Standard of care for venous ulcers has been addressed by several organizations, including the Wound Healing Society, American Venous Forum, investigators from the University of Pennsyvania,[3,4] British Association of Dermatology, and the University of York/Manchester, and numerous other individual authors and researchers.[7–18] These papers focus on accurate diagnosis, local wound care, infection control, and the application of compression therapy. The standard of care for venous disease implies following a “minimum” set of parameters and treatment regimens for all practitioners. Appropriate care as defined in this paper would address the specific needs of the patient and that which reasonably may be expected based on degree, skill, and experience of the profession or class to which the healthcare provider belongs. The following clinical examples are presented to clarify the point. An immunosuppressed patient may have an infection with a lower bioburden than the traditionally considered threshold. Some patients are physically unable to apply compression garments. Others may have mild to moderate arterial insufficiency, making compression contraindicated or necessitating the use of a modified compression technique. Some patients with venous ulcers suffer from hypercoagulable states and prior deep vein thrombosis. These patients require concomitant systemic anticoagulation therapy or medications, which improve the microcirculatory system. Variations in the specific form of compression therapy are needed for the nonambulatory patient versus the typical ambulatory outpatient-clinic patient. Some patients have recalcitrant wounds with clinical features (increased size, long duration) that transfer them into a very hard-to-heal category with long-time-to-healing courses. Is simple standard of care appropriate for these patients? When does standard of care become inappropriate care? At what point in time does referral to a wound specialist become a consideration and a necessity? Are there predictors of healing that can be used to help classify and differentiate these patients when additional care is needed? Numerous advanced care technologies for venous ulcers are available today. Growth factors, bioengineered tissues, surgical advances, thermal therapy, and systemic medications have all been evaluated for the treatment of venous ulcers. The most commonly used clinical guideline not yet mentioned is the personal guideline that each individual clinician has developed over time in his or her practice. These individual guidelines are experiential, anecdotal, and frequently not evidence based. Evidence-based guidelines, however, need to incorporate flexibility into their structure to allow for the introduction of new concepts and to improve clinician acceptance by simulating their current clinical reality.
This paper will attempt to review the pathogenesis of venous ulcers, describe diagnostic and classification schemes, and review treatment options keeping in mind the different concepts of standard care, appropriate care, and advanced care options.
Accurate prevalence information is difficult to obtain because the diagnosis of venous disease is so imprecise. Two and a half million people in the United States have venous ulcers resulting in two million lost work days at a cost of two to four billion dollars for treatment. The problem will continue to escalate, as 20 percent of the US population will be over the age of 65 by the year 2010. There is a 62-percent predominance of women suffering from venous ulcers, many of which have had their ulcers for greater than one year. The literature states that only 50 to 60 percent of venous ulcers will heal within six months of therapy.[22,23] Leg ulcers can have a major impact on quality of life in addition to the clinical and cost implications. Researchers have recently validated a quality-of-life measuring tool specifically for venous ulcers. It has been reported that patients with leg ulcers suffer from a decreased quality of life. As a result of this, recent therapeutic advances for venous wounds have now incorporated quality-of-life measurements as part of the overall therapeutic outcomes data.
Despite the fact that 66 percent of the circulating blood is located on the venous side of the circulation at any one time, there is a paucity of definitive information concerning the pathophysiology of venous disease. Most of the focus has been placed on the diagnosis and treatment of arterial disorders. Reasons for this discrepancy include lack of vascular surgeon interest, lack of funding opportunities, fewer available venous diagnostic studies, lack of general awareness of atherosclerosis and heart disease in the general population, and the mistaken concept that there is a lack of life- or limb-threatening sequelae of venous diseases. Another limitation has been the difficulty in developing an adequate animal model to study venous disorders.
