Chronic Wounds

Comment

of whether there will be a similar problem in larger clinical trials. Sibutramine, another multimonoaminereuptake inhibitor, substantially increases blood pressure as an undesirable side-effect.5 Although Astrup and colleagues did a good job of evaluating potential CNS events, this is an area that needs careful attention in phase III trials because CNS side-effects have posed a problem for rimonabant.9,10 Drugs that modulate the functions of monoamines have been in use since dexamfetamine was shown to reduce bodyweight more than 70 years ago.11 Fenfluramine was the first drug to act through serotonergic mechanisms. As monotherapy, fenfluramine had only modest effects (table). When phentermine and fenfluramine were combined, weight loss improved substantially. In Astrup’s and colleagues’ trial, if the runin period (1·1 kg) is added to the intervention period, the overall 6-month weight loss would be 7·8, 12·4, and 13·9 kg for the three doses of tesofensine, respectively. By contrast, sibutramine produced only modest effects. The reason for this difference between drugs with a similar mechanism is unclear. Weight loss with tesofensine is larger than that with other single drugs, and approaches that of fenfluramine with phentermine. The main side-effect was an increase in pulse rate and a small rise in blood pressure at the highest dose. Pharmacotherapy for obesity is a rapidly moving field, but one fraught with difficulties. On Oct 23, the European Medicines Agency recommended the suspension of the marketing authorisation for rimonabant, because of an approximate doubling

of the risk of pyschiatric disorders, compared with placebo, in obese or overweight patients who were taking the drug.12 George A Bray Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA [email protected] I am a member of the Data and Safety Monitoring Board for this trial. 1 2

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CDC. State-specific prevalence of obesity among adults: United States, 2007. MMWR Morb Mortal Wkly Rep 2008; 57: 765–68. Astrup A, Madsbad S, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1906–13. Simons-Morton DG, Obarzanek E, Cutler JA. Obesity research—limitations of methods, measurements, and medications. JAMA 2006; 295: 826–28. Haddock CR, Poston WSC, Dill PL, Foreyt JP, Ericsson M. Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials. Int J Obes 2002; 26: 262–73. Rucker D, Padwal R, Li SK, Curioni C, Lau DC. Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ 2007; 335: 1194–99. Weintraub M, Sundaresan PR, Madan M, et al. Long-term weight control study I (weeks 0 to 34): the enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo. Clin Pharmacol Ther 1992; 51: 586–94. Bray GA, Greenway FL. Current and potential drugs for treatment of obesity. Endocr Rev 1999; 20: 805–75. Bray GA, Greenway FL. Pharmacological treatment of the overweight patients. Pharmacol Rev 2007; 59: 151–73. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 2007; 370: 1706–13. Nissen SE, Nicholls SJ, Wolski K, et al, for the STRADIVARIUS Investigators. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA 2008; 299: 1547–60. Bray GA. The battle of the bulge. Pittsburgh, PA: Dorrance Publishing, 2007. European Medicines Agency. The European Medicines Agency recommends suspension of the marketing authorisation of Acomplia. Oct 23, 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAR/acomplia/ 53777708en.pdf (accessed Oct 29, 2008).

Chronic wound care Chronic wounds are defined as wounds that have not proceeded through an orderly and timely reparation to produce anatomic and functional integrity after 3 months. All wound types have the potential to become chronic and, as such, chronic wounds are classified by cause, identification and treatment of which are essential.1–3 Venous or arterial insufficiency, diabetes, and local-pressure effects are the most common pathophysiological causes, whereas systemic factors, such as compromised nutritional status, infection, and altered immunological status further contribute to poor wound healing (table). 1860

General wound-management principles can be applied to many types of chronic wounds. The Wound Healing Society has promoted the use of the TIME acronym to comprehensively define, communicate, and address key elements of impaired wound healing.4 T is for tissue: establishment of the presence of either devitalised or necrotic tissue, and identification of specific deficits. I is for the presence of inflammation or infection, or both. M describes the state of moisture balance, ranging from desiccation to maceration. E refers to the wound edge, whether non-advancing or undermined, or the extent of re-epithelialisation.4 www.thelancet.com Vol 372 November 29, 2008

