CHAPTER 97: DIAGNOSIS AND MANAGEMENT OF DISEASES OF THE PERIPHERAL VENOUS SYSTEM

The lower extremity venous system includes the deep, superficial, and perforating veins, which work in concert to return blood to the heart (Fig. 97–1).¹ Unlike the arterial system, the venous system has low resistance and must overcome gravitational and hydrostatic pressure forces to achieve blood return to the heart. The venules and veins have very thin walls and low resting basal tone, which allows for enormous distensibility. As a result, small changes in hydrostatic forces, central pressure, and/or external forces result in changes of the vein diameter. Venous blood flow is reliant upon muscular leg contraction, historically referred to as “the peripheral heart,”² as well as bicuspid venous valves that open and close to prevent backflow. Together, muscular leg contraction and venous valves help to overcome hydrostatic forces within the vein itself. Venous disease results from degeneration and dysfunction of the veins and/or valves, which may occur following an obstruction such as deep vein thrombosis or in the setting of increased central pressures, as in congestive heart failure. Venous disease is associated with a wide array of clinical manifestations caused by complex hemodynamic and anatomic failures. A basic understanding of these complexities is essential in the evaluation, diagnosis, and appropriate treatment of venous disease.

The veins of the lower extremities are divided into three main subgroups, which are interconnected and together ultimately drain into the external and common iliac veins to the inferior vena cava: (1) perforator veins, (2) superficial veins, and (3) deep veins. The fascia muscularis divides the deep and superficial vein compartments; the perforator veins cross the fascial plane to connect the deep and superficial venous systems.³ A network of bicuspid venous valves exists in the deep and superficial veins to assist in venous return and prevent backflow. In the lower extremity, the deep veins accompany the corresponding arteries and their branches.⁴ The popliteal vein is formed by the confluence of the calf veins, which include the gastrocnemius vein draining into the popliteal vein and the soleal veins emptying into the tibial and then popliteal veins. Subsequently, the popliteal vein empties into the femoral vein (previously called superficial femoral vein), common femoral and iliac veins. The common femoral and external iliac vein each have one venous valve approximately 63% of the time; in 37% of patients, there is no valve present in this location.^5,6

The largest of the superficial veins, the great saphenous vein (GSV), is also the longest vein in the human body. It courses from the ankle medially up the calf and into the thigh to ultimately confluence with the common femoral vein at the saphenofemoral junction (see Fig. 97–1). Normal GSV caliber ranges from 3 to 4 mm in diameter, and 10 to 20 valves scattered along its course aide in venous outflow.⁶ Almost all patients have a “terminal valve” located at the saphenofemoral junction. The second largest superficial vein is the small saphenous vein (SSV), which courses along the lateral calf and typically drains into the popliteal vein at the saphenopopliteal junction. The SSV contains 7 to 13 venous valves and is typically 3 mm in diameter. Notably, anatomic variants of the venous system are common, and alternative drainage routes can be seen in as many as 50% of patients.⁶ Rich networks of subcutaneous and dermal vein plexuses exist as embryologic remnants of the venous system, which are spread across the lateral thigh and calf. In some conditions, abnormal development of the superficial veins may result in large varices across these networks, as seen in Klippel-Trénaunay or Parkes-Weber syndromes.⁷

Venous thrombosis may occur as a result of the risks as identified in Virchow’s Triad—stasis, endothelial injury, and the hypercoagulable state—or may occur without any known risk factors (unprovoked venous thrombosis). The treatment approach and duration rely upon the patient’s underlying risk factors, extent of thrombus, and/or affected venous segments. We will consider venous thrombosis in the superficial and deep venous systems separately.

