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HOW TO HEAL A WOUND FAST
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DERMATOLOGIC THERAPY
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HOW TO HEAL A WOUND FAST Hugo J. Degreef, MD
Wounds and wound healing are as old as mankind. Throughout the centuries, all kinds of techniques have been used and recommended. For acute wounds, the greatest progress has been made by asepsis, antisepsis, the development of safe and effective microbial agents, modern surgery, and anesthesia. The treatment of chronic wounds was certainly not considered great medicine, as this citation made in 1805 shows: "The treatment of such cases is generally looked upon as an inferior branch of practice, an unpleasant and unglorious task where much labor must be bestowed, and little honor gained."43 Since the 1980s, the joint efforts of clinicians and researchers from several disciplines have generated an air of excitement about the progress being made in the field of wound healing. The healing process is being better understood, new dressings are being developed, and growth factors are being discovered. This process has resulted in the formation of wound-healing societies and journals dedicated exclusively to wound healing. Numerous congresses are now being devoted to wound healing and to the several factors involved in this process. In specialized centers for wound healing and diabetic foot clinics, better results are being achieved by a multidisciplinary approach. In dermatology, however, it is certainly not yet the most popular subject. Still, I think that dermatologists should occupy a prominent
place in this area. This article gives an overview of therapeutic approaches, nonsurgical dermatologic treatments in particular. The types of wounds we discuss include acute wounds, infected acute wounds, chronic wounds, infected and colonized chronic wounds, and incurable wounds. ACUTE WOUNDS
The treatment of acute wounds and certainly of large acute wounds belongs primarily to the domain of the surgeon. With many causes, wounds will always heal, but they can have life-threatening or dramatic consequences for the life of the patient not only during the sometimes very long healing phase with much pain and discomfort but also by eventual consequences such as loss of function and permanent disfigurement. Some causes include surgical wounds, penetrating wounds, avulsion injuries, crushing injuries, shearing injuries, burns, and others (bites, chemical burns, factitious wounds, etc.). In general, the cause of an acute wound is well known and a single event. The treatment consists of skin closure, whenever possible, by first intention (primary healing) or by delayed primary closure, together with the application of an appropriate dressing. Often, however, such a method of treatment is not possible, and then the treatment has to proceed over several stages (secondary healing). To initiate a correct therapy
From the Department of Dermatology, University Hospital Sint-Rafael, Catholic University, Leuven, Belgium
DERMATOLOGIC CLINICS
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VOLUME 16 NUMBER 2 APRIL 1998
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and to provide a prognosis, a careful determination of the seriousness is needed. For example, in burns, the depth and the size determine the therapeutic approach (fluid replacement, conservative approach, or more aggressive surgical procedures). Local wound care consists of cleansing the wound, debridement, prevention of infection, and dressing of the wound. These conservative measures are discussed, together with the local symptomatic treatment of chronic wounds. Surgical interventions to close the skin defect may be lifesaving. The outcome of surgical interventions has improved considerably with the development of surgical skin transplantation techniques such as split skin grafts and mesh autografting. New therapeutic possibilities such as keratinocyte autografting or allografting and skin equivalents or the temporary application of homologous donor skin can stimulate tissue granulation and offer new ways of replacing the patient’s own skin when autologous skin is scarce or even result in better cosmetic outcome. Infected Acute Wounds
The great fear with acute wounds is infection, with intense inflammation and tissue destruction. Further spread of the infection can be life-threatening. Removal of organisms by cleansing and also debridement of nonviable and necrotic tissue, combined with an appropriate dressing to prevent the entry of bacteria, are very important in the prevention of infection. In acute wounds hypoxia can result in infection. Some causes of hypoxia are iatrogenic such as excess of tissue trauma, excess of wound tension, and inadequate hemostasis. Some endogenous conditions such as arteriosclerosis or diabetes may be present. Wounds in poorly perfused tissues become infected far more often than wounds in well perfused tissues. Resistance to bacteria requires a transcutaneous oxygen tension (TcpO,) over 30 mm Hg.35Indeed, oxygen is required by neutrophils for the creation of free oxygen radicals that kill bacteria. Bacteria deplete the old tissue and newly forming tissue of oxygen and nutrients, resulting in anoxia, and also produce a wide variety of endotoxins and exotoxins, which directly cause cell injury and cell death. Hypovolemia, cold, and fear can
further deteriorate wound oxygenation secondary to reflex constriction of the cutaneous microvascular bed.23 In acute wounds, clinical infection and wound breakdown occur when a bacterial load greater than 100,000 per gram of tissue is reached. This threshold number of bacteria holds true for all bacterial species other than streptococci, which can cause infection in lesser quantities.3O To determine the bacterial load several methods can be used.12The biopsy method is the gold standard but is not available in many hospitals. The standardized quantitative swab is the method that is used the most and expresses in a semi-quantitative way the number of colony-forming-units(CFU/volume). It is conducted in most hospitals, is nonaggressive, and has high specificity, but in some instances the presence of an infection is overestimated. A simple rapid slide technique (gram-stained smears) can tell within 1 hour whether or not more than 100,000 bacteria per gram of tissue are present in a wound. Early diagnosis and treatment of infection with targeted systemic antibacterials, combined with removal of foreign material and good wound drainage, can restore the healing process and prevent the breakdown of a wound. CHRONIC WOUNDS
The dermatologist is often confronted with chronic wounds, which are wounds or ulcers that heal slowly or not at all. When the tissue’s ability to maintain its integrity or to heal damage is no longer or only partially present, it is absolutely necessary to detect the cause of this failure through examination. Accurate Diagnosis The physician cannot apply the proper therapeutics without a correct diagnosis -AURELIUS CORNELIUS CELSUS, 25 BC TO 50 AD
Wound healing is the result of several separate but related and partially overlapping processes. These processes do not occur all in the same place or at the same time and can be retarded by many factors. Listing and discussing the very many factors that can disturb normal wound healing would take us
HOW TO HEAL A WOUND FAST
beyond the scope of this article. Impaired metabolism and especially impaired oxygen supply to the tissues are the main causes of such wounds. Venous ulcers, ulcers caused by arterial insufficiency, pressure sores, and metabolic defects in diabetic patients are the chronic wounds that the dermatologist will most frequently encounter. Genetic disorders, factitious wounds, chronic ulcerating infections, vasculitis, and iatrogenic ulcers (radiotherapy, cytotoxic drugs, heparin, etc.) are other, but rarer, causes. For an accurate diagnosis, clinical inspection and good clinical examination often do not suffice, although they are generally indicative for further approach. Targeted biochemical examination, supplemented by certain technical examinations (Doppler, TcpOz, arteriography, phlebography, etc.), complete the e ~ a m i n a t i o n These . ~ ~ examinations help to provide a more precise classification. For example, there are four stages of classification for pressure sores, a classification and grading system for venous dysfunction (American Venous Forum, 1994),’ and classification of Wagner (1987)50 or classification of Sims (1988)41for the diabetic foot. These classifications also provide a good basis for further therapeutic approaches because dealing with the cause or all of the negative factors is the best way for a successful treatment.
Etiologic Treatment It is impossible to discuss all etiologic treatments, so I will only discuss some of them briefly: Improvement of nutrition. Better control of blood sugar in diabetes. Cessation of smoking. Surgical treatment of peripheral arterial disease can not only contribute to the healing of arteriosclerotic ulcers but also prevent recurrence. In these patients and in patients with mixed arterio-venous ulcers, the desirability and possibility of surgical intervention to improve tissue hypoxia must be considered. Relief of prolonged excessive pressure for pressure sores but also with neurotrophic ulcers as in diabetics is the very first therapeutic step. In this last group of patients, this is preferably done by relieving the pressure by means of a removable or even a permanent cast: possibly with
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a hydrocolloid dressing. The adaptation of the footwear with correct pressure distribution is essential postcare to prevent recurrence. For pressure sores, the use of pressure-distributing seat cushions, mattresses, and beds will promote healing. Muscle and musculocutaneous flaps are often the most appropriate treatments for the definitive healing of pressure sores in paraplegic patients or in patients with ulcers above osteomyelitis areas and ulcers in radiation areas. Treatment of immunologic processes such as pyoderma gangrenosum or treatment of vasculitis. A biopsy of such lesions is sometimes necessary for making the correct diagnosis and also for providing correct treatment.
Leg ulcers in patients with chronic venous insufficiency are a major problem for the dermatologist. For patients with a history of inexplicable deep venous thrombosis as the cause of their deep venous insufficiency, one should always consider the possibility of acquired or congenital clotting syndromes and, if possible, treat them. In addition to the local symptomatic treatment, which is discussed in an upcoming section, other measures are needed to obtain good healing. Compression therapy has a long history, having been used by the Egyptians. But, as for many modes of treatment for ulcers, there is still much discussion today about its practical application, although everybody is convinced of its utility. Many doctors ”forget” to prescribe the treatment, and patient compliance often leaves something to be de~ired.2~ There are different ideas about the practical application between the continents, but even in Europe there is still no uniform concept. In continental Europe and in our department, the use of nonelastic bandages until total reduction of edema or healing of ulceration occurs is r e c ~ m m e n d e d In . ~ ~the United Kingdom, the four-layer bandage is often used,& whereas an Unna boot is still common practice in the United States.28 Pressure needs to be modified as a function of the underlying disease. The application of a compression bandage is not easy, and experience is necessary to develop good technique. As pressure is applied, account must be taken of the bandage tension and the radius of the surface. The retromalleolar sulci must be filled with cotton wool, and the pre-
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tibia1 area must be protected with the same material. The bandage must be worn during the daytime because the technique depends on an interaction between the bandage and the muscle pump. At night, the bandage can be removed.29 In the maintenance phase, we advise the use of elastic therapeutic hosiery. The choice of elastic compression stockings depends on the patient, and ready-made hosiery is indicated only for the “average leg.” In the other cases, custom-made hosiery is best. The major indicator for good elastic stockings is the absence of edema. Compression therapy is not indicated for leg ulcers due to arteriosclerosis and should be used only with the greatest caution with mixed arterio-venous ulcers. Surgical treatment or sclerotherapy of the insufficient veins and ligation of underlying insufficient perforantes may reduce the likelihood of recurrence.
