iodine/iodide

Type of varices and recommended concentration

Teleangectasias

Spider veins

Small/medium varices

Large varicose veins

Saphenous vein segments

inserire i dati dalla tab.I, p.16, cambiando le virgole in punti!

 

 

Efficacy

 

The initial obliteration of the vein is obtained in more than 80% of cases; however, part of the sclerosed veins will subsequently open again.

 

INSTRUMENTAL STUDY OF INDIVIDUAL VEINS

In studies monitored using Doppler examination or ultrasound the greater saphenous vein was obliterated in 81-85% of cases (109, 110), but one year later between 17% and 35% of cases had opened again (111, 112), 33%, 60% and 80% of cases after two years (113, 114, 75) and 48% after three years (112).

       Similar results have been obtained with the small saphenous vein, which was initially closed in 87% of cases (109) but after two years there was blood flowing again in 33% of cases (113), while after five years recanalisation was found in 27% when the popliteal vein was competent (primary varicose veins) and 77% when the popliteal vein was incompetent (secondary varicose veins) (115).

       In the single trial covering collateral veins, at two years 26% were patent again (113).

 

CLINICAL TRIALS

         From 1984 to 1996 four prospective randomised clinical trials with clinical monitoring were conducted. These showed that at the beginning sclerotherapy gave results comparable with those of surgical extirpation; but, over time, the recurrence of varicose veins was definitely more frequent after sclerotherapy. 

        In Doran's trial (116), after two years the results of sclerotherapy and surgery were the same. Chant and Beresford (118, 117)  found that after three and five years recurrence with sclerotherapy was respectively 22% and 40%, in contrast to 14% and 24% with surgery.  In Hobb’s trial (119), one, five and ten years after sclerotherapy recurrences were seen in 8%, 57% and 90% respectively, compared with 6%, 25% and 34% after surgery. Jacobson (58) found 63% of recurrences after three years, as opposed to 10% after surgery.

 

TRIALS WITH CLINICAL AND INSTRUMENTAL MONITORING

        In Einarsson’s trial (120), after five years the recurrence rate was 74%, in contrast to 10% with surgery.  In this trial the results were checked by measuring hemodynamic parameters (volumetric measurements of the feet), but even using these criteria the results of surgery were better.

 

COMBINED THERAPY

        Between 1973 and 1975 three unsigned editorials in the British Medical Journal and the Lancet (121-123), proposed that, as regards both the results and the cost/efficacy ratio, a combination of surgery at the sapheno-femoral junction and sclerotherapy for the remaining varicose veins was the best option. However, though combined therapy proved more effective than sclerotherapy alone, it was always less effective than surgical removal of the varicose veins.

       Lofgren (124) already reported this in the Fifties, on the basis of a retrospective study: at five years, there was 70 % recurrence with combined therapy but only 30% with surgery.  In Jacobson's prospective trial (58) recurrence at three years was 35% with combined therapy, 63% with sclerotherapy alone and 10 % with surgery alone.

In Neglén’s trial (125) after combined therapy 21% of patients had residual varices, while after five years the recurrence rate was 84%. Volumetric measurements of the feet, normal after treatment, had already deteriorated after one year and after five years had returned to the pre-treatment values.

In Rutger’s trial (61), after three years the recurrence rate was 61% with ligature and sclerotherapy and 39% with stripping and phlebectomy. Doppler scanning showed saphenous reflux in 46% of patients in the first group and 15% of the second.  This is the only study in which there were more clinical failures with sclerotherapy (61%) than saphenous recanalisations detected on Doppler scanning (46%). In all the other studies, half the cases of recanalisation detected instrumentally showed clinical improvement. However, these objective failures with sclerotherapy were partially mitigated by the patients’ subjective evaluations which were invariably better than the surgeon’s.

 

EVALUATING THE EVIDENCE

 Despite some criticisms, all the trials published so far – six prospective and randomised (116-120, 58, 61), one retrospective (124) and one prospective controlled (125) – have given unanimous results, definitively showing the superiority of surgical excision over sclerotherapy and combined therapy, at least for varicose veins with incompetence of the greater saphenous vein.

 

Recommendations:

 Surgical removal is more effective than sclerotherapy for varicose veins due to incompetence of the greater saphenous vein.  Grade A.

 

Indications

         The high rates of recanalisation and recurrence mean that sclerotherapy is a secondary choice, not an alternative to surgery.  It becomes the treatment of choice only in cases in which surgery is inadvisable (because it is difficult, with uncertain results or high risk), or is specifically requested by the patient, who must be fully informed of the likely results, complications, advantages and disadvantages of sclerotherapy in comparison with surgery.

       Sclerotherapy was introduced in France in 1853, but the first attempts at producing guidelines were only made in 1996, by the International Consensus Conference (1996), the American Academy of Dermatology (126) and the American Venous Forum (74).  However, only the American Venous Forum specifically formulated the indications for sclerotherapy, which are the same as the ones the Collegio Italiano di Flebologia is proposing here. These indications include: Casella di testo:  
Table I – The common sclerosing drugs. Indications and concentrations.
 
Drug
Type of varicose vein and recommended concentration
 
Telangiectases
Reticulated varices 
Small-medium varices
Large varices
Saphenous trunk
Chromated Glycerin
Sodium salicylate
Polidocanol
Sodium tetradecyl  sulphate
Iodine/sodium iodide   
72 %
8 %
0.25-0.5 %
0.1-0.2 %
-
-
12 %
1 %
0.2-0.3 %
-
-
20 %
1-2 %
1-2 %
2 %
-
-
3-4 %
3 %
2-4 %
-
-
3-4 %
3 %
4-8-12 %
 

1)      telangiectasias;

2)      small diameter varices (1-3 mm);

3)      residual veins after surgery (purposely left by the surgeon)

4)      varicose veins recurring after surgery (if originating from a perforating vein <4 mm diameter)

5)      varices from venous malformations (Klippel-Trenaunay type) for which surgery is not advisable;

6)      emergency treatment for bleeding ruptured varicose veins

7)      perforating veins <4 mm diameter

8)      varicose veins around an ulcer

 

As this list shows, sclerotherapy is an important and indispensable method for the optimal treatment of a wide range of varicose veins, from spider veins, which are not just anesthetic problem but can cause skin pathologies and even serious hemorrhage, to the serious, disabling forms of CVI such as lipodermatosclerosis, stasis ulcers and congenital venous malformations.

 

 

Recommendations:

 

The AVF indications apply. There is an open verdict on the indications for sclerotherapy of the perforating veins of any diameter and of the small saphenous vein.  Grade B.

 

 

Contraindications

       The contraindications to sclerotherapy include allergy to the sclerosing solution, serious decompensated systemic disease, recent DVT, local or systemic infection, non-reducible edema of the lower limb, immobilisation and critical ischemia of

 


 

the lower limb.  Caution is needed in patients with a history of recurring DVT, with confirmed thrombophilia, women taking estrogen/progestogen preparations, or who are pregnant.

 

Techniques

 

Like any manual technique, sclerotherapy has to be learned.  The various techniques currently in use are derived from three European schools, Tournay (127), Sigg (128) and Fegan (129), and are described in Italian in two publications (130,131).

The type and concentration of sclerosing fluid varies according to the type of varicose vein and is shown in Table 1. Injections are given in more than one sitting, a few days or a few weeks apart, depending on the individual technique.  Better results are obtained, with fewer adverse effects, if the injected vein and the leg are immediately compressed with either adhesive or free bandages or with elastic-compression stockings (132). Compression is all the more important, and needs to be more prolonged (from three to six weeks or more) if the varicose veins are particularly large and diffuse. In some cases – e.g. large varicose veins or legs with a tendency to edema - compression is indispensable.

In the last few years injection of sclerosing fluids under ultrasound guidance (ultrasound sclerotherapy) has been introduced (109), but it has not yet been confirmed more efficient in the long term. Also requiring confirmation  is the utility of injecting detergent-based sclerosing compounds (polydocanol or tetradecyl sodium sulphate) in microfoam form rather than liquid (133,134).

 


 

 

Recommendations:

 

There is no standardisation of the technique, or of the concentrations and amounts of sclerosing agents. Compression improves the results of sclerotherapy.  Grade B.

 

 

 7.        COMPRESSION

 

Definitions

       Compression is the pressure applied to a limb, using a variety of materials, elastic or firm, to prevent and treat diseases of the venous or lymphatic systems.

 

Historical outline

       Elastic compression treatment has been used throughout the history of medicine. Traces of the use of bandages have been found among the Ancient Egyptians and the tribes living along the River Tigris. The prophet Isaiah in the 8th century B.C. wrote about the utility and purposes of bandaging the legs, as did Hippocrates and his school of medicine.  The Roman legionnaires in 20 B.C. bandaged their legs tightly during long marches to prevent stiffness. Aurelio Cornelius Celso, a Roman author writing at the time of Tiberius, recommended occlusive and compressive linen bandages for treating ulcus cruris. And throughout the medieval period, influenced by Arabic medicine, compressive dressings were widely employed.

 

Physiopathology

 

       The venous system, assisted by the lymph vessels, returns the blood from the tissues to the heart. Every time the venous flow is slowed or impeded a sort of “traffic jam” build up: ischemia occurs in the cells, as the stasis prevents oxygen and nutrients leaving the arterial capillary wall to enter the interstitial space and get to the cell walls where they are absorbed. This is because of an inversion of the local pressure ratios; the slowing of the blood flow causes an increase in interstitial pressure which counterbalances the residual arterial hydrostatic pressure.
The lack of flow leads to an increase in perivascular oncotic and osmotic pressures, causing water retention and edema, a self-sustaining cycle.

       Compression therapy works by changing the venous hemodynamics; there is an increase in the flow speed (evaluated using plethysmography and venous occlusion), a reduction in the vessel dimensions, and valvular competence returns (confirmed by Duplex scan).  Rheographic examination shows an increase in the refilling time after exercise, an indication of improved venous compliance. Overall, the reduction in pericellular edema limits tissue damage (135-137).

 

Physiological and technical rationale

        In phlebolymphology the materials used to achieve compression are bandages, elastic and inelastic hose (138,139).

 

BANDAGES

        Bandages are generally used to protect the lower leg. The most important property of bandages is that they can stretch or expand.  The expansion factors in relation to the initial size are:

-   small expansion (<70%);

-   medium expansion (70-140%);

-       long expansion (>140%).

       The inelastic or barely elastic bandage produces a considerable amount of “working” pressure when walking, as it prevents the increase in the circumference of the leg caused by contraction of the calf muscles, whilst the pressure at rest is minimal.  In contrast, the elastic bandage exerts a moderate amount of "working" pressure and high "resting" pressure, the difference between the two being inversely proportional to the elasticity. An elastic bandage maintains continuous pressure on the superficial venous system which is relatively independent of muscular activity.

       Elastic bandages made of fibers with a long expansion factor act in a similar way. Inelastic or barely elastic bandages can be worn day and night whereas bandages that stretch more than 70% and support stockings should be taken off at night, as they are not designed to be worn when the patient is lying down (140,141).

       Taking into account the various types of bandage, the pressure exercised is always found by using the Laplace law:

 

P = t/r

 

modified as follows for a bandage:

 

P = tn/ra

 

where t is the tension, n the number of turns of the bandage, r the radius of the circumference of the compression, and a the width of the bandage.  Compression can thus be “dosed” to meet treatment requirements.

       The length of time the bandages are worn is not standardised.  Some studies show equal efficacy with bandages worn for a few hours or for six weeks; there is a significant drop in the amount of compression exerted by a bandage 6-8 hours after application (142,143).

 

ELASTIC SUPPORT HOSE

 

       Elastic support hose, for prevention or therapy (144-146) are manufactured in various sizes, either standard or to measure, and are classified according to their length as:

-       knee-length socks

-       mid-thigh stockings

-       stockings

-       single leg tights

-       tights.

There are also “cuffs”  for the arms.

       When pressure on the ankle is less than 18 mm Hg the support is defined as preventive or resting.  There is controversy over whether this is effective, just as debate continues on the utility of hosiery whose pressure is expressed in “deniers” (den).

       When the pressure on the ankle is greater than 18 mm Hg the support is defined as therapeutic. Graduated, defined compression is achieved on the lower limb, decreasing from the bottom towards the top, being 100% at the ankle, 70% at the calf and 40% at the thigh.  Depending on the compression at the ankle, expressed in mm Hg, therapeutic support hose are grouped in four classes, which differ according to whether the German standards or the French standards are followed.

       Manufacturers of therapeutic elastic support stockings based on the German RAL GZ 387 standards give four classes of compression:

Class

Compression in

mm Hg

1

2

3

4

18.7 – 21.7

25.5 – 32.5

36.7 – 46.5

> 58.5

 

       Based on the French NFG 30-102 B standards therapeutic elastic support stockings are also grouped into four compression classes but these have lower values:

Class

Compression in

mm Hg

1

2

3

4

10 -15

16 - 20

21 – 36

> 36

        Besides these support stockings for prevention and therapy there are also “antiembolism” support stockings for the prophylaxis of thromboembolism. These are different from the other models as they give a standard compression of 18 mm Hg at the ankle and 8 mm Hg at the thigh and can be worn comfortably even when resting.

 

Manufacturing standards

        The manufacturing standards for an elastic support stocking were drawn up at the request of the German authorities, as these appliances are eligible for national health system reimbursement, and appear in the official German drug formulary (CEN documents).

       These standards comprise:

-       a table establishing the four classes of compression to which all the support hose for compression treatment belong;

-       a table showing the pressure distribution for the different classes, so the elastic support will guarantee the correct gradient along the length of the lower limb;

-   specifications for the manufacture of the hosiery, with details of both the longitudinal and circumferential stretch;

-   specific methods for the stitching, the seams, the heel,  etc.