A brief description of the calf pump is necessary to understand venous physiology. The pump, or deep compartment, is located below the knee in the leg. The deep veins of the lower leg all empty into the outflow tract (popliteal vein). The superficial compartment includes the long and short saphenous veins and a network of subcutaneous venules and veins that empty into the deep system. An analogy to cardiac pump physiology can be drawn. During systole, blood is ejected from the superficial compartment to the deep and then on through the outflow tract via the calf pump. Causes of calf pump failure include muscle weakness, overall chamber size reduction (i.e., analogous to decreased end-diastolic filling), valvular incompetency (either superficial, deep, communicating, or any combination therein), or outflow obstruction. Normally, the resting venous pressure in the foot and leg decreases during calf contraction (ambulation or muscle contraction/compression). With any of the above-mentioned disorders, the venous pressure remains elevated throughout the gait cycle leading to chronic venous hypertension and its associated sequelae. By definition, a venous ulcer cannot exist in the presence of normally functioning calf pump. The difficulty lies in deciding which disorder is most responsible for the pump dysfunction. The inter-relationship between venous insufficiency and calf pump function was nicely researched by Araki, et al., in 1994. Recently, exercise therapy directed at the calf pump has been proposed as a mechanism to increase healing and prevent venous ulcer recurrence.
Most of the published work on pump dysfunction focuses on the impact of varicose veins and valvular incompetency. The first appreciation of the association between varicose veins and venous ulcers is attributed to Hippocrates in the Greek text De Ulceribus. In 1867, John Gay stated, “The ulceration is not a direct consequence of the varicosity but of other conditions of the venous system with which varicosity is not infrequently a complication.” Lower-limb symptoms have correlated poorly with the presence of varicosities. However, there has been a shift in thinking towards a positive correlation between primary varicose veins and ulceration.[32,33]
Homans first noted the important role of incompetent valves in the communicating veins of the calf as a cause of venous ulcerations. The problem is in determining which system of incompetent valves (deep, superficial, communicating) is either the most critical or the sole cause of calf pump dysfunction. Many patients have coexisting incompetence in all three locations, further compounding the problem. The most recent evidence supports the linear correlation of the number, size, and incompetence of calf communicating veins with the deteriorating clinical grade of the venous insufficiency. Others have shown a distribution of incompetence among the three systems.[36–38] Further complicating the issue has been the poor correlation between the prior anatomic site of a deep venous clot and the anatomical site of the subsequent valvular damage. Other researchers have focused on the hemodynamic effects of outflow obstruction when studying venous disease.
Recently, much attention has been focused on the local, cellular, and biochemical impact of calf pump dysfunction and sustained elevated venous pressures. The resultant tissue damage, ulceration, and lipodermatosclerosis may be a product of both venous pressure and time. The significance of high pressures for short duration versus low pressures for longer time frames needs to be elucidated. Clearly, an analogy can be drawn here to the pathogenesis of callus formation and diabetic foot ulceration. Much of the recent research on venous ulcer treatment options has been founded on the cellular physiology.