Comment

Wound-bed preparation, the first step in the treatment of any chronic wound, removes the local impediments to healing by eliminating devascularised tissue, necrotic material, and excessive bacterial burden.2–4 Judicious debridement preserves vital tissue, and converts the poorly healing or impeded wound to one resembling an acute wound.5 Numerous techniques are available for debridement of wounds, including sharp surgical instruments, enzymes, mechanical devices (curettage, waterjet), biological agents (maggots), and autolytic debridement (hydrocolloid, occlusive dressings).5 No definitive evidence exists that one technique reduces healing time better than another.2,3 However, sharp forms of debridement are generally deemed fast and effective, particularly for venous, diabetic, and pressure ulcers.5 In cases of arterial insufficiency, radical debridement should be used after revascularisation, unless sepsis is a complication.5 Uncontrolled and self-sustaining inflammatory mechanisms are deemed responsible for the failure of chronic wounds to heal in many wound types.1 This phenomenon is focally addressed by decreasing bioburden to subinfection concentrations. Objective control can be characterised by quantitative tissue biopsy or by validated semi-quantitative swab techniques. Bacterial concentrations exceeding 10⁵–10⁶ bacteriacolony-forming units per gram of tissue, or any amount of β-haemolytic streptococci, will impair wound healing and surgical closure.6 Staphylococcus aureus is the most commonly identified pathogen, with meticillin-resistant forms accounting for more than 20–50% of chronic wound cases in wound-care centres and inpatient dermatological services in Europe and the USA.6 As a result, a resistogram is essential when bacterial cultures are taken.6 Although topical antibiotics can reduce the number of bacteria in chronic wounds, systemic infections, acute foot infections, and local cellulitis should be treated with systemic antibiotics.6 Osteomyelitis—best confirmed by bone biopsy—requires systemic antibiotics, vascularised soft-tissue coverage when absent, and possibly surgical intervention.7 Choice of an appropriate wound dressing should consider the necessity of a moist wound environment, the present phase of wound healing and its unique requirements, and potential side-effects.8,9 Ideally, www.thelancet.com Vol 372 November 29, 2008

Pathology

Specific therapy

Common types Venous ulcer

Deep venous insufficiency, post-thrombotic syndrome, primary varicosis

Graduated compression bandaging (if ABI >0·6), physical activity, elevation, pain assessment, superficial vein surgery (with compression)

Arterial ulcer

Macroangiopathy

Angioplasty, major vascular surgery, pharmacological improvement of blood flow, physical activity, reduction of risk factors

Diabetic ulcer

Neuropathy, small-vessels disease

Glycaemic control, off-loading or orthopaedic footwear, therapy of possible arterial or venous insufficiency

Mixed ulcer

Venous/arterial

See above (under venous and arterial ulcer)

Pressure sore

Immobility, neuropathy

Mobilisation and positioning, pressure-relieving support surfaces (alternating and continuous low-pressure systems), nutritional support (eg, MUST assessment), surgical intervention (no evidence, but expert opinion)

Vasculitis

Rheumatoid arthritis, scleroderma, polyarteritis nodosa, pyoderma gangrenosum

··

Haematological

Cryoglobulinaemia, sickle-cell disease, haemolytic anaemia, Waldenström’s macroglobulinaemia, leukaemia

··

Neoplastic

Marjolin’s ulcer, ulcus rhodens basalioma, spinalioma

··

Others

Trauma, self-inflicted wounds, Martorelli’s ulcer

··

Rare types

ABI=ankle-brachial index. MUST=Malnutrition Universal Screening Tool. Treatment for rare types includes therapy of underlying disease.

Table: Types of chronic wounds and their specific therapy

dressings should be selected that are easy to use, minimise pain, and remain in place and so minimise shear and friction forces while protecting periulcer skin.8,9 Hydrogels for the debridement phase, foam at the granulation stage, and hydrocolloids and low-adherence dressings for the epithelialisation phase are advocated.9 Yet a recent review showed that a single-modality therapy, saline or paraffin-gauze dressings, can also be used as an effective wound dressing.8 Little evidence exists that modern dressings are superior to traditional dressings in terms of general performance criteria (pain, ease of use, avoidance of wound trauma on removal, ability to absorb and contain exudates), except perhaps for hydrocolloid dressings.8 A small amount of evidence is emerging that negative-pressure therapy applied after debridement is helpful in removing fluid, promoting granulation tissue, and reducing wound size in leg ulcers.2,3 Wound assessment and progress should be monitored regularly, ideally by the same caregiver.2 An appropriate therapeutic response is a reduction in ulcer size, and if 1861