-   the materials which must be used are given, with precise limits for the thickness of the yarn, so the product will be strong enough to ensure its properties remain constant over time;

-   finally, there is a section on the inspection methods for the finished stocking.

       The RAL-GZ 387 standards are entrusted to two authorities, one in Germany and the other in Switzerland. The preliminary tests (HOSY system) certify that the support hose complies with the technical specifications, with particular attention to the visual checks, tests for transverse and longitudinal elasticity, and analysis of the materials used.  There is also a sophisticated test to measure the compression and how it decreases from the base of the stocking towards the top. This test is conducted using special equipment which can measure any type of elastic stocking and record its static and dynamic performance.

       These very strict and restrictive standards have been used for thirty years to monitor the production and distribution of elastic support hose in Germany and are proposed as the model for European Union regulations.

 

INELASTIC COMPRESSION

 

Intermittent Pneumatic Compression

 

       This is indicated for the prophylaxis of venous thromboembolism and the treatment of venous ulcers.   Intermittent pneumatic compression (IPC) increases venous blood flow during periods of immobilisation.  IPC devices are adjuvant measures for the treatment of lower limb edema, venous ulcers or both, and for the prevention of pulmonary thromboembolism.

       IPC should be considered for patients with a high risk of hemorrhagic complications or in whom a minor bleed could have serious consequences.  IPC is indicated for patients who have had neurosurgical surgery, major urological, eye, spinal and knee surgery. It is also indicated in patients with suspected or documented intracranial hemorrhage or after recent cerebral or spinal traumas.

        IPC as coadjuvant therapy for venous ulcers.

       IPC is indicated in the treatment of venous ulcers, giving a higher recovery rate, in a shorter time.

 

Clinical applications

 GENERAL POINTS

        Compression is indicated for any chronic or acute venous insufficiency, either associated with other treatments or alone.  The efficacy of compression for the symptomatic treatment of CVI or the prevention of complications is supported by clinical experience and by a substantial amount of scientific literature, particularly for the advanced stages of venous disease.  However, only the most recent publications satisfy the extremely rigorous case/control comparison criteria, with adequate sample sizes.

       The type of compression used, the method of application and length of time used will vary according to the clinical context and for each patient even in groups with the same pathologies.  Therefore the choice of compression hose needs to be centered on individual requirements and the severity of the disease.

       In order to unify the evaluation criteria for acute and chronic venous insufficiency, and its prophylaxis and treatment, generalised classification standards must be used. These are the CEAP international classification for CVI and the high/moderate/low risk classifications from the Consensus Statement on Prevention of Venous Thromboembolism. 

 

ACUTE FORMS

 Superficial thrombophlebitis

        Superficial thrombophlebitis is considered benign if there are no thrombophilic risk factors, and is one of the common complications of varicose veins.  However, it may progress to pulmonary embolism and this can be fatal.  In the majority of thrombophlebitis cases, with or without varicose veins, after drug therapy (anti-inflammatory drugs and heparin) elastic compression hose and mobilisation are the first line of defence for both treatment and prevention. (147).

Recommendations:

Compression and mobilisation are always indicated for patients with superficial thrombophlebitis. Grade B

 

Deep vein thrombosis

 Prevention

        The graduated-pressure elastic stocking reduces the incidence of DVT after surgery, using an optimum pressure of 18 -20 mm Hg at the ankle and 8 mm Hg at the thigh (148,149).

 

Recommendations:

Low risk

In the absence of sufficient data, there is general agreement that graduated compression is useful. Grade C

Moderate risk

Elastic stockings in combination with, or as an alternative to, heparin prophylaxis. Grade B

High risk

As for moderate risk or in combination with other methods of prophylaxis. Grade B.

 

Treatment

         Although evidence from controlled trials is still lacking, the current treatment for DVT remains based on heparin.  Mobilisation and compression have long been recommended by some specialists,  even in the acute phase of DVT (150,151). However, opinions still vary about the early mobilisation of patients with DVT or the preferred method of compression using inelastic, mobile or adhesive bandaging, or elastic stockings.

       For the time being it is not possible to make recommendations.

 

PREVENTION OF POST-THROMBOTIC SYNDROME

         Post-thrombotic syndrome (PTS) is an aftermath of DVT in between 10 and 100% of cases; it may cause moderate to painful disabling edema, and trophic cutaneous changes leading to ulceration. The use of elastic knee-socks with 40 mmHg compression at the ankle for at least two years has been endorsed by a randomised controlled trial where it halved the incidence of DVT when the stocking was used regularly (152).

 

 Recommendations:

 After DVT elastic stockings should be worn for at least two years, with compression of at least 20 mm Hg. Grade A

 

COMPRESSION AFTER SURGERY OR SCLEROTHERAPY FOR VARICOSE VEINS

         Compression after surgery is indicated for the prevention of venous thromboembolism, the prevention of hematoma, the treatment of postoperative problems and the prevention of recurring varicose veins (141,153,154).

 

 Recommendations:

 Patients who have had active treatment for varicose veins (surgery and sclerotherapy) require compression support hose, but it is not possible to specify the types. Grade B.

 

CHRONIC FORMS

 a)      Functional symptoms of mild venous

insufficiency (CEAP 0 = no visible signs of venous disease)

There is no reliable data on the efficacy of “resting” or “preventive” commercial support stockings (155).

 

Recommendations:  

There is not sufficient data to give indications for the use of resting or preventive elastic support hose. Grade C

 

b)      Telangiectasias and spider veins (CEAP 1)

    Venous ectasia accompanied by clinical symptoms of CVI are an indication to increase compression at the ankle and consequently on the calf and thigh (156).

 

 Recommendations:

 As the physiopathological data is not compatible with the indications described it is not possible to recommend compressive support hose for long-term use in these conditions. Grade B

 

c)      Varicose veins (CEAP class 2)

       Compression is considered fundamental in the clinical management of patients with varicose veins, as it reduces the feeling of heaviness and pain and acts on trophic changes in the tissues, either alone (117, 157, 71) or in combination with drug therapy (158). For a small group of 31 patients who had varices without complications, low- compression stockings, exerting 20 mm Hg at the ankle, were as effective clinically and hemodynamically as stockings giving 30 mm Hg compression, and compliance was better (159).

 

 Recommendations:

 Compression treatment is recommended. As only a small number of published trials included an adequate number of subjects it is not possible to give firm advice on the compression levels at the ankle, although it should be more than 18 mm Hg. Grade B

 

d)      Edema (CEAP class 3)

       Edema is a common complication of venous insufficiency even in early clinical stages. There is slight swelling around the ankles towards the end of the day in CVI, more marked in varicose diseases with skin disorders and stasis ulcers. It is caused by changes in the interstitial pressure ratios caused by venous hypertension (144).

 

Recommendations:

Given the small amount of literature, the few clinical trials, and considering that the indiscriminate use of compression therapy could spoil the quality of life for patients, it is impossible to give any general indications for compression therapy. Grade C

 

e) Trophic changes of venous origin, pigmentation, eczema, subcutaneous inflammation, healed ulcers (CEAP classes 4 and 5).

       Skin changes in chronic venous disease are indicators of serious tissue damage caused by hypoxia from chronic stasis. A review of the literature by Moffat (160), showed recurring ulcers in 2/3 patients without compression therapy.

 

 Recommendations:

 Compression therapy is recommended for the prevention of recurring ulcers (30-40 mm Hg at the ankle).  Grade B. 

 

f) Venous ulcers (CEAP class 6)

        Venous ulcers can be effectively treated with compressive therapy after local surgical and/or pharmacological therapy. Elastic stockings, Unna bandages, multilayer bandages or IPC are useful. A review of the literature, published in the BMJ in 1997 (161), which considered all the available trials on the treatment of venous ulcers, concluded that compression improved the prognosis of this condition, preferably using high pressure.  There does not seem to be any one system which is better than the others (multi-layer, short-stretch bandaging, Unna boot).

 

 Recommendations:

 Compressive therapy is recommended for the treatment of venous ulcers (inelastic bandaging, knee-socks with compression >40 mm Hg). Grade A 

 

Table II – Venous physiopathological processes affected by drug therapy

-         Reduced venous tone

-         Hemoconcentration

-         Depressed venous-arteriolar reflux

-         Vasomotor disturbances

-         Increase in capillary permeability

-         Edema

-         Pericapillary fibrin cuff

-         Reduced fibrinolysis

-         Increase in plasma plasminogen

-         Changes in leucocyte and erythrocyte rheology

-         Leucocyte activation

-         Capillary microthrombi

-         Stasis of the microcirculation

-         Reduced lymph drainage

 

 8.        DRUG THERAPY

        Pharmacotherapy for CVI has greatly developed over the last 40 years. It is therefore surprising that there are no clinical or experimental trials to study the tone and contractility of the veins nor venous pressure in relation to treatment problems (162).

       Drugs for the venous system were initially called phlebotonics as they were believed to act on venous tone.  They are still largely used in the symptomatic treatment of CVI and to make patients more comfortable (163).

       Phlebotrophic drugs in their modern form are aimed at a wide range of processes (Table II).  They are naturally occurring, semi-natural and synthetic products, some of them combining two or more active principles to improve the efficacy. Most of these belong to the flavonoid family; 600-  800 of these substances have been identified and grouped by Geissman and Hinreiner under the name of flavonoids, plant polyphenols containing a flavone chemical structure, which in 1955 were given the name “bioflavonoids” by the New York Academy of Sciences (164). Their mechanisms of action vary, but their main property is activation of venous and lymph return.

       Phlebotrophic drugs are the therapeutic strategy of choice for CVI patients who are unsuitable or not indicated for surgery, or for whom surgery is coadjuvated by drug therapy (165-170).

 

Table III – CO5 vasoprotectors

 

CO5 B Anti-varicose treatment

 

CO5 BA Preparations containing heparin for topical use

 

CO5 C Capillary protecting substances

 

CO5 CA Bioflavonoids

 

 

CO5 CX Other capillary protecting substances

 

 

 

        Phlebotrophic drugs are widely prescribed and marketed in Italy, France, Germany and most of Europe but are less used in English-speaking and Scandinavian countries, presumably because of the scarcity of published data.  With new research methods this should change.

The effects of phlebotrophic drugs on physiological parameters such as venous tone, venous hemodynamics, capillary permeability and lymph drainage can be evaluated with a range of diagnostic procedures, preferably non-invasive (1). However, the main tool for assessing the clinical effects of a phlebotrophic drug is a well-conducted clinical trial satisfactorily meeting clinical, scientific and ethical requirements (171).  The trial must be randomised, possibly double-blind, and strong enough to at least attempt to answer firm questions regarding the patient’s state of health. Having the CEAP classification now means that the same scoring system can be used for the clinical picture before and after treatment. The symptoms, signs and quality of life should all be taken into consideration.

Efficacy on the different outcomes can be obtained using drugs with different chemical structures but the same clinical indications. The ATC classifications define phlebotrophic drugs as “vasoprotectors”, and makes a distinction between topical treatments for varicose veins and “capillary protective substances”, mainly bioflavonoids (Table III).

The clinical efficacy on the symptoms (feeling of heaviness, pain, paresthesia, heat and burning sensations, night cramps, etc.) has long been confirmed by Level III, IV and V evidence, but there are now Level I and II trials on specific drugs. For the bioflavonoids double-blind, randomised trials have used diosmin-hesperidin (172,173), troxerutin (174); rutoside (175); escin (176); bilberry anthocyanosides (164); and synthetic calcium deobesilate (177). Phlebotrophic action has been demonstrated in pharmaceutical classes other than the flavonoids,  such as Ruscus aculeatus (178) and  Centella asiatica (179).

Various protective agents have been shown to have clinical efficacy on the main sign, edema, acting on the microcirculation by lowering endothelial permeability, reducing the release of lysosomal enzymes and inflammatory substances, inhibiting free radicals and reducing white cell adhesion (158,180,181).

A surprising improvement in quality of life after a dose of 1g of micronised diosmin-hesperidin was observed in a study of 934 patients with CVI (182). This improvement was seen in all areas of life, physical, psychological and relational.

In the last ten years the relationship between macro- and microcirculation in the more severe types of CVI has become clearer; it was already clear that the relationship between reflux and venous hypertension was a factor in capillary damage (183,184). Much basic research, and some studies in man, have confirmed the effect of some phlebotrophic drugs, particularly micronised diosmin-hesperidin, on microcirculations that have been impaired by CVI. (170,182,185-187).

In the light of these findings a series of drugs have been introduced into clinical practice; however, their clinical usefulness has not always been confirmed in enough clinical trials of sufficient power. These drugs are used as coadjuvants in severe CVI (CEAP Stages 4/5/6) and are listed in the ATC classification as BO1, Anti-thrombotics, and in some cases as CO4/CO1E, Vasodilators, for their action on the altered endothelium and blood flow patterns, for their action on microthrombi and their oxygen barrier effect.

The effect of the fibrinolytic enzyme, urokinase, is documented in two papers (188,189); the glycosaminoglycans such as sulodexide have profibrinolytic activity (190) as does heparan sulphate (191), and defibrotide (192); but the utility of stanozolol is considered fairly limited (193,194).

Among the vasodilators, the effects of pentoxifyllin have been well documented (195,196) as has prostaglandin E1 (197) for the treatment of ulcers.  The only indication for platelet anti-aggregation with aspirin is as coadjuvant treatment for healing ulcers in CVI (198).