Homans is credited with the suggestion that “stasis” of venous return was responsible for the problem of venous ulcers as a result of stagnant anoxia. The term stasis is actually a misnomer. The concept has been disproved in the literature, but the term is still frequently used. It has actually been shown that venous blood has a normal or increased oxygen level and the flow characteristics failed to demonstrate stasis. The increased pressures previously described in chronic venous insufficiency have been shown to propagate all the way back to the nutritive capillaries. Current investigations analyze the microcirculation in venous ulcers and the periulcer tissue with conflicting results.[44–47] Recently, this type of analysis has demonstrated a prognostic index used for venous ulcer healing. Another theory has focused on the role of arteriovenous shunting as the etiology for increased microvascular flow and subsequent venous disease.[49,50]
The original theories of venous ulceration centered around the concept of the “fibrin cuff,” proposed by Browse and Burnand in 1982. Elevated venous pressures lead to biochemical disturbances when the analysis is taken out to the cellular level. Transcutaneous oxygen (TcpO2) measurements at the ulcer margin showed significantly lower values than control; however, there was marked heterogeneity in two clinical trials.[52,53] Falanga, et al., confirmed the presence of fibrin cuffs but disputed their contribution to ulcer formation. The extent to which edema contributes to venous ulcer formation is now being assessed by such techniques as high frequency ultrasound. Fluid dynamics clearly play a role in the evolution of venous ulcerations; however, the exact mechanisms are still being analyzed.[56,57] Additional theories have focused on the “trapping” of growth factors and white blood cells (WBCs).[58–62] Free radical formation secondary to perfusion-reperfusion effects and even gut-derived oxidative stress reactions have been implicated at the cellular level.[63,64] Systemic fibrinolysis abnormalities and hypercoaguable conditions can add to the complexity of venous disease.[65–69] A recent model proposes “senescent” cells, which are living but not biologically active or responsive to cytokine stimulation, as additional mechanisms at play in the pathogenesis of venous ulcerations. It should be apparent from this brief review of the pathophysiology of venous disease that debate still continues as to the exact mechanism that leads to the ulceration. As mentioned, the lack of adequate animal models further compounds the problem and blocks scientific inquiry. The cause is likely a balance between calf pump abnormalities and the microcirculatory cellular response to elevated venous pressures.
Diagnosis and Classification
An initial classification system was developed by a subcommittee of the Society for Vascular Surgery (SVS) and the International Society of Cardiovascular Surgery (ISCVS) in 1988. Because of the tremendous increase in diagnostic testing options and a broader understanding of venous disorders, a consensus statement was released by the American Venous Forum in 1994. The new classification system grouped venous patients into four categories known as CEAP (clinical, etiology, anatomic, pathophysiological).[72,73] Although the system is somewhat cumbersome, it is thorough and allows for a uniform language to help compare research findings and communicate with other clinicians on venous diseases issues. As clinical procedures continue to develop (i.e., subfascial endoscopic perforator surgery), the system will undergo modifications but appears to be clinically sound and an accepted standard.
Any patient who presents with a leg ulcer needs to undergo a complete history and physical examination as the differential diagnosis is long and complex. Wound duration, location, factors that ameliorate/exacerbate, prior treatments, pain, drainage, and the condition of the surrounding skin should all be reviewed. A complete examination of the extremity should include checking pulses and assessing for secondary signs of venous insufficiency (hemosiderin deposits, eczematous dermatitis, atrophie blanche, lipodermatosclerosis, varicose veins, and edema).[75,76] Wound biopsy is an often neglected step in the standard workup of a venous ulcer patient. Biopsy should be considered as part of the workup if the wounds are greater than six months to one year in duration, have irregular appearances, or when concerns exist for underlying inflammatory conditions or carcinoma. Frequently, a patient who was treated with a provisional diagnosis of venous disease turns out to have another condition (e.g., lymphoma and rheumatoid arthritis). The classic appearance of a venous ulcer involves a medial-leg, irregularly shaped, partial-thickness ulcer with well-defined borders surrounded by erythematous or hyperpigmented skin. Telangiectatic veins are often present along the medial ankle known as a “corona phlebectatica.” Arterial disease, which can exist in up to 30 percent of cases, must be ruled out. This can be done easily in the office by performing an ankle-brachial index. In the absence of arterial insufficiency and a normal sensory exam, venous disease is confirmed in the majority of cases with a typical appearing ulcer. The addition of a disability score to the CEAP classification scheme is important in clinical practice, as many patients have work-related problems with venous disease. Standard of care focuses on ruling out arterial disease. The proposed investigations focus on the macrocirculation. Patients with advanced lipodermatosclerosis have tissue oxygen deficits despite their normal macrovascular flow. Appropriate care would include assessment of the microcirculation in addition to standard testing (e.g., ankle/brachial index [ABI]).
