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Research and clinical issues in chronic venous disease
PII: S0967-2109(97)00025-2
Cardiovascular Surgery, Vol. 5, No. 4, pp. 343–349, 1997 1997 The International Society for Cardiovascular Surgery Published by Elsevier Science Ltd. Printed in Great Britain 0967–2109/97 $17.00 + 0.00
VASCULAR REVIEW Research and clinical issues in chronic venous disease J. J. Ricotta*, M. C. Dalsing†, K. Ouriel‡, T. W. Wakefield§ and T. G. Lynch储 *SUNY at Buffalo, USA and †University of Indiana, USA and ‡University of Rochester School of Medicine, USA and §University of Michigan, USA and 储University of Nebraska, USA The purpose of this study was to summarize the current issues in chronic venous disease by reviewing of the literature relating to the condition. The review was conducted by members of the Committee on Research of the American Venous Forum and includes the Committee’s venous disease and current/future directions. Progress in the understanding and management of chronic venous problems has lagged behind that in arterial disease, despite the large number of patients affected. The complex pathophysiology of venous problems, lack of accepted evaluation standards and lack of prosthetic conduits are some of the factors which contribute to this. New information in these areas has laid the foundation for advances in both operations and non-operative therapy. In conclusion, many opportunities for clinical and basic research in the area of chronic venous disease are available. Application of basic science techniques, including those of molecular biology, will lead to new insights into pathophysiology of chronic venous syndrome. Developments in technology, classification and basic science suggest multiple new potentials therapeutic approaches in the next decade. 1997 The International Society for Cardiovascular Surgery Keywords: chronic venous disease, pathophysiology, venous anatomy, microcirculation, diagnosis
Chronic venous disease is perhaps the most common problem encountered in vascular medicine. It is estimated that 1–3% of adults will develop a chronic venous insufficiency and about 1.5% will experience a venous stasis ulcer during their lives [1, 2]. The economic impact of venous disease on medical cost and lost productivity is significant. Despite these facts, relatively slow progress has been made over the past three decades in the management of chronic venous problems, in comparison with the developments in therapy for arterial disease. A contrast between venous and arterial problems may serve to highlight reasons for this phenomenon. Signs of venous disease are subtle and often remain symptomless, or mildly symptomatic, for long periods of time. Consequently, its early manifestations are often overlooked by both patient and physician. When they become clinically manifest, the disease is
Correspondence to: Dr J. J. Ricotta, Department of Surgery, Millard Fillmore Hospital, 3 Gates Circle, Buffalo, NY 14209, USA
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often multifocal. The presence of superficial, deep and communicating veins makes the evaluation and quantification of venous pathophysiology complex. At present, there are no universally accepted standards for the anatomic or physiologic evaluation of venous problems, analogous to segmental arterial pressures. This deficiency makes it difficult to compare series of patients or objectively evaluate different therapies. Clinical venous problems evolve from and are related to complex interactions of venous obstruction and reflux; in contrast to the overwhelming obstructive nature of arterial problems. In addition, there are distinct microcirculatory changes which may play an equal or more significant role than macrocirculatory disturbances in the genesis of chronic venous insufficiency’s most serious manifestation, venous ulcers. Finally, chronic venous problems are rarely limb- or life-threatening and medical treatment has remained the mainstay of management in the practice of most physicians. In many ways, the status of chronic venous disease is similar to that of chronic arterial disease four dec343
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ades ago. Progress in arterial disease was fueled by improved understanding of arterial pathophysiology, development of accepted evaluation techniques and reporting standards, progress in surgical techniques and development of suitable conduits for reconstruction. One might reasonably expect that similar developments in the area of venous disease will be needed for equivalent progress to occur. In an effort to focus interest on venous disease, the Committee on Research of the American Venous Forum has developed a series of review articles on important issues of venous disease. In this article, we will review the basic anatomy and pathophysiology of the venous system and current theories of the etiologies of chronic venous disease. We will then briefly discuss the diagnosis and classification of chronic venous problems and review current medical and surgical treatments. Finally, we will attempt to highlight some of the current and future challenges in chronic venous disease. The issues of venous thrombosis and pulmonary embolism are the subject of another report and will not be discussed here.
Normal venous anatomy and physiology Understanding venous pathophysiology is dependent on a clear appreciation of venous anatomy. The venous anatomy of the upper and lower extremities is characterized by the presence of both superficial and deep venous systems which are connected by perforating veins. There are generally two routes of superficial drainage in each extremity (basilic– cephalic in the arm, cf. greater–lesser saphenous in the leg) and a single deep system consisting of paired veins distally draining into single veins more proximally. The venous wall is thin and collapsible in contrast to the arterial system. This feature allows veins to change from an elliptical to circular configuration as they fill, with minimal changes in pressure, and is responsible for the capacitance function of the venous circulation. In addition, extremity veins, particularly the veins of the lower extremity, contain bicuspid valves which direct flow from the superficial to the deep system and from distal to proximal. Finally, the lower extremity contains valveless venous sinuses in the foot and calf which play important roles in regulation of venous flow. Under normal circumstances, venous flow proceeds against gravity propelled by two ‘pumps’ in the lower extremity – the plantar venous plexus (‘foot pump’) and the soleal sinuses (‘calf pump’). The plantar plexus serves as a reservoir for venous blood which empties when walking begins and with plantar flexion, propelling blood through the superficial and deep systems. Experiments have shown that activation of this ‘foot pump’ mechanism can significantly augment blood flow. Similarly, calf contraction compresses the soleal plexus and drives blood 344
proximally [3]. Disease states which interfere with these two pumping mechanisms can impede proximal blood flow and result in venous stasis. The direction of venous blood flow is maintained by valves in the superficial, deep and perforating systems. Valve function may be compromised by congenital laxity or hypoplasia, venous dilatation, or thrombosis which results in trapping or scarring of previously normal valves. Valvular incompetence may be isolated to the superficial, deep or perforating systems, but involves more than one system in about three-fourths of cases [4, 5]. In some instances, primary abnormalities in one system may cause secondary, and potentially reversible incompetence in a second system as a result of venous overload [6]. In such cases, treatment of the primary problem (e.g. superficial incompetence with varicosities) may return the physiology of the remaining systems to normal [7]. Abnormalities can occur on a macrovascular or microvascular level, and are often ubiquitous. Macrovascular changes can be divided into obstructive or refluxive. Venous obstruction is most commonly due to venous thrombosis which impairs venous outflow and can cause distal venous reflux and dilatation [8]. Resolution of this acute process involves both recanalization of occluded venous segments and development of venous collaterals. Such collaterals are valveless and because of their smaller cross-sectional venous diameter, may provide residual resistance to venous outflow