 

Recommendations:

There is ample evidence in favor of treating CVI ulcers with phlebotrophic drugs when surgery is not indicated, not possible or can be flanked by coadjuvant therapy. Phlebotrophic drugs are indicated for subjective and functional symptoms of CVI (fatigue, night cramps, restless legs, heaviness, tension) and edema. Grade A

 

9.        PHYSIOTHERAPY

 

        Patients with chronic venous and lymphatic insufficiency should generally be advised on appropriate lifestyle habits (199). Nowadays, the press publishes a large amount of dietary and health advice, particularly as regards prevention. General practitioners and specialists should dedicate a part of the consultation to giving their patients advice on this subject, taking time to convince them. There is plenty of easily accessible explanatory literature and record forms, and the doctor can personalise these to motivate the patient, by underlining the important information or adding extra advice.

       The correct amount of physical activities should be prescribed, with advice on good posture, and the contraindications outlined (200,201). Clinical and phlebodynamic testing, plethysmography, percutaneous oxygen pressure all demonstrate the advantageous effects of an exercise schedule on the macro- and micro-circulation (202).

 

Manual venous-lymphatic drainage (lymphodrainage)

        One of the most widespread and popular massage treatment methods for all forms of venous and lymphatic stasis, manual lymphatic drainage, was introduced by E. Vodder in 1936 (203).  Current usage was codified by Leduc (204) and the Vodder school (205). It is also indicated for CVI (206,207).

       Vodder’s concept of mechanical action is based on the harmonic displacement of fluids and interstitial solutes through the lymphatic capillaries towards the ganglia or main drainage areas. The massage must be rhythmic and smooth and must not exceed the physiological drainage capacity of the tissues.  It is important to evaluate the overall anatomical area as a basis for deciding the amount of strength and coordination during manual compression.

The patient should enjoy immediate relief of the symptoms if the technique is carried out properly; this will obviously depend on the experience and the manual skill of the person doing the massage. Results are shown by the immediate reduction in the circumference of the limb and can be checked using indirect lymphoscintigraphy.

In Germany physiotherapy for lymphedema based on lymphodrainage is termed KPE (Komplexe Physikalische Entstauungstherapie) which can be translated as “multi-factor decongesting physiotherapy treatment” (208).

 

Recommendations:

Recent clinical and instrumental studies confirm the utility of healthy lifestyle habits, physiotherapy and manual lymphodrainage. Grade C

 

 

10.        MINERAL WATER THERAPY

        The beneficial action of water on venous and lymphatic stasis in the limbs has been noticed and is used empirically by the patients themselves (209,210).   However, the wide variety of forms of this treatment means that precise indications and “dosage” recommendations are needed to establish contraindications and avoid complications.            In general, home, sea or spa treatments are based on the effects of hydrostatic pressure, and the temperature of the bath, while the “medicinal” effects are provided by the salts in the water (211).  The therapeutic effect is achieved by two mechanisms:

 

1) aspecific or hydrotherapeutic action, given by the physical properties of the water:

-       temperature

-       hydrostatic pressure

-       active and/or passive movement

      2) specific action, meaning the therapeutic action related to the chemico-physical characteristics of the water:

-       mineral salts

-       trace elements

-       heat

-       concentration

 

Although from the physical viewpoint the use of any type of mineral water can be beneficial, chemically there are only certain types of water which are specifically indicated for treatment and rehabilitation in chronic venous and lymphatic insufficiency (Table IV)

 

Table IV  Mineral waters indicated in angiology and used for prevention, treatment and rehabilitation in venous and lymphatic insufficiency.

 

Bromide salts               Fluid removal from the                                                edematous tissue

Sulphur                        Anti-inflammatory

Ferruginous arsenicals Tonic, stimulant,                                                           anti-stress

Calcium sulphate Venous contractility                                                              stimulant

Radioactive                  Sedative, analgesic,                                                     antispasmodic

Carbonic                     Tonic

 

Patients can have mineral water treatments at any time during the year. If possible, they should have two cycles a year, preferably in autumn and spring, with at least three months’ interval. The treatment should last at least three weeks for the patient to gain the full effect, and less than two weeks is not worth while (212,213).

  

Recommendations:

Controlled trials have shown that mineral water treatment for CVI, carried out in a suitable place and with suitable methods, is effective. Grade B

 

 

11.        TREATMENT OF VENOUS ULCERS

 Introduction

        Epidemiological studies done in the 1980’s showed that 1-2% of the adult population suffer from leg ulcers (10, 214). Although the etiological factors are fairly varied, most patients with leg ulcers have venous disease (215,216). 

        CVI, although it has received less attention than chronic arterial insufficiency (CAI), affects ten times as many adults (217). Consequently, its treatment is neglected or completely inadequate. Many patients walk around for months, or even years, with ulcers treated only with local medication, with no effort being made to cure the venous insufficiency causing them (13).

 

Appearance of venous ulcers

        Venous ulcers of the leg usually present as an irregular area of loss of skin, the base covered with a yellow exudate, with well-defined margins, surrounded with erythematous, hyperpigmented or liposclerotic skin. The ulcers vary in size and site, but in patients with varicose veins they are usually seen in the medial region of the lower third of the leg (218).   A venous ulcer in the lateral portion of the leg is often associated with small saphenous vein insufficiency (Bass, 1997).            ref.no ???

       Patients with venous ulcers may suffer intense pain even though there is no infection.  The pain is worse when they are upright and relieved when the leg is elevated (219).

 

Treatment

        Venous ulcer treatment is based on an understanding of the physiopathological mechanisms involved in producing the ulcer. These mechanisms are not exclusively concerned with macrovascular hemodynamics, but involve the microcirculation and endothelium too (220, 1).

        Since the venous ulcer is a manifestation of a chronic condition with slow repair and a tendency to recur, therapy must aim not only at curing the ulcer but, above all, at preventing it recurring (221). At the same time the patient’s mental attitude must be improved, either so as to convince them to enter and comply with a treatment program or to improve their quality of life (3).

       Treatment of a venous ulcer can involve one or more of the following (13):

-       basic treatment;

-       pharmacological treatment;

-       compression;

-       topical medication;

-       surgery;

-       sclerotherapy;

-       other therapies;

-       general measures.

 

BASIC TREATMENT

        The basic treatment must obey the general rule of considering the patient as a whole and not just focusing on treating the ulcer (222). Patients’ lifestyles are extremely important: their ability to walk, their work, whether they are obese, diabetic or have other concomitant diseases (13).

 

PHARMACOLOGICAL TREATMENT

        The main targets are venous tone,  hemoconcentration, increased capillary permeability, edema, reduced fibrinolytic activity, increased plasma fibrinogen, anomalies in leucocyte function, pain relief, and management of superinfections and concomitant diseases.   Fibrinolytic agents or substances that favor fibrinolysis, hydroxyrutosides (223,224, Wright, 1991 ref.no ?), micronised diosmin-hesperidin (225,226), prostaglandin E1 (Beitner, 1980; 197) and pentoxifyllin (227) are widely used.

       As there have been few high-level clinical trials on support drug therapy in patients with venous ulcers, it is still debated how effective some of these drugs are for curing these lesions. However, the methodological limitations of the past have been overcome in recent trials, at least in trials of certain bioflavonoids in combination with elastocompression (225,226).

 

COMPRESSION

        All patients with venous ulcers require compressive treatment. Whatever treatment is given for the venous ulcer must always be combined with compression.  The patient must also be able to move about so as to obtain maximum benefit from the compression (228).

       Compression stimulates the venous flow, reduces the pathological reflux when the patient is walking (Partsch, 1990 ref.no ?), improves the microcirculation and boosts lymphatic drainage (161). The chronic edema and the ulcer exudate are reduced and the lesion not only regresses sooner but is also less likely to recur.

       Compressive therapy can be done with elastic bandages or stockings (219,229). In the acute phase, inelastic bandages, zinc oxide bandages, or multilayer bandaging are the most effective type of compression. A multilayer bandage can be left in place for at least a week, but at the start of treatment, until the exudate and the edema have subsided, it is advisable to remove and reapply the bandaging more often.  Good healing has been reported using four-layer compressive bandaging (230,231) which seem to give effective compression even when applied by unskilled personnel (232).  However, at the moment, there is no agreement on whether the multilayer system is more effective than two layers.

       The bandage must give a resting pressure of at least 20-30 mm Hg at the ankle and the lower third of the leg with gradually less compression towards the upper third of the leg and thigh (144,13).

       In patients with moderate occlusive arterial disease, with an ankle-brachial index (ABI) between 0.6 and 0.8, bandaging must be done very carefully. Inelastic material must be used, so as to exert low resting pressure.   If the arterial insufficiency is very severe, with an ABI below 0.6, any type of bandaging is contraindicated (13).

       Compression with elastic stockings helps maintain the results gained from treating the ulcers and to prevent recurrence. Generally, they are Class II compression stockings (30-40 mm Hg at the ankle) or Class III (40-50 mm Hg). Elderly patients or people with joint mobility problems may find it easier to put on two Class I stockings (20-30 mm Hg at the ankle), one on top of the other (229). For bed-ridden patients, or those who walk very little, anti-thrombus stockings should be considered. Intermittent pneumatic compression may be beneficial in selected cases (233).

       Recurrence may occur after healing, in the short or longer term, in 20-70% of patients (234,14). Recurrence is linked to a variety of risk factors, but particularly to the persistence of the hemodynamic changes and inadequate or unacceptable compression (230,154).   The success of compression also depends on how much the patient moves;  patients must be encouraged to walk and take regular physical exercise and rehabilitation therapy (228,235).

 

TOPICAL MEDICATIONS

        When planning topical treatment for patients with venous ulcers it is important to take account of clinical observations such as the presence of dead tissue, exudates, infections and the state of the skin surrounding the ulcer (229).

       Topical treatment for venous ulcers is designed to keep the lesion clean, to preserve the microenvironment, protect the lesion from infectious agents and stimulate cell repair mechanisms (219). Ideal medications should meet the following criteria:

-       they should not adhere, and should leave no residues on the ulcer

-       they should keep the surface of the ulcer moist

-       they should be impermeable to liquids, but allow for gaseous exchange

-       they should create a barrier against bacteria and fungi

-       they should stimulate granulation tissue

-       they should give some pain relief

-       they should be affordable.

 

        At the present time, despite the wide variety of medications available, none of them are ideal and it is not possible to draw up rigorous protocols valid for the treatment of all venous ulcers (222). Experience shows that any product may be effective initially, but the benefits will decrease over time and another product may eventually heal the ulcer.  Consequently, the physician’s attitude must be dynamic, taking account of the different phases of natural healing: necrotic, fibrinous, exudative, infectious, cleansing, granulation, re-epithelialization.

        In years past the only treatment was rigid compressive bandaging and local medication with a few cleansing and/or disinfecting products.  Now, however, there are many treatments available with a variety of indications for the different stages of the disease. There are occlusive and semi-occlusive medications, absorbents, medications based on carboxymethyl cellulose, alginates, polyurethane, collagen, fibrin glue, chitosan;   they come as pastes, granules, foams and gels.   Local application of growth factor has been proposed (236) and can administered by infiltration (237).

 The exudate from infected ulcers should be cultured and systemic antibiotics started. Topical antibodies are not generally indicated as they can facilitate the onset of contact dermatitis (238,239).  A prospective trial showed that patients with venous ulcers treated with silver sulfadiazine emulsion combined with elastocompression healed sooner than the group treated with compression alone (240).

As healing progresses and there is little secretion and the ulcer becomes superficial, the medication can be changed to a so-called “biological” treatment: a thin cellulose or hyaluronic acid-based film, which protects the wound, stops the ulcer getting infected and gives good support for the migration and proliferation of basal epidermal cells while maintaining a good level of moisture so the lesion does not dry out. (219).

 

SURGERY

 Surgery should not be considered as the only treatment or as an alternative treatment for venous ulcers, but as a complement to conservative therapy.  Surgery for ulcers has two fundamental objectives:

-    correcting the hemodynamic changes

-    covering the ulcer with grafted skin to reduce the healing time.

This procedure must be preceded by detailed morphological and hemodynamic study of the superficial and deep venous systems and by the usual diagnostic procedures (31,241).

It is commonly considered that surgery of the superficial venous system in patients with varicose ulcers achieves the best results, reducing healing time and delaying recurrences, especially if there is no changes in the deep vein system (222).   Surgery for post-thrombotic ulcers is less satisfactory (242).

Surgery on perforating veins in CVI has improved recently with the development of the endoscopic technique for tying the subfascial veins (36). Although the early results are excellent, the failure and recurrence rates are between 2.5 and 22% (86,243,244).  One technical limitation is the difficulty of access to perimalleolar perforating veins.  It has been observed that 50% of incompetent perforating veins within 10 cm of the ground, identified pre-operatively with Duplex scanning, cannot be treated with the endoscopic technique. (243).

Insufficiency in superficial and perforating veins must always be fully corrected before considering any interventions on the deep venous circulation.

Valvuloplasty, valves and venous grafts must be used as a last resort. These procedures are still in the development phase, and can only be considered in specialist centers and during controlled clinical trials (13).

Skin grafts are possible, using various methods:

-       meshed split skin grafting (243)

-       pinch grafting (246)

-       allograft of human keratinocytes           cultured in vitro (247)

-       free flap grafts of venous sections with valves, preceded by ulcerectomy and ligature of the incompetent perforating veins (248).

-       “shave therapy”, i.e. ulcerectomy, removal of the lipodermatosclerotic tissue and meshed grafts (249).

The meshed grafting technique gives the best results, whilst human keratinocyte allografts and human skin substitutes are under critical review, with no data as yet to show the effect on recurrence (250).

