Guidelines for the treatment of venous ulcers

Abstract

An advisory panel of academicians, private practice physicians, podiatrists, nurse clinicians, research nurses, industrial scientists, and an epidemiologist was chosen to develop guidelines for the treatment of venous ulcers of the lower extremity. Previous guidelines, meta-analyses, PubMed, MEDLINE, EMBASE, The Cochrane Database of Systematic Reviews, recent review articles of venous ulcer treatment, and the Medicare/CMS consensus of usual treatment of chronic wounds were all reviewed for evidence. Guidelines were formulated, the underlying principle(s) enumerated, and evidence references listed and coded. The code abbreviations for the evidence citations were as follows: STAT Statistical analysis, meta analysis, consensus statement by commissioned panel of experts RCT Randomized clinical trial LIT REV Literature review CLIN S Clinical case series RETRO S Retrospective series review EXP Experimental laboratory or animal study TECH Technique or methodology description PATH S Pathological series review There were major differences between our approach to evidence citations and past approaches to evidence-based guidelines. Most past approaches relied only on publications regarding clinical human studies. Laboratory or animal studies were not cited. We have used well-controlled animal studies that present proof of principle, especially when a clinical series corroborated the laboratory results. It was also clear that principles that have been validated for other chronic wound types often are applicable to venous ulcers. Therefore, evidence was sometimes cited that was not specific for venous ulcers. Because of these variations, a different system was used to grade the evidence weight supporting a given guideline. The level strength of evidence supporting a guideline is listed as Level I, Level II, or Level III. The guideline levels are: Level I: Meta-analysis of multiple RCTs or at least two RCTs support the intervention of the guideline. Another route would be multiple laboratory or animal experiments with at least two clinical series supporting the laboratory results. Level II: Less than Level I, but at least one RCT and at least two significant clinical series or expert opinion papers with literature reviews supporting the intervention. Experimental evidence that is quite convincing, but not yet supported by adequate human experience is included. Level III: Suggestive data of proof of principle, but lacking sufficient data such as meta-analysis, RCT, or multiple clinical series. NB: The suggestion in the guideline can be positive or negative at the proposed level (e.g., meta-analysis and two RCTs stating intervention is not of use in treating venous ulcers). Guidelines have been formulated in eight categories for the treatment of venous ulcers of the lower extremities. The categories are: Diagnosis Compression Infection Control Wound Bed Preparation Dressings Surgery Adjuvant Agents (Topical, Device, Systemic) Long-Term Maintenance Each of the separate guidelines underwent a Delphi consensus among the panel members to be critically evaluated. There was a consensus of at least ten panel members on each individual guideline. The majority of the guidelines had unanimous concurrence. The draft guidelines were presented at an open conference on October 3, 2005. Following the conference and audience discussion, a period of one month was allowed for written comments and submission of additional evidence literature. The draft guidelines were then modified, taking into consideration all verbal and written comments. The resultant Guidelines for the Treatment of Venous Ulcers follows. Preamble: Ulcers of the lower extremity may be caused by a variety of conditions. Elevation of ambulatory venous pressure (venous hypertension) is the most common. However, as treatment of the ulcer may vary depending on ulcer etiology, it is paramount that a correct diagnosis is made before treatment. Guideline #1.1: Gross arterial disease should be ruled out by establishing that pedal pulses are present on physical examination and/or that the ankle : brachial index (ABI) is >0.8. (Any ABI less than 1.0 suggests a degree of vascular disease and compression therapy