Symptomatic Therapy
It is not always possible to eliminate the provoking factor(s), but even in such cases, correct measures can still lead to improvement or healing of ulcers. The goals are improvement of the patient’s general condition and improvement of quality of life with great concern for pain reduction. The local therapy for chronic ulcers consists of cleansing, debridement, dressings, and sometimes surgery. Cleansing
Wounds likely to be contaminated require thorough cleansing to remove loose debris, foreign material, and bacteria. Cleansing should not cause further damage to viable tissue. Abundant irrigation with tap water, saline solution, or a nontoxic antiseptic solution (hibitane aqueous solution 0.05% or povidone iodine) is recommended as the gentlest method. One may also use a bath or shower to cleanse ulcers. The use of strong antiseptic solutions is not recommended because there is the risk of damaging vital cells. In exceptional cases, it may be necessary to do this cleansing under general anesthesia. Debridement
Debridement is the removal of nonviable yellow or black tissue.55Its importance in en-
hancing healing is undisputed. The nonviable tissue is often spontaneously removed (autolysis), but this process is time consuming and retards the healing of the wound. One should not promote the formation of crusts, scabs, or eschars by dehydrating the wound. A dry wound is a dead wound, and an eschar is not ”God’s dressing.” Only in exceptional cases of dry, black necrosis (as in a pressure sore on the heel) is it preferable not to debride the necrotic skin.’* Surycal Debridement
Surgical debridement is certainly the most rapid way to remove necrotic material and is often unavoidable. This is generally done by a surgeon, and general anesthesia is often necessary (severe gangrenous ulcers, traumatic ulcers, osteomyelitis). In less serious cases, debridement can be done by the dermatologist with scissors and forceps. In order to ease the pain, a lidocaine-prilocaine cream (EMLA cream) can be used.21 Promotion of Autolysis
The process of autolysis can be promoted by hydration of the necrotic tissue, which also facilitates the mechanical removal and accelerates the healing process. This method can be used especially for smaller yellow or black necrosis. There are a number of possibilities. The Conventional Method. The conventional method consists of long-term application of wet compresses with saline, hibitane 0.05 aqueous solution, or chloramine solutions (wet-to-wet or wet-to-moist dressings). Occlusive Dressings. Hydrocolloid dressings and amorphous hydrogels under semipermeable transparent polyurethane film dressings are good alternatives. They are less time consuming to apply and have better patient compliance. Hydrocolloid dressings, when used to debride a wound, must be frequently renewed. Not only can toxic substances and necrotic material then be regularly removed but also regular wound inspection permits the timely discovery of infecti~n.~~ Mechanical Debridement
The mechanical removal of necrotic tissue can be done by forceful irrigation and wet-todry dressings. Wet-to-dry dressings are usually associated with some discomfort or pain
HOW TO HEAL A WOUND FAST
and can be traumatic to granulation tissue. Soft, moist yellow necrosis can also be removed by foam dressings and dextranomer under occlusive plastic films. Enzymatic Debridement
In enzymatic debridement, proteolytic enzymes of bacterial, vegetable, or animal origin are used (fibrinolysin, streptokinase, streptodornase, trypsin,2O collagenase,4°,49 or krill enzymes.ls They dissolve dead tissue. Because of the production of protease inhibitors by live cells, the live cells remain intact. Although proteolytic enzymes are certainly to be considered for theoretical reasons, the clinical results are generally insufficient, and some products cause itching or pain (trypsin). Osmotic Debridement 47 honey,I5 or karayagum-powder can be used for osmotic debridement. These agents are not only good debriding agents, but they can also absorb large amounts of exudate. The dry conditions under these products are unfavorable for bacterial growth and prevent infection. Some recent xerodressings (alginates, dextranomer, etc.) are good dehydrating agents but are mainly indicated for strongly exudative wounds and not, in the first place, for debridement.51
Biosurgery
Biosurgery is a new term for a rather old technique. It is the debridement of a wound by proteases from the mouth parts of living maggots. The activity and clinical applicability are presently being in~estigated.~~ Dressings
A dressing is applied to protect the wound or ulcer, to prevent infection, and, perhaps in somewhat of a utopian view, to promote granulation. The ideal dressing has already often been described, and its requirements are listed as follows by Nemeth and EaglesteinZ8: Foster rapid healing Prevent infection Eliminate pain Debride the ulcer painlessly Be easy to apply and remove Be free of toxic and allergenic substances Absorb exudate
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Hide the ulcer Be inexpensive Many dressings are available, but an ”ideal” dressing, which satisfies all the requirements, does not yet exist. One can distinguish here between the traditional dressings, the synthetic dressings, and, more recently, biological dressings. Traditional Dressings
A traditional dressing consists generally of a multilayer, cotton-gauze dressing under which salves, creams, pastes, and so on are applied. In this dressing, antiseptics, antibiotics, or “growth-stimulating” substances are often incorporated. Such dressings are still in general use and belong to traditional dermatology. (The advantages and disadvantages of local antiseptics and antibiotics are discussed with the infected or colonized wounds.) Some agents could enhance epidermal resurfacing (benzoyl peroxide 2070, allantoin 37%, zinc oxide 2070, cod liver oil 33%, etc.),’ but large, controlled studies are rare. On the other hand, traditional dressings have some disadvantages: (1) They have to be applied daily or twice a day, which is time consuming. Although they are generally inexpensive, they do become costly, certainly when used in hospitals or by community nurses. (2) An important disadvantage is certainly their sensitizing capacity not only for the ”active” ingredients but also for the components of the vehicle. This is a major problem particularly with chronic leg ulcer^.^ In order to reduce the risks of contact sensitization, attention should be given to avoid common antigens. Wool alcohols are the most common sensitizers in our country in venous leg ulcer patients. Therefore, we adapted the very popular Carrel cream (chloramine 80 mg, cod liver oil 10 g, anhydrous lanolin 50 g, water ad 100 g) into a new formulation (chloramine 80 mg, cholesterol 1.8 g, liquid paraffin 6 g, vaseline 52 g, water ad 100 g), resulting in a clear reduction in the frequency of contact dermatitis in these patients. Synthetic Dressings
After G.D. Winter53demonstrated in 1962 that wound healing occurs more rapidly in a moist environment and the characteristics of the ideal dressing formulated, numerous, generally synthetic dressings appeared on the
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market. Even now, the sheer number of dressings available is confusing.s,@,54 The first objective of these new dressings is to create and maintain a moist environment in which the physiologic wound healing can take place, but occlusive dressings fulfill many other requirements of the ideal dressing. In order to facilitate the choices of synthetic dressings, one can go by the clinical aspect, the macromorphologic appearance, and the degree of exudation. There is a gradual shift from black or yellow necrotic ulcers to healthy red granulating wounds. Occlusive Dressings (Hydrocolloid Dressings). Occlusive dressings are gel-forming dressings. They will produce debridement of necrotic tissues (promote autolysis) by hyperhydration. In this phase, they are changed rather frequently (daily or every other day) to remove necrotic tissues and toxic substances. For more exudative wounds, they often need to be changed daily or can be used in conjunction with other hydrophilic gelmaking substances (alginates, hydroactive hydrocolloidal particles). After debridement, when a red granulating wound is present, they can be left in place for several days. For debridement of small, dry, adherent necrotic tissues (e.g., small black eschars) hydrophilic gels can be used under polyurethane dressings. Large black necrotic ulcers are not a good indication for synthetic dressings. Here, surgery is the treatment of choice. One of the disadvantages of hydrocolloid dressings is maceration of the surrounding skin. To overcome this unwanted side effect, occlusive dressings with a hydrocolloid adhesive and an absorbent pad in the center were recently introduced (Combiderm, Convatec). Semiocclusive Dressings. Semiocclusive dressings are permeable to water vapor and gasses but impermeable to water. Yellow necrotic moderately exudating wounds can be treated with foam dressings (polyurethane foam dressings, polyvinylalcohol foam dressings). They can cope with moderate amounts of fluid. For deep, irregular ulcers or wounds, siliconefoam dressings are indicated. The dressing is shaped in situ to form an exact cast of the cavity of the wound. Cavity polyurethane foam dressings can also be used for the same indications. The foam dressings act by a combination of absorption into the dressing and a degree of vapor loss by evaporation from the dressing. On the other hand, they maintain thermal insulation and provide a moist
environment. Red, sterile superficial wounds with (very) limited production of exudate are good indications for transparent polyurethanefilm dressings. When clear superinfection is present, antibiotics and surgical debridement are of most importance, but foam dressings can be used as auxillary treatment. Dehydrating Dressings (Xerogels, Xerodressings). A moist environment has to be maintained at the wound surface in order to create a good environment for wound healing. When a wound or an ulcer gives off too much moisture, it can be desirable to dry it out before proceeding to other dressings. For this purpose, hydrogels, available as flat sheets for large red superficial wounds or as an amorphous gel for deeper wounds (sometimes in combination with polyurethane dressings), can be used. Alginates dissolve into a gel and are ultraabsorbent and moisture-retaining products. They also have hemostatic properties. Other products non-gel making xerodressings based on activated charcoal, modified starch, or dextranomer beads can be used for the same purpose. In order to facilitate the changing of these "non-gel-making" xerodressings and to prevent adhesion to the base of the ulcer and crystallization in the wound, it is advisable to cover the ulcer base with a nonadhering dressing. If there is a risk that the dehydration will be too extreme, a moist environment can be maintained by applying a transparent semi-occlusive film sheet. New materials such as hydrocolloid fibers (sodium carboxymethylcellulose) or even native collagen sponges are being introduced for this purpose. These new dressings are able to absorb a large amount of exudate, to create a moist environment, and can even remain in place for several days. Dressings for Special Indications. Nonadhering dressings or silicone-coated nonadhering dressings can be used to protect the base of an ulcer or a graft (punch graft). Odorabsorbing dressings are foam dressings with an odor-absorbing shield of activated carbon. Biological Dressings
Biological material like donor cadaver homografts, pigskin, and human amnion are used for burns and chronic ulcers. Amnion releases a number of growth and angiogenic factors; but these materials are rejected, and pigskin has to be removed after several days. They can be considered as temporary dress-
HOW TO HEAL A WOUND FAST
