TWO2

The treatment of chronic venous disease (CVD) and its complications can be frustrating. CVD can be defined as an abnormally function-ing venous system caused by venous valvular incompetence with or without associated venous outflow obstruction. The accepted statistics indicate that a Venous Leg Ulcer (VLU) requires an average of 24 weeks to heal; approximately 15% never heal; and recurrence is found once or multiple times in 15%–71% of cases. (1,2) In reported populations of venous ulcers, 15%–71% are found to be recurrent lesions. (3) Healed ulcerations possibly can have a five year recurrence rate as high as 40%. (4) With a diabetic foot ulcer, the accepted endpoint for healing is 12 weeks, while with a VLU it is 24 weeks.

A detailed history should be performed, especially if there is a healed or active ulcer. If there is a current venous ulcer, a physical exam with descriptive terms is important. The exam should be done with both the patient being supine and standing. Venous Dilatation should be described and examined by both visualization and palpation. Descrip-tion of a dilated vein can range from telangiectases to reticular veins to varicose veins. Edema indicates that the disease has progressed and is functionally advanced. The extent of the edema should be described and the limbs should be circumferentially measured. Skin Pigmen-tation changes such as venous eczema and lipodermatosclerosis are important signs of severe chronic disease. Any and all pigmentation changes should be described. Venous Ulceration is the sign of the most advanced disease. The location and the measurement of the ulcer should be well described along with any healed ulcers that have any scarring. Venous Refill Time provides an overall measurement of venous reflux.

A comprehensive venous duplex scan and ultrasound of the lower ex-tremities should be performed for all patients with significant venous disease, especially patients with venous ulceration. The information

gained from the evaluation is helpful for classifying the anatomic cause. The evaluation should be a complete mapping of the deep and superficial venous systems, from the inguinal ligament to the foot. There are three systems of veins in the lower extremities:deep, superficial, and perforating. The anatomy and physiology of each of the three venous systems need to be evaluated. The great saphenous, small saphenous, intersaphenous, accessory saphenous and all incompetent perforating veins are sized and the diameters are recorded. The absence and/or closure of a great saphenous vein or small saphenous vein from a previous surgical procedure should also be noted. Areas of acute or chronic thrombosis, scarring or thickening, tortuosity, and reflux are marked. If incompetent perforating veins are found, their location and size are noted. The location and vein of origin of all varicose clusters are noted as well. The deep venous system is evaluated for thrombosis, scarring, and reflux. Non-Invasive Arterial tests such as ABI’s and PVR’s should be done.

In 1994 an international consensus conference was held at the Ameri-can Venous Forum to develop a new classification system of (CVD). The CEAP classification was developed and implemented. (5) It is broken down into 4 components:Clinical Classification: There are seven clinical classes from 0 to 6, with 0 being no disease, 1 with signs of telengecstatis or reticular veins, 2 varicose veins, 3 edema without skin changes, 4 skin changes that are associated with venous disease, 5 skin changes with healed ulcers and 6 skin changes with active ulceration. Etiologic Classification: The type of dysfunction is classified as either congenital, primary, or secondary. Congenital are noted at birth, but don’t manifest till later in life. Primary dysfunction is of an unknown cause, while secondary dysfunction is an acquired condition such as a DVT.

Anatomic Classification: Anatomic sites of venous disease are either su-perficial, deep, and/or perforating. Either one system or all the systems can be involved in the same time.Pathophysiologic Classification: Signs or systems of CVD result from reflux, obstruction or both.

This classification system is very detailed and can be used to direct treatment for surgical versus conservative treatment. The one fault of the system is that there is no classification for other concurrent con-ditions that might affect the severity or treatment of CVD. Important considerations for other diseases such as diabetes and lymph-edema need to be taken into account because they might affect the treatment and healing times.

Healing and TreatmentWhen compared with Diabetic Foot Ulcers (DFU), healing and treat-ment for VLU’s presents with significant variability. The following are predictors for venous leg ulcers not healing: ulcer size ≥ 10 cm2, duration ≥ 12 months, history of venous ligation or venous stripping, history of hip or knee replacement surgery, ABI of < 0.80, and the presence of fibrin on more than 50% of the wound surface for 24-week healing. These were taken from a large retrospective study done by Margolis. ( 6, 7) Similar to Sheehan’s diabetic foot ulcer study, the data suggests that a venous leg ulcer that fails to decrease in size by 30% of its initial size over the first 4 weeks of treatment has a 68% probability of failing to heal within 24 weeks. (8,9)

The treatment options can be broken down to a few of categories: com-pression, local wound care, surgical intervention, medical treatment and advanced technology.