is usually considered to be contraindicated with an ABI<0.7.) In elderly patients, patients with diabetes mellitus, or patients with an ABI>1.2, a toe : brachial index of >0.6 or a trans-cutaneous oxygen partial pressure of >30 mmHg in the region of the ulcer may help to suggest an adequate arterial flow (Level I). Principle: Venous ulcers can exist in the presence of mixed arterial/venous pathology. However, treatment of only the elevated venous pressure will not succeed when significant arterial disease is present. Evidence: Porter JM, Moneta GL. International consensus committee on chronic venous disease: reporting standards in venous disease: an update. J Vasc Surg 1995; 21: 635–45 [STAT]. Beebe HG, Bergan JJ, Bergqvist D et al. Classification and grading of chronic venous disease in the lower limbs: a consensus statement. Eur J Vasc Endovasc Surg 1996; 12: 487–92 [STAT]. Beebe HG, Bergan JJ, Bergqvist D et al. Classification and grading of chronic venous disease in the lower limbs: a consensus statement. Internat Angiology 1995; 14: 197–201 [STAT]. Porter JM, Rutherford RB, Clagett GP et al. Reporting standards in venous disease. J Vasc Surg 1988; 8: 172–81 [STAT]. Kjaer ML, Mainz J, Soerensen LT et al. Clinical quality indicators of venous leg ulcers: development, feasibility, and reliability. Ostomy/Wound Manage 2005; 51: 64–74 [STAT]. Trent JT, Falabella A, Eaglstein WH et al. Venous ulcers: pathophysiology and treatment options. Ostomy/Wound Manage 2005; 51: 38–54 [LIT REV]. Robson MC, Hanfnt J, Garner W et al. Healing of chronic venous ulcers is not enhanced by the addition of topical repifermin (KGF-2) to standardized care. J Appl Res 2004; 4: 302–11 [RCT]. Hirsch AT, Criqui MH, Treat-Jacobson D et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001; 286: 1317–24 [CLIN S]. Guideline #1.2: Many definitions have been used to diagnose venous leg ulcers including clinical history and examination, invasive, and noninvasive testing. It is important to understand how the diagnosis was made and to understand the limitations of the method. Color duplex ultrasound scanning performed with proximal compression or a Valsalva maneuver is useful in providing anatomic and physiologic data helping to confirm a venous etiology for the leg ulcer (Level I). Principle: Although clinical history and physical examination can be very suggestive of a venous etiology of the lower extremity ulcer after insufficient arterial inflow has been eliminated, a definitive diagnosis of the venous disease is desirable. This is not always possible. When using various tests to document venous disease, it is paramount that the information needed by the clinician be clearly communicated to the test performer. Evidence: Porter JM, Moneta GL. International consensus committee on chronic venous disease. Reporting standards on venous disease: an update. J Vasc Surg 1995; 21:635–45 [STAT]. Beebe HG, Bergan JJ, Bergqvist D et al. Classification and grading of chronic venous disease in the lower limbs: a consensus statement. Eur J Vasc Endovasc Surg 1996; 12: 487–92 [STAT]. Beebe HG, Bergan JJ, Bergqvist D et al. Classification and grading of chronic venous disease in the lower limbs: a consensus statement. Int Angiol 1995; 14: 197–201 [STAT]. Porter JM, Rutherford RB, Clagett GP et al. Reporting standards in venous disease. J Vasc Surg 1988; 8: 172–81 [STAT]. Kjaer ML, Mainz J, Soerensen LT et al. Clinical quality indicators of venous leg ulcers: development, feasibility, and reliability. Ostomy/Wound Manage 2005; 51: 64–74 [STAT]. Mekkes JR, Loots MA, VanDerWal AC et al. Causes, investigation, and treatment of leg ulceration. Br J Dermatol 2003; 148:388–401 [LIT REV]. Guideline #1.3: Patients presenting with an apparent venous ulcer and who are suspected of having sickle cell disease should have a sickle cell prep and a hemoglobin electrophoresis (Level II). Principle: Patients with homozygous, heterozygous, or trait sickle cell hemoglobin can present with lower extremity ulcers resembling venous ulcers. Evidence: Karayalcin G, Rosner F, Kim KY et al. Sickle cell anemia—clinical manifestations in 100 patients and review of the literature. Am J Med Sci 1975; 269: 51–68 [LIT REV]. Wolfort FG, Krizek TJ. Skin ulceration