ings. Most attention now goes into biosynthetic membranes. Epidermal Replacements. Since 197514,37 it has been possible to cultivate keratinocytes serially in vitro in order to produce viable epithelial sheets. Keratinocyte sheets derived from the patient (autologous) or from a donor (allogenous)are now being used for the treatment of various skin defects, including chronic ulcers.”, l7 Very poor take rates are reported for keratinocyte autografts, probably because of bacterial contamination and the presence of chronic granulation tissue. The presence of optimal dermal connective tissue appears to be critical. Indeed, optimal keratinocyte autografting only occurs on a pretreated dermal bed. A major disadvantage in the use of autografts is the 3- to 4-week delay required for the production of cultured keratinocyte autografts. This delay has led to the use of allogenic grafts from unrelated skin donors. Because these keratinocytes can be cryopreserved and stored for a long time in skin banks, they are readily available and can be used on a large scale.42 Another disadvantage of keratinocyte grafting, in particular in the first months after grafting, is spontaneous blistering and a fragility of the In contrast to the initial reports, there is now evidence that allogenic keratinocyte grafts are not permanently a ~ c e p t e d .Never~,~ theless, these allografts promote and stimulate healing of chronic ulcers from the margin as well as from the residual epidermal appendages. They seem to act as a temporary biological dressing and produce epidermal cell-derived factors in the appropriate type, amount, and sequence that stimulate closure of the wound. Moreover, the application of cultured keratinocytes to the wound may also provide matrix material necessary for growth or locomotion. Because of this complex interaction of growth factors, matrix proteins, and migration factors, which can be produced by keratinocytes in vitro, keratinocyte sheets have performed better presently than known growth factors alone. Dermal Replacements. Dermal replacements provide a support structure able to support the infiltration, adherence, proliferation, and neo-matrix production by fibroblast. The biodegradable dermis may consist of diverse components like fibroblast-collagen gels; cross-linked complex gels of human, bo-
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vine, or rodent collagens; and glycosaminoglycans with and without dermal cells. Skin Substitutes. Skin substitutes (artificial skin) are a combination of the previously described dressings. Recently, a commercially available artificial skin was introduced in some countries (ApligraftB, Organogenesis, Canton, Massachusetts), not only for the treatment of large acute wounds but also for use in healing venous leg ulcers.39,52 It is not clear yet if we have to consider artificial skin as a real graft or as a biological, active, temporary dressing, producing growth factors, cytokines, and extracellular matrix, and also providing a substrate for adherence. Eventually, perhaps, the artificial skin could be replaced by the patient’s own skin. Surgery
The therapeutic possibilities of surgical interventions in acute wounds were previously discussed. Various grafting techniques can be used to enhance wound healing in chronic ulcers (split-thickness skin grafts, pinch grafts, medium-thickness punch biopsy grafts, free flaps, and pedicles). Pharmacologic Treatment (Systemic Therapy)
Systemic therapy that treats the underlying causes of the retarded healing is always indicated if possible. Systemic treatments that accelerate the wound healing as such are rare. Vitamin A (25,000 IU/day) for several weeks is indicated in patients with wound healing retarded by anti-inflammatory drugs (corticosteroids).” There is no proof that vitamins C, K, B, or zinc supplements accelerate wound healing unless there is a deficiency of these substances. However, the possibility of such a deficiency must be considered in chronically ill patients and elderly patients and when there is malabsorption or malnutrit i ~ n .36~ , Many products are claimed to accelerate healing of venous or arterial ulcers. Unfortunately, the number of studies is very large that do not meet the modern criteria for clinical trials of being prospective, randomized, controlled, and double blind with objectives and end points. Possible candidates are the prostanoids for arterial and possibly venous ulcers. Pentoxifylline and buflomedil hydrochloride may have a beneficial effect, in relation
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to both the fibrin cuff and white cell trapping hypothesis in venous ulcers. A beneficial effect has also been claimed for arterial diseases6 For these and other substances, wellcontrolled clinical studies are needed before one can decide that a pharmacologic effect also results in clinical efficacy. Growth Factors
Maximizing the nutritional status of the patient, treating the causative factors, preventing and eliminating infection, and applying a proper dressing constitute our present therapeutic arsenal for creating an ideal environment in which physiologic repair can take place. The pivotal role of growth factors in wound healing is known. The striking results of in vitro and animal studies have sparked the hope that growth factors can accelerate normal healing and put impaired healing back on the good track again. On the basis of the demonstrated activity of growth factors in laboratory settings and in animal studies, a number of them have been selected for studies in chronic ulcers in people.24 The results of clinical studies in chronic wounds have shown a careful positive trend. Further research is still needed before cytokine/growth factor-based pharmacologic treatments will be available to correct or accelerate the wound-repair process. Questions that still must be answered include the following: Can the healing of wounds be safely influenced by one growth factor or a cocktail of growth factors? How do they have to be administered? Where, at what time, how often, and how long do they have to be used? The great expectations for rapid answers to these questions have certainly subsided. But there are possibilities that they will be realized in the medium term. Other Treatments
In order to speed up the healing of chronic wounds, not only growth factors but also other agents such as lactate, proteases, and antagonists, these factors are under investigation, but also to physical modalities such as low-level laser treatment, low-frequency ultrasound, negative pressure, and electric current.
INFECTED OR COLONIZED CHRONIC WOUNDS
The aspect of chronic wounds, covered with a yellow slough, the presence of necrotic areas, and the positive bacterial cultures, leads rapidly to the conclusion of superinfection and, hence, to the frequent use, and perhaps misuse, of local antibiotics and antiseptics and of systemic antibiotics. A distinction has to be made between colonization, whereby few or no signs of inflammation are present, and infection. In such cases, the following symptoms are present: wound pain; infiltration, redness, and shiny aspect of the surrounding skin; and sometimes fever and painful lymphadenitis. Generally, the infection remains limited, but sometimes an infectious disease such as erysipelas, bacteremia, or even sepsis can occur. Chronic vascular wounds are very often colonized by several kinds of germs, and the number of bacteria can be very large. The colonizing bacteria of chronic ulcers often include the following: 1. Staphylococcus aureus can be found in normal conditions in the nose and in damp areas of the skin. From there, the ulcers can be colonized. However, airborne infection and infection by direct contact are very important, certainly in hospitals and nursing homes. Methicillin-resistant Staphylococcus aureus (MRSA) infections can be introduced in this way. Washing hands and wearing gloves are important preventive measures. 2. Coagulase-negative staphylococci are often found and cause wound infection in specially predisposed patients. 3. Self-contamination is important not only for skin bacteria but also for fecal microorganisms such as Escherichia coli, Klebsiella spp, Proteus spp, and Streptococcus faecalis. These saprophytes are found very often in chronic ulcers. Personal hygiene is important. 4. Pseudomonas aeruginosa are gram-negative rods with a polar flagella. They are encountered in the soil and in surface water. They have a striking preference for large, oozing wounds, particularly in hospital environments. The transfer takes place via the hospital staff and from patient to patient. 5. Pseudomonas can remain locally limited, but sometimes the wound or the ulcer becomes necrotic, oozing, hemorrhagic,
HOW TO HEAL A WOUND FAST
and covered with a fibropurulent coating. A typical odor and a green-blue discoloration suggest strong colonization of, or infection with, this microorganism. Numerous other colonizing bacteria can sometimes be found. One may also cite Candida spp and, particularly, Candida albicans. This yeast-cell infection is not rarely found in chronic wounds that are being treated occlusively. Administration of antibacterial therapy in chronic wounds is generally not crucial, is still controversial, and is generally only supplementary to other care. Cleansing of the wound with saline solution, debridement, and a dressing selected in function of the aspect and the degree of exudation are more important. Still, the use of topical antiseptics remains the greatest controversy in the management of chronic wounds.16 Nevertheless, there are situations in which antibacterial therapy is indicated:
1. Systemic antibiotics, possibly in conjunction with local anti-infection therapy with very clear, clinical signs of infection with erysipelas or surrounding cellulitis. A culture is not taken from the surface but deep at the edge of the wound. 2. Diabetics, patients with serious immunodeficiency, and patients with serious underlying suffering should be followed closely, and antibiotics are given when a beginning infection is assumed. 3. Wound contamination and wound infec.~~ tion with Streptococcus p y o g e n e ~ The main factor of virulence is the M-protein, inhibiting phagocytosis of the host. These streptococci spread very easily in the tissues by the production of various enzymes (streptolysin 0, streptolysin S, hyaluronidase, streptokinase, DNase, erythrogenic toxin) with cellulitis and erysipelas as the consequence. They can also cause glomerulonephritis. 4. Chronic wounds resulting from infections (for example, tuberculosis or cryptococcal infections). 5. Staphylococcus aureus and Pseudomonas aeruginosa, in particular, can seriously retard the healing process of skin grafts and even cause the complete destruction of the grafts. Wounds infected or colonized by these bacteria have to be treated first. Here, we prefer local antibiotics (for example, mupirocin for StaphyZococcus aureus and silver sulfadiazine for
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Pseudomonas aeruginosa). High antibacterial concentrations can be obtained exclusively on the infection site. Sometimes, systemic antibiotics are needed before proceeding to the placement of grafts.13 There are several reasons not to administer local antibiotics, antiseptics, or systemic antibiotics if there are not strict indications to do so. Systemic antibiotics generally reach the environment very well because of the increased microcirculation and will hinder the spread of the infection, but the microbiological flora of the ulcer itself are often insufficiently changed or the ulcer is colonized by other bacteria. Rarely will one succeed in completely sterilizing the ulcer. It does not promote granulation of the ulcer.'O Local antibiofics have the advantage that high concentrations can be obtained at the infection site without systemic side effects. There are several disadvantages: 1. Cutaneous sensitization. Almost all local antibiotics, but particularly antibiotics of the aminoglycoside group such as neomycin, gentamicin, and tobramycin, cause contact allergy. Contact allergy to one or more components of the vehicle is a very common problem, particularly in patients with chronic wounds9 2. Development of bacterial resistance: The development of bacterial resistance is certainly promoted by the local application of antibiotics. Therefore, "reserve antibiotics," such as gentamicin, which are absolutely necessary in the event of serious complications, are not applied locally.27 3. Inhibition of wound healing. In animal experiments, several antibiotics have clearly inhibited granulation or epithelialization. Tetracyclines, gentamicin, and chloramphenicol, in particular, hinder healing.30 4. Inactivation of the antibiotic by the wound. In an acid environment or in the presence of pus by binding to the nucleic acids, the activity of several antibiotics (particularly the aminoglycosidesgentamicin) is strongly reduced.33
Local antiseptics manifest good results i n vitro against microorganisms and have the theoretic advantage of not inducing resis-
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tance. Still, there are many negative points that argue against their multiple and certainly against injudicious use. 1. The activity is strongly reduced in vivo by the presence of debris, pus, and proteins on the surface of the wound. 2. Many antiseptics are strong inhibitors of wound healing, and dyes are an example. Eosin causes no inhibiiion but is not a good anti~eptic.~~ 3. Resorption can give rise to systemic side effects (for example, iodine). 4. Contact allergy and irritation.
