1. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. In the Clinic Venous Leg Ulcers

2. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. Why do patients with chronic venous insufficiency develop VLU?  CVI most common cause of VLU  VLU patients have venous hypertension, or abnormally sustained elevation of venous pressure on walking  Caused by vein valve reflux, outflow problems or both  Venous outflow issues  Venous obstruction  Poor function of calf muscle pump impairs venous system's ability to return venous blood to heart  Ankle movement limitations contribute to calf muscle pump failure

3. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What are the risk factors for VLU?  Age older than 55 years  Family history of CVI  Ulcer history, parental history of ankle ulcers  Higher body mass index  History of pulmonary embolism  Venous reflux in deep veins, history of superficial/DVT  Lower extremities skeletal or joint disease  Number of pregnancies  Physical inactivity  Severe lipodermatosclerosis

4. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. Are there measures that can prevent VLU or their recurrence?  Aggressive management of reversible risk factors  Control of relevant comorbid conditions (CHF, PVD)  Healthy diet, appropriate exercise, weight control  Management of a hypercoagulable state  Stockings that achieve at least 20-30 mm Hg pressure  Patients should use highest level of compression tolerable  Surgical venous ablation

5. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. CLINICAL BOTTOM LINE: Prevention...  CVI is the leading cause of VLU  Venous hypertension with calf muscle pump dysfunction  Manage comorbid risk factors  CVI, obesity, hypercoagulable states  Skeletal and joint disease of the lower extremities  Compression stockings  For primary and secondary prevention  Venous intervention  For secondary prevention

6. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What symptoms and physical findings are suggestive of CVI?  Swelling and aching of legs, worse at end of day and improved by leg elevation  History of ulcer recurrence, particularly at same location  Dependent edema, telangiectasias, varicose veins, reddish-brown pigmentation and purpura, and subsequent hemosiderin deposition  Eczematous changes with redness, scaling, pruritus  Smooth, ivory-white, stellate atrophic plaques of sclerosis with telangiectases (atrophie blanche)  Chronic lipodermatosclerosis (LDS) and acute LDS

7. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. Chronic venous insufficiency

8. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. Atrophie blanche

9. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What symptoms and physical findings suggest that VLU are due to CVI?  VLU may be painful—dull, aching, or burning pain  Location over medial lower third of the legs  Usually 1 ulcer w/ irregular, flat, or only slightly steep borders  Ulcer bed shallow, with granulation tissue or fibrinous material  Wound surface rarely shows necrosis, exposed tendons, bone  Venous dermatitis, LDS, or atrophie blanche around ankle  Assessment: Test for neuropathy  Severity of CVI correlates with decreased range of motion at ankle and is associated with peripheral neuropathy  VLU pain neuropathic in origin in some patient

10. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. Venous leg ulcer

11. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What other conditions should be considered during evaluation of a patient with possible VLU?  Common causes of lower extremity ulcers  CVI  Arterial insufficiency  Diabetic neuropathy  Prolonged pressure  Less common causes  Trauma  Inflammatory or metabolic conditions  Cancer  Infections

12. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What is the role of laboratory testing?  No single laboratory test is diagnostic  Testing may be indicated depending on specific patient history, comorbidities, and family history  In patients with history of recurrent ulceration or thrombosis, evaluate for hypercoagulable states

13. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What is the role of noninvasive tests, such as ankle-brachial index and duplex ultrasonography?  Ankle-brachial index should be performed  For PAD screening: concomitant arterial disease in ~20%  Compression therapy could worsen an arterial ulcer  Color duplex ultrasonography  For accurate diagnosis and to provide prognostic info  Photo and air plethysmography  Whole-limb venous hemodynamics at rest and after exercise  CT exam  Intractable edema associated with pain despite compression

14. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What is the role of routine testing for infection?  Swab culture testing unwarranted w/o signs of infection  If atypical infection suspected: send tissue from wound biopsy for microscopic examination and culture  Use antibiotic therapy only for clinically infected ulcers  Evidence supports topical cadexomer iodine for healing  No evidence supports use of systemic antibiotics

15. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. When should clinicians consider obtaining a biopsy or referring the patient to a surgical or nonsurgical specialist for diagnosis?  To rule out other causes of VLU, especially cancer  When ulcers are atypical-appearing ulcers  When ulcers have not healed after 4 weeks of active treatment

16. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. CLINICAL BOTTOM LINE: Diagnosis...  Typically based on clinical history and physical examination  Presence of CVI  Single, painful ulcer with irregular, flat borders and granulating or fibrinous bed on medial lower third of legs  Color duplex ultrasonography to characterize venous disease in all patients  Ankle-brachial index to exclude concurrent PAD  If VLU do not improve within 4 weeks of active therapy: consider referral to specialist or biopsy

17. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What is the overall approach to treatment?  Treatment goals  Reduce edema and pain  Heal ulcers  Prevent recurrence  Systematic approach needed  Assess frequently and escalate treatment if unresponsive  Simplest treatment: bed rest with leg elevation  Elevate legs above heart 30 minutes, 3 to 4x/d + at night  Reduces swelling, improves venous microcirculation  Most patients struggle to follow this recommendation

18. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What is the role of compression therapy?  Cornerstone of therapy  Because sustained leg elevation often difficult to achieve  Gold standard: multiple elastic layers for graduated compression  Increases interstitial hydrostatic pressure  Improves venous return  Reduces venous hypertension and edema  Improves ulcer healing rates  Use cautiously with CHF and with arterial insufficiency  Don’t use with severe arterial insufficiency

19. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. How long should clinicians prescribe compression therapy?  Continue until the ulcer heals  Continue indefinitely after healing to prevent recurrence  To enhance adherence, instruct how to put on stockings  Ensure proper measurement and fit  Assistive devices may help arthritic, obese, elderly patients  Replace at least every 6 months

20. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What is the role of medication?  To improve healing in combination with compression  Aspirin (300 mg daily)  Pentoxifylline (400-800 mg 3x/d)  To reduce LDS inflammation, pain, induration  Stanozolol  Oxandrolone  Horse chestnut seed extract (active ingredient: aescin)  To reduce pain (based on neuropathic origin)  Amitriptyline, gabapentin, pregabalin

21. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What is the role of growth factors?  Granulocyte macrophage colony-stimulating factor  Topical and perilesional injection increases ulcer healing  Promotes wound healing through many mechanisms (homeostasis, inflammation, proliferation, maturation)  Increases vascularization  FDA-approved for neutropenia but not wound healing  Phase 3 trials stopped due to bone pain associated with perilesional injections

22. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What is the role of physical therapy or exercise?  Aim: to improve range of ankle movement and calf muscle pump function  Might enhance ulcer healing  But evidence conflicting and RCTs lacking  RCT underway: comparing compression therapy with compression therapy + 12 weeks of supervised exercise

23. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What is the role of hyperbaric oxygen therapy?  Adjunct to standard wound care  Controversial because evidence for treating VLU extremely limited  100% oxygen at 2-2.5 atmosphere absolute for 60- to 120- minute periods over 15-30 sessions  Goal: increase partial pressure of oxygen at the wound  Role in pathogenesis and treatment unclear  Fibrin cuff theory: fibrin cuffs formed around precapillary vessels may result in wound hypoxia, so increased oxygen might aid healing

24. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What is the role of surgical debridement or skin grafting?  Debridement  Removes nonviable tissue to achieve an appropriate wound bed with granulation tissue  Standard care despite lack of controlled data on healing  Skin grafting  Enhances healing for large or slow-healing ulcers  May rapidly decrease pain and aid functional status  Pinch grafts, split-thickness skin grafts, and micro-skin grafts used successfully but RCTs lacking  Skin equivalents (cellular, acellular) may aid healing

25. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. What is the role of venous surgery in treatment and prevention?  Venous surgery  Doesn’t improve healing but reduces recurrence  Open surgery has significant potential morbidity  Cochrane review found no evidence for benefit or harm  Subfascial endoscopic perforator surgery  Safer, possible improved healing, decreased recurrence  Minimally invasive procedures  Treat CVI and recurrence  Endovenous thermal ablation (laser, radiofrequency, steam)  US-guided foam sclerotherapy; cyanoacrylate embolization

26. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. When should clinicians consider referring the patient to a surgical or nonsurgical specialist for treatment?  Prognostic factors associated with slower healing  Larger wound area (>5 cm 2 ) and long duration (>6 months)  LDS and ulcer history, BMI >33 kg/m, physical inactivity  Prolonged venous filling time, deep venous insufficiency  Ulcer depth >2 cm, atypical ulcer location (posterior calf)  Refer to wound specialist when wounds fail to decrease in size during first month of treatment  Expertise may be found in a variety of specialties  Vascular medicine and surgery, podiatry, dermatology

27. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. How should clinicians educate patients?  Encourage patients to adhere to compression therapy  Provide educational materials on pathophysiology, management, and prevention  Consider video-based educational interventions to teach patients about the disease  Consider patient support groups for education on self- management

28. © Copyright Annals of Internal Medicine, 2016 Ann Int Med. 165 (2): ITC2-1. CLINICAL BOTTOM LINE: Treatment...  Goals: reduce edema, improve pain and LDS, heal ulcer, prevent recurrence  Maintenance:  Moist wound bed and regular sharp debridement  Infection control  Compression with elastic multilayer bandages  If no improvement in 4 weeks: consider referral to wound expert and adjuvant therapies  Prevent recurrence: indefinite use of compression stockings and vascular intervention