under stress. Recanalization may be complete or partial [9]. In a series of studies, Strandness and colleagues have demonstrated that most post-thrombotic limbs develop some combination of reflux and residual venous obstruction and that more rapid recanalization leads to a reduction in the incidence of late venous reflux [10–12]. Residual obstruction and insufficiency may lead to the clinical signs of postthrombotic skin changes and ulceration. This appears to be most common with pathology in the popliteal and calf veins [13–15]. Post-thrombotic changes may also interfere with calf muscle pump function which impairs venous clearance. Finally, primary venous reflux, resulting from valvular incompetence without thrombosis may also lead to inefficient venous clearance and local venous hypertension. It is presently unclear whether this primary incompetence is associated with biochemical, structural, or functional abnormalities of the vein wall. Under normal circumstances in erect man resting venous pressure is 80–90 mm Hg at the ankle and reflects the hemodynamic effects of a column of blood between the ankle and right atrium. With exercise, venous pressure drops to 20–30 mmHg as the result of muscle pump activity and slowly returns to normal (>30 s) with cessation of exercise. When significant venous obstruction is present, exercise CARDIOVASCULAR SURGERY
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induces an increase in venous pressure because of impaired outflow. In cases of venous insufficiency, venous refill time is shortened due to rapid reflux from above. When the calf muscle pump is ineffective, venous pressure does not increase, but venous emptying is incomplete. By evaluating pressure response to exercise, efficiency of calf emptying and the rapidity of venous refill, one can dissect the various components of chronic venous insufficiency. Microcirculatory changes also occur [16]. It is presumed that the majority of these result from stagnation of venous blood in the lower extremity. Such changes include increased capillary permeability, particularly to macromolecules such as fibrin [17], leukocyte sequestration and activation [18–21], reduced local fibrinolysis [22], and release of cytokines and free radicals [23]. In addition, there appears to be increased regional blood flow with decreased oxygen extraction and decreased ability to regulate microcirculatory flow [24–27]. Both macroand micro-circulatory changes appear to be necessary for development of venous ulceration [28].
after exercise may also be used to determine the efficiency of venous emptying. The invasive nature of these measurements and the lack of their direct correlation with clinical response, has somewhat limited their application [41, 42]. Finally, venous reflux can be evaluated by descending venography using standardized valsalva maneuvers. The level to which dye refluxes into the lower extremity provides an indication of the severity of valvular incompetence [43]. In clinical practice, neither the extent of or technique for venous evaluation is currently standardized. This probably results from the fact that many of the techniques can be difficult to master and standardize and are perceived to be of research, but not clinical relevance, because of the low incidence of intervention for venous disease. However, as venous intervention becomes more frequent, the need for standard evaluation protocols will increase. A standard nomenclature for classifying venous disease has been proposed by the International Consensus Committee on Venous Disease [44].
Diagnostic testing
Medical therapy for chronic venous disease
Testing has focused, up to the present, on the macrocirculation. Anatomic studies such as venography, radionuclide studies, and magnetic resonance imaging focus on identifying areas of intrinsic or extrinsic obstruction, or reflux, but do not provide physiologic data. Physiologic studies include plethysmography of various types and duplex ultrasound. These studies have been exhaustively evaluated in a separate publication [29]. Microcirculatory studies are currently under development and include measurement of local blood flow, oxygen tension and metabolism. It is likely that these will be further extended to the evaluation of oxidative state, leukocyte activation and cytokine release. A thorough diagnostic evaluation should include information on the superficial, deep and perforating systems, an estimate of calf muscle pump function, and an estimate of venous pressure. These data can be provided by a combination of duplex ultrasound, plethysmography and venography [30]. Venous duplex ultrasound can be used to interrogate the superficial, deep and perforating systems of the extremities and localize areas of reflux or obstruction. Application of duplex technology has allowed measurement of flow in major axial veins and thereby quantification of venous emptying and reflux [31–35]. Venous outflow and reflux can also be measured using plethysmographic techniques [34–40]. Nicolaides, in particular, has advocated the use of air plethysmography to measure venous outflow, venous reflux and calf muscle pump efficiency (residual volume fraction) [30, 38–40]. Direct ambulatory venous pressure measurements taken at rest and
Medical therapy is aimed at reducing edema and treatment of local complications and has been the mainstay of treatment for patients with chronic venous disease. Control of edema includes elevation and the use of elastic or non-elastic compression bandages, sequential pumps and compression stockings. While this therapy is effective, long-term patient compliance remains a major problem. Younger active patients are often resistant to a regimen of prolonged bed rest with elevation, as well as the use of compression hose on a chronic basis. In older patients, bed rest with elevation is also difficult and may lead to problems with mobility, while compression hose may be difficult to use effectively. In both groups, use of compression bandages is laborintensive and may give inconsistent results. Devices such as the Circaid orthosis have been developed to overcome some of these problems with application of support, but have a low rate of patient acceptance in many practices. While the importance and efficacy of elevation and compression cannot be denied, it is frequently difficult to apply these modalities over the long term in complex chronic venous problems. Systemic medical therapy has been directed at correcting impairments of fibrinolysis, inflammation, and free radical generation. Systemic administration of fibrinolytic agents is based on the observations that fibrinolytic capacity is reduced in patients with venous insufficiency and that capillary permeability to fibrin is increased. Stanozolol showed initial promising results, but was not effective in controlled trials [45, 46]. However, two other fibrinolytic agents, defibrotide and sulodexide, have shown effi-
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cacy in reducing the signs and symptoms of venous insufficiency [47–49]. The hydroxyrutosides, which decrease capillary permeability, have been shown to reduce the edema and symptoms of chronic venous insufficiency, but do not improve ulcer healing [50]. Pentoxyfylline [51, 52] and prostaglandin E1 [53], both of which decrease platelet and leukocyte adhesion, have been shown to improve healing of venous ulcers when administered systemically. The former, which is available orally, also has significant ability to inhibit free radical release. Multiple topical agents have been used to promote the healing of venous ulceration. Topical free radical scavengers such as dimethyl sulfoxide and allopurinol [54], the serotonin antagonist ketanserin [50] and recombinant growth factors have shown promise in this regard. Agents which promote epithelialization such as ammnion, RGD peptide and even fibroblasts are under investigation. Topical antimicrobials and hydrocolloid dressings were once felt to be potentially useful to reduce infection or sequester local growth factors at the wound site, but have not proved effective. Antimicrobials are cytotoxic and inhibit epithelialization, while the hydrocolloid dressings are associated with local dermatitis and at times increased rates of wound infection. The mainstays of medical treatment have changed little over the past several decades, although this is an area of increasing interest and research. Clearly, prospective randomized therapeutic trials are needed.