 

SCLEROTHERAPY

        Sclerotherapy combined with compression treatment is indicated in selected patients with superficial venous system insufficiency, particularly if there are only short segments with reflux from incompetent perforating veins (251), even if there is an open ulcer (252). Sclerotherapy with ultrasound guidance was proposed in one study (109).

 

OTHER TREATMENTS

       These include

-        hyperbaric oxygen;

-        ozone therapy;

-       electro-ionotherapy;

-       vacuum therapy;

-       polarised light;

-       laser therapy.

 

These are experimental treatments with limited caselists, and as yet there is no full documentation for the results and follow-up.

 

GENERAL MEASURES

         Patients with venous ulcers must be advised to keep as close to their ideal body weight as possible. Regular walks on flat ground, 2-3 times a day for at least 30 minutes, should be encouraged.   Patients should avoid standing for long periods.   They should also position themselves occasionally during the day with their legs higher than the level of their heart,  and sleep with their legs slightly raised.

 Manual lymphatic drainage can be considered for patients with edema caused by CVI.   Physiotherapy can improve joint mobility of the ankles.

       Treatment for venous ulcers is a very old problem, much discussed but not resolved – as we have seen - because these lesions are slow to heal and quick to return.

Many clinical trials have been published but they are too selective to be representative of the general population. They usually only report short-term cure rates, without giving longer-term data on recurrences. To supply reliable clinical evidence and validate the techniques still under investigation more rigorous methods and investigation standards are needed.

The international literature calls for the establishment of special units dedicated to the study and cure of ulcers of the legs.  These would be responsible for home care and rehabilitation services, with a view to improving the quality of the services offered, keeping down costs, and - last but not least – ensuring a better quality of life for the patient.

 

 Recommendations:

 Conservative therapy has an important role to play in the first instance but does not prevent long-term recurrence unless it is supported, in many cases, by  surgical correction of the hemodynamic problems. Surgery gives good results only in  cases with isolated insufficiency of the venous system. Grade B

Compressive therapy, when applied correctly, will cure and prevent the recurrence of ulcers.    Grade A.

 

12.     VENOUS MALFORMATIONS

        Venous malformations (VM) are the most widespread vascular anomalies in the general population (253-256). These congenital malformations involve various morphological and functional alterations in the central or peripheral venous system.

        The pathogenesis of VM appears to be linked to genetic anomalies in various biochemical mediators (e.g. angiopoietin) and the membrane receptors that regulate the interactions between endothelial and smooth muscle cells in the end stages of angiogenesis.  The resulting maturation defect leads to the formation of anomalous veins with a monolayer of flat endothelial cells on the walls, but no real smooth muscular tunic. 

       VM mostly presents in the sporadic form in subjects with no family history, but there are also descriptions of hereditary and familial forms.  In the majority of cases there is an isolated malformation, but multifocal and even systemic disseminated forms are also seen.

       VM are usually located on the skin and mucous membranes, but they are often intramuscular or even intra-articular, and any organ may be involved. Distribution by site shows a marked prevalence of peripheral VM, particularly in the lower limbs, and cranio-facial VM, particularly in the temporo-masseteric, fronto-palpebral and lingual and labial regions. Other, less common, locations are the chest, abdomen and genitals.

       VM can lead to multiple secondary effects or complications. The most striking are esthetic and psychological, though these are by far from the only ones, and certainly not the most important. VM in the cranio-facial area can cause serious functional disorders, with problems in swallowing, speech, respiration, sight or hearing); in peripheral regions they can cause problems disorders in grasping, posture and walking), sometimes with disabling effects.

       Circulation complications take the form of venous stasis, peripheral forms leading to CVI, and loco-regional hypercoagulation with localised thrombosis and the possible depletion of coagulation factors (Table V).

 

Table V – Physiopathological effects of venous malformations

 

Esthetic                   Superficial blemishes

                               Skeletal deformations

Psychological          Patient

                               Family

Functional               Motor deficiencies:  swallowing

                                                              speech

                                                              respiration

                                                              grasping

                                                              walking

                                                               sensory disorders:    sight

                                                              hearing

Hemodynamic           Chronic venous stasis

Coagulation               Localised thrombosis

                                 Consumption coagulopathy

 

       The natural history of VM tends to vary. Generally, these malformations are evident from birth but sometimes they only become detectable later, during childhood or adolescence. In most cases, the maximum development is during puberty, with a marked increase in size, while later the malformation expands much more slowly, linked to the progressive slackening of surrounding tissues. The hemodynamic repercussions of the venous anomalies can become clinically evident and get progressively worse over the years, even if there is no real increase in the malformation.

       Table VI gives a schematic classification of simple and complex VM, based on their anatomical and pathological criteria.

 

Table VI – Anatomical and clinical classification of venous malformations (VM)

 

Simple VM           Subcutaneous form

                            Intramuscular form

                            Intra-articular form

Complex VM       Venous hypo/aplasia

                            Congenital valvular  incompetence

                            Persistent embryonal veins

 

SIMPLE VENOUS MALFORMATIONS

         In simple forms the anomalous veins may be abnormally dilated, with very thin walls consisting of a single layer of endothelial cells, and a markedly hypoplastic smooth muscular coat (lacunar veins).

       Subcutaneous VM are the most frequent and are usually lacunar or reticular veins in the subcutaneous adipose tissue, at variable depth but often over the fascial layer.

Intramuscular VM are more rare but are now being seen increasingly frequently. Generally these malformations look like lacunar veins;  they may be large and extensive, and lie between the large muscle bundles, for instance in the quadriceps femoris muscle or the brachial biceps.

The intra-articular form is the least frequent and the hardest to diagnose clinically; large venous lacunae may be located inside a joint, causing gradual synovial erosion with degenerative lesions in the joint head as is typically observed in the femoral-tibial joint.

 

COMPLEX VENOUS MALFORMATIONS

        Complex VM involve a combination of congenital venous anomalies such as hypoplasia or agenesis of the superficial and/or deep venous system, primary valvular incontinence, and persistence of embryonal trunk veins such as the marginal vein.

       In the hypo/aplastic form there may be complete agenesis, or varying degrees of hypoplasia and reduction in caliber in one or more segments of the superficial and/or deep venous systems of a limb. One of the most frequent complex VM is agenesis of the poplito-femoral and/or the femoral-iliac tract, with compensatory hypertrophy of the greater saphenous vein which,  in some cases, continues, typically in a large suprapubic vein cross-over confluent with the contralateral iliac axis.

In congenital valvular incontinence  there is primary deep vein insufficiency, caused by complete atresia of the cusps of one of the venous valves or by dysplastic changes producing a mechanical defect in valve flap closure. These anomalies are mostly found in the superficial femoral vein, but can also involve the deep femoral vein, the common femoral vein and the internal iliac vein.

In the form with persisting embryonal veins there are anomalous, large-caliber venous trunks which develop in the early stages of vasculogenesis and normally regress during the later phase of modeling of the vascular tree. The most common embryonal veins are the sciatic and marginal veins.  The sciatic vein presents as a large trunk continuous with the popliteal vein which runs posteriorly in the thigh and terminates in the pelvis, meeting the ipsilateral iliac.  The marginal vein is a large-caliber venous collector originating in the external malleolar region and running along the lateral surface of the lower limb for varying distances, draining into various vessels in the deep venous system.  This has been illustrated in a classification of the multiple variants of this vein’s course (Table VII).

 

Table VII Classification of the outlets of the marginal vein

-       Superficial femoral vein

-       Deep femoral vein

-       Common femoral vein

-       External iliac vein

-       Inferior gluteal vein

-       Internal iliac vein

-       Common iliac vein

-       Multiple confluences

 

Clinical picture

 

The signs and symptoms of VM widely: differences are seen in the site, the depth, the extension and the extent of anatomical and hemodynamic changes.  Malformed veins on the surface are visible as a subcutaneous swelling of variable size and form, soft and elastic in consistency, collapsing easily with pressure, covered with bluish or purple-colored skin of normal temperature.  The veins do not have an intrinsic pulse but typically expand in the anti-gravity position; this sign is very useful for diagnosis and must be checked carefully.    On palpation there are small hard nodules: these are “phleboliths” – venous stones - caused by local thrombosis.

Intramuscular or intra-articular VM are less evident on objective examination, particularly if they are small, as they are deep and are often covered by healthy skin. However, careful clinical observation will generally show a typical asymmetry of the anatomical region compared to the contralateral area. This is accentuated when the patient is lying down.

Embryonal veins present as twisted and irregular ectatic venous trunks which extend into the acral regions for varying distances in the direction of the root of the limb. In hypo/aplasia of the deep venous circulation or congenital valvular incontinence, there will be clinical signs of chronic venous hypertension: edema, secondary varicose veins, lipodermatosclerosis and stasis ulcers.

       Skeletal and soft tissue changes, with hypertrophy or hypotrophy, are less frequent than with venous-arterial malformations, but may be present, particularly in the peripheral forms.

       VM are frequently associated with anomalies in the lymph system, and signs of lymphostasis are frequent.

       In the mixed venous-capillary form subcutaneous VM are often associated with flat superficial angiomas.

       The triad of a complex peripheral VM, cutaneous capillary malformation and skeletal and soft tissue hypertrophy in a limb is known as the Klippel-Trenaunay syndrome. The Proteo syndrome has multifocal capillary-venous and lymph system malformations with anomalies of the muscles and skeleton and the peripheral nerves. It causes extreme hypertrophy and deformation of the affected limb.

       Maffucci syndrome is the combination of  a superficial VM and multiple enchondromatosis of the upper or lower extremities, leading to marked skeletal deformations with shortening of the limb and possible later chondrosarcoma.  The presence of multiple subcutaneous VM may be an element in the rare Bean syndrome, characterised by the simultaneous presence of disseminated VM of the gastrointestinal tract.

 

       Diagnosis

 Venous malformations are generally diagnosed by clinical examination.

 Table VIII – Diagnostic approach to patients with venous malformations

 

Cranio-facial venous  Cranial X-ray

malformations            Colour echoDoppler

Direct phlebography   Cranio-facial MR

Peripheral venous       Comparative limb

malformations             X-ray

                                    Colour echoDoppler

                                    Descending phlebography

                                    Ascending phlebography

                                    Direct phlebography

                                    MR or CT scan of the limb

 

       However, every patient should also have a thorough preoperative clinical and instrumental diagnostic evaluation, as the treatment indications are closely correlated with the morphological and functional characteristics of the VM.  The elements investigated will include the site and the anatomical relationships, the extent and dimensions, hemodynamic effects, patency and competence of the superficial and deep venous systems.

       A rigorously standardised diagnostic protocol must be employed based on the following instrumental examinations: standard X-ray, colour echoDoppler, computerised tomography (CT), magnetic resonance imaging (MRI) and phlebography (Table VIII).

       Standard X-rays show the indirect signs of VM such as phleboliths and any associated skeletal dysplasia and size abnormalities.  Colour echoDoppler is the preliminary examination, for studying the extent of the VM, the patency and competence of the superficial and deep venous systems, the morphology and functional status of the venous valves and to exclude the presence of arterio-venous fistulas.

       CT and MRI scans permit an accurate definition of the extent of the VM and their anatomical relationships with internal organs and the musculo-skeletal structures, particularly when the malformations are deep.   The diagnosis will be completed with a phlebography examination. This is indispensable to obtain a complete morphological and hemodynamic picture of the malformations and the entire superficial and deep venous system. The examination should be done in the ascending and descending phases and with direct puncture of the malformation, as these all give complementary information.

       The ascending phase explores the patency and conformation of the main venous axes, showing up any hypo/aplasia with great diagnostic accuracy. The descending phase gives a picture of valve competence, showing any primary venous insufficiency;  the degree can be assessed on the basis of the retrograde opacity in the deep venous system. 

       These investigations are completed with a selective hemodynamic study by direct injection, which is vital for the examination of lacunar VM with low-velocity flow, or for embryonal veins which can be visualised throughout their length as far as the confluence.

       By using tourniquets and hemostatic cuffs or other systems of selective compression, isolated parts of the venous circulation can be examined in all phlebography phases.

Casella di testo: Table IX – Treatment choices for patients with venous malformations
 
Cranio-facial venous malformations                                               Percutaneous sclerotherapy (++)
                                                                                                   Guided sclerotherapy (++++)
                                                                                                   Surgery (+)
Simple subcutaneous peripheral venous malformations                    Percutaneous sclerotherapy (+++)
                                                                                                   Guided sclerotherapy (+++)
                                                                                                   Surgery (++)
Simple intramuscular peripheral venous malformations                    Percutaneous sclerotherapy (+)
                                                                                                   Guided sclerotherapy (++++)
Simple intraosseous peripheral venous malformations                      Guided sclerotherapy (++++)
Complex peripheral venous malformations with hypoplasia              Abstention (+++)
                                                                                                   Surgery (+)
Complex peripheral venous malformations with                               Surgery (++)
valvular incompetence
 
Complex peripheral venous malformations with                               Percutaneous sclerotherapy (+++)
embryonal veins                                                                            Guided sclerotherapy (++)
                                                                                                   Surgery (+++)
 
       This procedure can even be done intraoperatively, so that the VM can be checked in real time during sceleroembolising treatment. It can also be used to give an immediate postoperative check on the results.

 

Treatment

 

       Treating VM poses serious problems for the vascular surgeon as these are often extremely complex malformations, appearing in babies or young children, with very serious hemodynamic, functional and esthetic implications.  The aims of treatment are the partial or complete regression of the malformation, reduction or disappearance of the signs of venous insufficiency, functional rehabilitation of the limb, elimination or reduction of unattractive varices.