The American Venous Forum recommendations begin with a complete history and physical to obtain the clinical and etiological components of the classification scheme. A tourniquet test demonstrating less than a 20-second refill time is a simple bedside test to confirm venous incompetence. The use of a continuous wave Doppler can also be a useful screen. The lack of increased flow with augmentation or the presence of increased flow with compression can indicate obstruction or reflux respectively. Once the clinical and etiological components have been completed with the history and physical exam and a working diagnosis has been agreed upon, advanced testing options are selected. The anatomic and pathophysiologic components of the classification will be made with these advanced tests.
The duplex scan has been shown to provide the most useful information and is considered by many to be the test of choice. This noninvasive, ultrasound-based test allows for the assessment of all three venous systems and provides anatomic extent and location of the disease. Duplex scanning also allows for the differentiation between obstruction and reflux. Other anatomic studies include ascending and descending venography, which are not utilized as frequently as they were in the past. A new tool, radionuclide venography, has been touted to detect incompetent perforating veins. Other examinations include photoplethysmography and strain-gauge plethysmography. A significant amount of work has been published on air plethysmography.[81,82] Physiological parameters, such as venous volume, ejected volume, and post-exercise residual volume, can be calculated using this device. Several measured parameters can be combined in useful ratio analyses, which correlate with the clinical severity of the venous disease. The American Venous Forum attempted to review the literature for clinicians to help them organize their approach to the diagnosis and classification of venous disease. Standard of care neglects the anatomical and pathophysiological components of the classification for venous disease. Many papers compare treatment techniques without classifying the underlying venous disease. Compression therapy may be inadequate if a patient has a large, incompetent perforator vein feeding the base of the ulcer. Compression therapy may also be inappropriate as sole therapy for recurrent ulcers. Appropriate care dictates that venous hemodynamics be completely analyzed in order to prescribe appropriate treatment plans.
The high prevalence of venous ulcers, variable healing rates, and costly new therapeutic options make it very important to attempt to identify patients who would benefit from these treatment options early in the course of therapy. Healing rates at 12 weeks range from 56 to 69 percent in one study based on the adequacy of the underlying arterial flow. Reported healing rates vary greatly in the literature, but very few wound healing papers have utilized the CEAP classification scheme, making comparisons impossible. One study noted improved healing outcomes in patients who were younger, who lacked deep vein involvement, who had wounds of shorter duration, and who had smaller initial surface areas. The initial rate of healing has been suggested to predict venous ulcer healing.[87–89] Authors are trying to identify predictive parameters to identify difficult-to-heal venous ulcer patients. Researchers disagree on terminology and study design.90 Interest has turned towards identifying biochemical markers that might offer predictions of subsequent healing. A recent paper describes the percentage change in area over four weeks as predictive for healing at 24 weeks. If validated by other researchers, this would be a simple, useful tool for stratifying patients and moving those patients identified as nonhealers into an “appropriate” care module instead of “standard” care. These same authors published similar works analyzing an evidence-based approach for the prediction of clinical outcomes. Clinicians frequently have a difficult time in agreeing on what is meant by a completely healed wound, further complicating understanding of the literature. In another study analyzing demographic and historical data, researchers found that fibrin covering greater than 50 percent of the wound bed and a history of prior venous surgery are significantly associated with decreased healing rates. Recent attempts at using the minimum data set (MDS) have helped uncover the prevalence of venous disease in long-term care residents. Will standard-of-care recommendations apply for this frail, elderly, immobilized patient population? Or will more advanced techniques be required?
As we discuss the treatment options in the next section, it is important to keep the information noted above in focus. Standard of care may be grossly inappropriate for a patient found by either measurement criteria or a biochemical marker to be recalcitrant. Clearly, the clinical and cost-effective method for treatment in such a case would be either appropriate or advanced care.