Antiseptics can be considered with very dirty or infected wounds, but preferably they are not used on clean granulating wounds. INCURABLE WOUNDS
The correct use of the techniques at our disposal, supplemented by the new therapeutic possibilities, should be able to sharply reduce the number of incurable wounds. This group will probably include oncogenic ulcerations, such as "carcinoma en cuirasse," some ulcerations in chronic radiodermitis areas, and large pressure sores in terminal patients. Combatting pain, attention to palliative care, and the use of dressings with an odor shield to improve the quality of life are of primary concern. CONCLUSION
In wound care, all kinds of techniques are used. An accurate diagnosis and an etiologic treatment whenever possible, in conjunction with a correct choice of symptomatic therapies, will lead to success in most cases. References 1. Alvarez OM: Pharmacological and environmental modulation of wound healing. In Utto J, Perejda AJ (eds): Connective Tissue Disease: Molecular Pathology of the Extracellular Matrix. New York, Marcel Dekker, 1987, p 367 2. Beebe HG, Bergan JJ, Bergqvist D, et al: Classification and grading of chronic venous disease in the lower limbs-a consensus statement: Organized by Straub Foundation with the cooperation of the American Venous Forum at the 6th annual meeting, February 22-25, 1994 (Maui, Hawaii) Vasa 24313, 1995 3. Burgos H Angiogenic factor from human term pla-
centa: Purification and partial characterization. Eur J Clin Invest 16:486, 1986 4. Burt A, Pallet C, Sloane JP, et al: Survival of cultured allografts in patients with bums, assessed with probe specific for Y chromosome. BMJ 298:915, 1989 5. Cabbade EB, Korock S W Wound healing in vitamin C-deficient and nondeficient Guinea pigs: A pilot study. Ann Plast Surg 17330, 1986 6. Chester J, Dormandy Y Pharmacological treatment of leg ulcers. In Westerhof W (ed): Leg Ulcers. Amsterdam, Elsevier, 1993, p 313 7. Coleman WC, Brand PW, Birke JA: The total cast: A therapy for plantar ulceration in insensitive feet. J Am Podiatric Assoc 74:548, 1984 8. Degreef H, Flour M Dressings as a new concept for topical treatment of ulcers. In Altmeyer P, Hoffmann K, et a1 (eds): Wound healing and skin physiology. Proceedings of the European Congress on Wound Healing and Skin Physiology. Berlin-Heidelberg, Springer Verlag, 1995, p 587 9. Dooms-Goosens A, Degreef H, Parys M, et a1 A retrospective study of patch test results from 163 patients with stasis dermatitis or leg ulcers. Dermatologica 159:93, 1979 10. Falanga V, Eagstein WM: A therapeutic approach to venous ulcers. J Am Acad Dermatol 14:1765, 1986 11. Gallic0 G, O'Connor N, Compton C, et a1 Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med 331:448,1984 12. Gilchrest B Wound infection: I. Sampling bacterial flora: A review of the literature. J Wound Care 5:386, 1996 13. Gilliland EL, Dore CJ, Nathwani V, et al: Bacterial colonisation of leg ulcers and its effect on the success rate of skin grafting. Ann R Coll Surg England 70:105, 1988 14. Green H, Kehinde 0, Thomas J: Growth of cultured human epidermal cells into multiple epithelia suitable for graftiig. Proc Natl Acad Sci USA 76:5665, 1979 15. Greenwood D Honey for superficial wounds and ulcers. Lancet 341:90, 1993 16. Harding MB Managing wound infection. J Wound Care 5:391, 1996 17. Hefton J, Caldwell P, Biozes D, et al: Grafting of skin ulcers with cultured autologous epidermal cells. J Am Acad Dermatol 14:399, 1986 18. Hellgren L, Vincent J: Debridement: An essential step in wound healing. In Westerhof W (ed): Leg ulcers. Amsterdam, Elsevier, 1993, p 305 19. Hellgren L, Vincent J: Debriding properties of krill enzymes in necrotic ulcerations. Experientia 42:403, 1986 20. Helligren L, Vincent J: Degradation and liquefaction effect of streptokinase-streptodomase and stabilized h-ypsin on necroses, crusts of fibrinoid purulent exudate and clotted blood from leg ulcers. J Int Med Res 5:334, 1977 21. Holm J, AndrCn B, Grafford K Pain control in the surgical debridement of leg ulcers by the use of a topical lidocaine-prilocaine cream, Emla. Acta Derm Venereol 70:132, 1990 22. Hunt TK, Ehrlich HP, Garcia JA, et al: Effects of vitamin A on reversing the inhibitory effect of cortisone on healing of open wounds in animals and man. Ann Surg 121:569, 1971 23. Hunt TK, Hussain Z: Wound microenvironment. In Cohen IK, Diegelmann RF, Lindblad WJ (eds): Wound Healing: Biochemical and Clinical Aspects. Philadelphia, WB Saunders, 1992, p 274
HOW TO HEAL A WOUND FAST 24. Lawrence WT: Clinical management of nonhealing wounds. In Cohen IK, Diegelmann RF, Lindblad WJ (eds): Wound Healing: Biochemical and Clinical Aspects. Philadelphia, WB Saunders, 1992, p 541 25. Mertz PM, Davis SC, Marshall DA, et al: Biosynthetic dressing materials and their influence on wound healing and infection. In Wadstrom T, Eliasson I, Holder I, et a1 (eds): Pathogenesis of Wound and Biomaterial Associated Infections. London, SpringerVerlag, 1990, p 139 26. Middleton KR, Seal D Sugar as an aid to wound healing. Pharm J 235:757, 1985 27. Miiller M Gehauftes Auftreten von Gentamycin-resistenten Staphylococcus aureus-Stammen bei Ulcus cruris venosum. Z Arztl Fortbild (Jena) 77685, 1983 28. Nemeth AJ, Eaglstein WH: Wound dressings and local treatment. In Westerhof W (ed): Leg Ulcers. Amsterdam, Elsevier, 1993, p 325 29. Neumann HAM, Tazelaar DJ: Compression therapy. In Bergan JJ, Goldman MP, et a1 (eds): Varicose Veins and Telangiectasias: Diagnosis and Treatment. St. Louis, Quality Medical Publishing, 1993, p 103 30. Niedner R: Beeinflussung der Wundgranulation durch Lokal-antibiotica und-antiseptica. In Colloquium Lokal-Antibiotikum (CLA ’85) Konstanz, Wissenschaftliche Buchreihe Byk Gulden, 1987, p 28 31. Niedner R, Schopf E: Inhibition of wound healing by antiseptics. Br J Dermatol 115:41, 1986 32. Niedner R, Schopf E: Wound infections and antibacterial therapy. In Westerhof W (ed): Leg Ulcers. Amsterdam, Elsevier, 1993, p 295 33. Niedner R, Vanscheidt W Ulcus cruris venosum. Lokaltherapie. Teil I. Hautarzt 42127, 1991 34. Rabentisch E: Zur Anwendung von Polyvinylpyrrolidon-Iod-Komplexen (Povidonjod:PVD-Jod). Mitteilung des Wissenschaftlichen Beirates der Bundesarztekammer. Deutsche Arzteblatt 54:1434, 1985 35. Reed B, Clark RAF: Cutaneous tissue repair: practical implications of current knowledge 111. J Am Acad Dermatol 13:919, 1985 36. Reed BR, Clark AF: Cutaneous tissue repair: Practical implications of current knowledge. J Am Acad Dermatol 13:919, 1985 37. Rheinwald J, Green H: Serial cultivation of strains of human epidermal keratinocytes: The formation of keratinizing colonies from single cells. Cell 6:331, 1975 38. Rosseeuw D, Coninck A, Lissens W, et al: Allogenic cultured epidermal grafts heal chronic ulcers although they do not remain as provided by DNA analysis. J Dermatol Sci 1:245, 1990 39. Sabolinski ML, Alvarez 0, Auletta M, et al: Cultured
40. 41. 42.
43. 44. 45. 46. 47. 48. 49. 50. 51. 52.
53. 54.
55. 56.