in sickle cell anemia. Plast Reconstr Surg 1969; 43: 71–7 [CLIN S]. Guideline #1.4: Apparent venous ulcers that have been open continuously without signs of healing for 3 months or that do not demonstrate any response to treatment after 6 weeks should be biopsied for histological diagnosis (Level III). Principle: Malignancy, vasculitis, collagen-vascular diseases, and dermal manifestations of systemic diseases may present as ulcers on the lower extremity. Evidence: Hansson C, Andersson E. Malignant skin lesions on the legs and feet at a dermatological leg ulcer clinic during five years. Acta Derm Venereol 1997; 78: 147–8 [CLIN S]. Snyder RJ, Stillman RM, Weiss SD. Epidermoid cancers that masquerade as venous ulcer disease. Ostomy/Wound Manage 2003; 49: 63–6 [CLIN S]. Mekkes JR, Loots MA, VanDerWal AC et al. Causes, investigation, and treatment of leg ulceration. Br J Dermatol 2003; 148: 388–01 [LIT REV]. Chakrabarty A, Phillips T. Leg ulcers of unusual causes. Int J Low Extrem Wounds 2003; 21: 207–16 [LIT REV]. Guideline #1.5: Apparent venous ulcers, as well as all wounds, that are excessively painful and that progressively increase in size after debridement and/or despite treatment should be considered for other diagnoses such as pyoderma gangrenosum, IgA monoclonal gammopathies, Wegener's granulomatosis, cutaneous chronic granulomatous disease, and mycobacterial or fungal etiologies. This suspicion should be especially high if the ulcer is darker in color, has blue/purple borders, or if the patient has a systemic disease such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, collagen vascular diseases, leukemia, or immunosuppression (Level II). Principle: Leg ulcers that worsen in size and symptoms despite treatment, or do not show any improvement over 4 weeks of treatment, should raise suspicion that the ulcer etiology is not venous in origin or that the therapy needs to be re-evaluated. At this point, specific cultures for mycobacteria and/or fungi are useful, as biopsies for histology. Evidence: Reichrath J, Bens G, Bonowitz A et al. Treatment recommendations for pyoderma gangrenosum: an evidence-based review of the literature based on more than 350 patients. J Am Acad Dermatol 2005; 53: 273–83 [STAT]. Su WP, Schroeter AL, Perry HO et al. Histopathologic and immunopathologic study of pyoderma gangrenosum. J Cutan Pathol 1986; 13: 323–30 [PATH S]. Hickman JG, Lazurus GS. Pyoderma gangrenosum: a reappraisal of associated systemic diseases. Br J Dermatol 1980; 102: 235–7 [LIT REV]. Wines N, Wines M, Ryman W. Understanding pyoderma gangrenosum: a review. Med Gen Med 2001; 3: 6–12 [STAT]. Bennett ML, Jackson JM, Jorizzo JL et al. Pyoderma gangrenosum. A comparison of typical and atypical forms with an emphasis on time to remission. Case review of 86 patients from 2 institutions. Medicine (Baltimore) 2000; 79: 37–46 [CLIN S]. Preamble: Venous ulceration results from an elevated ambulatory venous pressure (venous hypertension). This frequently causes edema of the limb. External compression has been the mainstay to combat these problems. Guideline #2.1: The use of a Class 3 (most supportive) high-compression system (three layer, four layer, short stretch, paste-containing bandages, e.g., Unna's boot, Duke boot) is indicated in the treatment of venous ulcers. Although these modalities are similar in effectiveness, they can differ significantly in comfort and cost. The degree of compression must be modified when mixed venous/arterial disease is confirmed during the diagnostic work-up (Level I). Principle: Venous ulcer healing is increased when adequate compression is applied to the lower extremity. Evidence: Cullum N, Nelson EA, Fletcher AW, Sheldon TA. Compression for venous leg ulcers. The Cochrane Database of Systematic Reviews. (2001 Issue 2) The Cochrane Collaboration. John Wiley & Sons Ltd. [STAT, 23 RCT]. Ennis WJ, Meneses P. Standard, appropriate, and advanced care and medical-legal considerations: part two—venous ulcerations. Wounds 2003; 15: 107–22 [LIT REV]. Burton CS. Treatment of leg ulcers. Dermatol Clin 1993; 11: 315–23 [TECH]. Falanga V. Care of venous ulcers. Ostomy/Wound Manage 1999; 45 (Suppl. 