Superficial Thrombophlebitis

Superficial thrombophlebitis (STP) classically presents as a tender, red, and indurated cord that follows the line of the affected superficial vein. Most often, the GSV is involved. The disease is reported in up to 3% to 11% of the general population, although the annual incidence of disease is not known. Higher rates are seen in malignancy, women over 60 years of age, obesity, thrombophilia, pregnancy or estrogen use, sclerotherapy, autoimmune disease, and those with varicose veins.^8,9 Overlap with deep vein thrombosis (DVT) or pulmonary embolism (PE) is reported in up to 25% of patients with STP.^10,11 Duplex ultrasonography is recommended to confirm the diagnosis of STP and exclude other causes of the swollen limb (Table 97–1), as well as screen for the presence of a concomitant DVT or extension of the clot into the deep venous system that would warrant treatment with anticoagulation.^9,12 First-line management of STP typically includes warm compresses and nonsteroidal anti-inflammatory agents for a period of 7 to 10 days. Most cases of STP are self-limited; however, anticoagulation should be considered in cases that do not respond to conservative management, or if the STP is in close proximity to the deep veins at the sapheno-popliteal (5 cm) or sapheno-femoral junction (10 cm).^12,13 Both low-molecular-weight heparin and fondaparinux at prophylactic or therapeutic doses are acceptable therapies for the prevention of DVT or PE in patients deemed to be high risk.^12,14 In cases of recurrent STP, testing for thrombophilias, search for systemic diseases (eg, thromboangiitis obliterans, Behçet syndrome), and investigation for underlying malignancy may be appropriate.⁹

Deep Vein Thrombosis

Presentation, Risk Factors, and Diagnosis

The classic clinical description of DVT includes unilateral pain, limb swelling, skin erythema, and warmth, with symptoms acute to subacute in onset. However, diagnostic testing is necessary to confirm the diagnosis, as the signs and symptoms of DVT are not reliable and cases may be clinically subtle.¹⁵ The use of clinical prediction scores, like the Wells score (Table 97–2), can be helpful in the initial evaluation of a patient with possible DVT to guide healthcare providers in deciding who may warrant additional testing with D-dimer and duplex ultrasound.^16,17 If DVT is suspected, an evaluation to confirm and define the extent of DVT should be pursued.¹⁷ Findings that support the diagnosis of DVT on duplex ultrasonography include a dilated noncompressible vein resulting from the presence of thrombus, direct visualization of thrombus, as well as altered venous flow dynamics with a lack of respiratory variation resulting from outflow obstruction or a lack of flow augmentation with calf muscle compression, indicating distal obstruction between the calf muscle and ultrasound transducer.¹⁸ Catheter-based venography, magnetic resonance (MR), and computed tomographic (CT) venography may have a role in specific situations (eg, evaluation of the pelvic veins, assessing for extrinsic vein compression), although duplex ultrasonography is the standard method for detection of acute DVT in most cases.^18,19,20 Challenges with CT venography surround appropriate contrast timing of the target vein and subsequent difficulty in obtaining a diagnostic study; MR venography, on the other hand, shows promise in overcoming the contrast issue seen with computed tomographic, although its use is limited in patients with metallic implants.²⁰ Catheter-based venography is the gold-standard for the direct visualization of venous flow and collaterals, and allows for intraluminal pressure gradient measurements and the use of intravascular ultrasound to detect a significant stenosis within the venous segment.²⁰ The use of catheter-based venography is generally limited to the evaluation of cases with possible stenosis or venous compression, and patients in whom a therapeutic intervention to relieve the obstruction is considered.^18,20

