THERAPEUTIC ASPECTS OF VENOUS DISEASE

P D Coleridge-Smith, Department of Surgery, University College London Medical School, The Middlesex Hospital, London W1N 8AA.

Contents

INTRODUCTION
Epidemiological studies indicate that about 20% of the adult population are affected by venous disease of the lower limb (10 million people in the United Kingdom). The most common problem, varicose veins, affects three times more women than men. Chronic venous insufficiency and venous ulceration affects at least 1% of the population (500 000 patients in the United Kingdom), with greatly increased prevalence in patients over the age of 65 years. This compares with 10 000 patients per year who present with critical ischaemia of the lower limb to the health services of the UK with critical ischaemia of the lower limb. Much of vascular surgery is built on this relatively small number of patients who may cost £50 millions to treat. In comparison the Health Service invests at least £400 millions per annum in treating patients with leg ulcers (Bosanquet N, 1992). Yet up to 50% of such patients may have surgically treatable incompetence in the superficial venous system (Sarin S, 1992). Patients with valvular incompetence of the deep venous system, especially those with post-thrombotic vein damage, present a more difficult surgical problem. Many operations have been described, but restorative surgery of the deep veins remains largely experimental and applicable to only a very small section of the population of patients with chronic venous insufficiency.

Technological advances, in particular, colour duplex ultrasound imaging now offers improved diagnostic accuracy in patients with disease without recourse to venography. This method allows a better understanding of both the anatomy and physiology.

ASSESSMENT OF PATIENTS WITH VARICOSE VEINS
Investigation of venous function
Proper pre-operative assessment is essential in designing an appropriate treatment for a patient with venous disease. Patients with uncomplicated varicose veins usually need assessment with a hand-held Doppler ultrasound probe. Patients with recurrent varicose veins or any suggestion of skin changes due to venous hypertension should undergo functional tests of the venous system using plethysmographic methods and duplex ultrasound imaging.

Methods of investigation
Until recently investigation of venous disease has been based on the use of tourniquet tests. These tests have substantial limitations, particularly in those limbs with the most severe symptoms, such as lipodermatosclerosis and ulceration, where it is often difficult to see the superficial veins. The introduction of modern investigation techniques means that it is now possible to investigate the pathophysiology of venous disease with far greater accuracy.

Hand-held Doppler ultrasound
Hand held Doppler ultrasound examination is one of the simplest and cheapest tests to perform (Lewis JD, 1973, McIrvine AJ, 1984). Venous reflux testing is usually performed with the patient standing, in a modification of the Trendelenberg test. The femoral vein and sapheno-femoral junction can be examined by insonating with the Doppler probe and locating the femoral vein lying medial to the femoral artery. Calf compression is applied by hand to produce forward flow which may be detected in the groin. On relaxation of calf compression a search is made for venous reflux. The popliteal fossa can be examined similarly, searching for popliteal or short saphenous vein reflux. Narrow cuffs or tourniquets can be used to compress the superficial veins and assist in the differentiation of superficial from deep venous reflux.

Plethysmographic methods
Many flow-based plethysmographic tests are available for the assessment of venous reflux. They all assess the amount of blood ejected from the calf during exercise and the time taken for the calf to refill afterwards from a combination of arterial inflow and venous reflux, using direct or indirect methods. These tests include air plethysmography (Christopoulos D, 1988), strain gauge plethysmography (Fernandes E, 1979), foot volumetry (Norgren L, 1974) and photoplethysmography (Abramowitz HB, 1979). All provide some functional information about the health of the calf muscle pump and the competence of the valves in the deep and superficial systems of veins.

Duplex ultrasound imaging
Ultrasound imaging allows the precise anatomy of the peripheral vessels to be examined, structures can be identified and precise anatomy defined. Blood within veins often has a hyperechoic pattern after a patient has been lying on the examination bed for a few minutes and this can be used to determine the direction of flow. Veins affected by thrombosis may be identified by their lack of compressibility. Normal veins can be completely flattened by gentle compression with the transducer, but thrombosed vessels resist this manoeuvre.