       A complete preoperative diagnostic evaluation is absolutely vital before any treatment is decided; the instrumental findings must guide each individual therapeutic program so that surgical procedures and/or percutaneous treatments can be combined as most appropriate for each patient.

       The indications and the strength of the recommendations for the various treatment options in the different forms of VM are summarized in Table IX.

____________________________________

Table IX – Therapeutic options for venous malformations (VM)

Cranio-facial VM

- Percutaneous sclerotherapy (++)

- Phlebo-guided sclerotherapy (++++)

- Surgery (+)

Simple subcutaneous peripheral VM

- Percutaneous sclerotherapy (+++)

- Phlebo-guided sclerotherapy (+++)

- Surgery (++)

 Simple intramuscular peripheral VM

- Percutaneous sclerotherapy (+)

- Phlebo-guided sclerotherapy (++++)

   Simple intra-articular peripheral VM

- Phlebo-guided sclerotherapy (++++)

Complex peripheral VM with hypo/aplasia

- Wait and see (+++)

- Surgery (+)

 - Complex peripheral VM with valvular incontinence

- Surgery (++)

- Complex peripheral VM with embryonal vein

- Surgery (+++)

- Phlebo-guided sclerotherapy (++)

- Percutaneous sclerotherapy (+)

____________________________________

 

Direct percutaneous sclerotherapy can be done on isolated, superficial, small VM. If they are more extensive and deeper it is better to do the sclerotherapy under radioscopic guidance, using the direct injection phlebography technique.   This allows close control of the injection site and the diffusion of the sclerosing mixture, giving immediate confirmation of the results.

       Various sclerosing mixtures are used. The choice will depend on the morphological characteristics, anatomical site and extent of the malformation. For spider veins and/or small-caliber VM, particularly on the lips and tongue, a 2-3% polydocanol solution is recommended. For large-caliber, extensive VM (lacunar veins), which are frequently found in the temporo-mandibular area, a more powerful sclerosing agent is called for, such as 95% ethanol and Ethibloc.

The dosage of the sclerosing agent will be established in proportion to the size of the malformed veins, up to a maximum dose of 2 ml/kg body weight.

The sclerotherapy technique must obviously be extremely rigorous because accidental injection of the sclerosing mixture outside the vein can provoke many serious complications, such as thrombophlebitis, cutaneous necrosis, granuloma, neurological damage.  A normal, reversible side effect is loco-regional inflammation/edema, varying in size which will disappear in a few weeks;  it can be treated, if necessary, with a steroidal anti-inflammatory drug.

Surgery plays a fundamental role in the complex overall treatment strategy for VM.  The most common surgical procedure is to strip lacunar or reticular malformed veins in the lower limbs; this should preferably be done by a micro-invasive technique, through micro-incisions in the skin and using  special phlebectomy hooks.

For a persisting embryonal venous trunk the only therapeutic procedure is surgical removal. This must also be done with the least invasive technique possible.  In the past large incisions were made along the outer surface of the limb, but nowadays only minimal skin incisions are needed, so the outcome is esthetically more acceptable. Detailed preoperative mapping must be done on the embryonal vein, and when feasible,  mini-strippers can be used.

When dealing with congenital valvular incompetence, and preoperative ultrasound examination indicates the presence of dysplastic valvular flaps, the venous valves can be surgically reconstructed by external venoplasty with reinforced Dacron or PTFE prostheses. The correct positioning of the prosthetic band – of the right caliber – will restore valve competence by drawing the dysplastic flaps closer together, while maintaining the patency of the veins.

For segmentary hypoplasia of the  deep venous circulation secondary to extrinsic compression from an abnormal fibrous muscle band,  as is often seen in the popliteal cavity, a decompression procedure can be done to facilitate development of the hypoplastic venous structures.

In cases of deep vein agenesis with compensatory hypertrophy of superficial veins such as the greater saphenous vein and its collaterals, surgical removal of the malformed veins is obviously contra-indicated, as they serve as hemodynamic substitutes.

To conclude, therefore, the therapeutic strategy must be carefully thought out and planned for each patient on the basis of the clinical and instrumental findings, with particular reference to the site, the morphology and the extent of the VM, and taking account of the architecture and the hemodynamics of the loco-regional venous circulation. 

The site of the malformation can be a major factor in choosing treatment.  In the facial and genital areas sclerotherapy is preferred as it has fewer esthetic and functional implications, whereas surgery, being more radical, is used more for the peripheral forms.

The complexity and size of the VM will have a directly proportional effect on the choice of surgical approach.  Simple or isolated VM are treated by elective intravascular percutaneous sclerotherapy under venographic guidance. Complex VM  call for corrective and/or reconstructive surgery, depending on the anatomical and hemodynamic changes present.

In the majority of cases, combined therapy is the preferred option. Percutaneous and surgical treatment combined offers the best clinical, morphological and functional results.  Ligature and stripping the malformed veins can be combined with preliminary or intraoperative sclerosing treatment, so that minimally invasive techniques can be employed to remove moderately sized dysplastic lacunar or spider veins.

Similarly, after stripping the main trunk of an embryonal vein the intervention can be completed by percutaneous sclerotherapy on the numerous collateral veins, particularly the terminal end near the confluence with the deep venous system.

In conclusion, surgery and percutaneous sclerotherapy should not be considered alternatives but can be usefully combined in the complex and delicate strategies for treating VM.  An important point, particularly in cases of extensive VM, is that numerous sequential surgical operations or sclerotherapies may be necessary to obtain complete regression of the malformations.

 Recommendations:

 In the past, the only treatment option for malformed veins was destructive surgery; this was often unsuccessful, gave disappointing esthetic results, and the veins often recurred. In recent years intravascular percutaneous sclerotherapy for VM has been much improved and is now widely used. This minimally invasive technique has been reported to give the best morphological and functional results.  It appears to be a valid alternative or useful complement to surgery, for facial, genital and peripheral VM.  Grade C

It is vitally important to choose the right time for surgery, to take account of the patient’s growth, the development of the malformation and its hemodynamic repercussions.      Grade C

 

 

13.       QUALITY OF LIFE

 There are many reasons for considering  the Quality of Life (QoL) as part of the therapeutic outcome, in CVI like in other diseases (Garrat, 1993, 256, 1).  The current method of generic measuring, considered the standard in the USA and in Europe, is the Medical Outcomes Study Short Form Health Survey – 36 (MOS SF36) (258,259).

       Specific questionnaires for CVI (CVIQ1 and CVIQ2) have been used since 1992, with surprising results for a disease that has hitherto been so severely underestimated. CVI has a profoundly negative effect on the patient’s daily life and the results illustrate the impact of CVI on morbidity and the efficacy of drug therapy (260,261).

       Evaluation of randomised controlled trials on surgery and its effect on QoL is more complicated (262). Trials are still in progress to assess recent surgical techniques for CVI such as subfascial endoscopic ligature of the perforating veins (SEPS) and valvuloplasty.

 

Recommendations:

The analysis of clinical parameters for evaluating the Quality of Life should use standard psychometric criteria which are reproducible, valid and acceptable. The Medical Outcomes Study Short Form Health Survey-36 and the Nottingham Health Profile (NHP) have proven scientific worth but their relevance to CVI needs to be confirmed.

Specific measurements are needed to study QoL in CVI.  They must be:

-         workable, valid and responsive,

-         practical for checking clinical results,

-         available in a wide variety of languages so they can be used in international trials. Grade C 

 

REFERENCES

AA. Vari. Lesioni ulcerative cutanee. Aspetto statistico. Milano. BIMS (IMS), 1997; 13: 10-7.

Abu-Own A, Scurr H, Coleridge-Smith PD: Saphenous vein reflux without incompetence at the saphenofemoral junction. Br J Surg, 1994; 81: 1452-4

Abu-Own A., ScurrJ.H., Coleridge Smith P.D.: effect o leg elevation on the skin microcirculation in chronic venous insufficiency. J. Vasc. Surg., 1994; 20: 705

Agenzia Nazionale Francese: Veinotropes 1996, in CAZAUBON M. et BOISSEAU M., Encycl. Med. Chir. (Elsevier, Paris) Angeiologie, 19-3520.

Agrifoglio G, Edwards EA: Results of surgical treatment of varicose veins. JAMA, 1961; 178: 906-11.

Agus G.B. : Complementarietà della terapia medica alla chirurgia delle varici.Flebologia, 3, 19-26, 1992.

Agus G.B., Sarcina A., Lorenzi G. et Al. : Nuovi orientamenti nel trattamento delle sequele trofiche della sindrome post-flebitica. Min. Medica, 72, 2805-8, 1981.

Agus G.B.: Prevenzione dell'insufficienza venosa. In Mancini S., Flebolinfologia, UTET Ed., Torino, 1999.

Agus GB, Bonadeo P: Indicazioni al trattamento chirurgico. In: Agus GB Chirurgia delle varici. Tendenze recenti. Minerva Medica Ed., 1991: 37-41.

Agus GB, Castelli P, Sarcina A: Varici recidive degli arti inferiori. Patogenesi e indicazioni al trattamento chirurgico. Min Cardioang 1982; 30(1-2): 25-27.

Agus GB: Chirurgia ambulatoriale in flebologia: un approccio realistico. In Advances in Surgery and Oncology. Monduzzi Ed., Bologna, 1996: 169-72

Allegra C, Antonini V, Bonifacio M et al:  Les phlèbostases constitutionnelles. Phlèbologie '89, Davy A,Stemmer R, eds, John Libbey Eurotext, London-Paris 1989; 265-7

Allegra C, Bartolo M jr, Carioti B et al.: “Micro Lynphography assessment of Daflon 00 mg activity in patients with chronic venous insufficinency”. Atti 16° International Congress of Linphology. Madrid, 1997. Pg. 12 – 6

Allegra C, Bartolo M Jr, Carioti B, Cassiani D: An Original Microhaemorheological Approach to the Pharmacological Effects of Daflon 500 mg in Severe Chronic Venous Insufficiency. Int J Microcirc Clin and Exper. 1995; 15 (suppl 1): 50-54.

Allegra C. : Guida alla terapia con antocianosidi nelle Flebopatie degli arti inferiori. Il Polso Ed., Milano. 1986

Allegra C. : Ruolo attuale dei glicosaminoglicani e prospettive in terapia.Min. Angiol., 18 (suppl. 3 al n. 1), 45-9, 1993.

Allegra C., Antonini V., Carlizza A., Tonelli V. : L'estratto titolato triterpenico di centella asiatica nella insufficienza venosa.Min. Angiol., 12, 107-16, 1987.

Allegra C., Carlizza A Rheoplethysmography and laser Doppler velocimetry in the study of microcirculatory flow variability. Vasomotion and Flowmotion: Progress in Applied Microcirculation. Vol.20. Allegra C, Intaglietta M., Messmer K. Eds. Karger 1991.

Allegra C: Relationship between relative hematocrit and blood cell velocity in human skin capillaires in chronic venous insufficiency. Int J Microcirc Clin and Exp, 1994; 14(suppl I): 52

Antignani PL, Di Fortunato T: La patologia venosa cronica: presentazione di una nuova classificazione internazionale. Clin Terap, 1997; 148: 521-526

Arnoldi C.C.: Venous pressure in patient with valvular incompetence of the veins of the lower limb. Acta Chir. Scand. 1966; 132: 628.

Babcock WW: A new operation for the extirpation of the varicose veins of the legs. N Y Med J, 1907; 86: 153-6.

Baccaglini U, Giraldi E, Spreafico G et al: étude multicentrique des ulcères veineux en Italie. Phlébologie Ann Vascul, 1997; 3: 371-8.

Bahnini A:  Traitement des varices des membres inférieurs : point de vue chirurgical . Osp Ital Chir, 1998; 6: 571-4

Baker SR, Stacey MC, Jopp-Mckay AG, Hoskin SE, Thompson PJ.: Epidemiology of chronic venous ulcers. Br J Surg 1991; 78:864-7.

Bartolo M: Impact socio-économique des maladies veineuses en Italie. Phlébologie, 1992; 45: 422-31.

Bass A, Chayan D et al.: Lateral venous ulcer and short saphenous vein insufficiency. J Vasc Surg 1997; 25:654-7.

Bassi G. e Stemmer R. Traitements mécaniques fonctionnels en phlébologie. Piccin Ed. - Padova 1983.

Bassi G.: Le varici degli arti inferiori. Ed. Minerva Medica, Torino 1962.

Belardi P, Lucertini G: Advantages of the lateral approach for re-exploration of the sapheno-femoral junction for recurrent varicose veins. Cardiovasc Surg 1994; 2(6): 772-4.

Belcaro G., Nicolaides A.N., Stansby G. The Venous Clinic. Imperial College Press, London, 1998.

Belov S., Loose D.A. , Müller E. eds.    Malformazioni vascolari congenite . Carlo Erba Ed., Milano 1992

Beresford SAA, Chant ADB, Jones HO, Piachaud D: Varicose veins: A comparison of surgery and injection/compression sclerotherapy. Five-year Follow-up. Lancet, 1978;1:921-24.

Bergan J.: Endoscopic subfascial perforator vein interruption. In Goldman MP and Bergan JJ, editors: Ambulatory treatment of venous disease. St Louis 1996, 173-8.

Bergan JJ, Murray J, Greason K Subfascial endoscopic perforator vein surgery: a preliminary report. Ann Vasc Surg 1996; 10: 211-9.

Bergan JJ: Experience with classification of venous disorders. Vasc Surg, 1997; 31: 218-21

Bergen JJ: Saphenous vein stripping and quality of outcome. Br J Surg, 1996; 83: 1025-7.