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skin as a ”smart material” for healing wounds: Experiences in venous ulcers. Biomaterials 17311, 1996 Scherer PR: An assessment of collagenase therapy for dermal ulcerations of the foot. J Am Podiatr Assoc 7425, 1984 Sims DS Jr, Cavanagh PR, Ulbrecht JS: Risk factors in the diabetic foot. Recognition and management. Phys Ther 681887, 1988 Teepe R, Koebrugge E, Ponec M, et al: Fresh versus cryopreserved cultured allografts for the treatment of chronic skin ulcers. British Journal of Dermatology 12281, 1990 The Inquirer: What are the comparative advantages of ulcerated legs? Edinb Med Surg J 1:187,1805 Thomas S Wound Management and Dressings. London, The Pharmaceutical Press, 1990 Thomas S, Jones M, Shutler S, et al: Using larvae in modern wound management. J Wound Care 560, 1996 Thomson B, Hooper P, Powell R, et al: Four-layer bandaging and healing rates of venous leg ulcers. J Wound Care 5:213, 1996 Topman J D Sugar paste in treatment of pressure sores, bums and wounds. Pharm J 241:118, 1988 Vanscheidt W, Partsch H Diagnostic procedures. In Westerhof W (ed): Leg Ulcers. Amsterdam, Elsevier, 1993, p 65 Vetra H, Whittaker D: Hydrotherapy and topical collagenase for decubitus ulcers. Geriatrics 30:53, 1975 Wagner FW. The diabetic foot. Orthopedics 10163, 1987 Weber DE, Parish LC, Witkowski JA: Dextranomer on chronic wound healing. Clin Dermatol2:116,1984 Wilkins LM, Watson SR, Prosky SF, et al: Development of a bilayered living skin construct for clinical applications. -8iotechnoiogy and Bioengineering 43:747, 1994 Winter GD. Formation of scab and the rate of epithelialization of superficial wounds in the skin of young domestic pigs. Nature (London) 193:293, 1962 Wiseman DM, Rover DT, Alvarez OM: Wound dressings: Design and use. In Cohen IK, Diegelmann RF, Lindblad WJ (eds): Wound Healing: Biochemical and Clinical Aspects. Philadelphia, WB Saunders, 1992, p 562 Witkowski JA, Parish L C Debridement of cutaneous ulcers: Medical and surgical aspects. Clin Dermatol 9:585, 1992 Woodley D, Peterson H, Herzog S, et al: Burn wounds resurfaced by cultured epidermal autografts show abnormal reconstruction of anchoring fibrils. J Am Acad Dermatol259:2566, 1988 Address reprint requests to Hugo J. Degreef, MD Department of Dermatology U.Z. Sint-Rafael Kapucijnenvoer 33 8-3000 Leuven, Belgium
DERMATOLOGIC THERAPY
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HOW TO HEAL A WOUND FAST Hugo J. Degreef, MD
Wounds and wound healing are as old as mankind. Throughout the centuries, all kinds of techniques have been used and recommended. For acute wounds, the greatest progress has been made by asepsis, antisepsis, the development of safe and effective microbial agents, modern surgery, and anesthesia. The treatment of chronic wounds was certainly not considered great medicine, as this citation made in 1805 shows: "The treatment of such cases is generally looked upon as an inferior branch of practice, an unpleasant and unglorious task where much labor must be bestowed, and little honor gained."43 Since the 1980s, the joint efforts of clinicians and researchers from several disciplines have generated an air of excitement about the progress being made in the field of wound healing. The healing process is being better understood, new dressings are being developed, and growth factors are being discovered. This process has resulted in the formation of wound-healing societies and journals dedicated exclusively to wound healing. Numerous congresses are now being devoted to wound healing and to the several factors involved in this process. In specialized centers for wound healing and diabetic foot clinics, better results are being achieved by a multidisciplinary approach. In dermatology, however, it is certainly not yet the most popular subject. Still, I think that dermatologists should occupy a prominent
place in this area. This article gives an overview of therapeutic approaches, nonsurgical dermatologic treatments in particular. The types of wounds we discuss include acute wounds, infected acute wounds, chronic wounds, infected and colonized chronic wounds, and incurable wounds. ACUTE WOUNDS
The treatment of acute wounds and certainly of large acute wounds belongs primarily to the domain of the surgeon. With many causes, wounds will always heal, but they can have life-threatening or dramatic consequences for the life of the patient not only during the sometimes very long healing phase with much pain and discomfort but also by eventual consequences such as loss of function and permanent disfigurement. Some causes include surgical wounds, penetrating wounds, avulsion injuries, crushing injuries, shearing injuries, burns, and others (bites, chemical burns, factitious wounds, etc.). In general, the cause of an acute wound is well known and a single event. The treatment consists of skin closure, whenever possible, by first intention (primary healing) or by delayed primary closure, together with the application of an appropriate dressing. Often, however, such a method of treatment is not possible, and then the treatment has to proceed over several stages (secondary healing). To initiate a correct therapy
From the Department of Dermatology, University Hospital Sint-Rafael, Catholic University, Leuven, Belgium
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and to provide a prognosis, a careful determination of the seriousness is needed. For example, in burns, the depth and the size determine the therapeutic approach (fluid replacement, conservative approach, or more aggressive surgical procedures). Local wound care consists of cleansing the wound, debridement, prevention of infection, and dressing of the wound. These conservative measures are discussed, together with the local symptomatic treatment of chronic wounds. Surgical interventions to close the skin defect may be lifesaving. The outcome of surgical interventions has improved considerably with the development of surgical skin transplantation techniques such as split skin grafts and mesh autografting. New therapeutic possibilities such as keratinocyte autografting or allografting and skin equivalents or the temporary application of homologous donor skin can stimulate tissue granulation and offer new ways of replacing the patient’s own skin when autologous skin is scarce or even result in better cosmetic outcome. Infected Acute Wounds
The great fear with acute wounds is infection, with intense inflammation and tissue destruction. Further spread of the infection can be life-threatening. Removal of organisms by cleansing and also debridement of nonviable and necrotic tissue, combined with an appropriate dressing to prevent the entry of bacteria, are very important in the prevention of infection. In acute wounds hypoxia can result in infection. Some causes of hypoxia are iatrogenic such as excess of tissue trauma, excess of wound tension, and inadequate hemostasis. Some endogenous conditions such as arteriosclerosis or diabetes may be present. Wounds in poorly perfused tissues become infected far more often than wounds in well perfused tissues. Resistance to bacteria requires a transcutaneous oxygen tension (TcpO,) over 30 mm Hg.35Indeed, oxygen is required by neutrophils for the creation of free oxygen radicals that kill bacteria. Bacteria deplete the old tissue and newly forming tissue of oxygen and nutrients, resulting in anoxia, and also produce a wide variety of endotoxins and exotoxins, which directly cause cell injury and cell death. Hypovolemia, cold, and fear can
further deteriorate wound oxygenation secondary to reflex constriction of the cutaneous microvascular bed.23 In acute wounds, clinical infection and wound breakdown occur when a bacterial load greater than 100,000 per gram of tissue is reached. This threshold number of bacteria holds true for all bacterial species other than streptococci, which can cause infection in lesser quantities.3O To determine the bacterial load several methods can be used.12The biopsy method is the gold standard but is not available in many hospitals. The standardized quantitative swab is the method that is used the most and expresses in a semi-quantitative way the number of colony-forming-units(CFU/volume). It is conducted in most hospitals, is nonaggressive, and has high specificity, but in some instances the presence of an infection is overestimated. A simple rapid slide technique (gram-stained smears) can tell within 1 hour whether or not more than 100,000 bacteria per gram of tissue are present in a wound. Early diagnosis and treatment of infection with targeted systemic antibacterials, combined with removal of foreign material and good wound drainage, can restore the healing process and prevent the breakdown of a wound. CHRONIC WOUNDS
The dermatologist is often confronted with chronic wounds, which are wounds or ulcers that heal slowly or not at all. When the tissue’s ability to maintain its integrity or to heal damage is no longer or only partially present, it is absolutely necessary to detect the cause of this failure through examination. Accurate Diagnosis The physician cannot apply the proper therapeutics without a correct diagnosis -AURELIUS CORNELIUS CELSUS, 25 BC TO 50 AD
Wound healing is the result of several separate but related and partially overlapping processes. These processes do not occur all in the same place or at the same time and can be retarded by many factors. Listing and discussing the very many factors that can disturb normal wound healing would take us
HOW TO HEAL A WOUND FAST
beyond the scope of this article. Impaired metabolism and especially impaired oxygen supply to the tissues are the main causes of such wounds. Venous ulcers, ulcers caused by arterial insufficiency, pressure sores, and metabolic defects in diabetic patients are the chronic wounds that the dermatologist will most frequently encounter. Genetic disorders, factitious wounds, chronic ulcerating infections, vasculitis, and iatrogenic ulcers (radiotherapy, cytotoxic drugs, heparin, etc.) are other, but rarer, causes. For an accurate diagnosis, clinical inspection and good clinical examination often do not suffice, although they are generally indicative for further approach. Targeted biochemical examination, supplemented by certain technical examinations (Doppler, TcpOz, arteriography, phlebography, etc.), complete the e ~ a m i n a t i o n These . ~ ~ examinations help to provide a more precise classification. For example, there are four stages of classification for pressure sores, a classification and grading system for venous dysfunction (American Venous Forum, 1994),’ and classification of Wagner (1987)50 or classification of Sims (1988)41for the diabetic foot. These classifications also provide a good basis for further therapeutic approaches because dealing with the cause or all of the negative factors is the best way for a successful treatment.
Etiologic Treatment It is impossible to discuss all etiologic treatments, so I will only discuss some of them briefly: Improvement of nutrition. Better control of blood sugar in diabetes. Cessation of smoking. Surgical treatment of peripheral arterial disease can not only contribute to the healing of arteriosclerotic ulcers but also prevent recurrence. In these patients and in patients with mixed arterio-venous ulcers, the desirability and possibility of surgical intervention to improve tissue hypoxia must be considered. Relief of prolonged excessive pressure for pressure sores but also with neurotrophic ulcers as in diabetics is the very first therapeutic step. In this last group of patients, this is preferably done by relieving the pressure by means of a removable or even a permanent cast: possibly with
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a hydrocolloid dressing. The adaptation of the footwear with correct pressure distribution is essential postcare to prevent recurrence. For pressure sores, the use of pressure-distributing seat cushions, mattresses, and beds will promote healing. Muscle and musculocutaneous flaps are often the most appropriate treatments for the definitive healing of pressure sores in paraplegic patients or in patients with ulcers above osteomyelitis areas and ulcers in radiation areas. Treatment of immunologic processes such as pyoderma gangrenosum or treatment of vasculitis. A biopsy of such lesions is sometimes necessary for making the correct diagnosis and also for providing correct treatment.
Leg ulcers in patients with chronic venous insufficiency are a major problem for the dermatologist. For patients with a history of inexplicable deep venous thrombosis as the cause of their deep venous insufficiency, one should always consider the possibility of acquired or congenital clotting syndromes and, if possible, treat them. In addition to the local symptomatic treatment, which is discussed in an upcoming section, other measures are needed to obtain good healing. Compression therapy has a long history, having been used by the Egyptians. But, as for many modes of treatment for ulcers, there is still much discussion today about its practical application, although everybody is convinced of its utility. Many doctors ”forget” to prescribe the treatment, and patient compliance often leaves something to be de~ired.2~ There are different ideas about the practical application between the continents, but even in Europe there is still no uniform concept. In continental Europe and in our department, the use of nonelastic bandages until total reduction of edema or healing of ulceration occurs is r e c ~ m m e n d e d In . ~ ~the United Kingdom, the four-layer bandage is often used,& whereas an Unna boot is still common practice in the United States.28 Pressure needs to be modified as a function of the underlying disease. The application of a compression bandage is not easy, and experience is necessary to develop good technique. As pressure is applied, account must be taken of the bandage tension and the radius of the surface. The retromalleolar sulci must be filled with cotton wool, and the pre-
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tibia1 area must be protected with the same material. The bandage must be worn during the daytime because the technique depends on an interaction between the bandage and the muscle pump. At night, the bandage can be removed.29 In the maintenance phase, we advise the use of elastic therapeutic hosiery. The choice of elastic compression stockings depends on the patient, and ready-made hosiery is indicated only for the “average leg.” In the other cases, custom-made hosiery is best. The major indicator for good elastic stockings is the absence of edema. Compression therapy is not indicated for leg ulcers due to arteriosclerosis and should be used only with the greatest caution with mixed arterio-venous ulcers. Surgical treatment or sclerotherapy of the insufficient veins and ligation of underlying insufficient perforantes may reduce the likelihood of recurrence.