Duplex ultrasound imaging systems furnish flow data by the addition of a pulsed Doppler facility. This is an invaluable investigation in examination of the venous system. Virtually all veins below the inguinal ligament can be imaged completely by this technique and the competence of individual valves may be assessed. Thrombosis resulting in complete occlusion of vessels may be detected by the absence of flow. Colour flow mapping is now available on many ultrasound imaging systems (Persson AV, 1986, Persson AV, 1988). In these the Doppler shift of each pixel of the ultrasound image in a (user defined) area is determined and converted to a colour of different saturation depending on the velocity of flow. Distinct colours are used for forward and reverse flow so that venous reflux assessment is simplified. Several vessels may be assessed at once for reflux with such a machine. Diagnosis of venous thrombosis is also substantially simplified with such systems.

Diagnosis of venous disease.
How should these investigations be employed in the assessment of patients with venous disease? The case for the use of ultrasound imaging is very strong in patients with suspected deep vein thrombosis (DVT). A skilled operator will detect 95 - 100% of DVTs demonstrated by phlebography in the femoral and popliteal veins (Hobson RW, 1991, Sumner DS, 1991). In the calf veins the sensitivity of this investigation is 80 - 90%. The examination takes about 30 - 45 minutes and may be repeated to assess the efficacy of treatment. Exposure to ionising radiation is avoided.

Patients presenting with primary varicose veins should have the clinical impression confirmed by Doppler ultrasound examination which should include insonation of both sapheno-femoral and sapheno-popliteal junctions. Venous disease is frequently bilateral and clinical examination may fail to identify the site of venous reflux. The diagnosis is readily demonstrated in the majority of cases using a hand-held Doppler probe. It should be possible to control superficial venous reflux by the application of a narrow tourniquet to the limb just below the level of the sapheno-femoral or sapheno-popliteal junction. In cases where there is doubt about the competence or patency of the deep veins duplex ultrasound examination is appropriate.

In patients who present following previous varicose vein surgery, duplex ultrasound imaging provides a simple technique for establishing whether the first operation was effected as intended. This will avoid unnecessary re-exploration of the sapheno-femoral junction or popliteal fossa. In addition, the source of any residual reflux or location of large longitudinal veins may be established.

Patients presenting with skin changes suggestive of chronic venous insufficiency including lipodermatosclerosis, haemosiderosis, eczema or ulceration require proper quantitative assessment of the calf muscle pump by one of the plethysmographic methods described above, to establish the severity of venous disease. Duplex ultrasound examination is the best method to use in establishing the anatomical nature of the venous problem, whether it be the consequence of a previous deep vein thrombosis or the result of simple varicose veins.

For patients undergoing operations on the popliteal fossa, intra-operative venography has been advocated to locate the level of the saphena-popliteal junction (Barabas AP, 1985). It has been shown that pre-operative duplex ultrasound imaging may be used to achieve the same end (Vasdekis SN, 1989), and we have found this effective in many patients treated during the last 5 years. Pre-operative determination of the anatomy of the popliteal fossa is invaluable in procedures to ligate the sapheno-popliteal junction and gastrocnemius veins. Perforating veins and residual sections of the long saphenous vein may also be located easily.

METHODS OF TREATMENT FOR VENOUS DISEASE
Sclerotherapy
Sclerotherapy for varicose veins remains an effective treatment in selected patients when used by trained operators for specific indications. The technique is suitable for the treatment of varices where there is no major superficial reflux from the sapheno-femoral or sapheno-popliteal junction and for treating the remaining or residual veins following a surgical procedure. To achieve good results, careful patient selection and attention to technique are essential.