Bishop CCR, Fronek HS, Fronek A. et al. Real time color duplex scanning sclerotherapy of the greater saphenous vein. J Vasc Surg, 1991; 14:  505-508

Bishop JB, Phillips LG et al.: A prospective randomized evaluator-blinded trial of two potential wound healing agents for the treatment of venous stasis ulcers. J Vasc Surg 1992; 16:251-7.

Blättler W.: Compression Therapy of Deep Vein Thrombosis. Phlebology, 1995, (Suppl.1), 1169 -73.

Boineau-Geniaux D.: Therapeutic activity of Daflon 500 mg. On trophic disorders of venous insufficiency. Act Med Int – Angiologie 1988; 5 suppl. 73: 20-21

Bradbury A, Evans C, Allan P et al: What are the symptoms of varicose veins? Edinburgh vein study cross sectional population survey. BMJ, 1999 ; 318: 353-6.

Bradbury AW, Stonebridge PA, Ruckley CV, Beggs I: Recurrent varicose veins: correlation between preoperative clinical and hand-held doppler ultrasonographic examination, and anatomical findings at surgery. Br J Surg , 1993;  80(7):  849-851

Brand FN, Dannenberg AL, Abbott RD et al: The epidemiology of varicose veins: The Framingham Study. Am J Prev Med, 1998; 4: 96-101.

Brandjes D.P.M., Büller H.R., Heijboer H., et Al.: Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. The Lancet, 1997, 349, 759-62.

Burnand KG, Layer GT.: Calze elastiche a compressione graduata. BMJ It. Ed. 1997, 6, 6-7

Cabrera Garrido JR, Cabrera Garcia-Olmedo JR, Garcia-Olmedo Dominguez MA: Elargissement des limites de la sclérotherapie: nouveaux produits sclérosants. Phlébologie, 1997;50:181-8.

Callam M.J., Harper D.R., Dale J.J. et al.: Arterial disease in chronic leg ulceration: an underestimated hazard ? BMJ 1987; 294: 929-31.

Callam MJ, Ruckley CV, Harper DR et al.: Chronic ulceration of the leg: extent of the problem and provision care. BMJ 1985; 290:1855-6.

Callam MJ: Epidemiology of Varicose Veins. Br J Surg, 1994; 8: 167-173.

Camilli S, Guarnera G: External banding valvuloplasty of the superficial femoral vein in the treatment of primary deep valvular incompetence. Int Angiol,1994; 13: 218-22.

Campanello M, Hammarsten J, ForsbergC. Et al: Standard stripping versus long saphenous vein-saving surgery for primary varicose veins: a prospective, randomized study with the patients as their own control. Phlebology, 1996; 11: 45-9.

Canonico S, Gallo C, Paolisso G et al: Prevalence of Varicose Veins in an Italian Elderly Population. Angiology, 1998; 49: 129-35.

Cappelli M, Molino Lova R, Ermini S. el al: Comparison entre cure CHIVA et stripping dans le traitement des veines variqueuses des membres inférieurs: suivi de trois ans. J mal Vasc, 1996; 21: 40-6.

Cesarone M.R., Belcaro G., Geroulakos G. et Al. . : Activation fibrinolytique par le defibritide dans le traitment des ulceres veineux. Angeiologie, 49,10-4,1997.

Cesarone MR, Belcaro G, Nicolaides MD et al. Epidemiology of Cost of Venous Diseases in Central Italy. The San Valentino Venous Disease Project. Angiology 1997; 48: 583-93.

Chant ADB, Jones HO, Weddel JM. Varicose veins: A comparison of surgery and injection/compression sclerotherapy. Lancet 1972;2:1188.

Chardenneau JM: Etiologies des lourdeurs de jambe. Phlébologie, 1999 ; 52: 37-40.

CHEATLE E. et Al. :  Drug treatment of chronic venous insufficiency and venous ulceration : a review. J. Roy. Sac. Med., 84, 354-7, 1991.

CHEATLE TR., STIBE ECL, SHAMI SK. et Al. : Vasodilatory capacity of the skin in venous disease and its relationship to transcutaneous oxygen tension. Br J Surg, 78: 607-10, 1991.

Choucair M, Phillips TJ.: Compression therapy. Inc Dermatol Surg 1998, 24, 141-8

Christopoulos DG, Nicolaides AN, Szendro G et al., Air-plethysmography and the effect of elastic compression on venous hemodynamics of the leg. J Vasc Surg 1987;5:148-59.

Coleridge Smith P.D., Sarin S, Hasty J, Scurr JH. Sequential gradient pneumatic compression enhances venous ulcer healing: a randomized trial. Surg 1990; 108:871-5.

Coleridge Smith P.D. :  More about Phlebotonic drugs. Editorial Phlebology, 11, 1, 1996.

Coleridge Smith P.D. :  Pharmacological treatment for venous disease. Editorial Phlebology, 9, 47, 1994.

Coleridge-Smith P.D.: How does a Leg Ulcerate ? In: Ruckley C.V., Fowkes F.G.R., Bradbury A.W. Eds. Venous Disease. London. Springer 1999: 51-70.

Colgan MP., Dormandy JA., Jones PW. et Al. :  Oxypentiphylline treatment of venous ulcer of the leg. Br Med J, 300: 972-5, 1990.

Consensus  Statement (Proposal): The role of oedema protective agents in the treatment of chronic venous insufficiency. Phlebology, 11, 39-40, 1996.

Consensus Statement: The investigation of chronic venous insufficiency. Circulation 2000. In press.

Corcos L, de Anna D, zamboni P et al.: reparative surgery of valves in the treatment of superficial venous insufficiency: external banding valvuloplasty versus high ligation or disconnection. A prospective multicentric trial. J Mal Vasc, 1997; 22: 128-36

Cornu-Thenard A, Uhl JF, Chleir F: The CEAP classification: usefulness and limitation. Phlebolymphology 1999; 24: 9-14

Cornu-Thénard A. La terapia elastocompressiva. La pressoterapia con bende e calze elastiche; in: "Le varici nella pratica quotidiana" di Bilancini S., Lucchi M., Minerva Medica Ed. - Torino 1991, pag. 335-60.

Cornu-Thénard A., Paris J.P., Girouin D.: Traitement ambulatoire des ulcers de jambe à l’aide d’une contention permanente par bas élastique. Phlébologie 1983; 36: 77-88.

Crane C: The surgery of varicose veins. Surg Clinics North Am, 1979; 59(4): 737-48

Danza R, Navarro T, Baldizan J: Reconstructive surgery in chronic venous obstruction of the lower limbs. J Cardiovasc Surg, 1991; 32: 98-103

De Luca M., Cancedda R.: Culture of human epithelium. Burns 1992; 18 suppl. 1: 5.

De Palma RG Surgical Treatment of chronic venous ulceration, in Phlebologie, Raympound Martinbeau P,  Prescott R, Zummo M. eds. J. Libbey-Eurotext, Paris, 1992: 1235-7

De Palma RG: CEAP in clinical practice. Vasc Surg 1997; 31: 223

De Palma RG: Management of incompretent perforators: conventional techniques. In: Handbook of venous Disorders. Edited by P. Gloviczki  and JST Yao. Published in 1996 by Chapman-Hall, London. ISBN 0 412 727307.

Diehm C, Trampisch HJ, Lange S et al. Comparison of leg compression stocking and oral horse chestnut seed extract therapy in patients with chronic venous insufficiency. The Lancet, 1996, 347, 292-294

Dinn E., Henry M.: Treatment of venous ulceration by injection sclerotherapy and compression hosiery: a 5-year study. Phlebology 1992; 7: 23-6.

Documenti CEN/TC 205 WG2 n° 179 (1996) e 196 (1998).

Dominguez C., Brautigam I., Gonzalez JA. et Al. :  Therapic effects of hidrosmin on chronic venous insufficiency of the lower limbs. Curr Med Res Opin 1992; 12: 623-630.

Doran FSA, White M: A clinical trial designed to discover if the primary treatment of varicose veins should be by Fegan’s method or by an operation. Br J Surg, 1975; 62: 72-6.

Dormandy JA.: Pharmacologic treatment of venous leg ulcers. J CV Pharm 1995; 25(suppl):161-5.

Douglas W.S., Simpson N.B.: Giudelines for the management of chronic venous leg ulceration. Report of a multidisciplinary workshop. Br.J.Dermatol. 1995; 132: 446-52.

Dunn R.M., Fudem G.M., Walton R.L. et al.: Free flap valvular transplantation for refractory venous ulceration. J. Vasc. Surg. 1994; 19: 523-31.

Duruble M., Ouvrey P.,  Haemodilution in venous disease. Phlebology 1991; 6: 31-6.

Dwerryhouse S, Davies B, Harradine K, Earnshaw JJ: Stripping the long saphenous vein reduces the rate of reoperation for recurrent varicose veins: five-year results of a randomized trial. J Vasc Surg, 1999; 29: 589-92

Edit. Economics of varicose veins. Br Med J 1973;2:626.

Edit. Tailored treatment for varicose veins. Br Med J 1975;1:593.

Edit. The treatment of varicose veins. Lancet 1975;2:311.

Ehrly AM., Schenk J., Bromberger U. :  Mikrozirkulationsstörungen bei Ulcus cruris venosum : niedrigdosierte systemische Langzeit-therapie mit Urokinase. Phlebol Proktol 1989, 18: 166-8.

Einarsson E, Eklöf B, Neglén P: Sclerotherapy or surgery as treatment for varicose veins: a prospective randomized study. Phlebology 1993;8:22-6.

Elbaz C: Chirurgie itérative dans les récidives après opération pour varices essentielles. Phlébologie, 1977;  30(3): 265-273

Ellison DA., Mc Collum CN.: Hospital or Community: How Should Leg Ulcer Care Be Provided ? In: Ruckley C.V., Fowkes F.G.R., Bradbury A.W. Eds. Venous Disease. London. Springer 1999: 222-9.

Ernst E., Saradeth T., Resch K.L.: Hydrotherapy or varicose veins: a randomized, controlled trial. In: Raymond-Martinbeau P., Prescott R., Zummo M. (Eds.) Phlébologie 92, Paris, John Libbey Eurotext, 1992; 944

Fagrell B. :  Microcirculatory disturbances: the final cause for venous leg ulcers? Vasa 1982; 11: 101-103.

Fegan GW: Varicose veins. Compression Sclerotherapy. London, William Heinemann Medical Books Ltd., 1967.

Fletcher A, Cullum N, Sheldon TA.: A sistematic review of compression treatment for venous leg ulcers - Review. BMJ 1997, 315, 576-580

Földi E., Földi M.: Physiothérapie complexe décongestive. Ed. Frison Roche, Paris, 1993

Franceschi C : Theorie et pratique de la Cure Conservatrice et Hemodynamique de l’Insuffisance Veineuse en Ambulatoire. Ed. de l’Armancon, Précy-sous-Thil, 1988.

Franks PJ: Quality of Life for Leg Ulcer Patients. In: Ruckley C.V, Fowkes F.G.R., Bradbury A.W. Eds. Venous Disease. London. Springer, 1999: 51-70.

Garde C.: Le dreinage veneux manuel. Phlebologie, Paris, 1992; 948-51

Gardon-Mollard C., Ramelet A.A. La contention médicale. Masson Ed., Paris 1999.

Garratt A.M., Macdonald L.M., Ruta D.A., et Al: Towards measurement of outcome for patients with varicose veins. Quality in Health Care 2:5-10, 1993.

Gillies T.G., Ruckley C.V.: Does surgery play a part in the management of venous ulcers? In: Greenhalgh R.M., Fowkes F.G.R. Trials and Tribulation of Vascular Surgery. London. WB Saunders 1996: 411-22.

Gilly R., Pillion G., Frileux C. :  Evaluation of a new veno active micronized Flavonoid-Fraction (S 5682) in symptomatic disturbances of the venolymphatic circulation of the lower limb: a double blind, placebo-controlled study. Phlebology 1994; 9:67-70.

Glinsky W, Chodynika B, Roszkiewicz J et al.: The beneficial augmentative effect of Micronised purified Flavonoid Fraction (MPFF) on the healing of leg ulcers: an open, multicentre controlled, randomised study. Phlebology,1999; 14: 151-7

Gloviczki P, Bergan JJ, Rhodes JM et al : Mid-term of endoscopic perforator vein interruption for chronic venous insufficiency : Lessons learned from the North American Subfascial Endoscopic Perforator Surgery registry J Vasc Surg 1999; 29: 489-502.

Gloviczki P. Bergan JJ, Menawat SS et al: Safety, feasibility and early efficacy o subfascial endoscopic perforator surgery: a preliminary report from the North American Registry. J vascl Surg, 1997; 25:94-105.

Godin MS, Rice JC, Kerstein MD: Effect of commercially available pantyhose on venous return in the lower extremity. J Vasc Surg. 1987, 5, 844-8.

Goldman MP: Scleroterapia. Trattamento delle varici e delle teleangiectasie degli arti inferiori. Torino, UTET, 1997.

Gongolo A, Giraldi E, Buttazzoni L et al: Il sistema duplex nel follow up della terapia sclerosante della vena grande safena. Radiol Med, 1991; 81: 303-8.

Good clinical practice for trials in medicinal products in the European Community:  EG- Note for guidance of the CPMP Working Party on Efficacy of Medical Products (iii/30976/88- EN, Final), 1990.

Grondin L, Young R, Wouters L. Sclérotherapie écho-guidée et sicurté: comparisons des techniques. Phlébologie 1997;50:241-5.

