Differential diagnosis of leg ulcers involves consideration of a broad range of conditions (Table 1). We must start from the premise that, no matter how good the wound care is, treatment of the underlying cause is important for healing the ulcer and therefore correct diagnosis is essential. In routine clinical practice, when patients attend their family physician with a leg ulcer, they are usually referred directly to the nursing service without any prior assessment. Most leg ulcers are of vascular origin (85%), including venous ulcers (60%), arterial ulcers, and those that are a combination of both. Neuropathic ulcers account for a further 5% of the total and occur mainly in patients with diabetes. The remaining 10% of these patients have ulcers of essentially dermatologic origin caused by a variety of conditions, including vasculitis, tumor infections (Fig. 1), pyoderma gangrenosum (Fig. 2), and necrobiosis lipoidica (Fig. 3).

Figure 1.

Ulcerated tumor lesion that has become a chronic ulcer, corresponding to basal cell carcinoma.

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Figure 2.

Pyoderma gangrenosum.

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Figure 3.

Plaque of necrobiosis lipoidica with initial ulceration.

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The most common difficulty in daily practice is to distinguish between a leg ulcer of venous origin (Fig. 4) and arterial origin (Fig. 5). The considerations presented in Table 2 can be used as a guide.

Figure 4.

Typical venous ulcer.

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Figure 5.

Arterial ulcer.

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Irrespective of the cause of the ulcer, a minimal assessment should be undertaken, and this should sometimes be complemented with a more in depth evaluation.

The treatment algorithm shown in Figure 7 is valid for any type of ulcer. The first step is to treat the cause of the ulcer, if possible. Appropriate treatment would be immunosuppressive agents for vasculitis, surgery for a tumor, compression therapy for a venous ulcer, and orthopedic therapy to avoid direct pressure in the case of an ulcer associated with diabetic foot. In addition, we should bear in mind general patient characteristics, such as nutritional status, social problems, and psychological state. These are all important in wound healing. Several studies have shown that delayed wound healing can be associated with stress and high levels of adrenaline.12,13 One of the mechanisms by which this occurs is thought to be activation of β-adrenergic receptors present in the keratinocytes. This would justify the use of β-blockers in these patients, although the role of such agents in this field is still under study.14

Figure 7.

Treatment algorithm for ulcers.

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A basic issue addressed in this review, and one that applies to any chronic wound, whatever the site, is the optimum preparation of the ulcer bed, that is, how can we provide the most appropriate environment for the ulcer to heal as fast as possible. Since the study by Winter15 in 1962, we know that a moist environment accelerates healing.16 This discovery revolutionized wound management, and increasingly sophisticated wound dressings were developed. A powerful sector emerged within the pharmaceutical industry aimed almost exclusively at nursing staff. Table 3 shows the various types of dressings that have been used, starting from the early dressings made of polyurethane films with little capacity for exudate retention, up to the dressings currently available. The table is not an exhaustive list, but rather shows those dressings that the author uses on a regular basis.

The TIME acronym (tissue removal, infection control, moisture balance, and edge of the wound) was coined by Falanga et al17 to remind us of all the aspects that need to be analyzed in the management of any ulcer, and to assist us in making appropriate decisions and preparing the wound bed for healing.

• -

  Tissue removal. Removal of nonviable tissue (necrotic tissue) is necessary to reduce the risk of infection and to eliminate senescent cells, proteolytic enzymes (such as matrix metalloproteases [MMPs], the overactivity of which affects healing, particularly in the case of MMP-2 and MMP-9),18 and corrupt extracellular matrix.19 The first step is to clean the ulcer by gently rinsing with saline solution. Traditional antiseptics, such as chlorhexidine, hydrogen peroxide, or povidone iodine, should not be used as these are toxic for keratinocytes and fibroblasts in vitro. Although the question is still open to debate, the occasional use of antiseptics is considered acceptable to reduce the bacterial load.20 However, in such circumstances, guidelines recommend the use of the less toxic antibacterial agents, such as dressings impregnated with silver, cadexomer iodine, or polyhexanide (Table 4). After cleaning, if necrotic tissue is present, one of the following debridement procedures should be chosen (Table 5). If there is abundant necrotic tissue, the method of choice is surgical debridement with scissors or a scalpel because such methods can be performed quickly. However, arterial ulcers should not be debrided as ischemia increases the risk of infection, although debridement of such ulcers can sometimes be performed in the operating room. In the event of eschar of ischemic origin on the heel or neck, the best approach it to leave the eschar and not use surgical techniques. In this case and in others where surgical debridement is ruled out, we use enzymatic debridement. The most widely used agent in Spain is a collagenase ointment. This method is slow and not particularly selective, particularly when papain is used, and it can also cause pain. In the case of very dry eschar, a scalpel can be used to make incisions to facilitate the penetration of the ointment.2 In autolytic debridement the ulcer is simply maintained in a moist environment to facilitate the elimination of necrotic debris by the body's own macrophages. This approach is indicated when there is little necrotic material or for maintenance. If the ulcer bed is dry, extra moisture should be applied, for example through the use of hydrogels.21 Other less widely used debridement methods are presented in Table 6.