Operative treatment of chronic venous disease The most common surgical therapy for chronic venous disease is obliterative, involving removal of incompetent superficial or perforating veins in patients with chronic lipodermatosclerosis with or without ulceration. While it was initially felt that chronic venous insufficiency must be associated with deep or perforator disease, it is clear that a subgroup of patients with chronic disease have isolated superficial insufficiency [5]. It is now well established that removal of the abnormal superficial veins in these patients can be curative [4–7]. Current therapy is aimed at removal of only abnormal venous segments, with liberal use of duplex ultrasound to direct surgical efforts. The greater saphenous is often normal below the knee and when this is so, removal of only the incompetent proximal vein is indicated. While there has been interest in ‘saving’ the saphenous vein by using high ligation alone or external venous banding, recurrence has been higher than when appropriate removal of abnormal segments is performed [55]. Modern surgical therapy has been customized to the pathology demonstrated by preoperative duplex or venography. The perforating veins which cause distal reflux are removed selectively. Recent 346
advances in endoscopic techniques have led to subfascial perforation ligation from remote sites [56], thus reducing local wound complications frequently seen with direct perforator ligation. Large indolent venous ulcers may be unresponsive to local care or venous ligation alone. In these cases, wide local excision down to and including fascia, followed by skin grafting or free flap closure has been used with good long-term success [57]. In such cases, long-term compression therapy is important. Venous reconstruction can be divided into bypass techniques for obstructive symptoms and valvular reconstruction or grafting for venous insufficiency. Selection of candidates for venous bypass depends on measurement of venous pressure gradients at rest and after exercise. Patients with significant obstruction will have a difference in mean venous pressure of >5 mmHg at rest or brought on by exercise [58– 60]. While documentation of such small gradients requires precision, their presence (and particularly their increase after exercise) is essential for proper patient selection. Using these criteria, good results for venous bypass have been reported. Venous bypasses are autologous when possible, conduits include the saphenous vein and spiral veins [60, 61]. In the reconstruction of large central veins such as the superior and inferior vena cava, prosthetic materials (usually externally supported polytetrafluoroethylene) may be required [59]. Gloviczki has found these conduits work well in high-flow (>1000 ml/min) circumstances. Under lower flow conditions, an adjunctive arteriovenous fistula may be needed to maintain patency [59, 60]. Successful bypasses have been reported for superficial, femoral, iliac, subclavian, and caval obstruction [61]. Proper tailoring of the operation to the patient’s pathology is essential. At present, it appears that the number of these operations will remain small due to the multifocal nature of venous disease in most patients with sufficient symptoms to warrant operation. However, as our diagnostic and clinical sophistication increases, this number will surely grow. Venous insufficiency can be treated by valvular reconstruction or transplantation. A transvalvular valve reconstruction technique was initially described by Kistner and colleagues [62] and a supravalvular approach was described by Raju and Fredericks [63]. Recently, external valve plication has been advocated, O’Donnell and others have suggested that this be performed using angioscopic control [64, 65]. The published series of valve reconstruction for primary valve insufficiency are small, although the results are quite positive [59–69]. Attention has been focused on repair of the first superficial femoral valve and results are optimal in patients with deep femoral competence. Questions which remain to be answered include the true frequency of isolated valvular incompetence in patients CARDIOVASCULAR SURGERY
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with chronic venous insufficiency, the optimal site of valve repair and the number of valves which require repair to achieve long-term success [70]. Valve transplantation is the only surgical therapy for patients whose valves have been destroyed by venous thrombosis recanalization [68, 69, 71, 72]. These patients are less amenable to reconstruction than those with primary insufficiency. This is due primarily to the extent of venous involvement and the problem of incomplete recanalization with residual vein wall pathology. Initially, repair was directed at the common or superficial femoral vein, but most recently has focused on the popliteal vein as the ‘gatekeeper’ [71, 72]. Autogenous valve substitutes include the brachial, axillary or jugular vein. The operation is currently technically successful and several series report good early clinical and functional results. However, late follow-up has demonstrated recurrent incompetence in many patients. This may be due to recurrent subclinical thrombosis or late valvular incompetence due to dilatation of the venous conduit. The latter may be the result of failure to reverse venous hypertension by only a single valve transplant. The site and number of valve transplants needed to assure long-term success is unknown at present. Clinical efficacy is further compromised by lack of a suitable size match for many veins and the complete absence of suitable artificial conduits. Finally, long-term functional and anatomic studies are lacking in many cases.