Sclerotherapy was first described by McPheeters in 1927 (McPheeters HO, 1927) and subsequently by De Takats in 1930 (de Takats G, 1930). Early sclerotherapy often resulted in thrombophlebitis and results were not very satisfactory. Sclerotherapy was popularised by Fegan in the 1950's (Fegan WG, 1963). He observed that the sclerosant was most effective when injected into an empty vein, and devised a method of bandaging to ensure that this was maintained. He also noticed that exercise seemed to help the treatment and avoid complications. There have been many imitators using modified techniques, some reporting poor efficacy of sclerotherapy, others frequent recurrence of varices. Studies by Hobbs suggested that sclerotherapy was associated with a high recurrence rate, and modified the technique to combine it with surgery (Hobbs JT, 1974). Fegan's original description involved the injection of a sclerosant material into the vein, causing total internal destruction and fibrosis. When this is achieved recurrence is unlikely. Injecting the sclerosant into a full vein produces clotting and marked superficial thrombophlebitis with eventual recanalisation and recurrence (Goren G, 1991).

The choice of sclerotherapy agent is perhaps less important than the technique employed. Great care is required to ensure that the injection is given into the lumen of the vein being treated. If a significant quantity of sclerosant is given extravascularly, skin pigmentation, necrosis and ulceration may occur, even if the sclerosant is hypertonic saline (Gallagher PG, 1992). Extravasation along the needle tract rarely causes complications. Following injection, appropriate compression should be applied to the limb. Fegan advised bandaging, although the use of compression stockings is at least as effective (Scurr JH, 1985) and since they maintain compression more effectively than crepe or elastocrepe bandages may be preferable.

Dermal flares are also amenable to sclerotherapy, but under these circumstances, great care should be given to use a very dilute sclerosant solution. Our own preference is for Sclerovein 0.5% (Resinag AG, Hotzestr 28, 8042 Zurich, Switzerland). Injection is best performed through a very fine needle (30 gauge) which, with experience, may be inserted into all but the finest vessels. Compression using bandages or stockings for up to one week is helpful following injection of dermal flares.

Surgical treatment of varicose veins
The principle behind the modern management of varicose vein by surgery involves disconnecting the superficial from the deep system and removing as many of the superficial veins as possible. A flush sapheno-femoral junction ligation should be performed, taking care to make sure there are no remaining tributaries. The superficial femoral vein should be identified with care and exposed for two centimetres above and below the junction. Injury to the superficial femoral vein probably occurs more frequently than is suspected. The actual number of incidents is unknown, but our own experience in assessing patients referred from other centres with problems in the post-surgical period, leads us to believe that it is not uncommon. The Medical Defence Union have advised us that 11 cases of litigation ensued in 1989 following surgical treatment of venous disorders (MDU, personal communication). Since the introduction of Crown Indemnity, data on medical litigation does not appear to be available (from the OPCS).

The debate as to whether or not to strip or leave the long saphenous vein continues. The advantage of leaving the long saphenous vein to provide a conduit for vascular reconstructive surgery at a later date has been advanced. The majority of veins, however, are unsuitable as arterial bypass grafts. In recent studies, McMullin (McMullin GM, 1991) and Sarin (Sarin S, 1992) have shown that leaving the long saphenous vein is associated with a very high incidence of persisting reflux. There is now good evidence to suggest that the long saphenous vein should be removed.

Apart from incisions in the groin and an incision behind the knee in those patients with sapheno-popliteal junction incompetence, all other surgical procedures on the leg can be carried out through incisions no greater than 2 mm in length (Rivlin S, 1975). The long saphenous vein should be stripped to just below the knee. Stripping to the ankle is associated with an unacceptably high level of saphenous nerve injury (Cox SJ, 1974). If the stripper is passed from the groin down the long saphenous vein, the end can be extracted through a 2 mm stab incision in the upper calf. The vein is then stripped down to this incision, the vein removed through the stab incision and the stripper then recovered by pulling it back up through the track of the long saphenous vein and delivering the head in the groin. To do this a tie is placed around the stripper head before it is pulled through the leg. The remaining superficial veins are removed through 2 mm stab incisions. Varicosities can be picked up using an Oesch or Muller hook through incisions of this size. The veins are sometimes extremely tough, particularly in male patients. Under these circumstances, a micro-Halstead, a fine artery forceps with teeth, gets a better grip. Once the vein is teased to the surface the vein is gently pulled, by a combination of traction and rotation, using a large clip so as not to cut through the vein. Usually a significant length can be delivered through the wound and in some patients, it is possible to deliver many centimetres of vein by this technique. The stab incisions are placed directly over the varices and the distance between adjacent incisions will depend on the amount of vein removed. We aim to remove as many of the varicose superficial veins as possible.