An analysis of the Cochrane review, a database of systemic reviews and meta-analyses which summarize and interpret the results of medical research, was conducted. The Cochrane Library aims to make the results of well-conducted controlled trials readily available and is a key resource in evidence based medicine.

According to the Cocharane review, multi-layered compression is the gold standard for treating VLUs. The database reviewed 39 random controlled trials and asked two questions, whether VLU’s healed more rapidly with compression than without and if single layer compres-sion gave better results than multi-layered compression. The authors concluded that multi-layered elastic compression increased healing rates. (10) The amount of compression typically should provide 30–40 mm Hg at the ankle, although compression pressure should be reduced in the setting of peripheral arterial disease (ABI < 0.8–0.7, use reduced compression pressure; < 0.7, compression relatively contraindicated).

When evaluating various dressings such as hydrocolloids, foams, alginates, and hydrogels, there were no significant healing rates of any dressings with compression. (11) Honey also showed no improved healing. (12) Various skin grafts have been compared: xenografts, frozen allografts, cultured keratinocyte grafts, and bilayered bio-engi-neered grafts. Skin autografts are the gold standard. Only the bilayered bio-engineered grafts increase venous ulcer healing. (13) It would be beneficial to use the bio-engineered tissue after edema and exudate are controlled and there is a healthy granular base.

Some medications have been administered for the treatment of VLUs. Oral zinc has been used, but there was no significant improvement.

(14) Various oral and topical antibiotics have demonstrated mixed results, with topical cadexomer iodine showing the most promising im-pact. (15) The best medication, oral or topical, is pentoxifylline. It is the only medication to be shown as an effective adjunct to compression. (16)

In a recent review of the impact of debridement on venous leg ulcer healing, ulcer surface area reduction was accelerated in visits after debridement. (17) Attention should be paid to removal of all necrotic tissue, densely adherent slough and exudates, and reshaping of the ulcer margins.

There are advanced modalities or machines that can be used to treat venous leg ulcers in conjunction with compression. Intermittent compression pumps have shown to be beneficial. The evidence is not completely clear whether the devices can be used instead of elastic bandage compression, but there are published studies to show that when used in conjunction with bandages, increased healing was demonstrated. (18)

AOTI’s Reusable Extremity Chamber

References

1. Kurz N, Kahn SR, Abenhaim L, et al., eds. VEINES Task Force Report:The management of chronic venous disorders of the leg (CVDL): an evidence-based report of an international task force. McGill University. Sir Mortimer B. Davis-Jewish General Hospital. Summary reports in: Angiology. 1997;48(1):59–66; and Int Angiol. 1999;18(2):83–102.

2. Heit JA. Venous thromboembolism epidemiology: implications for prevention and man-agement. Semin Thromb Hemost. 2002;28(suppl 2):3–13.

3. Coleridge-Smith PD. In: Negus D, Coleridge-Smith PD, Bergan JJ, eds. Leg ulcers. Diagnosis and Management. London, UK: Hodder Arnold; 2005: 12.

4. Margolis DJ, Berlin JA, Strom BL. Risk factors associated with the failure of a venous leg ulcer to heal. Arch Dermatol. 1999;135(8):920-6.

5. Kistner RL, Eklof B, Masuda EM.. Diagnosis of chronic venous disease of the lower extremi-ties: the “CEAP” classification. Mayo Clin Proc. 1996 Apr;71(4):338-45. Review.

6.Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA. The accuracy of venous leg ulcer prognos-tic models in a wound care system. Wound Rep Regen. 2004;12(2):163–168.

7.. Margolis DG, Berlin JA, Strom BL. Risk factors associated with the failure of a venous leg ulcer to heal. Arch Dermatol. 1999;135(8):920–926.

8. Kantor J, Margolis DJ. A multicenter study of percentage change in venous leg ulcer area as a prognostic index of healing at 24 weeks. Br J Dermatol.2000;142(5):960–964.