Summary Progress in the treatment of venous disease has lagged behind that of the arterial system. Several potential reasons for this include the insidious development of clinical venous problems, lack of accepted standards for measurement of abnormal venous pathophysiology, and the lack of readily available conduits for venous reconstruction. These factors have led many clinicians to regard venous disease as a chronic and incurable disease of little interest. In practice, this results in treatment of many patients by observation and half-hearted attempts at compression therapy combined with episodic use of outpatient therapy such as Unna’s boots or even hospital admission for control of severe complications. Recent advances in the diagnosis and pathophysiology of venous disease has raised the possibility of effective long-term intervention in patients with these problems. Many questions remain unresolved in the area of venous disease. The natural history of venous thrombosis and its sequelae have only begun to be defined. The phenomenon of spontaneous clot lysis and its effect on long-term valve function and post-phlebitic syndrome are being studied, but much remains to be done. The corollary question of the indications for CARDIOVASCULAR SURGERY
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and effect of thrombolysis in peripheral venous thrombosis is unanswered. At a more basic level, the relation between thrombosis, inflammation, alteration in cellular biology (both circulating blood elements and the cells of the vascular wall) and changes of the post-thrombotic process are an inviting target for further investigation. Molecular biology, currently being applied to the phenomenon of atherosclerosis, is an equally appropriate area for study of venous pathophysiology. Clinical studies using anticoagulants, fibrinolytics, anti-inflammatories and free radical scavengers are all appropriate areas of investigation. Chemical and structural differences between normal and primarily incompetent veins remain to be identified. The microenvironment of the post-phlebitic limb and the venous ulcer needs further sophisticated evaluation. Such work should include not only a study of oxygen delivery, tissue permeability and cytokine/free radical generation, but also clinical trials of pharmacologic intervention with compounds which can influence one or more of these processes. Classification and evaluation of venous problems needs to be standardized and quantified. Once this is generally accepted, venous problems will be reliably categorized by anatomy and physiology, clinical comparisons and follow-up will be possible and various medical and surgical intervention will be compared in a meaningful manner. This should result in a renewed interest in more aggressive management of venous problems, better understanding of the varied pathophysiology and the development of more physiologically based operative therapy. Finally, technologic developments are required in the area of venous conduits and venous valves. As progress in these areas proceeds, appropriately designed surgical interventions will be developed and evaluated. Since the chronic venous syndromes have their basis in physiologic alterations, well designed operations to correct this deranged physiology should prove effective once the physiology is understood and appropriate techniques and conduits become available. This brief review is intended to summarize the state of knowledge in the area of clinical venous problems and to point out some of the areas where future work is needed. The authors hope that it will stimulate investigation in this large and very fertile area.
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(APG): a new technique to evaluate patients with chronic venous insufficiency. Journal of Vascular Technology, 1991, 15, 23–27. Raju, S. and Fredericks, R., Venous obstruction: hemodynamic basis of stasis ulceration. Journal of Vascular Surgery, 1991, 13, 491–495. Nicolaides, A. N., Hussein, M. K. and Szendro, G. et al., The relation of venous ulceration with ambulatory venous pressure measurements. Journal of Vascular Surgery, 1993, 17, 414–419. Kistner, R. L., Ferris, E. B., Randhawa, G. and Kamida, C. B., A method of performing descending venography. Journal of Vascular Surgery, 1986, 4, 464–468. Porter, J. M. and Moneta, G. L., Reporting standards in venous disease: an update. Journal of Vascular Surgery, 1995, 21, 634– 645. Burnand, K., Lemenson, G. and Morland, M. et al., Venous lipodermatosclerosis treatment by fibrinolytic enhancement and elastic compression. British Medical Journal, 1980, 280, 7–11. McMullin, G. M., Watkin, G. T., Coleridge Smith, P. D. and Scurr, J. H., The efficacy of fibrinolytic enhancement with stanozolol in the treatment of venous insufficiency. Australian and New Zealand Journal of Surgery, 1991, 61, 306–309. Belcaro, G., Legnin, M. and Cianchetti, E. et al., Clinical evaluation of defibrotide in the treatment of arterial and venous vascular disease: a preliminary report. Panminerva Medica, 1989, 31, 34–41. Belcaro, G. and Marelli, C., Treatment of venous lipodermatosclerosis and ulceration in venous hypertension by elastic compression and fibrinolytic enhancement with defibrotide. Phlebology, 1989, 4, 91–106. Saviano, M., Maleti, O. and Liguori, L., Double blind double dummy randomized multicenter clinical assessment of the efficacy tolerability and dose effect relationship of sulodexide in chronic venous insufficiency. Current Medical Research, 1993, 13, 96–108. Cheatle, T. R., Scurr, J. H. and Coleridge Smith, P. D., Drug treatment of chronic venous insufficiency and venous ulceration: a review. Journal of the Royal Society of Medicine, 1991, 84, 354–358. Angelides, N. S. and Weil Vonder Ahe, C. A., Effect of oral pentoxifylline therapy on venous lower extremity ulcers due to deep venous incompetence. Angiology, 1989, 40, 752–763. Colgan, M. P., Dormandy, J. A. and Jones, P. W. et al., Oxpentifylline treatment of venous ulcers of the leg. British Medical Journal, 1990, 300, 972–975. Rudofsky, G., Intravenous prostaglandin E1 in the treatment of venous ulcers–a double blind placebo controlled trial. Vasa, 1989, Suppl. 28, 39–43. Salim, A.S., The role of oxygen derived free radicals in the management of venous (varicose) ulcerations. A new approach. World Journal of Surgery, 1991, 15, 264–269. Schanzer, H. and Skladany, M., Varicose vein surgery with preservation of the saphenous vein: a comparison between high ligation-avulsion versus saphenofemoral banding valvuloplastyavulsion. Journal of Vascular Surgery, 1994, 20, 684–687. Gloviczki, P., Cambria, R. A., Rhee, R. Y., Canton, L. G. and McKusick, M. A., Surgical technique and preliminary results of