Following this procedure, compression is applied to the leg using a heavy elastic compression stocking. Stockings producing approximately 30 mm Hg (class 3 compression) are routinely used (Coleridge Smith PD, 1987). After surgery, the patient should elevate the lower limbs for 12 hours to reduce haematoma formation and ensure haemostasis. Regular ambulation should be encouraged to aid return of mobility. When the patient is not walking, he should rest with the legs elevated and avoid standing at all times. The stocking is applied for 10 days, but can be removed at any stage to allow the patient to shower and to wash the stocking. All patients should then be reviewed at 6 weeks to assess the final result and arrange any sclerotherapy for residual veins, or dermal flares if they persist.

Surgery for perforating veins
The presence of incompetent perforating veins in close approximation to venous ulcers had been noted by Homans (Homans J, 1917). Turner Warwick also described incompetence of perforating veins in his extensive cadaveric dissections in 1931 (Turner Warwick W, 1931). He postulated that on contraction of the calf muscle, blood was squeezed at high pressure from the deep veins to the superficial veins through these incompetent veins causing the skin changes and subsequent ulceration. He described the "bleed back" test at operation to determine whether perforating veins were competent or not.

In 1938 Linton described incompetence of "communicating" veins between the saphenous and deep venous systems found at operation in a series of 50 patients (Linton R, 1938). He recommended the ligation of these incompetent veins at their origin beneath the deep fascia and described three long incisions down the leg, medial, antero-lateral and postero-lateral, for adequate exposure. This was combined with ligation of the saphenous veins if they were incompetent and, in a proportion of patients with deep vein reflux, he performed ligation of the superficial femoral vein. In 1953 after a 10 year follow up he reported a 55% ulcer recurrence rate following ligation of the communicating veins and a 60% recurrence rate after concomitant ligation of the superficial femoral vein (Linton R, 1953).

Cockett described the large medial calf perforating veins and their association with overlying varicosities and ulceration (Cockett FB, 1953) and placed considerable emphasis on the treatment of venous ulcers by ligation of these vessels. The causal association deduced by Cockett is not obvious to the objective observer. Since the efficacy of perforator ligation in healing ulcers was not rigorously tested by him in a clinical trial his assertions must be treated with care. Subsequent investigation of this problem has resulted in mixed findings, with some papers reporting efficacy of perforator ligation in preventing ulcer recurrence (Negus D, 1985). Browse and Burnand have assessed the results of established venous surgical procedures by means of pre- and post-operative venous pressure measurements. They showed that ambulatory venous pressure measurements were improved in limbs with superficial vein incompetence when the incompetent veins were excised. Where there was deep vein incompetence or perforating vein incompetence, venous pressures were not improved by ligation of superficial and perforating veins (Burnand KG, 1977). This was corroborated by a clinical study in which a series of 41 patients with venous ulcers underwent ligation of perforating veins. Those limbs with venographic evidence of deep vein damage all suffered recurrence of ulceration whereas only one of the limbs with normal deep veins re-ulcerated post operatively (Burnand KG, 1976). A recent study using functional methods of assessment found it necessary to include local deep vein incompetence in the calf as well as calf perforator incompetence in their model of pathogenesis (Zukowski AJ, 1991). The precise role of calf perforating veins in the pathogenesis of varicose veins and venous ulceration remains to be fully elucidated. Our own work suggests that the direction of blood flow in these vessels is highly dependent on disease in other veins (McMullin GM, 1991) with inward or outward flow observed depending on the perturbation of blood flow in other vessels.