Symptomatic Therapy
It is not always possible to eliminate the provoking factor(s), but even in such cases, correct measures can still lead to improvement or healing of ulcers. The goals are improvement of the patient’s general condition and improvement of quality of life with great concern for pain reduction. The local therapy for chronic ulcers consists of cleansing, debridement, dressings, and sometimes surgery. Cleansing
Wounds likely to be contaminated require thorough cleansing to remove loose debris, foreign material, and bacteria. Cleansing should not cause further damage to viable tissue. Abundant irrigation with tap water, saline solution, or a nontoxic antiseptic solution (hibitane aqueous solution 0.05% or povidone iodine) is recommended as the gentlest method. One may also use a bath or shower to cleanse ulcers. The use of strong antiseptic solutions is not recommended because there is the risk of damaging vital cells. In exceptional cases, it may be necessary to do this cleansing under general anesthesia. Debridement
Debridement is the removal of nonviable yellow or black tissue.55Its importance in en-
hancing healing is undisputed. The nonviable tissue is often spontaneously removed (autolysis), but this process is time consuming and retards the healing of the wound. One should not promote the formation of crusts, scabs, or eschars by dehydrating the wound. A dry wound is a dead wound, and an eschar is not ”God’s dressing.” Only in exceptional cases of dry, black necrosis (as in a pressure sore on the heel) is it preferable not to debride the necrotic skin.’* Surycal Debridement
Surgical debridement is certainly the most rapid way to remove necrotic material and is often unavoidable. This is generally done by a surgeon, and general anesthesia is often necessary (severe gangrenous ulcers, traumatic ulcers, osteomyelitis). In less serious cases, debridement can be done by the dermatologist with scissors and forceps. In order to ease the pain, a lidocaine-prilocaine cream (EMLA cream) can be used.21 Promotion of Autolysis
The process of autolysis can be promoted by hydration of the necrotic tissue, which also facilitates the mechanical removal and accelerates the healing process. This method can be used especially for smaller yellow or black necrosis. There are a number of possibilities. The Conventional Method. The conventional method consists of long-term application of wet compresses with saline, hibitane 0.05 aqueous solution, or chloramine solutions (wet-to-wet or wet-to-moist dressings). Occlusive Dressings. Hydrocolloid dressings and amorphous hydrogels under semipermeable transparent polyurethane film dressings are good alternatives. They are less time consuming to apply and have better patient compliance. Hydrocolloid dressings, when used to debride a wound, must be frequently renewed. Not only can toxic substances and necrotic material then be regularly removed but also regular wound inspection permits the timely discovery of infecti~n.~~ Mechanical Debridement
The mechanical removal of necrotic tissue can be done by forceful irrigation and wet-todry dressings. Wet-to-dry dressings are usually associated with some discomfort or pain
HOW TO HEAL A WOUND FAST
and can be traumatic to granulation tissue. Soft, moist yellow necrosis can also be removed by foam dressings and dextranomer under occlusive plastic films. Enzymatic Debridement
In enzymatic debridement, proteolytic enzymes of bacterial, vegetable, or animal origin are used (fibrinolysin, streptokinase, streptodornase, trypsin,2O collagenase,4°,49 or krill enzymes.ls They dissolve dead tissue. Because of the production of protease inhibitors by live cells, the live cells remain intact. Although proteolytic enzymes are certainly to be considered for theoretical reasons, the clinical results are generally insufficient, and some products cause itching or pain (trypsin). Osmotic Debridement 47 honey,I5 or karayagum-powder can be used for osmotic debridement. These agents are not only good debriding agents, but they can also absorb large amounts of exudate. The dry conditions under these products are unfavorable for bacterial growth and prevent infection. Some recent xerodressings (alginates, dextranomer, etc.) are good dehydrating agents but are mainly indicated for strongly exudative wounds and not, in the first place, for debridement.51
Biosurgery
Biosurgery is a new term for a rather old technique. It is the debridement of a wound by proteases from the mouth parts of living maggots. The activity and clinical applicability are presently being in~estigated.~~ Dressings
A dressing is applied to protect the wound or ulcer, to prevent infection, and, perhaps in somewhat of a utopian view, to promote granulation. The ideal dressing has already often been described, and its requirements are listed as follows by Nemeth and EaglesteinZ8: Foster rapid healing Prevent infection Eliminate pain Debride the ulcer painlessly Be easy to apply and remove Be free of toxic and allergenic substances Absorb exudate
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Hide the ulcer Be inexpensive Many dressings are available, but an ”ideal” dressing, which satisfies all the requirements, does not yet exist. One can distinguish here between the traditional dressings, the synthetic dressings, and, more recently, biological dressings. Traditional Dressings
A traditional dressing consists generally of a multilayer, cotton-gauze dressing under which salves, creams, pastes, and so on are applied. In this dressing, antiseptics, antibiotics, or “growth-stimulating” substances are often incorporated. Such dressings are still in general use and belong to traditional dermatology. (The advantages and disadvantages of local antiseptics and antibiotics are discussed with the infected or colonized wounds.) Some agents could enhance epidermal resurfacing (benzoyl peroxide 2070, allantoin 37%, zinc oxide 2070, cod liver oil 33%, etc.),’ but large, controlled studies are rare. On the other hand, traditional dressings have some disadvantages: (1) They have to be applied daily or twice a day, which is time consuming. Although they are generally inexpensive, they do become costly, certainly when used in hospitals or by community nurses. (2) An important disadvantage is certainly their sensitizing capacity not only for the ”active” ingredients but also for the components of the vehicle. This is a major problem particularly with chronic leg ulcer^.^ In order to reduce the risks of contact sensitization, attention should be given to avoid common antigens. Wool alcohols are the most common sensitizers in our country in venous leg ulcer patients. Therefore, we adapted the very popular Carrel cream (chloramine 80 mg, cod liver oil 10 g, anhydrous lanolin 50 g, water ad 100 g) into a new formulation (chloramine 80 mg, cholesterol 1.8 g, liquid paraffin 6 g, vaseline 52 g, water ad 100 g), resulting in a clear reduction in the frequency of contact dermatitis in these patients. Synthetic Dressings
After G.D. Winter53demonstrated in 1962 that wound healing occurs more rapidly in a moist environment and the characteristics of the ideal dressing formulated, numerous, generally synthetic dressings appeared on the
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market. Even now, the sheer number of dressings available is confusing.s,@,54 The first objective of these new dressings is to create and maintain a moist environment in which the physiologic wound healing can take place, but occlusive dressings fulfill many other requirements of the ideal dressing. In order to facilitate the choices of synthetic dressings, one can go by the clinical aspect, the macromorphologic appearance, and the degree of exudation. There is a gradual shift from black or yellow necrotic ulcers to healthy red granulating wounds. Occlusive Dressings (Hydrocolloid Dressings). Occlusive dressings are gel-forming dressings. They will produce debridement of necrotic tissues (promote autolysis) by hyperhydration. In this phase, they are changed rather frequently (daily or every other day) to remove necrotic tissues and toxic substances. For more exudative wounds, they often need to be changed daily or can be used in conjunction with other hydrophilic gelmaking substances (alginates, hydroactive hydrocolloidal particles). After debridement, when a red granulating wound is present, they can be left in place for several days. For debridement of small, dry, adherent necrotic tissues (e.g., small black eschars) hydrophilic gels can be used under polyurethane dressings. Large black necrotic ulcers are not a good indication for synthetic dressings. Here, surgery is the treatment of choice. One of the disadvantages of hydrocolloid dressings is maceration of the surrounding skin. To overcome this unwanted side effect, occlusive dressings with a hydrocolloid adhesive and an absorbent pad in the center were recently introduced (Combiderm, Convatec). Semiocclusive Dressings. Semiocclusive dressings are permeable to water vapor and gasses but impermeable to water. Yellow necrotic moderately exudating wounds can be treated with foam dressings (polyurethane foam dressings, polyvinylalcohol foam dressings). They can cope with moderate amounts of fluid. For deep, irregular ulcers or wounds, siliconefoam dressings are indicated. The dressing is shaped in situ to form an exact cast of the cavity of the wound. Cavity polyurethane foam dressings can also be used for the same indications. The foam dressings act by a combination of absorption into the dressing and a degree of vapor loss by evaporation from the dressing. On the other hand, they maintain thermal insulation and provide a moist
environment. Red, sterile superficial wounds with (very) limited production of exudate are good indications for transparent polyurethanefilm dressings. When clear superinfection is present, antibiotics and surgical debridement are of most importance, but foam dressings can be used as auxillary treatment. Dehydrating Dressings (Xerogels, Xerodressings). A moist environment has to be maintained at the wound surface in order to create a good environment for wound healing. When a wound or an ulcer gives off too much moisture, it can be desirable to dry it out before proceeding to other dressings. For this purpose, hydrogels, available as flat sheets for large red superficial wounds or as an amorphous gel for deeper wounds (sometimes in combination with polyurethane dressings), can be used. Alginates dissolve into a gel and are ultraabsorbent and moisture-retaining products. They also have hemostatic properties. Other products non-gel making xerodressings based on activated charcoal, modified starch, or dextranomer beads can be used for the same purpose. In order to facilitate the changing of these "non-gel-making" xerodressings and to prevent adhesion to the base of the ulcer and crystallization in the wound, it is advisable to cover the ulcer base with a nonadhering dressing. If there is a risk that the dehydration will be too extreme, a moist environment can be maintained by applying a transparent semi-occlusive film sheet. New materials such as hydrocolloid fibers (sodium carboxymethylcellulose) or even native collagen sponges are being introduced for this purpose. These new dressings are able to absorb a large amount of exudate, to create a moist environment, and can even remain in place for several days. Dressings for Special Indications. Nonadhering dressings or silicone-coated nonadhering dressings can be used to protect the base of an ulcer or a graft (punch graft). Odorabsorbing dressings are foam dressings with an odor-absorbing shield of activated carbon. Biological Dressings
Biological material like donor cadaver homografts, pigskin, and human amnion are used for burns and chronic ulcers. Amnion releases a number of growth and angiogenic factors; but these materials are rejected, and pigskin has to be removed after several days. They can be considered as temporary dress-
HOW TO HEAL A WOUND FAST