1A): 33S–43S [LIT REV]. Robson MC, Hanfnt J, Garner W et al. Healing of chronic venous ulcers is not enhanced by the addition of topical repifermin (KGF-2) to standardized care. J Appl Res 2004; 4: 302–11 [RCT]. DePalma RG, Kowallek D, Spence RK et al. Comparison of costs and healing rates of two forms of compression in treating venous ulcers. Vasc Surg 1999; 33: 683–90 [RCT]. Guideline #2.2: Intermittent pneumatic pressure (IPC) can be used with or without compression dressings and can provide another option in patients who cannot or will not use an adequate compression dressing system (Level I). Principle: Intermittent pressure stimulates venous return and can be utilized when constant compression is not tolerated. Evidence: Smith PC, Sarin S, Hasty J et al. Sequential gradient pneumatic compression enhances venous ulcer healing: a randomized trial. Surgery 1990: 108: 871–5 [RCT]. Rowland, J. Intermittent pump versus compression bandages in the treatment of venous leg ulcers. Aust NZ J Surg 2000; 70: 110–3 [RCT]. Ennis WJ, Meneses P. Standard, appropriate, and advanced care and medical-legal considerations: part two—venous ulcerations. Wounds 2003; 15: 107–22 [LIT REV]. Because venous hypertension is an ongoing condition, a degree of compression therapy should be continued constantly and forever. (see Long-Term Maintenance Guidelines.) Preamble: Infection results when the bacteria : host defense equilibrium is upset in favor of the bacteria. Infection plays various roles in the etiology, healing, operative repair, and complications of venous ulcers. Guideline #3.1: Remove all necrotic or devitalized tissue by sharp, enzymatic, mechanical, biological, or autolytic debridement (Level I). (Detailed discussion of debridement is in Wound Preparation Guidelines.) Principle: Necrotic tissue is laden with bacteria while devitalized tissue impairs the body's ability to fight infection and serves as a pabulum for bacterial growth. Evidence: Edlich RF, Rodeheaver GT, Thacker JG et al. Technical factors in wound management. In Dunphy, JE, Hunt, TK, editors. Fundamentals of Wound Management in Surgery. South Plainfield, NJ: Chirurgecom, 1977 [EXP]. Bradley M, Cullum N, Sheldon T. The debridement of chronic wounds: a systematic review. Health Tech Assess 1999; 3(17 Part 1): 1–78 [STAT]. Steed D, Donohue D, Webster M et al. Effect of extensive debridement and rhPDGF-BB (Becaplermin) on the healing of diabetic foot ulcers. J Am Coll Surg 1996; 183: 61–4 [RCT]. Witkowski JA, Parrish LC. Debridement of cutaneous ulcers: medical and surgical aspects. Clin Dermatol 1992; 9: 585–91 [LIT REV]. Falanga V. Wound bed preparation and the role of enzymes: a case for multiple actions of therapeutic agents. Wounds 2002; 14: 47–57 [LIT REV]. Hamer MI, Robson MC, Krizek TJ et al. Quantitative bacterial analyses of comparative wound irrigations. Ann Surg 1975; 181: 819–22 [EXP]. Saap LJ, Falanga V. Debridement performance index and its correlation with complete closure of diabetic foot ulcers. Wound Rep Reg 2002; 10: 354–9 [RCT]. Davies CE, Turton G, Woolfry G et al. Exploring debridement options for chronic venous ulcers. Br J Nurs 2005; 14: 393–7 [LIT REV]. Guideline #3.2: If infection is suspected in a debrided ulcer, or if epithelialization from the margin is not progressing within 2 weeks of debridement and initiation of compression therapy, determine the type and level of infection in the debrided ulcer by tissue biopsy or by a validated quantitative swab technique (Level II). Principle: High levels of bacteria ≥1 × 106 CFU/g of tissue or any tissue level of beta hemolytic streptococci impede the various wound-healing processes and have been demonstrated to impede spontaneous healing and surgical closure of venous ulcers. Cultures should be performed to isolate both aerobic and anaerobic bacteria. Evidence: Robson MC, Stenberg BD, Heggers JP. Wound healing alterations caused by infection. Clin Plast Surg 1990; 17: 485–92 [LIT REV]. Robson MC. Wound infection: a failure of wound healing caused by an imbalance of bacteria. Surg Clin North Am 1997; 77: 637–50 [LIT REV]. Lookingbill DP, Miller SH, Knowles RC. Bacteriology of chronic leg ulcers. Arch Dermatol 1978; 114: 1765–8 [RCT]. Tobin GR. Closure of contaminated wounds: biologic and technical considerations. Surg Clin North Am 1984; 64: 