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endoscopic subfascial division of perforating veins. Journal of Vascular Surgery, 1996, 23, 517–523. Marsan B. U. and Ricotta J. J. Radical excision and skin grafting for large indolent venous ulcers. In Current Critical Problems in Vascular Surgery, Vol. 7, ed. F. J. Veith. Quality Medical Publishing, St. Louis, MO, USA, pp. 475–483. Negus, D. and Cockett, F. B., Femoral vein pressures in postphlebitic iliac vein obstruction. British Journal of Surgery, 1967, 54, 522–525. Gloviczki P. and Pairolero P. C. Prosthetic replacement of large veins. In Atlas of Venous Surgery, ed. J. J. Bergan and R. L. Kistner. W.B. Saunders, Philadelphia, 1992, pp. 191–214. Lalka S. G. Venous bypass graft for chronic venous occlusive disease. In Handbook of Venous Disease, ed. P. Gloviczki and J. S.T. Yao. Chapman & Hall, London, 1996, pp. 446–470. Doty, D. B., Doty, J. R. and Jones, K. W., Bypass of superior vena cava. Fifteen years’ experience with spiral vein graft for obstruction of superior vena cava caused by benign disease. Journal of Thoracic and Cardiovascular Surgery, 1990, 99, 889–895. Kistner, R. L., Eklof, B. and Masuda, E. M., Deep venous valve reconstruction. Cardiovascular Surgery, 1995, 3, 129–140. Raju, S. and Fredericks, R., Valve reconstruction procedures for nonobstructive venous insufficiency: rationale, techniques, and results in 107 procedures with two-to eight-year follow-up. Journal of Vascular Surgery, 1988, 7, 301–310. Gloviczki, P., Merrell, S. W. and Bower, T.C., Femoral vein valve repair under direct vision without venotomy: a modified technique with use of angioscopy. Journal of Vascular Surgery, 1991, 14, 645–648. Welch, H. J., McClaughlin, R. L. and O’Donnell, T.F., Femoral vein valvuloplasty, intraoperative angioscopic evaluation and hemodynamic improvement. Journal of Vascular Surgery, 1992, 16, 694–700. Cheatle, T. R. and Perrin, M., Venous valve repair: early results in fifty two cases. Journal of Vascular Surgery, 1994, 19, 404–413. Masuda, E. M. and Kistner, R. L., Long-term results of venous valve reconstruction: a four to 21 year follow-up. Journal of Vascular Surgery, 1994, 19, 491–503. Nash, T., Long-term results of vein valve transplants placed in the popliteal vein for intractable postphlebitic venous ulcers and pre-ulcer skin changes. Journal of Cardiovascular Surgery, 1988, 29, 712–716. Wilson, R. M., Rutt, D. L. and Browse, N. L., Repair and replacement of deep vein valves in the treatment of venous insufficiency. British Journal of Surgery, 1991, 78, 388–394. Dalsing, M. C., Lalka, S. G., Unthank, J. C., Grieshop, R. J., Nixon, C. and Davis, T., Venous valvular insufficiency. Influence of a single venous valve. Journal of Vascular Surgery, 1991, 14, 576–587. O’Donnell, T. F., Mackey, W. C., Sheppard, A. D. and Callow, A. D., Clinical hemodynamic and anatomic follow-up of direct venous reconstruction. Archives of Surgery, 1987, 122, 474–482. Raju S. Axillary vein transfer for postphlebitic syndrome. In Atlas of Venous Surgery, ed. J. J. Bergan and R. L. Kistner, W.B. Saunders, Philadelphia, 1992, pp. 147–152.
Paper accepted 11 February 1997
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Cardiovascular Surgery, Vol. 5, No. 4, pp. 343–349, 1997 1997 The International Society for Cardiovascular Surgery Published by Elsevier Science Ltd. Printed in Great Britain 0967–2109/97 $17.00 + 0.00
VASCULAR REVIEW Research and clinical issues in chronic venous disease J. J. Ricotta*, M. C. Dalsing†, K. Ouriel‡, T. W. Wakefield§ and T. G. Lynch储 *SUNY at Buffalo, USA and †University of Indiana, USA and ‡University of Rochester School of Medicine, USA and §University of Michigan, USA and 储University of Nebraska, USA The purpose of this study was to summarize the current issues in chronic venous disease by reviewing of the literature relating to the condition. The review was conducted by members of the Committee on Research of the American Venous Forum and includes the Committee’s venous disease and current/future directions. Progress in the understanding and management of chronic venous problems has lagged behind that in arterial disease, despite the large number of patients affected. The complex pathophysiology of venous problems, lack of accepted evaluation standards and lack of prosthetic conduits are some of the factors which contribute to this. New information in these areas has laid the foundation for advances in both operations and non-operative therapy. In conclusion, many opportunities for clinical and basic research in the area of chronic venous disease are available. Application of basic science techniques, including those of molecular biology, will lead to new insights into pathophysiology of chronic venous syndrome. Developments in technology, classification and basic science suggest multiple new potentials therapeutic approaches in the next decade. 1997 The International Society for Cardiovascular Surgery Keywords: chronic venous disease, pathophysiology, venous anatomy, microcirculation, diagnosis
Chronic venous disease is perhaps the most common problem encountered in vascular medicine. It is estimated that 1–3% of adults will develop a chronic venous insufficiency and about 1.5% will experience a venous stasis ulcer during their lives [1, 2]. The economic impact of venous disease on medical cost and lost productivity is significant. Despite these facts, relatively slow progress has been made over the past three decades in the management of chronic venous problems, in comparison with the developments in therapy for arterial disease. A contrast between venous and arterial problems may serve to highlight reasons for this phenomenon. Signs of venous disease are subtle and often remain symptomless, or mildly symptomatic, for long periods of time. Consequently, its early manifestations are often overlooked by both patient and physician. When they become clinically manifest, the disease is
Correspondence to: Dr J. J. Ricotta, Department of Surgery, Millard Fillmore Hospital, 3 Gates Circle, Buffalo, NY 14209, USA
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often multifocal. The presence of superficial, deep and communicating veins makes the evaluation and quantification of venous pathophysiology complex. At present, there are no universally accepted standards for the anatomic or physiologic evaluation of venous problems, analogous to segmental arterial pressures. This deficiency makes it difficult to compare series of patients or objectively evaluate different therapies. Clinical venous problems evolve from and are related to complex interactions of venous obstruction and reflux; in contrast to the overwhelming obstructive nature of arterial problems. In addition, there are distinct microcirculatory changes which may play an equal or more significant role than macrocirculatory disturbances in the genesis of chronic venous insufficiency’s most serious manifestation, venous ulcers. Finally, chronic venous problems are rarely limb- or life-threatening and medical treatment has remained the mainstay of management in the practice of most physicians. In many ways, the status of chronic venous disease is similar to that of chronic arterial disease four dec343
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ades ago. Progress in arterial disease was fueled by improved understanding of arterial pathophysiology, development of accepted evaluation techniques and reporting standards, progress in surgical techniques and development of suitable conduits for reconstruction. One might reasonably expect that similar developments in the area of venous disease will be needed for equivalent progress to occur. In an effort to focus interest on venous disease, the Committee on Research of the American Venous Forum has developed a series of review articles on important issues of venous disease. In this article, we will review the basic anatomy and pathophysiology of the venous system and current theories of the etiologies of chronic venous disease. We will then briefly discuss the diagnosis and classification of chronic venous problems and review current medical and surgical treatments. Finally, we will attempt to highlight some of the current and future challenges in chronic venous disease. The issues of venous thrombosis and pulmonary embolism are the subject of another report and will not be discussed here.