  Table 4.

  Nontoxic Antiseptics Suitable for Chronic Ulcers.

  A. Cadexomer iodine: Iodosorb
  - Slow-release iodine
  - Pain in 5% of applications
  - Precaution in children and patients with thyroid disease
  - Powder, gel, and strip forms
  B. Polyhexanide Prontosan
  - Gel and solution forms
  Table 5.

  Debridement Methods.

  Type	Characteristics
  Enzymatic	Slow, nonspecificMake cuts in extensive escharMay be painful
  Surgical	Fast, nonspecificMethod of choice for extensive escharNot suitable on heels or neck
  Biological (using Phaenicia sericata larvae)	Very specificNot available in Spain
  MechanicalWet to dry dressingAspiration systems	NonspecificPainful
  Autolytic	Specific, slowMethod of choice if there is limited slough
  Table 6.

  Hypotheses Proposed to Explain Chronic Ulcers.

  Theory	Therapeutic Focus
  High bacterial load or formation of biofilms	Silver dressing, lactoferrin gel, negative pressure therapyQuorum sensing inhibitors
  Disorganized or corrupted extracellular matrix	Artificial skinAmelogenin
  Excessive metalloproteinase activity	Metalloproteinase inhibiting dressingCollagen powder
  Decrease in growth factors	Application of recombinant factorsPlatelet-rich plasmaGene therapy
  Excessive activity of proinflammatory cytokines	Blockade of implicated cytokines (anti-TNF agents, etc)
  Cells with senescent phenotype	Stem cell therapies

  Abbreviation: TNF, tumor necrosis factor.
• -

  Infection control. Almost all ulcers are contaminated by bacteria. However, since the bacteria do not proliferate and their presence does not interfere with healing, routine cultures are not useful. The term colonization is used when the bacteria replicate and influence the healing process but do not invade adjacent tissues or induce signs of infection. Critical colonization refers to a situation in which the bacteria proliferate to such a degree that they start to have an impact on the healing process. The signs of critical colonization include the following: friable, grayish granulation tissue; absence of granulation tissue; increased exudate production without accompanying edema; discharge with an abnormal smell; increased pain compared to previous dressing changes; failure to improve despite correct treatment. The ulcer is said to be infected when the number of bacteria exceeds 100 000 per gram of tissue. Infection is usually accompanied by other signs, such as fever, enlarged lymph nodes, cellulitis, or purulent exudate. Samples should be taken for culture only when critical colonization or infection is suspected. Quantitative cultures are preferred, as discussed above, and treatment in the form of nontoxic antiseptics and empirical oral antibiotics can be given while waiting for the results of susceptibility testing. As is the case with traditional antiseptics, most experts do not recommend the use of topical antibiotics. In recent years, there has been much debate about the mechanisms by which bacteria can influence healing in the absence of clinical infection. Currently, most experts agree that the main mechanism by which healing is delayed is through the formation of biofilms.22 Biofilms are aggregated bacterial colonies encased in an extracellular matrix of polysaccharides that protects them against antibiotics and the immune system. Bacteria in these biofilms can produce substances that inhibit the proliferation of keratinocytes, such as lipopolysaccharides in the case of Pseudomonas aeruginosa,23 or induce the accumulation of polymorphonuclear cells and their MMPs.24 Biofilms are implicated in a number of pathologic processes in addition to chronic wounds, such as for example the formation of bacterial plaque in the oral cavity, chronic otitis media, cystic fibrosis, and chronic prostatitis.25 The means by which bacteria communicate to initiate expression of the genes that determine the synthesis of the matrix is known as quorum sensing. Intensive research into this process is underway with the hope that it will be possible to inhibit this intercellular communication. The presence of biofilms in an ulcer can be demonstrated by biopsy.26 They are found in 60% of chronic ulcers to a greater or lesser extent,27 compared to 6% of acute ulcers. The question is what to do when the presence of biofilms in the ulcer is suspected or confirmed. While we await the development of quorum sensing inhibitors, it has been shown that debridement, cadexomer iodine, lactoferrin gel, silver dressings, negative pressure therapy, and even honey are active against biofilms.28