9. Sheehan P, Jones P, Caselli A, et al. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care 2003;26:1879-1882

10. O’Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD000265. DOI:0.1002/14651858.CD000265.pub2

11. Palfreyman SSJ, Nelson EA, Lochiel R, Michaels JA. Dressings for healing venous leg ulcers. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD001103. DOI: 10.1002/14651858.CD001103.pub2

12. Jull AB, Rodgers A, Walker N. Honey as a topical treatment for wounds. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD005083. DOI: 10.1002/14651858.CD005083.pub2

13. Jones JE, Nelson EA. Skin grafting for venous leg ulcers. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD001737. DOI: 10.1002/14651858.CD001737.pub3

14. Wilkinson EAJ, Hawke CC. Oral zinc for arterial and venous leg ulcers. Cochrane Database of Systematic Reviews 1998, Issue 4. Art. No.: CD001273. DOI: 10.1002/14651858.CD001273

15. O’Meara S, Al-Kurdi D, Ologun Y, Ovington LG. Antibiotics and antiseptics for venous leg ulcers. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD003557. DOI: 10.1002/14651858.CD003557.pub3

16. Jull AB, Arroll B, Parag V, Waters J. Pentoxifylline for treating venous leg ulcers. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD001733. DOI: 10.1002/14651858.CD001733.pub2

17. Cardinal M, Eisenbud DE, Armstrong DG, et al. Serial surgical debridement: A retro-spective study on clinical outcomes in chronic lower extremity wounds. Wound Rep Reg. 2009;17(3):306–311.

18. Nelson EA, Mani R, Thomas K, Vowden K. Intermittent pneumatic compression for treating venous leg ulcers. Cochrane Database of Systematic Reviews 2011, Issue 2. Art. No.: CD001899. DOI: 10.1002/14651858.CD001899.pub3

19. Athanasiou A, Karkambounas S, Batistatou A, Lykoudis E, Katsaraki A, Kartsiouni T, et al.The effect of pulsed electromagnetic fields on secondary skin wound healing: an experi-mental study. Bioelectromagnetics 2007;28(5):362–8.

20. Aziz, Zoriah, Cullum, Nicky A, Flemming, Kate. Electromagnetic therapy for treating ve-nous leg ulcers. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD002933. DOI: 10.1002/14651858.CD002933.pub4.

21. Gordillo GM, Sen CK. Revisiting the essential role of oxygen in wound healing. Am J Surg. 2003;186(3):259–263.

22. Hunt TK, Ellison EC, Sen CK. Oxygen: at the foundation of wound healing – introduction. World J Surg. 2004;28:291–293.

23. Hammarlund C, Sundberg T. Hyperbaric oxygen reduced size of chronic leg ulcers: a randomized double-blind study. Plastic and Reconstructive Surgery 1994;93(4):829–33.

24. Kranke, Peter, Bennett, Michael H, Debus, Sebastian E, Roeckl-Wiedmann, Irmgard, Schnabel, Alexander. Hyperbaric oxygen therapy for chronic wounds. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD004123. DOI: 10.1002/14651858.CD004123.pub2.

25. Heng MCY. Topical hyperbaric therapy for problem skin wounds. J Dermatol Surg Oncol 1993;19:784e93.

26. Hunt TK, Pai MP. The effect of varying ambient oxygen tensions on wound metabolism and collagen synthesis. Surg Gynecol Obstet 1972;135(4):561e7.

27. Prost-Squarcioni C, Fraitaq S, Heller M, Boehm N. Functional histology of dermis. Ann Dermatol Venereol 2008;135(1 Pt 2): 1S5e20.

28. Upson AV. Topical hyperbaric oxygenation in the treatment of recalcitrant open wounds. Phys Ther 1986;66(9):1408e12.

29. Scott GF. New Therapeutic Angiogenesis Biomarkers for Chronic Diabetic Foot Ulcers Treated with Transdermal Hyperoxia/Topical Wound Oxygen (TWO2). Department of Cell Biol-ogy and Genetics, University of North Texas Health Science Center at Fort Worth. 2005

30. Gordillo GM and Sen CK. Evidence-based recommendations for the use of topical oxygen therapy in the treatment of lower extremity wounds. The International Journal of Lower Extremity Wounds. 2009; 8 (2): 105-11.

31. Tawfick W, Sultan S. Does topical wound oxygen (TWO2) offer an improved outcome over conventional compression dressings (CCD) in the management of refractory venous ulcers (RVU) A Parallel Observational Study. European Society for Vascular Surgery, 2009;38:125-132.