Comment

this does not occur, further diagnostic procedures are needed. Chronic wounds with exposed functional structures, such as bone, tendons, blood vessels, or nerve, often need prompt surgical intervention for protection. Even when skin grafts are used for the treatment of venous ulcers, no evidence exists that overall healing time is shortened. In cases complicated by severe lipodermatosclerosis, free flaps can accelerate healing.2 Surgical closure of pressure ulcers is generally only recommended if, despite all efforts at optimisation and prevention, the wound does not heal in a timely way.3 In such cases, composite-tissue transfer affords the best chance of sustained closure.7 Closure of wounds without optimisation of underlying comorbidities is not a long-term solution and can be expected to fail.2,3 Many adjuvants are available to help with the treatment of chronic wounds, but there are no good-quality randomised trials of them. Evidence does exist that the use of cilostazol in the treatment of arterial ulcers results in improved functional status, quality of life, and ankle-brachial index.10 Bilayered artificial skin2 and pentoxifylline,11 used with elastic multilayer high-compression bandaging for the treatment of venous ulcers, and the application of platelet-derived growth factors for neuropathic12 and pressure ulcers3 have been investigated. Primary diagnosis, attention to risk factors, management of comorbidities, and education are key to successful prevention of recurrence.1–3 Antiplatelet therapy13 and reduction of risk factors (smoking, diabetes, hyperlipidaemia, hypertension, and raised concentrations of homocysteine) are specifically advocated for arterial ulcers.13 Physical activity is helpful to prevent arterial13 and venous2,14 ulcers. Consistent use of compression and surgical correction of superficial venous reflux is essential for healing and prevention of venous ulcers.3,15 Meticulous attention to foot care, including proper bathing, nail trimming, and the use of protective footwear reduces ulceration in diabetic feet.7 Up to a 60% reduction in the incidence of pressure-sore development is possible with pressure-reducing strategies and an appropriate surface and bed type.7 An often neglected aspect of wound management is education of patients and their families in wound care.1,2 Such education improves the quality, frequency, 1862

and efficacy of dressing changes, compliance, and the treatment and prevention of recurrence.2 Wound-related education leads to improved communication, greater continuity of care, shortened hospital stays, and reduced costs, and promotes future progress in chronic wound care.1 Optimum remunerative strategies, implementation of an efficient infrastructure, and support mechanisms are often lacking and so the situation is further complicated. *Frank Werdin, Mayer Tenenhaus, Hans-Oliver Rennekampff Department of Plastic, Hand and Reconstructive Surgery, Burn Centre, University of Tübingen, 72076 Tübingen, Germany (FW); Division of Plastic Surgery, University of California San Diego School of Medicine, San Diego, CA, USA (MT); and Department of Plastic, Hand and Reconstructive Surgery, Medical School Hannover, Hannover, Germany (H-OR) [email protected] FW declares that he has no conflict of interest. HR and MT declare that they have received honoraria from Smith and Nephew for presentations. 1 2

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McInnes E, Cullum N, Nelson A, Duff L. RCN guideline on the management of leg ulcers. Nurs Stand 1998; 13: 61–63. Royal College of Nursing. Clinical practice guidelines: the nursing management of patients with venous leg ulcers: recommendations for assessment, compression therapy, cleansing, debridement, dressing, skin grafts and skin replacements, contact sensitivity, therapeutic ultrasound, laser electrotherapy, topical negative pressure and pharmacological agents, training/education and quality assurance. London: Royal College of Nursing, 2006. Royal College of Nursing. The management of pressure ulcers in primary and secondary care: a clinical practice guideline. London: Royal College of Nursing, 2005. Ayello EA, Dowsett C, Schultz GS, et al. TIME heals all wounds. Nursing 2004; 34: 26–41. Steed DL. Debridement. Am J Surg 2004; 187: 71–74. Dissemond J. Practical consequences after MRSA identification in chronic wounds. Hautarzt 2007; 12: 1–6 [in German]. Wraight PR, Lawrence SM, Cambell DA, Colman PG. Creation of a multidisciplinary, evidence based, clinical guideline for the assessment, investigations and management of acute diabetes related foot complications. Diabet Med 2005; 22: 127–36. Chaby G, Senet P, Vaneau M, et al. Dressings for acute and chronic wounds: a systematic review. Arch Dermatol 2007; 143: 1297–304. Vaneau M, Chaby G, Guillot B, et al. Consensus panel recommendations for chronic and acute wound dressings. Arch Dermatol 2007; 143: 1291–94. Hiatt WR. Pharmacologic therapy for peripheral arterial disease and claudication. J Vas Surg 2002; 36: 1283–91. Jull A, Arroll B, Parag V, Waters J. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev 2007; 1: CD001733. Miell JM, Wieman J, Steed DL, Perry BH, Sampson AR, Schwab BH. Efficacy and safety of becaplemin (recombinant human platelet-derived, growth factor-BB) in patients with non-healing, lower extremity diabetic ulcers: a combined analysis of four randomized studies. Wound Rep Reg 1999; 7: 335–46. Norman PE, Eikelboom JW, Hankey GJ. Peripheral arterial disease: prognostic significance and prevention of the atherothrombotic complications. Med J Aust 2004; 181: 150–54. Padberg FT, Johnston MV, Sisto SA. Structured exercise improves calf muscle pump function in chronic venous insufficiency: a randomized trial. J Vasc Surg 2004; 39: 79–87. Gohel MS, Barwell JR, Taylor M, et al. Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial. BMJ 2007; 335: 83.

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