The morbidity and mortality associated with DVT are related to the proximal extent of the thrombus and risk for PE.²¹ Upper extremity DVT, at the level of the axillary veins or higher, carries risk for PE that is estimated to be as high as ~12%.^21,22 Up to 30% of patients with venous thromboembolism (VTE) suffer a mortal event within 30 days,²³ most often caused by PE, of which 25% to 30% present with hemodynamic compromise and higher risk of associated sudden death.²⁴ The number of people who experience VTE per year in the United States is not known. However, it is estimated that as many as 900,000 could be affected (1-2 per 100,000).^23,25 It is estimated that 60,000 to 100,000 people per year die from VTE in the United States. In general, unprovoked VTE, including DVT and PE, tends to recur with a cumulative incidence of 10% at one year and 30% at 8 years after the first event.²⁶ Risk factors for DVT and PE are many, and may include both intrinsic and extrinsic factors such as sex, ethnicity, inherited or acquired thrombophilia, malignancy, pregnancy, exogenous estrogen hormones, chronic disease with prolonged bedrest, stroke, recent surgery, or injury. Anatomic variants leading to extrinsic vein compression, such as in May-Thurner (Fig. 97–2), are found in up to 20% to 24% of the general population^27,28 and may account for the left-sided predominance of DVT described in the lower extremity.²⁹ In the upper extremity, thoracic outlet obstruction (ie, pacemaker implantation, thoracic outlet syndrome, or “Paget-Schroetter” effort thrombosis) and the use of central venous catheters account for most cases.³⁰ Inherited thrombophilias such as factor V Leiden, prothrombin (G20210A) gene mutation, plasminogen-activator-inhibitor 1 (PAI-1) levels or gene abnormal PAI-1 gene polymorphism, antithrombin and protein C/S deficiency are present in approximately 30% of patients presenting with VTE and may confer up to a fivefold increased risk of DVT or PE in their heterozygous state.^31,32,33 Despite these rates, routine testing for thrombophilia is not recommended as the presence of an abnormal allele only rarely affects the management of a patient with DVT or PE. Of note, in 25% to 50% of all DVT and PE, no underlying cause or risk factor is identified (unprovoked VTE).²⁵

Treatment

In the case of distal calf vein DVT, it is estimated that approximately 15% to 25% will progress to the popliteal vein and/or result in a PE.^34,35 For this reason, it is recommended that patients be treated with anticoagulation (especially if symptomatic) or an ultrasound surveillance program (ie, 1-2 week follow-up, especially if there is a significant risk of bleeding on anticoagulation) to evaluate for thrombus propagation if anticoagulation is to be withheld.^21,36 Cases in which anticoagulation should be considered over surveillance include severe associated symptoms, extensive thrombus (> 5 cm in length or involving multiple veins), thrombosis in close proximity to the deep veins (5 cm from the sapheno-popliteal junction and 10 cm from the sapheno-femoral junction), lack of identifiable and reversible provoking factors, active cancer, recurrent VTE, and in-patient status.²¹

Treatment of DVT involving the popliteal veins, or subclavian-axillary veins in the upper extremity, and more proximal segments is dictated by the presence of reversible or modifiable provoking factors (eg, surgery or exogenous hormone use), the extent of thrombus (DVT versus PE), the patient’s risk of bleeding with anticoagulation therapy, and patient preference. The guidelines for anticoagulation recommend that patients with an identifiable and reversible risk factor be treated with anticoagulation for at least 3 months prior to discontinuation.^21,37 In contrast, those without modifiable or identifiable risk factors should be considered for longer treatment duration if the risks of anticoagulation do not outweigh the perceived benefit.^21,37 Newer guidelines recognize the direct oral anticoagulants (DOACs) as first-line alternatives to warfarin therapy for the treatment of acute DVT and PE.^21,38 The DOACs include one direct thrombin inhibitor, dabigatran, as well as the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban (Table 97–3). There is variability in the recommended dosing regimens, use of heparin versus oral run-in to therapy, cost of drug, and recommended use in the setting of renal insufficiency. All have demonstrated noninferiority in comparison to warfarin for the acute treatment of venous thromboembolic disease.^{39,40,41,42,43} Apixaban was superior compared to warfarin with regard to rates of major bleeding.⁴² In patients that have completed the planned duration of anticoagulation and are deemed candidates for extended therapy, low-dose apixaban (2.5 mg twice daily) demonstrated a safety profile equal to placebo and was as effective as full-dose apixaban (5 mg twice daily) for the prevention of recurrent VTE.⁴⁴