32. Khilnani NM, Grassi CJ, Kundu S, et al. Multi-society consensus quality improvement guidelines for the treatment of lower-extremity superficial venous insufficiency with endovenous thermal ablation from the society of interventional radiology, cardiovascular interventional radiological society of Europe, American college of phlebology, and Canadian interventional radiology association. J Vasc Interv Radiol. 2010;21(1):14–31.

33. Gloviczki P, Yao J (eds.). Handbook of venous disorders: Guidelines of the American Venous Forum, 3rd Edition. New York, NY: Oxford University Press USA; 2009.J Dermatol Surg Oncol 1993;19:784e93.

As we know, Oxygen (O2) is essential to wound healing. Local tissue hypoxia, caused by disrupted or compromised vasculature, is a key factor that limits wound healing. (21) Clinical use of O2 to promote wound healing began in the 1960s with the administration of systemic full body hyperbaric oxygen therapy (HBO) to treat wounds. (22)

Today, HBO is usually administered in single- or multiplace chambers utilizing pressures of 2,500 mb and higher. There has been only one study on venous ulcers which indicated a significant reduction in wound area at 6 weeks following the administration of HBO. (23) Challenges and adverse events resulting from HBO include complica-tions such as ruptured tympanic membrane, sinus irritation, oxygen and pressure induced pulmonary toxicity, temporary worsening of short-sightedness, Central Nervous System (CNS) oxygen toxicity and claustrophobia. Although serious adverse events are rare, systemic HBO cannot be regarded as an entirely benign intervention. Furthermore, HBO in the treatment of recalcitrant ulcers requires transportation to the treatment site (RCTs suggest 38 dives required over a 7 week period) and is associated with a significant increase in cost. Any cost/benefit advantage should be carefully considered. (24)

Cyclically pressured, humidified oxygen (TWO2) applied topically to the open wound bed has demonstrated similar and possibly more beneficial results. The traditional limitations of a full body hyperbaric chamber have been overcome by an approach that allows the topical application of humidified oxygen directly to the open wound, at above ambient pressure cycled between 4 and 38mmHg every 35 seconds, to only the specific wound site, in the home setting. This maximizes the beneficial wound healing effects while avoiding the inconvenience and cost of transportation and minimizing the negative systemic side effects seen in traditional HBO. (25) The intermittent cycled pressure, under which TWO2 is delivered, enhances circulation, reduces edema and provides a sealed humidified environment essential for healing. (26) TWO2 promotes epithelialization and capillary angiogenesis. (27) This leads to higher tensile strength collagen being formed during wound healing, which reduces scarring and the risk of recurrence. (28) TWO2 therapy reduces wound bed hypoxia, promoting the antimi-crobial effect of ROS and the respiratory burst, and improving the signal transduction pathway through increases in cellular mediating biomarkers such as FGF for collagen formation and VEGF promoting neovascularization (angiogenesis) (29,30).

Tawfick et. al, conducted a pivotal Level II study comparing TWO2

(study group) with elastic compression dressings (control group). The following is a summary of their study: Patients with CEAP C6,s VLUs, assessed by duplex ultrasonography, were managed with either TWO2

(n=46) or conventional compression dressings (CCD) (n=37) for 12 weeks or until full healing. Patients were followed up at 3 monthly intervals. The results at 12 weeks revealed that 80% of TWO2 managed ulcers were completely healed compared to 35% of CCD ulcers (p < 0.0001). Median time to full healing was 45 days in TWO2 patients and 182 days in CCD patients (p < 0.0001). The pain numerical rating scale (PNRS) threshold in TWO2 managed patients improved from 8 to 3 within 13 days. After 12-month follow-up, 5 of the 13 healed CCD ulcers demonstrated signs of recurrence while none of the ulcers closed using TWO2 had recurred. (31)

Surgical management of VLUs has its role. Surgical intervention can be proactive to prevent venous ulcers, as s treatment to help unhealed venous ulcers, and help with prevention of recurrence. (32,33)

The algorithm is divided into evaluation and treatment of VLUs. On the left side of the algorithm describes a complete work up including stud-ies to test both the venous and arterial system. The treatment portion is based on high level evidence of what has been shown to work. This evidence is based on either articles with Level 2 or better evidence and/or using the Cochrane database. By following the algorithm, patients have a higher likely hood that their ulcer will heal and possibly not come back.