On the basis of our current information, there can be little justification for extensive subfascial ligation procedures. In those patients where a perforating vein may be contributing significantly, accurate localisation using duplex ultrasound imaging, followed by local ligation or avulsion, produces a very satisfactory result without the disadvantages of extensive incisions.

PHARMACOLOGICAL TREATMENTS
Pharmacological treatments are widely employed for the treatment of venous disease in a number of southern European countries. Many of the symptoms of varicose veins are mitigated by the use of drugs such as hydroxyethyl rutosides and flavonoids, derived from plants. These drugs are used to a very limited extent in northern European countries.

In patients with venous ulceration there has been a search from drugs which aid the healing process.

Pharmacological treatment in venous ulceration
Although bandaging and stockings have been used effectively in the treatment of chronic venous insufficiency for many years, modern pharmacological science may provide additional assistance in healing venous ulcers. Enhancing fibrinolysis has been attempted to promote removal of the fibrin cuff. Stanozolol is an anabolic steroid which enhances fibrinolysis and promotes the removal of fibrin cuffs (Browse NL, 1977) as well as reducing the area of liposclerotic skin when used with compression stockings (McMullin GM, 1991). Treatment of patients with this drug for a period of 6 months did not result in any improvement in venous ulcer healing (Layer GT, 1986).

Drugs which reduce white cell activation may be useful in healing venous ulcers, assuming that this mechanism is important in the perpetuation of ulceration. Pentoxifylline (Trental, Hoechst AG, Germany), has already been evaluated in this respect. This drug reduces the likelihood of white cell activation by an effect which appears to be independent of other known activators of neutrophils such as TNF*, resulting in much lower likelihood of endothelial adhesion (Sullivan GW, 1988). In a multi-centre study in which 82 patients were entered, pentoxifylline has been shown to result in much better healing rates of ulcers than placebo (Colgan MP, 1990). It has been recommended that this drug may be useful for the treatment of resistant ulcers (Anon. 1991). Prostaglandin E1 inhibits the respiratory burst of neutrophils, preventing the release of superoxide radicals. A preliminary study has suggested that this too is effective in healing venous ulcers (Rudovsky G, 1989). Other pharmacological treatment strategies are possible and await evaluation. We think that adjuvant pharmacological treatment will eventually become commonplace in the management of venous ulceration and will be used alongside compression modalities.

DEVELOPMENT OF NEW TREATMENTS FOR VENOUS DISEASE
A better understanding of the mechanisms which lead to the development of venous disease will help on the development of new treatments for this problem.

Venous ulceration is caused by the inability to reduce venous pressure in the superficial veins of the calf during walking (Pollack AA, 1949). The mechanisms which lead from this to the development of ulceration are not yet fully elucidated. A number of theories has been advanced to explain the pathogenesis of venous ulceration.