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  Moisture balance. In line with the rationale for wet dressings discussed earlier, we should choose a dressing that retains part of the exudate in the ulcer bed, while avoiding maceration at the edge of the lesion. As shown in Table 4, several types of dressing are currently available for an uncomplicated ulcer.

  • a.

    Hydrocolloids. These dressings are coated with a combination of 3 hydrocolloids, for example sodium carboxymethylcellulose, pectin, and gelatin. Since they are fairly occlusive, their use is not recommended on infected ulcers. They are only moderately absorbent and can therefore be used in mildly exudative ulcers or when it could be useful to maximize autolytic debridement. One of the characteristics of this type of product, which can limit its use, is the formation of a viscous, pseudopurulent, and foul-smelling gel that can give the impression of infection if the physician is not aware of this possibility. These dressings have now been largely replaced by foam products.

  • b.

    Polyurethane foams. Hydrocolloids have largely been replaced by polyurethane foams in mildly or moderately exudative ulcers, not because foam dressings are any more effective but because they are more comfortable. Foam dressings are made from a combination of polyurethanes, acrylates and other substances and comprise an hydrophobic outer layer and a hydrophilic and absorbent inner layer. Adhesive and nonadhesive dressings are available. They are semiocclusive, and can be used on infected ulcers.

  • c.

    Alginates. Alginates are made of sodium alginate extracted from brown seaweed. They are extremely absorbent and are used in highly exudative ulcers. They also have hemostatic properties, making them useful in patients receiving anticoagulant therapy who have bleeding ulcers or after debridement. They should be cut to the shape of the ulcer as they can macerate the edge and, as they are not adhesive, a secondary dressing is often required.

  • d.

    Hydrofibers. Hydrofiber dressings are formed from microfibers of pure carboxymethylcellulose. These are the most absorbent dressings and they are used in the most exudative ulcers. They are not adhesive or impermeable so a secondary dressing is required.

  • e.

    Hydrogels. Hydrogels are preparations with a high water content and microcrystalline systems of polysaccharides and synthetic polymers. They come as gels or sheets, and are minimally absorbent. For this reason, they are used in dry ulcers and to facilitate autolytic debridement. The gel, which is the most widely used form, requires a secondary dressing.

  • f.

    Other dressings for consideration include the following: those containing MMP binding agents, although the in vivo efficacy of these products has yet to be demonstrated; honey dressings; silicone sheets; and extra fine foam dressings or hydrocolloid dressings, which are useful in epitheliating ulcers or for graft donor areas.

  The reader should be aware that it is impossible to review all the dressings available and that there are very few studies to guide usage.29

  Another aspect to take into account is the size of the dressing and the interval between changes. Except for alginate dressings, which have to be cut to fit the ulcer because the wound edges tend to become macerated, the dressing should extend beyond the ulcer edges by several centimeters. The interval between changes will vary according to how much exudate is produced. The exudate should not be allowed to seep through the dressing as this would render it ineffective. In general, with an appropriately absorbent dressing, we can wait 2 to 3 days between changes.