Gruss JD: Venous bypass for chronic venous insufficiency, in Venous Disorders, Bergan JJ, Yao JST eds WB Saunders, Philadelphia, 1991: 316-30

Gualtierotti R.: La riabilitazione flebologica e linfologica: il termalismo. Flebologia, 1992; 3: 37

Guex J.J.: Thrombotic complications of varicose veins. A literature review of the role of superficial venous thrombosis. Dermatol. Surg. 1996, 22, 378-82

Guidelines of American Venous Forum. Ed. P. Gloviczki, J.S.T. YAO: London – Chapman-Hall Medical, 1996.

Guidelines of care for sclerotherapy treatment of varicose and telangiectatic leg veins. J Am Acad Dermatol 1996; 34: 523-8.

Guidelines of the American Venous Forum. Sclerotherapy for varicose veins: practice guidelines and sclerotherapy procedures. In: Gloviczki P e Yao JST eds., Handbook of venous disorders. Guidelines of the American Venous Forum, London, Chapman & Hall Medical, 1996.

Guilhou JJ, Dereure O, Marzin L et al.: Efficacy of Daflon 500 in venous leg ulcer healing: a duble blind, randomized, controlled versus placebo trial in 107 patients. Angiology 1997; 48,1: 77-85

Guilhou JJ, Guillot B, de Champvallins M.: Skin systolic pressure in lower limb ulcers: results with Daflon 500 mg. Phlebology 1992; Suppl. 2: 50-52

Haegher K: 1084 legs with recurrent varicose veins. An analysis after previous unsuccessful operations. Zbl Phlebol, 1967;  6: 12

Hammarsten J, Pedersen P, Cederlund CG, Campanello M.: Long saphenous vein saving surgery for varicose veins. A long term follow-up. Eur J Vasc Surg, 1990; 4: 361-4

Hansson C., Hoborn J., Moller A. et al. : The microbial flora in venous leg ulcer without clinical signs of infection. Acta Derm. Venereol. 1995; 75: 24-30.

Harenberg J. : Review of pharmacodynamics, pharmacokinetics, and therapeutic properties  of  Sulodexide. Med. Res Rev., 1998, 18, 1-20.

Hobbs J: Surgery or sclerotherapy for varicose veins: 10 year results of a random study. In: Tesi M, Dormandy J, eds. Superficial and Deep Venous Diseases of the Lower Limbs. Torino, Minerva Medica, 1984: 243-6.

Hobbs JT.: Varicose veins. BMJ 1991, 303, 707-710

Hobson J: Venous Insufficiency at Work.Angiology 1997; 48: 577-82.

International Task Force - The management of chronic venous disorders of the leg: an evidence-based report. Phlebology, 1999, 14 (Suppl.1).

Isaacs M, Forrestal M, Harp J, Gardener M: Sclérothérapie écho-guidée des troncs saphéniens. Phlébologie 1997; 50: 247-9.

Jacobsen B: The value of different forms of treatment of varicose veins. Br J Surg, 1979; 66: 182-4

Jantet G.: Relief Study: first consolidated European data. Angiology 2000. In press

Jantet G: What is new in phlebology – from the orizon of the Sydney meeting. Scope on Phlebology and Lymphology. 1999; 6(2): 32-5.

Jeffery P.C., Nicolaides A.N.: Graduated compression stockings in the prevention of postoperative deep vein thrombosis. Br.J.Surg.,1990,77,380-3.

Jugenheimer M., Jugjnger TH: Endoscopic subfascial sectioning of incompetent perforating veins in treatment of primary varicosis.  World J Surg, 1992; 16: 971-975.

Jungbeck C, Thulin I, Darenheim C, Norgren L.: Graduated compression treatment in patients with chronic venous insufficiency: a study comparing low and medium grade compression stocking. Phlebology 1997, 12, 142-145

Jünger M., Jünger I., Rahmel B., Rassner G.: Physical exercise training as terapia of chronic venous incompetence. In: Raymond-Martinbeau P., Prescott R., Zummo M. (Eds), Phlebologie 92, John Libbey Eurotext, 1992; 947

Kistner R.L.: Venous Valve Surgery. An Otherview. In: Raju S., Villaviciencio J.L. Surgical Management of Venous Disease. Baltimora. Williams & Wilkins 1997: 306-24.

Klyscz T., Junger M., Schanz S., et Al. Quality of life with chronic venous insufficiency. Results of a study using the newly developed Tubingen questionnaire for measuring quality of life in  patinets with CVI (TLQ-CVI). Hantarzt, 1998, 49, 371-81.

Labropoulos N et al. Superficial venous insufficiency : correlation of anatomic extent of reflux with clinical symptoms and signs J. Vasc. Surg. 1994; 20: 953-958.

Labropoulos N, Touloupakis E, Giannoukas AD et al: Recurrent varicose veins: investigation of the pattern and extent of reflux  with color flow duplex scanning. Surgery, 1996; 119(4): 406-409

Labropoulos N: CEAP in clinical practice. Vasc Surg 1997; 31: 224-225

Lacroix P.: Thermalisme et médecine vasculaire. Encycl Méd Chir. (Elsevier, Paris), Angéiologie, 13-3700,1997, 4 p.

Lamping D.L.: Measuring Health-Related Quality of Life in Venous Disease: Practical and Scientific Considerations. Angiology, 48, 51-7, 1997.

Langeron P: Une classification qui se discute. Acta Vasc Int, 1996; 38: 43

Lapilli A., Zendron R., Miccoli B. et Al.: Principi di fisiologia e di idrodinamica nella riabilitazione in acqua del paziente vasculopatico.Giorn. di Riabilit., 1988; 4: 273

Larson RH, Lofgren EP, Myers TT, Lofgren KA: Long term results after vein surgery: study of 1000 cases after 10 years. Mayo Clin Proc 1974;  49: 114-117

Launois R. :  At the crossroads of venous insufficiency and hemorrhoidal disease: Daflon 500 mg - repercussions of venous insufficiency on everyday life. Angiology, 1994, 45 (6 part 2), 495-504.

Launois R., Reboul-Marty J., Henry B.: Construction et validation d’un indicateur spécifique de qualité de vie: Le cas de l’insuffisance veineuse chronique des membres inférieurs. J.Economie Médicale 12:109-126.1994.

Laurikka J, Sisto T, Auvinen O et al: Varicose veins in a Finnish population aged 40-60. J Epidemiol Community Health, 1993; 47: 355-7.

Layton AM., Ibbotson SH., Davies JA., Goodfield MJ. :  Randomised trial of aspirin from chronic venous leg ulcers. Lancet 1994; 344: 164-5.

Leach RD.:  Venous ulceration, fibrinogen and fibrinolysis. Ann R Coll Surg Eng 1984; 66: 258-63.

Leduc A.: Le drainage lymphatique manuel. Thèorie et pratique. Paris, Masson Ed., 1978

Leipziger LS, Glushko V, Di Bernardo B, Shafaie F, Noble J, Nichols J, Alvarez OM. Dermal wound repair: role of collagen matrix implant and synthetic polymer dressings. J Am Acad Dermat 1985; 12:409-419.

Leu A.J., Leu H.J., Franzeck U.K., Bollinger A. :  Microvascular changes in chronic venous insufficiency. A Review. Cardiovasc. Surg., 1995, 3, 237-45.

Li AK: A tecnique for re-exploration of the saphenophemoral junction for recurrent varicose veins. Br J Surg, 1975; 62(9): 745-6.

Lofgren EP, Lofgren KA: Recurrence of varicose veins after stripping. Arch Surg, 1971; 102: 111

Lofgren K.A., Lauvstad W.A., Bonnemaison M.F.E.: Surgical treatment of large stasis ulcer: review of 129 cases. Mayo Clin. Proc. 1965; 40: 560-3.

Lofgren KA, Ribisi AP, Myers TT: An evaluation of stripping versus high ligation for varicose veins. Arch Surg 1958; 76: 310.

Loose D.A. ed.   Congenital vascular defects.   Intern.Angiol. , 1990 ,9,n.3,133-224.

Lorenzi G, Bavera P, Cipolat L, Carlesi R: The prevalence of primary varicose veins among workers of a metal and steel factory. In Negus D, Jantet G: Phlebology ’85. London. John Libbey e C. 1986: 18-21.

Malan E. ed.    Vascular malformations (Angiodysplasias).   Carlo Erba Foundation , Milano 1974

Mancini S, Botta G, Mariani F, Mancini S.: External valvuloplasty of the long saphenous vein. Personal series. Scope on Phleb/Lymph ,1997; 4, n° 1: 12-4

Mancini S.: La terapia delle ulcere venose degli arti inferiori. Ed Grafica Sturli, 1990

Mann RJ: A double blind trial of oral O(b-hydroxyethyl)-rutosides for stasis leg ulcers. The British Journal of Clinical Practice, 1981; 35: 79-81

Mariani F, Binaghi F, Pitzus F. Scleroterapia. Testo Atlante. Torino, Edizioni Minerva Medica, 1996.

Markwardt F.:  Pharmacology of oedema protective drugs. Phlebology 1996; 11: 10-15.

Marques da Costa R., Jesus F.M., Aniceto C. et al.: Double-blind randomized placebo-controlled study of granulocyte-macrophage colony- stimulating factor in chronic leg ulcers. Am. J. Surg. 1997; 173: 165-8.

Marques SJ: varices post-stripping de la saphene interne. Etude stereophlebographique. Phlebologie, 1987; 40(4): 889-97

Mascherpa P. :  Farmaci del sistema venoso. Gazzetta Sanitaria, 1939, XVIII, 3-5.

Masuda EM, Kistner RL: Long-term results of venous valve reconstruction:
a four-to twenty-one-year follow-up.
J Vasc Surg 1994; 19: 391-403.

Mayo C: Treatment of varicose veins. Surg Gynec Obst, 1906; 2: 385-8.

McMullin GM, Coleridge-Smith, PD, Scurr JH.: Objective assesment of high ligation without stripping the long saphenous vein. Br J Surg ,1991; 78: 1139-42

Merlen J.F. :  Rutines et troxerutine. John Libbey Eurotext, London, 1985.

Meyers K.A. et al. Duplex ultrasonography scanning for chronic venous disease : Patterns of venous reflux. J Vasc. Surg. 1995; 2: 605-612.

Moffatt C.: Prevention of venous ulcer recurrence. Scope on Phlebology and Lymphology. 1997, 4, 10-15

Moffatt C.J., Franks P.J., Oldroyd M. et al.: Community clinics for leg ulcers and impact on healing. BMJ 1992; 305: 1389-92.

Moneta et al.: Nonoperative Management of Venous Leg Ulcers: Evolving Role of Skin Substitutes. Skin Substitutes Consensus Development Panel. Vasc. Surg. 1999; 33: 197-210.

Monfreux A: Traitement sclérosant des troncs saphéniens et leurs collatérales de gros calibre par la méthode MUS. Phlébologie, 1997;50:351-3.

Muller R: Traitment des varices par phlébectomies ambulatoires. Phlébologie, 1966; 19: 227-9.

Munn SR, Morton JB, Macbeth VAAG, McLeish AR.: To strip or not to strip the long saphenous vein? A varicose vein trial. Br J Surg, 1981; 68: 426-8

Myers TT: Results and technique of stripping operation for varicose veins. JAMA, 1957 ; 163: 87-92.

Neglén P, Einarsson E, Eklöf B: High tie with sclerotherapy for saphenous vein insufficiency. Phlebology, 1986; 1:105-111.

Neglen P, Einarsson E, Eklot B.: The functional long term value of different types of treatment for saphenous vein incompetence. J Cadiovasc Surg (Torino), 1993; 34: 295-301

Neglen P,Seshadri R: A comparison between descending phlebography and duplex doppler investigation in the evalutation of reflux in chronic venous insufficiency: a challenge to phlebography as the "gold standard ". J Vasc Surg, 1992; 16: 687-93.

Nehler MR, Moneta GL, Woodard DM, et al.: Perimalleolar subcutaneous tissue pressure effects of elastic compression stockings. J Vasc Surg 1993, 18, 783-8

Nelzen O: How Can We Improve Outcomes for Leg Ulcer Patients ? In: Ruckley CV, Fowkes FGR, Bradbury AW eds: Venous disease. London Springer, 1999: 246-53.

Neumann M.H.A.: Compression therapy with medical elastic stockings for venous diseases. Dermatol.Surg. 1998, 24:765-770.

Nicolaides A.N.: Venous disease and phleboterapy. Phlebology, 1992, 7 (Suppl. 2), 1-3.

Nicolaides A.: How Do We Select the Appropriate Tests of Venous Function ? In: Ruckley CV, Fowkes FGR, Bradbury AW eds: Venous disease. London Springer, 1999: 80-8.

Nicolaides A.N. , Sumner D.S.      Investigation of patients with deep vein thrombosis and chronic venous insufficiency . Med - Orion , London , 1991.

Nicolaides AN, Miles C. Photoplethysmography in the assessment of venous insufficiency. J Vasc Surg 1987;5:405-

O’Donnell TF Jr: Chronic venous insufficiency: an overview of epidemiology, classification and anatomic considerations. Seminars Vasc Surg 1988; 1:60-5.

O’Donnell TF: Lessons from the past guide the future: Is history truly circular ? J. Vasc. Surg. 1999; 30: 775-86.

O’Leary DP, Chester JF, Jones SM: Management of Varicose Veins According to Reason for Presentation. Ann R Coll Surg Engl, 1996; 78: 214-6.

Ohgi S., Tanaka K., Maeda T. et Al.: Comparison of Three Exercises for Evaluation of the Calf Muscle Pump. Phlebology, 1995, 10, 23-7

Pagni A. (Editoriale): Il termalismo: una pratica terapeutica da rivalutare? Federazione Medica, 1993; 46: 85

Partsch H. :  Treatment of resistant leg ulcers by retrograde intravenous pressure infusions of urokinase. Phlebology 1991; 6: 13-21.