Advanced therapies including thrombolysis and inferior vena cava (IVC) filter placement may be considered in specific scenarios, although in general these treatments are recommended only on a case-by-case assessment. For patients with a contraindication to anticoagulation, IVC filter placement may be considered for the prevention of PE.^21,37,38 However, a recent randomized trial failed to demonstrate any benefit for the use of retrievable IVC filters in patients receiving concomitant treatment with anticoagulation or thrombolysis,⁴⁵ and the most recent guidelines do not recommend routine use in this setting.^21,37,38 Catheter-directed thrombolysis (CDT) and mechanical thrombectomy are typically reserved for patients with occlusive iliofemoral DVT and symptoms ≤ 14 days duration. CDT is used in this setting to correct the outflow obstruction, rapidly relieve patient symptoms, and prevent the complication of the postthrombotic syndrome (PTS).²¹ However, the data for use of CDT to prevent PTS are limited to small and/or nonrandomized studies.^46,47,48,49 A large randomized trial entitled Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis (ATTRACT) has completed recruitment and is still actively following patients. The results of this trial will help to determine if the PTS can be prevented with more aggressive treatment.⁵⁰

Phlegmasia Cerulea Dolens

Phlegmasia cerulea dolens (PCD) is the most severe manifestation of DVT and occurs when there is near-total venous outflow obstruction of the lower extremity, resulting in limb ischemia.⁵¹ PCD is a life- and limb-threatening emergency with up to 50% of cases progressing to venous gangrene following complete occlusion of all deep and superficial veins, as well as microvascular venous collaterals.⁵¹ Although literature is scarce, associated mortality of 25% to 40% is reported and up to 15% to 25% of survivors will require amputation.^51,52 The clinical triad of PCD includes acute limb pain, massive swelling, and cyanosis, which herald a reversible phase of venous occlusion before gangrene sets in (Fig. 97–3A). Urgent management is imperative at this phase and may include systemic or catheter-directed thrombolysis, mechanical or surgical thrombectomy with or without fasciotomy, or a combination of these modalities in addition to systemic anticoagulation.^37,52,53,54 The characteristic changes of gangrene begin distally and move proximal as ischemia progresses (Fig. 97–3B). There is a strong association with malignancy, as well as inherited thrombophilia.

Venous insufficiency occurs as a result of inadequate venous outflow resulting from incompetent venous valves or obstruction. It is estimated that up 25% of the adult population in the United States and Western Europe has varicose veins, and cross-sectional studies demonstrate that > 50% of the population has some clinical manifestations of venous disease.^55,56,57 The presentation is variable, and the CEAP Classification (Table 97–4) is often used to classify disease based on clinical, etiologic, anatomic, and pathophysiologic features.^58,59 Today, the clinical classification alone is most often used. For venous disease secondary to deep vein thrombosis, the Villalta scale⁶⁰ for the PTS is most often used to define and grade the severity of disease (Table 97–5).⁶¹

Etiology, Risk Factors, and Presentation

Venous insufficiency may be either primary or secondary in etiology. Primary disease is thought to be autosomal dominant with incomplete penetrance; patients may have up to a 90% chance of developing varicose veins if both parents are affected.⁶² No candidate genes have been identified; however, familial studies in twins confirm a heritable influence on the development of disease.⁶³ Additional risk factors include female sex, obesity, prolonged standing, multiparity, and age.^64,65 Secondary causes of venous insufficiency include the PTS related to DVT or increased hydrostatic pressure as in congestive heart failure. The clinical signs and symptoms are widely varied and may range from cosmetic complaints such as spider veins and asymptomatic varicose veins to painful varicosities, edema, skin hyperpigmentation, lipodermatosclerosis, and ulceration.^1,64 A large proportion of patients may live indefinitely without symptoms related to their venous disease; however, the more severe manifestations like ulceration have a poor overall prognosis when present, with frequently delayed healing times and a high risk of recurrent ulceration.⁶⁶ Medical costs related to the management of venous disease in the United States are estimated to be upwards of $1 billion annually.^1,64 Additional indirect costs may be incurred as a result of missed workdays related to leg symptoms of chronic venous insufficiency often described as bursting, leg fullness and heaviness, burning, cramping, pruritis, and restlessness.^67,68 Symptoms are exacerbated by prolonged standing and dependency, as well as during pregnancy or other volume overload states. Elevation typically relieves the symptoms.