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  Edge of the wound. The edge of the wound should be kept in optimal conditions for healing.30 One technique used is to prevent maceration by applying a water-based paste at the edge of very exudative ulcers. Another approach is to debride the edges of the ulcer if they become sclerotic (a common problem in longstanding ulcers and those associated with diabetic neuropathies); in such cases we make an acute wound in a chronic ulcer to accelerate healing. If dermatitis is detected in the surrounding skin, a topical corticosteroid should be prescribed. These agents are also very useful when abundant granulation tissue protrudes beyond the edges of the ulcer; the application of a topical corticosteroid during 2 or 3 dressing changes will flatten the lesion in all cases.

This section deals with pharmacological treatments that accelerate healing and compression therapy, an essential component in the management of venous ulcers.

• a.

  Drugs in the treatment of chronic wounds. The use of drugs to promote wound healing is currently limited. Pentoxyfylline appears to speed up the healing of venous ulcers when it is administered together with compression therapy.31 Fibrinolytic and antithrombotic effects and inhibition of proinflammatory cytokines are some of the pharmacological mechanisms that could explain the action of this agent. Other potentially useful drugs include retinoic acid, applied topically at concentrations of 0.025%-0.05% to the granulation tissue to stimulate angiogenesis,32 and β-blockers to block the effect of stress-related adrenaline release on keratinocyte migration.33 However, there is little solid evidence to recommend their widespread use.

• b.

  Compression therapy. Compression therapy is the treatment of choice for venous leg ulcers.34 Unless contraindicated, it should always be used to avoid delayed venous ulcer healing. The aim of this therapy is to reduce edema and distension of the superficial venous system and to reinforce the effect of the calf muscle pump on the deep venous system. In addition, it may reduce the presence of proinflammatory cytokines in the exudate.35 There are two distinct types of compression therapy. Containment therapy, which uses short-stretch bandages, only prevents expansion of the calf when walking. This approach is not useful in patients confined to their beds as no pressure is exerted when the patient is at rest. True compression therapy, on the other hand, uses elastic systems. The pressure is governed by the Laplace law, which states that the pressure exerted on a cylindrical structure is proportional to the external pressure and inversely proportional to the radius of the structure (P=T/r). Before compression therapy is prescribed, the patient's ankle-brachial pressure index should be calculated using a Doppler ultrasound; if this index is less than 0.6, compression therapy should not be applied without consultation with a vascular surgeon. If the index is between 0.6 and 0.8, short-stretch systems should be used. For values greater than 0.8, compression therapy can be used. If, however, the index exceeds 1.2, calcification may be present, particularly in patients with diabetes, and magnetic resonance angiography should be ordered. Compression therapy can be applied with either elastic bandages or elastic stockings. For these to be useful in ulcer healing, they should apply a pressure of more than 35-40mmHg to the ankle. The conventional type of elastic bandage always has a layer of cotton in contact with the skin. The alternative is a multilayer system, in which different types of bandages (2 to 4 layers) are applied in a specific order to ensure appropriate pressure is applied. The multilayer system is more expensive, but it is simpler to apply and makes it easier to achieve the correct pressure. It is also more effective in my opinion. The drawback of using bandages is that the patient has to keep them on until the next dressing change, and trained personnel are required to achieve appropriate compression. Elastic stockings, on the other hand, have the advantage that patients can take them off at night and put them on in the morning before they start walking, although this requires a degree of skill and physical strength. Special shoehorns can, however, make it easier to put on the stockings. Elastic stockings can be classified according to the pressure they exert. Strong or grade III compression (pressure between 25-40mmHg) is indicated for active ulcers, whereas medium or normal compression, that is grade II compression (pressure between 18-25mmHg), is indicated for preventing recurrence. If the limb is deformed in the shape of a champagne bottle because of the presence of lipodermatosclerosis, elastic stockings are not useful and several layers of cotton bandage should be wrapped around the narrowest part of the limb to give it a cylindrical form before applying an elastic bandage.11 A Cochrane meta-analysis showed that compression therapy is more effective than no therapy and that multilayer systems are superior to conventional bandages.36

Between 10% and 20% of ulcers do not progress favorably notwithstanding appropriate diagnosis and treatment and even when treated in chronic ulcer units. There is no generally accepted explanation for this failure to heal, although several hypotheses have been put forward (Table 6). Some of these, such as the formation of biofilms, have been discussed earlier, and others are briefly discussed below, along with therapeutic approaches that have been proposed to address these issues.

The author declares no conflicts of interest.