ings. Most attention now goes into biosynthetic membranes. Epidermal Replacements. Since 197514,37 it has been possible to cultivate keratinocytes serially in vitro in order to produce viable epithelial sheets. Keratinocyte sheets derived from the patient (autologous) or from a donor (allogenous)are now being used for the treatment of various skin defects, including chronic ulcers.”, l7 Very poor take rates are reported for keratinocyte autografts, probably because of bacterial contamination and the presence of chronic granulation tissue. The presence of optimal dermal connective tissue appears to be critical. Indeed, optimal keratinocyte autografting only occurs on a pretreated dermal bed. A major disadvantage in the use of autografts is the 3- to 4-week delay required for the production of cultured keratinocyte autografts. This delay has led to the use of allogenic grafts from unrelated skin donors. Because these keratinocytes can be cryopreserved and stored for a long time in skin banks, they are readily available and can be used on a large scale.42 Another disadvantage of keratinocyte grafting, in particular in the first months after grafting, is spontaneous blistering and a fragility of the In contrast to the initial reports, there is now evidence that allogenic keratinocyte grafts are not permanently a ~ c e p t e d .Never~,~ theless, these allografts promote and stimulate healing of chronic ulcers from the margin as well as from the residual epidermal appendages. They seem to act as a temporary biological dressing and produce epidermal cell-derived factors in the appropriate type, amount, and sequence that stimulate closure of the wound. Moreover, the application of cultured keratinocytes to the wound may also provide matrix material necessary for growth or locomotion. Because of this complex interaction of growth factors, matrix proteins, and migration factors, which can be produced by keratinocytes in vitro, keratinocyte sheets have performed better presently than known growth factors alone. Dermal Replacements. Dermal replacements provide a support structure able to support the infiltration, adherence, proliferation, and neo-matrix production by fibroblast. The biodegradable dermis may consist of diverse components like fibroblast-collagen gels; cross-linked complex gels of human, bo-
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vine, or rodent collagens; and glycosaminoglycans with and without dermal cells. Skin Substitutes. Skin substitutes (artificial skin) are a combination of the previously described dressings. Recently, a commercially available artificial skin was introduced in some countries (ApligraftB, Organogenesis, Canton, Massachusetts), not only for the treatment of large acute wounds but also for use in healing venous leg ulcers.39,52 It is not clear yet if we have to consider artificial skin as a real graft or as a biological, active, temporary dressing, producing growth factors, cytokines, and extracellular matrix, and also providing a substrate for adherence. Eventually, perhaps, the artificial skin could be replaced by the patient’s own skin. Surgery
The therapeutic possibilities of surgical interventions in acute wounds were previously discussed. Various grafting techniques can be used to enhance wound healing in chronic ulcers (split-thickness skin grafts, pinch grafts, medium-thickness punch biopsy grafts, free flaps, and pedicles). Pharmacologic Treatment (Systemic Therapy)
Systemic therapy that treats the underlying causes of the retarded healing is always indicated if possible. Systemic treatments that accelerate the wound healing as such are rare. Vitamin A (25,000 IU/day) for several weeks is indicated in patients with wound healing retarded by anti-inflammatory drugs (corticosteroids).” There is no proof that vitamins C, K, B, or zinc supplements accelerate wound healing unless there is a deficiency of these substances. However, the possibility of such a deficiency must be considered in chronically ill patients and elderly patients and when there is malabsorption or malnutrit i ~ n .36~ , Many products are claimed to accelerate healing of venous or arterial ulcers. Unfortunately, the number of studies is very large that do not meet the modern criteria for clinical trials of being prospective, randomized, controlled, and double blind with objectives and end points. Possible candidates are the prostanoids for arterial and possibly venous ulcers. Pentoxifylline and buflomedil hydrochloride may have a beneficial effect, in relation
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to both the fibrin cuff and white cell trapping hypothesis in venous ulcers. A beneficial effect has also been claimed for arterial diseases6 For these and other substances, wellcontrolled clinical studies are needed before one can decide that a pharmacologic effect also results in clinical efficacy. Growth Factors
Maximizing the nutritional status of the patient, treating the causative factors, preventing and eliminating infection, and applying a proper dressing constitute our present therapeutic arsenal for creating an ideal environment in which physiologic repair can take place. The pivotal role of growth factors in wound healing is known. The striking results of in vitro and animal studies have sparked the hope that growth factors can accelerate normal healing and put impaired healing back on the good track again. On the basis of the demonstrated activity of growth factors in laboratory settings and in animal studies, a number of them have been selected for studies in chronic ulcers in people.24 The results of clinical studies in chronic wounds have shown a careful positive trend. Further research is still needed before cytokine/growth factor-based pharmacologic treatments will be available to correct or accelerate the wound-repair process. Questions that still must be answered include the following: Can the healing of wounds be safely influenced by one growth factor or a cocktail of growth factors? How do they have to be administered? Where, at what time, how often, and how long do they have to be used? The great expectations for rapid answers to these questions have certainly subsided. But there are possibilities that they will be realized in the medium term. Other Treatments
In order to speed up the healing of chronic wounds, not only growth factors but also other agents such as lactate, proteases, and antagonists, these factors are under investigation, but also to physical modalities such as low-level laser treatment, low-frequency ultrasound, negative pressure, and electric current.
INFECTED OR COLONIZED CHRONIC WOUNDS
The aspect of chronic wounds, covered with a yellow slough, the presence of necrotic areas, and the positive bacterial cultures, leads rapidly to the conclusion of superinfection and, hence, to the frequent use, and perhaps misuse, of local antibiotics and antiseptics and of systemic antibiotics. A distinction has to be made between colonization, whereby few or no signs of inflammation are present, and infection. In such cases, the following symptoms are present: wound pain; infiltration, redness, and shiny aspect of the surrounding skin; and sometimes fever and painful lymphadenitis. Generally, the infection remains limited, but sometimes an infectious disease such as erysipelas, bacteremia, or even sepsis can occur. Chronic vascular wounds are very often colonized by several kinds of germs, and the number of bacteria can be very large. The colonizing bacteria of chronic ulcers often include the following: 1. Staphylococcus aureus can be found in normal conditions in the nose and in damp areas of the skin. From there, the ulcers can be colonized. However, airborne infection and infection by direct contact are very important, certainly in hospitals and nursing homes. Methicillin-resistant Staphylococcus aureus (MRSA) infections can be introduced in this way. Washing hands and wearing gloves are important preventive measures. 2. Coagulase-negative staphylococci are often found and cause wound infection in specially predisposed patients. 3. Self-contamination is important not only for skin bacteria but also for fecal microorganisms such as Escherichia coli, Klebsiella spp, Proteus spp, and Streptococcus faecalis. These saprophytes are found very often in chronic ulcers. Personal hygiene is important. 4. Pseudomonas aeruginosa are gram-negative rods with a polar flagella. They are encountered in the soil and in surface water. They have a striking preference for large, oozing wounds, particularly in hospital environments. The transfer takes place via the hospital staff and from patient to patient. 5. Pseudomonas can remain locally limited, but sometimes the wound or the ulcer becomes necrotic, oozing, hemorrhagic,
HOW TO HEAL A WOUND FAST
and covered with a fibropurulent coating. A typical odor and a green-blue discoloration suggest strong colonization of, or infection with, this microorganism. Numerous other colonizing bacteria can sometimes be found. One may also cite Candida spp and, particularly, Candida albicans. This yeast-cell infection is not rarely found in chronic wounds that are being treated occlusively. Administration of antibacterial therapy in chronic wounds is generally not crucial, is still controversial, and is generally only supplementary to other care. Cleansing of the wound with saline solution, debridement, and a dressing selected in function of the aspect and the degree of exudation are more important. Still, the use of topical antiseptics remains the greatest controversy in the management of chronic wounds.16 Nevertheless, there are situations in which antibacterial therapy is indicated:
1. Systemic antibiotics, possibly in conjunction with local anti-infection therapy with very clear, clinical signs of infection with erysipelas or surrounding cellulitis. A culture is not taken from the surface but deep at the edge of the wound. 2. Diabetics, patients with serious immunodeficiency, and patients with serious underlying suffering should be followed closely, and antibiotics are given when a beginning infection is assumed. 3. Wound contamination and wound infec.~~ tion with Streptococcus p y o g e n e ~ The main factor of virulence is the M-protein, inhibiting phagocytosis of the host. These streptococci spread very easily in the tissues by the production of various enzymes (streptolysin 0, streptolysin S, hyaluronidase, streptokinase, DNase, erythrogenic toxin) with cellulitis and erysipelas as the consequence. They can also cause glomerulonephritis. 4. Chronic wounds resulting from infections (for example, tuberculosis or cryptococcal infections). 5. Staphylococcus aureus and Pseudomonas aeruginosa, in particular, can seriously retard the healing process of skin grafts and even cause the complete destruction of the grafts. Wounds infected or colonized by these bacteria have to be treated first. Here, we prefer local antibiotics (for example, mupirocin for StaphyZococcus aureus and silver sulfadiazine for
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Pseudomonas aeruginosa). High antibacterial concentrations can be obtained exclusively on the infection site. Sometimes, systemic antibiotics are needed before proceeding to the placement of grafts.13 There are several reasons not to administer local antibiotics, antiseptics, or systemic antibiotics if there are not strict indications to do so. Systemic antibiotics generally reach the environment very well because of the increased microcirculation and will hinder the spread of the infection, but the microbiological flora of the ulcer itself are often insufficiently changed or the ulcer is colonized by other bacteria. Rarely will one succeed in completely sterilizing the ulcer. It does not promote granulation of the ulcer.'O Local antibiofics have the advantage that high concentrations can be obtained at the infection site without systemic side effects. There are several disadvantages: 1. Cutaneous sensitization. Almost all local antibiotics, but particularly antibiotics of the aminoglycoside group such as neomycin, gentamicin, and tobramycin, cause contact allergy. Contact allergy to one or more components of the vehicle is a very common problem, particularly in patients with chronic wounds9 2. Development of bacterial resistance: The development of bacterial resistance is certainly promoted by the local application of antibiotics. Therefore, "reserve antibiotics," such as gentamicin, which are absolutely necessary in the event of serious complications, are not applied locally.27 3. Inhibition of wound healing. In animal experiments, several antibiotics have clearly inhibited granulation or epithelialization. Tetracyclines, gentamicin, and chloramphenicol, in particular, hinder healing.30 4. Inactivation of the antibiotic by the wound. In an acid environment or in the presence of pus by binding to the nucleic acids, the activity of several antibiotics (particularly the aminoglycosidesgentamicin) is strongly reduced.33
Local antiseptics manifest good results i n vitro against microorganisms and have the theoretic advantage of not inducing resis-
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tance. Still, there are many negative points that argue against their multiple and certainly against injudicious use. 1. The activity is strongly reduced in vivo by the presence of debris, pus, and proteins on the surface of the wound. 2. Many antiseptics are strong inhibitors of wound healing, and dyes are an example. Eosin causes no inhibiiion but is not a good anti~eptic.~~ 3. Resorption can give rise to systemic side effects (for example, iodine). 4. Contact allergy and irritation.