Recent studies have implicated leucocytes in the pathological process leading to ulceration. The phenomenon of white cell trapping in the lower limb was first noticed by Moyses (Moyses C, 1987) in control subjects in whom the lower limb venous pressure was raised for an extended period (40 minutes). Increased venous pressure resulted in a rise in red cell count, but not white cell count in blood taken from the long saphenous vein at the ankle, implying that some white cells had become 'lost' or 'trapped' in the peripheral circulation. Moyses suggested that this might be part of the mechanism resulting in skin injury in patients with chronic venous insufficiency. Subsequently Thomas showed that patients with venous disease resulting in ulceration in the lower limb trapped more white blood cells than control subjects when the venous pressure was raised (Thomas PRS, 1988). At the same time we had undertaken capillary microscopy studies which suggested that raised venous pressure resulted in a reduction in the number of visible capillary loops in the skin of patients with venous disease. Combining this with the work of Thomas we suggested that the trapped white cells might result in tissue damage by causing capillary occlusion during periods of venous hypertension (Coleridge Smith PD, 1988). In keeping with Moyses suggestions, we indicated that the capillaries occluded by white cells would not provide an oxygen supply to the tissues, explaining the reduced transcutaneous oxygen readings seen in liposclerotic skin by many authors. In addition, we suggested that the inflammatory mechanisms mediated by white cells may be important in hastening skin destruction. The effects of neutrophils and monocytes which are important in the pathology of critical ischaemia (Dormandy JA, 1990), which can be abolished in animal experiments by rendering the animal neutropaenic before an ischaemic insult (Romson JL, 1983). It seems now that the powerful destructive mechanisms of phagocytes (neutrophils, monocytes, macrophages) have a much greater role than previously suggested (fig. 1).

What are the actual mechanisms of skin damage? We originally suggested that free radical injury might occur (Fig 2), in a manner analogous to that in critical ischaemia. This is difficult to investigate, but assessment of thromboxane A2 and neutrophil free radical production has been undertaken in the blood from lower limb veins. A period of venous hypertension in patients with chronic venous insufficiency (CVI) resulted in an increase in the levels of these, which did not occur in control subjects (Edwards AT, 1992). In our own laboratory it has been found that patients with all classes of venous disease, from varicose veins to active venous ulceration, have higher serum neutrophil elastase levels, measured by radio-immunoassay, than subjects without venous disease (unpublished observations). These data suggest that neutrophil activation may be responsible for at least part of the final manifestations of venous disease.

There new treatments to promote healing of venous ulcers may be directed towards reducing white cell adhesion to the endothelium, preventing neutrophil activation and scavenging free radicals released by activated neutrophils. Many drugs are currently under investigation that might be suitable for the treatment of venous disease.

CONCLUSION
Improvements in methods of diagnosis, particularly duplex ultrasound imaging, permit better planning of treatment for patients with venous diseases of the lower limb. Reliable information may be obtained on the state of venous competence and patency of all lower limb veins. A better clinical outcome will be achieved, particularly in patients with chronic venous insufficiency, when all sources of venous reflux have been controlled. Combined with surgery through small sized incisions more aesthetic results will be achieved in patients with varicose veins.

Figure legends:
1. White cell mechanisms suggested to be important in the production of venous ulcers. Potential interactions between neutrophils, monocytes and endothelium are shown in this diagram.
2. Mechanisms suggested the result in venous ulceration, redrawn from Coleridge Smith (1988)
3. White cell adhesion to endothelium is favoured by low flow rates which occur during venous hypertension.
4. Adherent white cells may release oxygen free radicals and proteolytic enzymes which might be the cause of endothelial damage.
5. The granules of neutrophils contain a number of enzymes, used as host defences. These may be measured in the plasma to assess the amount of neutrophil activation. We have studied both elastase and lactoferrin in the blood of patients with venous disease.
6. Capillary changes in the skin of patients with lipodermatosclerotic skin changes. Endothelial activation is seen with expression of adhesion molecules. A peri-capillary fibrin cuff may be observed, as well as infiltration with white T-lymphocytes and macrophages around the capillaries.
7. Results of measuring plasma elastase and lactoferrin in the arm blood in patients with venous disease (all types from varicose veins to active ulceration) and age-matched control subjects. Both measurements show increased neutrophil degranulation in venous disease.
8. Data from figure 7 divided to show results of plasma elastase measurement in patients with varicose veins (VVs), lipodermatosclerosis (LDS) and active venous ulceration (Ulcer). Increased neutrophil degranulation is seen in each group.
9. Data from figure 7 divided to show results of plasma lactoferrin measurement in patients with varicose veins (VVs), lipodermatosclerosis (LDS), healed ulceration (Healed ulcer) and active venous ulceration (Active ulcer).

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