Normal venous anatomy and physiology Understanding venous pathophysiology is dependent on a clear appreciation of venous anatomy. The venous anatomy of the upper and lower extremities is characterized by the presence of both superficial and deep venous systems which are connected by perforating veins. There are generally two routes of superficial drainage in each extremity (basilic– cephalic in the arm, cf. greater–lesser saphenous in the leg) and a single deep system consisting of paired veins distally draining into single veins more proximally. The venous wall is thin and collapsible in contrast to the arterial system. This feature allows veins to change from an elliptical to circular configuration as they fill, with minimal changes in pressure, and is responsible for the capacitance function of the venous circulation. In addition, extremity veins, particularly the veins of the lower extremity, contain bicuspid valves which direct flow from the superficial to the deep system and from distal to proximal. Finally, the lower extremity contains valveless venous sinuses in the foot and calf which play important roles in regulation of venous flow. Under normal circumstances, venous flow proceeds against gravity propelled by two ‘pumps’ in the lower extremity – the plantar venous plexus (‘foot pump’) and the soleal sinuses (‘calf pump’). The plantar plexus serves as a reservoir for venous blood which empties when walking begins and with plantar flexion, propelling blood through the superficial and deep systems. Experiments have shown that activation of this ‘foot pump’ mechanism can significantly augment blood flow. Similarly, calf contraction compresses the soleal plexus and drives blood 344
proximally [3]. Disease states which interfere with these two pumping mechanisms can impede proximal blood flow and result in venous stasis. The direction of venous blood flow is maintained by valves in the superficial, deep and perforating systems. Valve function may be compromised by congenital laxity or hypoplasia, venous dilatation, or thrombosis which results in trapping or scarring of previously normal valves. Valvular incompetence may be isolated to the superficial, deep or perforating systems, but involves more than one system in about three-fourths of cases [4, 5]. In some instances, primary abnormalities in one system may cause secondary, and potentially reversible incompetence in a second system as a result of venous overload [6]. In such cases, treatment of the primary problem (e.g. superficial incompetence with varicosities) may return the physiology of the remaining systems to normal [7]. Abnormalities can occur on a macrovascular or microvascular level, and are often ubiquitous. Macrovascular changes can be divided into obstructive or refluxive. Venous obstruction is most commonly due to venous thrombosis which impairs venous outflow and can cause distal venous reflux and dilatation [8]. Resolution of this acute process involves both recanalization of occluded venous segments and development of venous collaterals. Such collaterals are valveless and because of their smaller cross-sectional venous diameter, may provide residual resistance to venous outflow under stress. Recanalization may be complete or partial [9]. In a series of studies, Strandness and colleagues have demonstrated that most post-thrombotic limbs develop some combination of reflux and residual venous obstruction and that more rapid recanalization leads to a reduction in the incidence of late venous reflux [10–12]. Residual obstruction and insufficiency may lead to the clinical signs of postthrombotic skin changes and ulceration. This appears to be most common with pathology in the popliteal and calf veins [13–15]. Post-thrombotic changes may also interfere with calf muscle pump function which impairs venous clearance. Finally, primary venous reflux, resulting from valvular incompetence without thrombosis may also lead to inefficient venous clearance and local venous hypertension. It is presently unclear whether this primary incompetence is associated with biochemical, structural, or functional abnormalities of the vein wall. Under normal circumstances in erect man resting venous pressure is 80–90 mm Hg at the ankle and reflects the hemodynamic effects of a column of blood between the ankle and right atrium. With exercise, venous pressure drops to 20–30 mmHg as the result of muscle pump activity and slowly returns to normal (>30 s) with cessation of exercise. When significant venous obstruction is present, exercise CARDIOVASCULAR SURGERY
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induces an increase in venous pressure because of impaired outflow. In cases of venous insufficiency, venous refill time is shortened due to rapid reflux from above. When the calf muscle pump is ineffective, venous pressure does not increase, but venous emptying is incomplete. By evaluating pressure response to exercise, efficiency of calf emptying and the rapidity of venous refill, one can dissect the various components of chronic venous insufficiency. Microcirculatory changes also occur [16]. It is presumed that the majority of these result from stagnation of venous blood in the lower extremity. Such changes include increased capillary permeability, particularly to macromolecules such as fibrin [17], leukocyte sequestration and activation [18–21], reduced local fibrinolysis [22], and release of cytokines and free radicals [23]. In addition, there appears to be increased regional blood flow with decreased oxygen extraction and decreased ability to regulate microcirculatory flow [24–27]. Both macroand micro-circulatory changes appear to be necessary for development of venous ulceration [28].