Diagnosis and Treatment

The diagnosis of chronic venous insufficiency is often clinical as the characteristic skin changes and symptoms readily expose the disease. Skin hyperpigmentation is caused by hemosiderin deposition resulting from long-standing venous hypertension. Venous hypertension causes edema, which leads to transudation of interstitial fluid and hemosiderin in the skin and subcutaneous space usually above the medial malleolus leading to stasis dermatitis. If this remains untreated (lack of compression), lipodermatosclerosis occurs. In this advanced manifestation of venous insufficiency, the skin is indurated and fibrotic with more extensive pigmentation and erythema. Lipodermatosclerosis is a stasis-associated panniculitis that may mimic acute cellulitis. In its most severe form, the leg has the appearance of a “bowling pin” or “inverted champagne bottle.” For most patients with venous insufficiency, conservative management including compression therapy and good skin care are mainstay. We advise that our patients keep the feet clean, dry, and well moisturized to prevent any skin breakdown or seeding of a potential infectious nidus that may complicate the disease. Control of edema is also imperative, as the excess fluid in the legs is a setup for poor wound healing in the case of venous ulceration. Compression therapy has been used for over 2000 years as treatment of chronic venous insufficiency.⁶⁹ The goals of compression therapy include (1) reduction of limb size by alteration of the venous pressure gradient and improved effectiveness of the muscle pump, (2) maintaining the limb at the smallest possible size, and (3) prevention of the complications of venous insufficiency.⁶⁹ Initially, compression wraps are recommended to achieve a reduction in limb size, as the wraps may be adjusted to the ever-decreasing limb girth day-to-day. Once edema control is achieved, a compression garment or stocking may be used to maintain edema control. Compression garments come in different grades of compression and lengths (knee-thigh, thigh-high, pantyhose). The most important area of compression is below the knee, where the standing venous pressure is greatest.¹ Most patients with varicose veins and venous insufficiency will require compression of 20 to 30 mm Hg, and some 30 to 40 mm Hg, for control. For those with an ulcer related to venous insufficiency, 30 to 40 mm Hg compression is usually needed. In patients with more severe disease related to lymphedema, compression therapy in the 40 to 50 mm Hg grade is recommended.^1,69.

Duplex Ultrasonography

For patients in whom therapies beyond conservative measures may be considered, such as recurrent venous ulceration or painful varicosities despite a trial of compression therapy, duplex ultrasonography is standard for evaluation. The goal of the exam is to define the anatomy and malfunctioning veins, as well as the extent of insufficiency. By consensus standards, evaluation should include the vein diameters, location, and competence of all saphenous junctions, perforating veins, and source veins of superficial varices.^70,71 The deep veins are also evaluated for competence, anatomy, and the presence of an obstructive lesion.⁷⁰ In addition to the maneuvers discussed in the evaluation for obstruction or DVT, the duplex exam for venous insufficiency includes provocative maneuvers to unmask abnormal reversal of flow in the vein. Normal valve mechanics include a period of proximal antegrade flow with calf muscle contraction followed by flow reversal, which leads to a reversal of the transvalvular gradient and allows for vein valve closure. Clinically relevant reflux can be measured as prolonged flow reversal. The vein is interrogated with color-Doppler and spectral waveform analysis; incompetence is demonstrated as retrograde flow occurring above the baseline (Fig. 97–4A).⁷¹ The Valsalva maneuver is performed by asking the patient to bear down, thereby increasing intrathoracic pressure and potentially reversing the transvalvular gradient. The Parana maneuver is more widely used outside of the United States, and works to initiate calf compression by having the patient stand and lean slightly forward and backward.⁷¹ Compression of the proximal limb and release of the distal limb, either manually or with standardized pressure cuffs, also work to disturb and test the normal resting pressure gradient across the valves. All maneuvers may be performed with the patient supine and standing to reveal otherwise subtle reflux disease. The majority of normal valves will close within 0.5 seconds of a maneuver, although the defined normal duration is shorter in perforating veins (< 0.35 seconds) and longer in the deeper venous segments (> 1 second).⁷² Although flow may also be detected by color-flow Doppler analysis, the duration of reflux may be underestimated as compared to measurement of flow via the spectral waveform.⁷³