Partsch H., Kechavarz B, Köhn H., Mostbeck A.: The effect of mobilisation of patients during treatment of thromboembolic disorders with low - molecular - weight heparin. Int. Angiol, 1997, 16, 189-92.

Perrin M, Hiltbrand B, Bayu JM: La reparation valvulaire an niveau du
reseau vein eux profond sous-inguinal Ganget technique on intervention
efficace.
Phlebologie, 1991; 44: 649-60.

Perrin M.: Compression élastique et chirurgie veineuse. Phlébologie, 1994, 47, 58-6.

Pierik Eg, Van Urk H, Wittens CHA.: Efficacy of subfascial endoscopy in eradicating perforating veins of the lower leg and its relation with venous ulcer healing. J Vasc Surg 1997; 26:255-9.

Pierik EG, Van Urk H, Hop WCJ, Wittens CHA: Endoscopic versus open subfascial division of incompetent perforating veins in the treatment of venous leg ulceration: A randomized trial. J Vasc Surg, 1997; 26:1049-54.

Porter JM, Moneta G and International Consensus Committee on Chronic Venous Disease: Reporting standards in venous disease. J Vasc Surg, 1995; 2: 635-45.

Poskitt K.R., James A.H., Lloyd-Davies E.R.V., Walton J. et al.: Pinch skin grafting of porcine dermis in venous ulcers. BMJ 1987; 294: 674-6.

Poynard T., Valterio C. :  Meta-analysis of hydroxyethylrutosides in the treatment of chronic venous insufficiency. Vasa, 1994, 23, 244-50.

Proposta di regolamentazione degli interventi chirurgici e delle procedure interventistiche diagnostiche e/o terapeutiche da effettuare in regime di assistenza chirurgica a ciclo diurno. Rivista di studi e ricerche sui servizi sanitari della Agenzia per i Servizi Sanitari Regionali 1997; 1, 4: 85-105

Raj T.B. e Makin G.S. A random controlled trial of two forms of compression bandaging in outpatient sclerotherapy of varicose veins. J.Surg.Res. 1981, 31, 440.

Raj T.B., Goddard M. e Makin G.S. How long do compression bandages maintain their pressure during ambulatory treatment of varicose veins ? Br.J.Surg. 1980, 67, 122-4.

Raju S, Fredericks RK, Neglen PN, Bass JD: Durability of venous valve
reconstruction techniques for “primary” and post-thrombotic reflux.
J Vasc
Surg, 1996; 23: 357-67.

Raju S., Neglèn P.,Doolitle B.S. et Al    Axillary vein transfer in trabeculated post thrombotic veins .J Vasc Surg, 1999; 29: 1050-64.

Rivlin S: The surgical cure of primary varicose veins. Br J Surg., 1975; 62: 913-7.

Robbins M, Frankel S, Nauchahal K et al: Research programme on epidemiologically based needs assessment. Report 9: Varicose vein treatments. Commissioned by the NHS Management Executive, 1992.

Rothe M.J., Falanga V.: Growth factors and wound healing. Clin. Dermatol. 1992; 9: 553-9.

Royle J.P, Eisner R, Fell G: The sapheno-femoral junction. Surg Gyn Obst, 1981; 152:  282-284

Ruckley C.V.: Can we help the postphlebitic limb ? In: Greenhalgh R.M., Jamieson C.W., Nicolaides A.N. Eds. Vascular Surgery: issues in current practice. Orlando. Grune & Stratton 1996: 409-16.

Ruckley CV: Socioeconomic Impact of Chronic venous Insufficiency and Leg Ulcers. Angiology, 1997; 48: 67-9.

Rudofsky G. :  Intravenous prostagladin E1 in the treatment of venous ulcers - a double-blind, placebo-controlled trial. Vasa 1989; 28  Suppl.,  39-43.

Rutgers PH, Kistlaar PJEHM.: Randomized trial of stripping versus high ligation combined with scleroterapy in the treatment of the incompetent greater saphenous vein. Am J Surg, 1994; 168: 311-5

Rutherford RB, Sawyer JD, Jones DN,: The fate of residual saphenous vein after partial removal or ligation. J Vasc Surg, 1990; 12: 426-8.

Rutherford RB: The CEAP classification system and assesing outcome. Vasc Surg, 1997; 31: 221-22

Sarin S, Scurr JH, Coleridge-Smith PD.: Stripping of the long saphenous vein in the treatment of primary varicose veins. Br J Surg 1994; 81: 1455-8

Sarin S. Scurr JH, Coleridge Smith PD. Medial calf perforators in venous insufficiency : correlation of outward flow. J Vasc Surg  1992, 16: 40-46.

Schadeck M, Allaert FA: Résultats à long terme de la sclérotherapie des saphénes internes. Phlébologie 1997;50:257-62.

Schmeller W., Roszinski S.: Shave-Therapie zur operativen Behandlung persistierender venöser Ulzera mit großflächiger Dermatoliposklerose. Hautarzt 1996; 47: 676-81.

Schultz-Ehrenburg U, Tourbier H: Doppler-kontrollierte verödungs Behandlung der Vena saphena magna. Phlebol Proktol 1984;13:117-22.

Schultz-Ehrenburg U: Sclerotherapy of the Popliteal Junction in Primary Varicose Veins. J Dermatol Surg Oncol 1992;18:61 (Abstr).

Scott T, Lamorte W, Gorin D et al: Risk factors for chronic venous insufficiency: a dual case-control study. J Vasc Surg, 1995; 22: 622-8.

Scriven JM, Hartshorne T, Bell PRF, Naylor AR, London NJ. Single-visit venous ulcer assessment clinic: the first year. Br J Surg 1997; 84:334-6.

Sigg K: Varizen Ulcus cruris und Thrombose. Berlin, Springer Verlag, 1976.

Simon D.A., Freak L., Kinsella A. et al.: Community leg ulcer clinics: a comparative study in two health authorities. BMJ 1996; 312: 1648-51

Solomon MJ., McLeod R.S.: Should we be performing more randomized controlled trials evaluating surgical operations? Surgery, 1995, 118, 459-67.

Stacey MC, Burnand KG, Layer GT, Pattison M. :  Transcutaneous oxygen tensions in  assessing the treatment of healed venous ulcers. Br J Surg 1990; 77:1050-1054.

Stegmann W, Hubner K, Deichmann B, Muller B: Efficacy of O(b-hydroxyetyl)-rutosides in th e treatment of venous varicose ulcer. Therapiewoche, 1986; 36: 1828-1833.

Stemmer R. Teoria e pratica del trattamento elasto-compressivo, in Chirurgia Vascolare di Belardi P., Ed. Minerva Medica, Torino (I) 1995.

Stewart A.L., Ware J.E. Jr., eds: Measuring Functioning and Well-Being: The Medical Outcomes Study Approach. Durham, N.C.: Duke University-Press, 1992.

Stockport J.C., Groarke L., Ellison D.A. et al.: Single-layer and multi-layer bandages in the treatment of venous leg ulcers: comparison of sub-bandage pressures. In: Proceedings of theEMWA/Journal of Wound Care Spring Meeting. New Approaches to the Management of Chronic Wounds. Milan, 27-29 April 1997: 58-62.

Struckman J, Mathiesen F. A non-invasive plethysmographic method for evaluation of the musculovenous pump in the lower extremities. Acta Chir Scand 1985;151:235-40.

The Alexander House Group. Consensus paper on venous leg ulcer. Phlebology, 1992; 7: 48-58.

Thomas PRS, Nash GB, Dormandy JA. :  White cell accumulation in dependent legs of patients with venous hypertension: a possible mechanism for trophic changes in the skin. Br Med J 1988; 296:1693-5.

Thomson D.: Drainage lymphatique manuel et insuffisance veineuse chronique. Kinesither. Sci., 1994, 330, 13-6

Tong Y, RoyleJ: Recurrent varicose veins following high ligation of long saphenous vein: a duplex ultrasound study. Cardiovasc Surg, 1995; 3(5): 485-7

Tournay R:Terapia sclerosante delle varici. Milano, Raffaello Cortina Editore, 1984.

Travers J.P., Makin G.S.: Reduction of varicose veins recurrence by use of postoperative compression stockings. Phlebology 1994; 9: 104-7.

Van Bemmelen PS, Bedford G, Beach K, Strandness DE: Quantitative segmental evaluation of venous valvular reflux and duplex ultrasound scanning. J Vasc Surg, 1989; 10: 425-31.

Van Der Molen H.R. L'atrophie blanche clinique et expérimentale. Phlébologie 1986, 39(3), 607-16.

Van Der Molen H.R. The choice of compressive methode in phlebology. Phlébologie 1982, 35(1), 73-99.

Van Der Stricht J : Saphénectomie par invagination sur fil. La presse médicale, 1963 ;  21: 1081-2.

Van Rij AM, Jiang P, Solomon C et al:  A prospective study of varicose vein surgery with air plethysmography and duplex scanning. XIII World Congress of Phlebology. Sydney, 1998; Abst. Book, 46.

Vanhouttr P.M.:  Return circulation and norepinephrine : an update. John Libbey Eurotext, Paris, 1991, 31-42.

Veraart J.C.J.M. Clinical aspects of compression therapy. Unigraphic, Universiteit Maastricht, Nederland 1997.

Vercellio G. ed.      Angiomi e malformazioni vascolari . EDSAI , Ferrara , 1999.

Vin F., Chabanel A., Taccoen A., et Al :  Double blind trial of the efficacity of troxerutin in chronic venous insufficiency. Phlebology 1994; 9 : 71-76.

Vin F: Controle d’efficacité des traitements sclérosants en phlébologie. Phlébologie 1990;43:673-80.

Viñas F.: Drenaggio linfatico manuale. Como, Les Nouvelles esthetiques Red. Ed., 1993

Vodder E.: Le drainage lymphatique, une nouvelle methode therapeutique. Revue d’hygiène individuelle. Paris, Santé pour tous, 1936

Wadworth A.N., Faulds D.:  Hydroxyethylrutosides a review of  its pharmacology, and therapeutic efficacy in venous insufficiency and related disorders.Drugs 1992; 44 : 1013-32.

Walsh JC, Bergan JJ Beaman S: Femoral venous reflux abolished by greater
saphenous stripping.
Ann Vasc Surg, 1994; 8: 566-70.

Ware J.E Jr., Kosinski M.A., Keller S.D.: SF-36 Physical and Mental Component Summary Measures: A User’s Manual. Boston: The Health Institute, New England Medical Center, 1994.

Weiss RA, Sadick NS, Goldman MP, Weiss MA: Post-Sclerotherapy Compression: Controlled Comparative Study of Duration of Compression and its Effects on Clinical Outcome. Dermatol Surg 1999;25:105-8.

Weiss RA, Weiss MA: Resolution of pain associated with varicose and teleangiectatic leg veins after compression sclerotherapy.  J Dermatol Oncol, 1990; 16: 333-6.

Weiss VJ, Surowiec SM, Lumsden MB: Surgical Management of Chronic Venous Insufficiency. Ann Vasc Surg, 1988; 12(5): 504-8.

Weitgasser H.:  The use of pentoxifylline (Trental 400) in the treatment of leg ulcers: results of a double-blind trial. Pharmatherapeutica 1983; 3 (Suppl 1): 143-51.

Welch HJ, Faliakou EC, Mc Laughlin RL, et al : Comparison of descending  phlebograpy with quantitative photoplethysmography, air plethysmography and duplex quantitative valve closure time in assessing deep venous reflux. J Vasc Surg, 1992; 16:  913-20.

Wells P.S.,Lensing A.W.A., Hirsh J.: Graduated compression stockings in the prevention of postoperative venous thromboembolism: a meta - analysis. Arch.Intern.Med.,1994,154,67-72.

Wenner A, Leu HJ, Spycher M, Brunner U :  Ultrastructural changes of capillaries in chronic venous insufficiency. Exp Cell Biol 1980; 48:1-14.

Whiteley MS, Smith JJ; Galland RB. Subfascial endoscopic perforator vein surgery (SEPS): current pratice among British surgeons. Ann R Coll Surg Engl, 1998; 80(2): 104-7

Widmer L, Biland L, Barras JP,:  Doxium 500 in chronic venous insufficiency: a double blind placebo. Controlled multicentre study. Int. Angiol. 1990; 9:105-10.

Widmer LD: Peripheral venous disorders-prevalence and socio-medical importance. Berna. Hans Huber 1978.

Wienert V, Willer H: Epidemiologia delle malattie venose. Faenza. C.E.L.I. Ed. 1992.

Woddyer AB, Dormandy JA.: Is it necessary to strip the long saphenous vein? Phlebology, 1986; 1: 221-4

Wolfe JHN, Morland M, Browse NL. :  The fibrinolytic activity of varicose veins. Br J Surg 1979; 66: 185-7.

Zamboni P, Feo CV, MarcellinoMG et al.: Haemodinamic correction of varicose veins (CHIVA): An effective treatment? Phlebology, 1996; 11: 98-101

Zaragoza Garcia F., Domingues Rodrigues J. C. : Mechanism of action of the venotonic drugs. Scope on Phlebol-Lymphol, 1998, 5, 16-20.

Zimmet SE: Leg ulcers. J Am Acad Derm 1992;27:487-8.

Zuccarelli F., Ducros JJ., Egal G., et al :  Efficacité clinique du Veinotonyl 75 dans l'insuffisance veineuse des membres inférieurs. Arteres Veines 1993; 12: 375-9.

 

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