after exercise may also be used to determine the efficiency of venous emptying. The invasive nature of these measurements and the lack of their direct correlation with clinical response, has somewhat limited their application [41, 42]. Finally, venous reflux can be evaluated by descending venography using standardized valsalva maneuvers. The level to which dye refluxes into the lower extremity provides an indication of the severity of valvular incompetence [43]. In clinical practice, neither the extent of or technique for venous evaluation is currently standardized. This probably results from the fact that many of the techniques can be difficult to master and standardize and are perceived to be of research, but not clinical relevance, because of the low incidence of intervention for venous disease. However, as venous intervention becomes more frequent, the need for standard evaluation protocols will increase. A standard nomenclature for classifying venous disease has been proposed by the International Consensus Committee on Venous Disease [44].
Diagnostic testing
Medical therapy for chronic venous disease
Testing has focused, up to the present, on the macrocirculation. Anatomic studies such as venography, radionuclide studies, and magnetic resonance imaging focus on identifying areas of intrinsic or extrinsic obstruction, or reflux, but do not provide physiologic data. Physiologic studies include plethysmography of various types and duplex ultrasound. These studies have been exhaustively evaluated in a separate publication [29]. Microcirculatory studies are currently under development and include measurement of local blood flow, oxygen tension and metabolism. It is likely that these will be further extended to the evaluation of oxidative state, leukocyte activation and cytokine release. A thorough diagnostic evaluation should include information on the superficial, deep and perforating systems, an estimate of calf muscle pump function, and an estimate of venous pressure. These data can be provided by a combination of duplex ultrasound, plethysmography and venography [30]. Venous duplex ultrasound can be used to interrogate the superficial, deep and perforating systems of the extremities and localize areas of reflux or obstruction. Application of duplex technology has allowed measurement of flow in major axial veins and thereby quantification of venous emptying and reflux [31–35]. Venous outflow and reflux can also be measured using plethysmographic techniques [34–40]. Nicolaides, in particular, has advocated the use of air plethysmography to measure venous outflow, venous reflux and calf muscle pump efficiency (residual volume fraction) [30, 38–40]. Direct ambulatory venous pressure measurements taken at rest and
Medical therapy is aimed at reducing edema and treatment of local complications and has been the mainstay of treatment for patients with chronic venous disease. Control of edema includes elevation and the use of elastic or non-elastic compression bandages, sequential pumps and compression stockings. While this therapy is effective, long-term patient compliance remains a major problem. Younger active patients are often resistant to a regimen of prolonged bed rest with elevation, as well as the use of compression hose on a chronic basis. In older patients, bed rest with elevation is also difficult and may lead to problems with mobility, while compression hose may be difficult to use effectively. In both groups, use of compression bandages is laborintensive and may give inconsistent results. Devices such as the Circaid orthosis have been developed to overcome some of these problems with application of support, but have a low rate of patient acceptance in many practices. While the importance and efficacy of elevation and compression cannot be denied, it is frequently difficult to apply these modalities over the long term in complex chronic venous problems. Systemic medical therapy has been directed at correcting impairments of fibrinolysis, inflammation, and free radical generation. Systemic administration of fibrinolytic agents is based on the observations that fibrinolytic capacity is reduced in patients with venous insufficiency and that capillary permeability to fibrin is increased. Stanozolol showed initial promising results, but was not effective in controlled trials [45, 46]. However, two other fibrinolytic agents, defibrotide and sulodexide, have shown effi-
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cacy in reducing the signs and symptoms of venous insufficiency [47–49]. The hydroxyrutosides, which decrease capillary permeability, have been shown to reduce the edema and symptoms of chronic venous insufficiency, but do not improve ulcer healing [50]. Pentoxyfylline [51, 52] and prostaglandin E1 [53], both of which decrease platelet and leukocyte adhesion, have been shown to improve healing of venous ulcers when administered systemically. The former, which is available orally, also has significant ability to inhibit free radical release. Multiple topical agents have been used to promote the healing of venous ulceration. Topical free radical scavengers such as dimethyl sulfoxide and allopurinol [54], the serotonin antagonist ketanserin [50] and recombinant growth factors have shown promise in this regard. Agents which promote epithelialization such as ammnion, RGD peptide and even fibroblasts are under investigation. Topical antimicrobials and hydrocolloid dressings were once felt to be potentially useful to reduce infection or sequester local growth factors at the wound site, but have not proved effective. Antimicrobials are cytotoxic and inhibit epithelialization, while the hydrocolloid dressings are associated with local dermatitis and at times increased rates of wound infection. The mainstays of medical treatment have changed little over the past several decades, although this is an area of increasing interest and research. Clearly, prospective randomized therapeutic trials are needed.