Other Noninvasive Testing

Physiologic testing with plethysmography relies on volume change in the limb as a result of venous outflow or reflux disease. The most common techniques are strain gauge plethysmography, air plethysmography, and impedance plethysmography (IPG). IPG is the best-studied technique, and useful for the evaluation of venous outflow obstruction (ie, DVT) as well as venous insufficiency.^74,75 To evaluate for venous insufficiency, the legs are raised to empty the veins followed by rapid lowering of the legs. If there is incompetence, blood rushes retrograde from the proximal veins into the calves, resulting in volume increase.⁷⁶ If in the superficial veins only, application of a light tourniquet around the legs will normalize the refilling time. Exercise plethysmography assesses ejection of blood by the calf pump as well as the subsequent refilling of the lower extremities. Unlike the duplex ultrasound assessment, these modalities do not precisely localize the level of disease and most vascular laboratories do not perform these physiologic tests.

Advanced Treatments

For patients with lifestyle-limiting symptoms or complications related to venous insufficiency, advanced therapies to ablate the offending veins may be considered.^77,78 There is variability in insurance requirements for these procedures, although most plans will consider advanced therapies for patients who have failed a period of conservative therapy. The techniques to treat venous insufficiency depend upon the size and location of the veins, patient preference, and etiology of their disease. To date, endovenous procedures such as laser therapy or radiofrequency ablation are most often used for treatment of reflux in the GSV and SSV.^1,79,80,81 Both modalities use a thermal source to cause injury to the vein wall, which leads to vein occlusion. The procedures are performed under ultrasound guidance, and often in the outpatient setting, with only local anesthesia and instillation of perivenous tumescent anesthesia, which serves to encase the vein and protect adjacent structures from the heat source. Distal access is obtained (Fig 97–4B) and the catheter is tip is positioned ~2 cm from the sapheno-femoral junction. The vein is then ablated in a retrograde fashion with withdrawal of the active laser fiber. Postprocedure, all patients should return within 48 to 72 hours for an office clinical assessment and a duplex ultrasound exam to evaluate the result and exclude the complication of DVT.^77,78 Additional potential complications may include parasthesias, skin burns, thrombophlebitis, and transient pain or bruising.⁸² Recently, mechanochemical endovenous ablation techniques have emerged in lieu of thermal therapies of the GSV and SSV, and this therapy does not require infiltration with perivenous tumescence.⁸³ The technique uses a rotational wire that induces vein spasm while infusing a chemical sclerosing agent to ablate the vein. The studies available to date report high short-term occlusion rates with lower reported pain scores in patients receiving mechanochemical endovenous therapies as compared to thermal ablation, although the long-term outcomes are not yet known.^84,85.

Chemical ablation with sclerosing agents is an alternative to thermal therapies, without the mechanical counterpart described above, most often for the treatment of varicose veins and larger spider veins. A variety of agents are available, including hypertonic saline, glycerin, polidocanol, and sodium tetradecyl sulfate, which cause endothelial damage and subsequent thrombosis and fibrosis of the treated veins (Fig. 97–4C).^1,78 Complications may include hyperpigmentation or staining, caused by extravasation of the agent with hemosiderin deposition into the surrounding skin, as well as allergic reactions, matting, and, rarely, cutaneous ulceration. Most patients achieve a cosmetic improvement initially, although with a high risk of recurrence in their lifetime.¹

Vein stripping and phlebectomy or microphlebectomy procedures are less often used today, because of the prolific availability of less invasive procedures with lower pain rates and good success. However, surgery may still be preferred in patients with very superficial veins (which carry a higher potential for skin thermal injury), extremely tortuous veins (which may not allow for passage of a catheter), previous failure of endovenous therapy, or the presence of thrombus.⁸⁶

Venous ulcers are the most common leg ulceration and the most severe manifestation of venous disease (Fig. 97–5A). Up to 10% of patients in the United States living with venous insufficiency have a healed or active venous ulcer (CEAP class 5 to 6 disease).^57,87 Despite the fact that most patients are treated in the outpatient setting, the per-patient cost of venous ulcer management is estimated to be $2500 per month.^88,89 This reflects the high intensity of care needed to manage these ulcerations, including wound care supplies, medications, patient education, facility costs, vascular testing, and provider reimbursements. For patients with a healed venous ulcer, up to 50% will experience a recurrence in their lifetime.