639–52 [LIT REV]. Heggers JP. Variations on a theme. In: Heggers JP, Robson MC, editors. Quantitative Bacteriology: Its Role in the Armamentarium of the Surgeon. Boca Raton: CRC Press, 1991: 15–23 [TECH]. Levine NS, Lindberg RB, Mason AD et al. The quantitative swab culture and smear: a quick method for determining the number of viable aerobic bacteria in open wounds. J Trauma 1976; 16: 89–94 [TECH]. Nystrom PO. The microbiological swab sampler—a quantitative experimental investigation. Acta Pathol Microbiol Scand 1978; 86B: 361–7 [TECH]. Volenec FJ, Clark GM, Manni MM et al. Burn wound biopsy bacterial quantification: a statistical analysis. Am J Surg 1979; 138: 695–8 [STAT]. Stephens P, Wall JB, Wilson MJ et al. Anaerobic cocci populating the deep tissues of chronic wounds impair cellular wound healing responses in vitro. Br J Dermatol 2003; 148: 456–66 [CLIN S]. Schraibman IG. The significance of beta-haemolytic streptococci in chronic leg ulcers. Ann R Coll Surg Engl 1990; 72: 123–4 [CLIN S]. Guideline #3.3: For ulcers with ≥1 × 106 CFU/g of tissue or any tissue level of beta hemolytic streptococci following adequate debridement, decrease the bacterial level with topical antimicrobial therapy. Once in bacterial balance, discontinue the use of the topical antimicrobial agent to minimize any possible cytotoxic effects due to the antimicrobial agent or emergence of bacterial resistance to the agent (Level I). Principle: Systemically administered antibiotics do not effectively decrease bacterial levels in granulating wounds; however, topically applied antimicrobials can be effective. Evidence: Robson MC. Wound infection: a failure of wound healing caused by an imbalance of bacteria. Surg Clin North Am 1997; 77: 637–50 [LIT REV]. Bishop JB, Phillips LG, Mustoe TA et al. A prospective randomized evaluator-blinded trial of two potential wound healing agents for the treatment of venous stasis ulcers. J Vasc Surg 1992; 16: 251–7 [RCT]. Lookingbill DP, Miller SH, Knowles RC. Bacteriology of chronic leg ulcers. Arch Dermatol 1978; 114: 1765–8 [RCT]. Fumal I, Braham C, Paquet P et al. The beneficial toxicity paradox of antimicrobials in leg ulcer healing impaired by a polymicrobial flora: a proof-of-concept study. Dermatology 2002; 204 (Suppl. 1): 70–4 [RCT]. Robson MC, Mannari RJ, Smith PD et al. Maintenance of wound bacterial balance. Am J Surg 1999; 178: 399–402 [RCT]. Schraibman IG. The significance of beta-haemolytic streptococci in chronic leg ulcers. Ann R Coll Surg Engl 1990; 72: 123–4 [CLIN S]. Halbert AB, Stacey MC, Rohr JB et al. The effect of bacterial colonization on venous ulcer healing. Australas J Dermatol 1992; 33: 75–80 [CLIN S]. White RJ, Cooper R, Kingsley A. Wound colonization and infection: the role of topical antimicrobials Br J Nurs 2001; 10: 563–78 [LIT REV]. Madsen SM, Westh H, Danielsen L et al. Bacterial colonization and healing of venous leg ulcers. APMIS 1996; 104: 815–99 [CLIN S]. Holloway GA, Johansen, KH, Barnes, RW et al. Multicenter trial of cadexomer iodine to treat venous stasis ulcer. West J Med 1989; 151: 35–8 [RCT]. Guideline #3.4: Cellulitis (inflammation and infection of the skin and subcutaneous tissue most commonly due to streptococci or staphylococci) surrounding the venous ulcer should be treated with systemic gram-positive bactericidal antibiotics (Level II). Principle: Edema fluid (plasma) neutralizes the fatty acids of sebum and inactivates the normal bactericidal properties of skin. This renders the skin and subcutaneous tissue susceptible to infection by streptococci and staphylococci. Evidence: Ricketts LR, Squire JR, Topley E et al. Human skin lipids with particular reference to the self-sterilizing power of the skin. Clin Sci Mol Med 1951; 10: 89–93 [EXP]. Baddour LM. Cellulitis syndromes: an update. Int J Antimicrob Agents 2000; 14:113–6 [LIT REV]. Chiller K, Selkin BA, Murakawa GJ. Skin microflora and bacterial infections of the skin. J Invest Dermatol Symp Proc 2001; 6: 170–4 [LIT REV]. Guay DR. Treatment of bacterial skin and skin structure infections. Expert Opin Pharmacother 2003; 4: 1259–75 [LIT REV]. Edlich RF, Winters KL, Britt LD et al. Bacterial diseases of the skin. J Long Term Eff Med Implants 2005; 15: 499–510 [LIT REV]. Dall