Operative treatment of chronic venous disease The most common surgical therapy for chronic venous disease is obliterative, involving removal of incompetent superficial or perforating veins in patients with chronic lipodermatosclerosis with or without ulceration. While it was initially felt that chronic venous insufficiency must be associated with deep or perforator disease, it is clear that a subgroup of patients with chronic disease have isolated superficial insufficiency [5]. It is now well established that removal of the abnormal superficial veins in these patients can be curative [4–7]. Current therapy is aimed at removal of only abnormal venous segments, with liberal use of duplex ultrasound to direct surgical efforts. The greater saphenous is often normal below the knee and when this is so, removal of only the incompetent proximal vein is indicated. While there has been interest in ‘saving’ the saphenous vein by using high ligation alone or external venous banding, recurrence has been higher than when appropriate removal of abnormal segments is performed [55]. Modern surgical therapy has been customized to the pathology demonstrated by preoperative duplex or venography. The perforating veins which cause distal reflux are removed selectively. Recent 346
advances in endoscopic techniques have led to subfascial perforation ligation from remote sites [56], thus reducing local wound complications frequently seen with direct perforator ligation. Large indolent venous ulcers may be unresponsive to local care or venous ligation alone. In these cases, wide local excision down to and including fascia, followed by skin grafting or free flap closure has been used with good long-term success [57]. In such cases, long-term compression therapy is important. Venous reconstruction can be divided into bypass techniques for obstructive symptoms and valvular reconstruction or grafting for venous insufficiency. Selection of candidates for venous bypass depends on measurement of venous pressure gradients at rest and after exercise. Patients with significant obstruction will have a difference in mean venous pressure of >5 mmHg at rest or brought on by exercise [58– 60]. While documentation of such small gradients requires precision, their presence (and particularly their increase after exercise) is essential for proper patient selection. Using these criteria, good results for venous bypass have been reported. Venous bypasses are autologous when possible, conduits include the saphenous vein and spiral veins [60, 61]. In the reconstruction of large central veins such as the superior and inferior vena cava, prosthetic materials (usually externally supported polytetrafluoroethylene) may be required [59]. Gloviczki has found these conduits work well in high-flow (>1000 ml/min) circumstances. Under lower flow conditions, an adjunctive arteriovenous fistula may be needed to maintain patency [59, 60]. Successful bypasses have been reported for superficial, femoral, iliac, subclavian, and caval obstruction [61]. Proper tailoring of the operation to the patient’s pathology is essential. At present, it appears that the number of these operations will remain small due to the multifocal nature of venous disease in most patients with sufficient symptoms to warrant operation. However, as our diagnostic and clinical sophistication increases, this number will surely grow. Venous insufficiency can be treated by valvular reconstruction or transplantation. A transvalvular valve reconstruction technique was initially described by Kistner and colleagues [62] and a supravalvular approach was described by Raju and Fredericks [63]. Recently, external valve plication has been advocated, O’Donnell and others have suggested that this be performed using angioscopic control [64, 65]. The published series of valve reconstruction for primary valve insufficiency are small, although the results are quite positive [59–69]. Attention has been focused on repair of the first superficial femoral valve and results are optimal in patients with deep femoral competence. Questions which remain to be answered include the true frequency of isolated valvular incompetence in patients CARDIOVASCULAR SURGERY
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with chronic venous insufficiency, the optimal site of valve repair and the number of valves which require repair to achieve long-term success [70]. Valve transplantation is the only surgical therapy for patients whose valves have been destroyed by venous thrombosis recanalization [68, 69, 71, 72]. These patients are less amenable to reconstruction than those with primary insufficiency. This is due primarily to the extent of venous involvement and the problem of incomplete recanalization with residual vein wall pathology. Initially, repair was directed at the common or superficial femoral vein, but most recently has focused on the popliteal vein as the ‘gatekeeper’ [71, 72]. Autogenous valve substitutes include the brachial, axillary or jugular vein. The operation is currently technically successful and several series report good early clinical and functional results. However, late follow-up has demonstrated recurrent incompetence in many patients. This may be due to recurrent subclinical thrombosis or late valvular incompetence due to dilatation of the venous conduit. The latter may be the result of failure to reverse venous hypertension by only a single valve transplant. The site and number of valve transplants needed to assure long-term success is unknown at present. Clinical efficacy is further compromised by lack of a suitable size match for many veins and the complete absence of suitable artificial conduits. Finally, long-term functional and anatomic studies are lacking in many cases.
Summary Progress in the treatment of venous disease has lagged behind that of the arterial system. Several potential reasons for this include the insidious development of clinical venous problems, lack of accepted standards for measurement of abnormal venous pathophysiology, and the lack of readily available conduits for venous reconstruction. These factors have led many clinicians to regard venous disease as a chronic and incurable disease of little interest. In practice, this results in treatment of many patients by observation and half-hearted attempts at compression therapy combined with episodic use of outpatient therapy such as Unna’s boots or even hospital admission for control of severe complications. Recent advances in the diagnosis and pathophysiology of venous disease has raised the possibility of effective long-term intervention in patients with these problems. Many questions remain unresolved in the area of venous disease. The natural history of venous thrombosis and its sequelae have only begun to be defined. The phenomenon of spontaneous clot lysis and its effect on long-term valve function and post-phlebitic syndrome are being studied, but much remains to be done. The corollary question of the indications for CARDIOVASCULAR SURGERY
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and effect of thrombolysis in peripheral venous thrombosis is unanswered. At a more basic level, the relation between thrombosis, inflammation, alteration in cellular biology (both circulating blood elements and the cells of the vascular wall) and changes of the post-thrombotic process are an inviting target for further investigation. Molecular biology, currently being applied to the phenomenon of atherosclerosis, is an equally appropriate area for study of venous pathophysiology. Clinical studies using anticoagulants, fibrinolytics, anti-inflammatories and free radical scavengers are all appropriate areas of investigation. Chemical and structural differences between normal and primarily incompetent veins remain to be identified. The microenvironment of the post-phlebitic limb and the venous ulcer needs further sophisticated evaluation. Such work should include not only a study of oxygen delivery, tissue permeability and cytokine/free radical generation, but also clinical trials of pharmacologic intervention with compounds which can influence one or more of these processes. Classification and evaluation of venous problems needs to be standardized and quantified. Once this is generally accepted, venous problems will be reliably categorized by anatomy and physiology, clinical comparisons and follow-up will be possible and various medical and surgical intervention will be compared in a meaningful manner. This should result in a renewed interest in more aggressive management of venous problems, better understanding of the varied pathophysiology and the development of more physiologically based operative therapy. Finally, technologic developments are required in the area of venous conduits and venous valves. As progress in these areas proceeds, appropriately designed surgical interventions will be developed and evaluated. Since the chronic venous syndromes have their basis in physiologic alterations, well designed operations to correct this deranged physiology should prove effective once the physiology is understood and appropriate techniques and conduits become available. This brief review is intended to summarize the state of knowledge in the area of clinical venous problems and to point out some of the areas where future work is needed. The authors hope that it will stimulate investigation in this large and very fertile area.
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Paper accepted 11 February 1997
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