The evaluation of a venous ulcer should include a thorough medical history and physical assessment, including area and depth measurements of the ulcer. A number of medical conditions are associated with leg ulcers, and these should be excluded.⁸⁹ Venous ulcers are generally wet, with good granulation tissue, and localize to the gaiter area of the leg with a predilection for the medial and malleoli. In contrast, arterial (ischemic) ulcers are extremely painful and often located distally (tip of toes, over pressure points). Unlike venous ulcers, they are dry and have a dark eschar because of lack of blood supply. Treatment involves revascularization and wound care. Neurotrophic ulcers (often referred to as diabetic ulcers) occur over pressure points on the foot (metatarsal area, toes, heel) and have the appearance of an open ulcer surrounded by callous. This type of ulcer occurs in patients with a peripheral neuropathy (most often from diabetes) because the patient cannot feel that they are putting abnormal pressure over a specific area. This ulcer is the most common ulcer to lead to osteomyelitis and amputation of the toe, foot, or leg. Treatment of this type of ulcer involves investigation (and treatment) for osteomyelitis, debriding the abnormal callous that is present, and fitting for a shoe that will unload this area of abnormal weight bearing. Once venous disease is confirmed, compression therapy with wound care is the foundation of venous ulcer treatment. However, four cardinal tenets (Table 97–6) promote wound healing, and in the setting of an active ulcer each should be considered and optimized. Notably, up to 26% of patients with a lower extremity ulcer have both peripheral artery (PAD) and venous disease, which may limit their tolerance of compression therapy because of impaired arterial perfusion.⁹⁰ PAD is diagnosed in the presence of an abnormal ankle-brachial index (ABI < 0.9), and PAD may be severe with an ABI < 0.5.⁹¹ Above this threshold (ABI > 0.5) or with absolute ankle pressure > 60 mm Hg, inelastic compression may be tolerated up 40 mm Hg without impaired arterial perfusion.^89,90,92 Below this threshold, modified compression and/or revascularization may be necessary to achieve wound healing. We favor adjustable compression devices (ACE wraps, Profore four-layer wrap, Unna Boot, etc.) over compression garments (stockings) when treating an active ulcer in order to optimize edema control, as well as to allow for clean wound care supplies that are regularly turned over. Multilayer compression is superior to single-layer compression for the promotion of ulcer healing.^89,93 There is limited evidence regarding the use of intermittent pneumatic compression as an alternative to compression therapy, and in general this modality is not preferred. Once ulcer healing is achieved, continued edema control with compression garments and good skin care should be optimized to minimize the risk of recurrence.

The main body of evidence surrounding the pharmacology of venous disease and venous ulcers includes pentoxifylline and the saposides (horse chestnut seed extracts). Horse chestnut seed (Aesculus hippocastanum L.) is thought to inhibit enzymes, such as hyaluronidase, which are activated by accumulated leukocytes in limbs affected by chronic venous disease, thereby reducing associated leg edema and pain, although long-term safety and efficacy have not been established.^94,95 In a Cochrane review examining the use of horse chestnut seed extract for the prevention of PTS, no improvement in symptoms of PTS was observed.⁹⁶ Pentoxifylline has been studied in the treatment of advanced venous disease and may promote venous ulcer healing via its anti-inflammatory properties and rheolytic activities.⁹⁷ Several trials suggest modestly improved healing rates with pentoxifylline, although the magnitude of effect is small and its role in the treatment of venous disease is unclear.^{98,99,100,101} Diuretics are not useful to control limb swelling related to venous insufficiency in the absence of congestive heart failure.

We would like to thank Dr. Paul W. Wennberg and Dr. Thom W. Rooke, who contributed to the previous version of this chapter in the 13th edition.