Compression techniques have been used since the 19th century. The German physician, Dr. Unna, developed a zinc-based bandage roll with a reinforcing elastic layer known today as the Unna boot. Compression therapy is accepted as a critical component in the standard of care for venous ulcers. Compression therapy is divided into two categories, inelastic and elastic, and is based on the underlying mechanism of action. Elastic compression works via constant compressive forces, whereas inelastic compression (e.g., Unna boot) actually functions as a rigid strut the calf muscles contract against for effective edema control. Knowledge of these differences is important because an immobilized patient would not fully benefit from inelastic compression. Papers that have not clearly identified the method of compression used are difficult to analyze and compare. Microcirculatory effects of compression relate to the Starling equilibrium model. Compression shifts the model towards absorption and decreased filtration. A classification scheme has been published that divides compression garments into Class 1 (conforming stretch bandages), Class 2 (light support bandages), and Class 3 (compression bandages). Class 3 is further subdivided into groups 3a through 3d based on the ankle level of pressure delivered. The use and effectiveness of short-stretch bandaging for the treatment of venous ulcers is well documented. A comparative trial looking at short-stretch bandaging, four-layer wrap, and support bandaging failed to identify differences. A four-layer system was recently shown to achieve a 67-percent healing rate at seven weeks. Hydrocolloid dressings have been shown to be more effective when combined with compression bandaging.[23,103] A recent meta-analysis of the compression therapy literature revealed high compression was more effective than low compression but failed to identify any particular procedure or product as more effective than the other.
Another form of compression is intermittent pneumatic compression (IPC). This device includes a leg-long cuff that applies pneumatic compression at a prescribed force with a programmed relaxation time included. This kind of compression stimulates venous return and has been shown to enhance fibrinolysis. This therapy can be applied at home usually once or twice a day. IPC and stockings outperformed stockings alone in a 12-week venous ulcer healing study. IPC performed equally as well as compression bandaging in another trial giving clinicians another option in the stocking-noncompliant patient. Other trials have shown other benefits of IPC, such as increased TcpO2 levels, and the effectiveness of the therapy when only used twice a week.[108,109]
Standard of care clearly defines the use of compression therapy for venous ulcer care. As described above, however, appropriate care dictates that the form of compression is carefully matched to the individual patient’s needs. In the cases of severe edema, lymphatic involvement, noncompliance, or inability to use compression bandages, advanced care, such as intermittent pumps, might be indicated. The ambulation status, the underlying arterial status, and financial concerns of the patient all require individualizing compression therapy to an appropriate level.
Many clinicians are still fearful of using occlusive, moisture-retentive dressings in wound care. Despite an abundance of literature in favor of moist healing, wet-to-dry gauze is still used as a primary therapeutic approach and is considered standard of care by many clinicians. Moisture-retentive dressings should be used in conjunction with compression therapy to manage the venous ulcer patient. No single dressing has been shown to unequivocally improve outcomes, and, in many instances, there are conflicting reports in the literature.[11,110–112] Dressing selection, therefore, should be individualized and focus on pain control, exudate management, odor, periwound skin condition, and cost. Moist dressings can aid in debridement, promote granulation tissue formation, and encourage epithelialization. Clinicians continue to use enzymatic agents and topical antimicrobials without definitive proof of efficacy, especially as part of a routine clinical treatment protocol. Patients with venous ulcers become easily sensitized, and some authors believe that venous dermatitis is more frequently a result of topical sensitization than true dermatitis. Numerous studies have failed to definitively correlate bacterial load or the use of systemic antibiotics with healing.[114–120]
Standard of care, therefore, directs the practitioner towards using a dressing that provides the appropriate level of moisture for optimal healing. Since no individual product has demonstrated improved significant outcomes, the clinician must be familiar with a large spectrum of products. If the patient has failed to show improvement in two to four weeks of adequate compression and a moist environment then a consideration for advanced technologies may be appropriate. Topical growth factors have been evaluated for the treatment of venous ulcers. Initially, expectations were high that growth factor technology would lead to significant improvements in healing outcomes for all chronic wounds. The FDA approved recombinant platelet-derived growth factor with a 10- to 15-percent improvement over placebo for diabetic foot ulcers. It now appears that improvements of this magnitude are actually high because chronic wound healing is multifactorial, and it is difficult to achieve significant improvements with one technology. Epidermal growth factor, transforming growth factor-beta, and tissue plasminogen activator factor have all been evaluated for the treatment of venous ulcers.[121–123] At this time, there is no definitive evidence-based support for the use of growth factor therapy for the standard treatment of venous ulcers. Patients failing to respond, however, to individualized compression therapy and appropriate dressings should be considered for these advanced therapies.