L, Peterson S, Simmons T et al. Rapid resolution of cellulites in patients managed with combination antibiotic and anti-inflammatory therapy. Cutis 2005; 75: 177–80 [RCT]. Guideline #3.5: Minimize the tissue level of bacteria, preferably to ≤105 CFU/g of tissue, with no beta hemolytic streptococci in the venous ulcer before attempting surgical closure by skin graft, skin equivalent, pedicled, or free flap (Level II). Principle: “A wound containing contaminated foci with greater than 105 organisms per gram of tissue cannot be readily closed, as the incidence of wound infection that follows is 50–100%” Tobin (1984). Evidence: Edlich RF, Rodeheaver GT, Thacker, JG et al. Management of soft tissue injury. Clin Plast Surg 1977; 4: 191–8 [LIT REV]. Liedberg NC, Reiss E, Artz CP. The effect of bacteria on the take of split thickness skin grafts in rabbits. Ann Surg 1955; 142: 92–6 [EXP]. Krizek TJ, Robson MC, Ko E. Bacterial growth and skin graft survival. Surg Forum 1968; 18: 518–9 [RCT]. Murphy RC, Robson MC, Heggers JP et al. The effect of contamination on musculocutaneous and random flaps. J Surg Res 1986; 41: 75–80 [EXP]. Tobin GR. Closure of contaminated wounds: Biologic and technical considerations. Surg Clin North Am 1984; 64: 639–52 [LIT REV]. Browne AC, Vearncombe M, Sibbald RG. High bacterial load in asymptomatic diabetic patients with neurotrophic ulcers retards wound healing after application of Dermagraft. Ostomy/Wound Manage 2001; 47: 44–9 [RCT]. Aspects of wound bed preparation are deliberately left out of this section because they are covered elsewhere. (Detailed discussions of infection control, dressings, and tissue engineering/growth factors are in Infection Control Guidelines, Dressings Guidelines, and Adjuvant Agents [Topical, Device, and Systemic] Guidelines.) Preamble: Wound bed preparation is defined as the management of the wound to accelerate endogenous healing or to facilitate the effectiveness of other therapeutic measures. The aim of wound bed preparation is to convert the molecular and cellular environment of a chronic wound to that of an acute healing wound. The principles of wound bed preparation have been enumerated: Schultz GS, Sibbald RG, Falanga V et al. Wound bed preparation: a systematic approach to wound management. Wound Rep Reg 2003; 11: 1s–23s. Sibbald RG, Williamson D, Orsted HL. Preparing the wound bed: debridement, bacterial balance, and moisture balance. Ostomy/Wound Manage 2000; 46: 14–35. Guideline #4.1: Examination of the patient as a whole is important to evaluate and correct causes of tissue damage. This includes factors such as: (A) systemic diseases and medications, (B) nutrition, and (C) tissue perfusion and oxygenation (Level II). Principle: (A) A general medical history and physical examination, including a medication record, will help in identifying and correcting systemic causes of impaired healing. The presence of a major illness or systemic disease and drug therapies such as immunosuppressive drugs and systemic steroids will interfere with wound healing by alterations in immune functioning, metabolism, inflammation, nutrition, and tissue perfusion. Autoimmune diseases such as rheumatoid arthritis, uncontrolled vasculitis, or pyoderma gangrenosum can all delay healing and may require systemic steroids or immunosuppressive agents before local wound healing can occur. Patients undergoing major surgery have a diminished wound-healing capacity as do chronic smokers. This information in addition to a detailed history of the wound itself is of benefit. Evidence: Lazarus GS, Cooper DM, Knighton DR et al. Definitions and guidelines for assessment of wounds and evaluation of healing. Arch Dermatol 1994; 130: 489–93 [STAT]. William DT, Harding K. Healing responses of skin and muscle in critical illness. Crit Care Med 2003; 31 (Suppl. 8): 547s–57s [LIT REV]. Beer HD, Fassler R, Werner S. Glucocorticoid-regulated gene expression during cutaneous wound repair. Vitam Horm 2000; 59: 217–39 [EXP]. Vaseliso M, Guaitro E. A comparative study of some anti-inflammatory drugs in wound healing in the rat. Experientia 1973; 29: 1250–1 [EXP]. Jorgensen LN, Kallehave F, Karlsmark T et al. Reduced collagen accumulation after major surgery. Br J Surg 1996; 83: 1591–4 [CLIN S]. Sorensen LT, Nielsen HB, Kharazini A et al. Effect of smoking and abstention on oxidative burst and reactivity of neutrophils and monocytes. Surgery 2004; 136: 1047–53 [RCT]. Mustoe T. Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy. Am J Surg 2004; 187 (5A): 65s–70s [LIT REV]. Principle: (B) Nutrition must be adequate to provide sufficient protein to support the growth of granulation tissue. Although most venous ulcer patients are ambulatory and not as nutritionally depleted as patients who require frequent or chronic hospitalization, nutritional support is required if an individual is undernourished. Evidence: Bourdel-Marchasson I, Barateau M, Rondeau V et al. A multicenter trial of the effects of oral nutritional supplementation in critically older inpatients. GAGE Group. Groupe Aquitain Gériatrique d'Evaluation. Nutrition 2000; 16: 1–5 [RCT]. Lansdown AB. Nutrition 2: a vital consideration in the management of skin wounds. Br J Nurs 2004; 13: 1199–210 [LIT REV]. Himes D. Protein-calorie malnutrition and involuntary weight loss: the role of aggressive nutritional intervention in wound healing. Ostomy/Wound Manage 1999; 45: 46–51, 54–5 [LIT REV]. Principle: (C) Wounds will heal in an environment that is adequately oxygenated. Oxygen delivery to a wound will be impaired if tissue perfusion is inadequate. Dehydration and factors that increase sympathetic tone such as cold, stress, or pain will all decrease tissue perfusion. Cigarette smoking decreases tissue oxygen by peripheral vasoconstriction. For optimal tissue perfusion, these factors must be eliminated or minimized. Evidence: Chang N, Goodson WH, Gottrup F et al. Direct measurement of wound and tissue oxygen tension in postoperative patients. Ann Surg 1983; 197: 470–8 [CLIN S]. Knighton DR, Halliday B, Hunt TK. Oxygen as an antibiotic. a comparison of the effects of inspired oxygen concentration and antibiotic administration on in vivo bacterial clearance. Arch Surg 1986; 121: 191–5 [EXP]. Hunt TK, Hopf HW. Wound healing and wound infection. What surgeons and anesthesiologists can do. Surg Clin North Am 1997; 77: 587–606 [LIT REV]. Jonsson K, Jensen JA, Goodson WH et al. Tissue oxygenation, anemia, and perfusion in relation to wound healing in surgical patients. Ann Surg 1991; 214: 605–13 [RCT]. Jensen JA, Goodson WH, Hopf HW et al. Cigarette smoking decreases tissue oxygen. Arch Surg 1991; 126: 1131–4 [RCT]. Hopf H, Hunt TK, West JM et al. Wound tissue oxygen tension predicts the risk of wound infection in surgical patients. Arch Surg 1997; 132: 997–1004 [CLIN S]. Gottrup F. Oxygen in wound healing and infection. World J Surg 2004; 28: 312–5 [LIT REV]. Hunt TK, Aslam RS. Oxygen 2002: wounds. Undersea Hyperb Med 2004; 31: 147–53 [LIT REV]. Guideline #4.2: Initial debridement is required to remove the obvious necrotic tissue, excessive bacterial burden, and cellular burden of dead and senescent cells. Maintenance debridement is needed to maintain the appearance and readiness of the wound bed for healing. The health care provider can choose from a number of debridement methods including sharp, enzymatic, mechanical, biological, or autolytic. More than one debridement method may be appropriate (Level I). Principle: Necrotic tissue, excessive bacterial burden, senescent cells, and cellular debris can all inhibit wound healing. Sharp debridement is often the most advantageous. However, the method of debridement chosen may depend on the status of the wound, the capability of the health provider, the overall condition of the patient, and professional licensing restrictions. Excessive debridement can result in a reinstitution of the inflammatory process with a consequent influx of inflammatory cytokines. Evidence: Steed DL. Debridement. Am J Surg 2004; 187 (Suppl. 5A): 71s–4s [LIT REV]. Ayello EA, Cuddigan J. Debridement: controlling the necrotic/cellular burden. Adv Skin Wound Care 2004; 17: 66-75 [LIT REV]. Sieggreen MY, Maklebust J. Debridement: Choices and challenges. Adv Wound Care 1997; 10: 32–7 [LIT REV]. Bradley M, Cullum N, Sheldon T. The debridement of chronic wounds: a systematic review. Health Technol Assess 1999; 3(17 Part 1): 1–78 [STAT]. Sibbald RG, Williamson D, Orsted HL. Preparing the wound bed: debride