Published rates of healing for venous ulcers utilizing moist wound healing and compression are frequently less than 65 percent at 24 weeks; therefore, many clinicians and researchers have sought adjunctive therapeutic alternatives. Systemic medical therapy presents an attractive potential option. As previously reviewed, there are numerous biochemical processes involved in venous ulcer formation, which are, theoretically, modifiable through systemic therapy. Pharmacologic therapy may be beneficial in modifying the microcirculatory changes that are secondary to raised ambulatory venous pressures. It must be emphasized that medical therapy for venous ulcers is currently adjunctive to good local wound care and compression bandaging. A brief review of the published literature concerning the systemic treatment for venous ulcers follows.
Fibrinolytics. Theoretically, fibrinolytic therapy should breakdown pericapillary fibrin. A group of compounds known as defibrotides, which have antithrombotic and fibrinolytic activity, have been studied. Stanozolol, an anabolic steroid with fibrinolytic activity, has been shown to decrease lipodermatosclerotic skin changes but has not shown a benefit in ulcer healing.[126–128]
Hydroxyrutosides. These agents are thought to restore endothelial barrier function. The clinical result has been reduction in both edema and symptoms of chronic venous insufficiency.[129–131] Recently, renewed interest in horse chestnut seed extract has resulted in over-the-counter health preparations touting edema control through similar mechanisms as the hydroxyrutosides.
Prostaglandins. Prostaglandin E (PGE) has properties of vasodilation and inhibition of both platelet aggregation and polymorphonuclear cell activation. The majority of studies in the literature with this compound have been on arterial disease. One trial with intravenous PGE demonstrated promising results in the treatment of recalcitrant venous leg ulcers.
Ifetroban. Ifetroban, a thromboxane receptor antagonist, failed to show benefit over compression therapy in a randomized, controlled trial. A daily regimen of oral aspirin resulted in a statistically significant improvement in venous ulcer healing in a randomized, controlled trial. There were only 20 patients and the control group demonstrated a zero-percent healing rate. Clinical confirmation of this trial is needed, as this type of therapy would be very easy to implement.
Pentoxifylline. The most extensively studied agent for the treatment of venous disease is pentoxifylline. The drug has mild fibrinolytic activity and an ability to decrease white blood cell aggregation. These properties are not as well known to the medical community where the red blood cell deforming properties are emphasized for the treatment of intermittent claudication. Early reports demonstrated improvement in venous ulcer healing.[135,136] Dale, et al., found no significance with 400mg three times a day versus control in a 200-patient trial. Recently, Falanga, et al., have demonstrated significantly faster healing rates by utilizing 800mg three times a day versus placebo or a standard regimen of 400mg three times a day. Further trials with varying dosing regimens are obviously needed before final recommendations can be made.
In conclusion, systemic medical therapy for venous ulcers should be considered adjunctive therapy. All patients should be treated with compression and appropriate local care prior to considering systemic therapy. In cases where patients fail to improve and underlying microcirculatory issues are thought to be causative the clinician should consider these therapies for his or her recalcitrant patients.
This article is continued under "Standard, appropriate, and advanced care and medical-legal considerations" Part two: Venous ulcerations (B)
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