Antiseptics can be considered with very dirty or infected wounds, but preferably they are not used on clean granulating wounds. INCURABLE WOUNDS
The correct use of the techniques at our disposal, supplemented by the new therapeutic possibilities, should be able to sharply reduce the number of incurable wounds. This group will probably include oncogenic ulcerations, such as "carcinoma en cuirasse," some ulcerations in chronic radiodermitis areas, and large pressure sores in terminal patients. Combatting pain, attention to palliative care, and the use of dressings with an odor shield to improve the quality of life are of primary concern. CONCLUSION
In wound care, all kinds of techniques are used. An accurate diagnosis and an etiologic treatment whenever possible, in conjunction with a correct choice of symptomatic therapies, will lead to success in most cases. References 1. Alvarez OM: Pharmacological and environmental modulation of wound healing. In Utto J, Perejda AJ (eds): Connective Tissue Disease: Molecular Pathology of the Extracellular Matrix. New York, Marcel Dekker, 1987, p 367 2. Beebe HG, Bergan JJ, Bergqvist D, et al: Classification and grading of chronic venous disease in the lower limbs-a consensus statement: Organized by Straub Foundation with the cooperation of the American Venous Forum at the 6th annual meeting, February 22-25, 1994 (Maui, Hawaii) Vasa 24313, 1995 3. Burgos H Angiogenic factor from human term pla-
centa: Purification and partial characterization. Eur J Clin Invest 16:486, 1986 4. Burt A, Pallet C, Sloane JP, et al: Survival of cultured allografts in patients with bums, assessed with probe specific for Y chromosome. BMJ 298:915, 1989 5. Cabbade EB, Korock S W Wound healing in vitamin C-deficient and nondeficient Guinea pigs: A pilot study. Ann Plast Surg 17330, 1986 6. Chester J, Dormandy Y Pharmacological treatment of leg ulcers. In Westerhof W (ed): Leg Ulcers. Amsterdam, Elsevier, 1993, p 313 7. Coleman WC, Brand PW, Birke JA: The total cast: A therapy for plantar ulceration in insensitive feet. J Am Podiatric Assoc 74:548, 1984 8. Degreef H, Flour M Dressings as a new concept for topical treatment of ulcers. In Altmeyer P, Hoffmann K, et a1 (eds): Wound healing and skin physiology. Proceedings of the European Congress on Wound Healing and Skin Physiology. Berlin-Heidelberg, Springer Verlag, 1995, p 587 9. Dooms-Goosens A, Degreef H, Parys M, et a1 A retrospective study of patch test results from 163 patients with stasis dermatitis or leg ulcers. Dermatologica 159:93, 1979 10. Falanga V, Eagstein WM: A therapeutic approach to venous ulcers. J Am Acad Dermatol 14:1765, 1986 11. Gallic0 G, O'Connor N, Compton C, et a1 Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med 331:448,1984 12. Gilchrest B Wound infection: I. Sampling bacterial flora: A review of the literature. J Wound Care 5:386, 1996 13. Gilliland EL, Dore CJ, Nathwani V, et al: Bacterial colonisation of leg ulcers and its effect on the success rate of skin grafting. Ann R Coll Surg England 70:105, 1988 14. Green H, Kehinde 0, Thomas J: Growth of cultured human epidermal cells into multiple epithelia suitable for graftiig. Proc Natl Acad Sci USA 76:5665, 1979 15. Greenwood D Honey for superficial wounds and ulcers. Lancet 341:90, 1993 16. Harding MB Managing wound infection. J Wound Care 5:391, 1996 17. Hefton J, Caldwell P, Biozes D, et al: Grafting of skin ulcers with cultured autologous epidermal cells. J Am Acad Dermatol 14:399, 1986 18. Hellgren L, Vincent J: Debridement: An essential step in wound healing. In Westerhof W (ed): Leg ulcers. Amsterdam, Elsevier, 1993, p 305 19. Hellgren L, Vincent J: Debriding properties of krill enzymes in necrotic ulcerations. Experientia 42:403, 1986 20. Helligren L, Vincent J: Degradation and liquefaction effect of streptokinase-streptodomase and stabilized h-ypsin on necroses, crusts of fibrinoid purulent exudate and clotted blood from leg ulcers. J Int Med Res 5:334, 1977 21. Holm J, AndrCn B, Grafford K Pain control in the surgical debridement of leg ulcers by the use of a topical lidocaine-prilocaine cream, Emla. Acta Derm Venereol 70:132, 1990 22. Hunt TK, Ehrlich HP, Garcia JA, et al: Effects of vitamin A on reversing the inhibitory effect of cortisone on healing of open wounds in animals and man. Ann Surg 121:569, 1971 23. Hunt TK, Hussain Z: Wound microenvironment. In Cohen IK, Diegelmann RF, Lindblad WJ (eds): Wound Healing: Biochemical and Clinical Aspects. Philadelphia, WB Saunders, 1992, p 274
HOW TO HEAL A WOUND FAST 24. Lawrence WT: Clinical management of nonhealing wounds. In Cohen IK, Diegelmann RF, Lindblad WJ (eds): Wound Healing: Biochemical and Clinical Aspects. Philadelphia, WB Saunders, 1992, p 541 25. Mertz PM, Davis SC, Marshall DA, et al: Biosynthetic dressing materials and their influence on wound healing and infection. In Wadstrom T, Eliasson I, Holder I, et a1 (eds): Pathogenesis of Wound and Biomaterial Associated Infections. London, SpringerVerlag, 1990, p 139 26. Middleton KR, Seal D Sugar as an aid to wound healing. Pharm J 235:757, 1985 27. Miiller M Gehauftes Auftreten von Gentamycin-resistenten Staphylococcus aureus-Stammen bei Ulcus cruris venosum. Z Arztl Fortbild (Jena) 77685, 1983 28. Nemeth AJ, Eaglstein WH: Wound dressings and local treatment. In Westerhof W (ed): Leg Ulcers. Amsterdam, Elsevier, 1993, p 325 29. Neumann HAM, Tazelaar DJ: Compression therapy. In Bergan JJ, Goldman MP, et a1 (eds): Varicose Veins and Telangiectasias: Diagnosis and Treatment. St. Louis, Quality Medical Publishing, 1993, p 103 30. Niedner R: Beeinflussung der Wundgranulation durch Lokal-antibiotica und-antiseptica. In Colloquium Lokal-Antibiotikum (CLA ’85) Konstanz, Wissenschaftliche Buchreihe Byk Gulden, 1987, p 28 31. Niedner R, Schopf E: Inhibition of wound healing by antiseptics. Br J Dermatol 115:41, 1986 32. Niedner R, Schopf E: Wound infections and antibacterial therapy. In Westerhof W (ed): Leg Ulcers. Amsterdam, Elsevier, 1993, p 295 33. Niedner R, Vanscheidt W Ulcus cruris venosum. Lokaltherapie. Teil I. Hautarzt 42127, 1991 34. Rabentisch E: Zur Anwendung von Polyvinylpyrrolidon-Iod-Komplexen (Povidonjod:PVD-Jod). Mitteilung des Wissenschaftlichen Beirates der Bundesarztekammer. Deutsche Arzteblatt 54:1434, 1985 35. Reed B, Clark RAF: Cutaneous tissue repair: practical implications of current knowledge 111. J Am Acad Dermatol 13:919, 1985 36. Reed BR, Clark AF: Cutaneous tissue repair: Practical implications of current knowledge. J Am Acad Dermatol 13:919, 1985 37. Rheinwald J, Green H: Serial cultivation of strains of human epidermal keratinocytes: The formation of keratinizing colonies from single cells. Cell 6:331, 1975 38. Rosseeuw D, Coninck A, Lissens W, et al: Allogenic cultured epidermal grafts heal chronic ulcers although they do not remain as provided by DNA analysis. J Dermatol Sci 1:245, 1990 39. Sabolinski ML, Alvarez 0, Auletta M, et al: Cultured
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skin as a ”smart material” for healing wounds: Experiences in venous ulcers. Biomaterials 17311, 1996 Scherer PR: An assessment of collagenase therapy for dermal ulcerations of the foot. J Am Podiatr Assoc 7425, 1984 Sims DS Jr, Cavanagh PR, Ulbrecht JS: Risk factors in the diabetic foot. Recognition and management. Phys Ther 681887, 1988 Teepe R, Koebrugge E, Ponec M, et al: Fresh versus cryopreserved cultured allografts for the treatment of chronic skin ulcers. British Journal of Dermatology 12281, 1990 The Inquirer: What are the comparative advantages of ulcerated legs? Edinb Med Surg J 1:187,1805 Thomas S Wound Management and Dressings. London, The Pharmaceutical Press, 1990 Thomas S, Jones M, Shutler S, et al: Using larvae in modern wound management. J Wound Care 560, 1996 Thomson B, Hooper P, Powell R, et al: Four-layer bandaging and healing rates of venous leg ulcers. J Wound Care 5:213, 1996 Topman J D Sugar paste in treatment of pressure sores, bums and wounds. Pharm J 241:118, 1988 Vanscheidt W, Partsch H Diagnostic procedures. In Westerhof W (ed): Leg Ulcers. Amsterdam, Elsevier, 1993, p 65 Vetra H, Whittaker D: Hydrotherapy and topical collagenase for decubitus ulcers. Geriatrics 30:53, 1975 Wagner FW. The diabetic foot. Orthopedics 10163, 1987 Weber DE, Parish LC, Witkowski JA: Dextranomer on chronic wound healing. Clin Dermatol2:116,1984 Wilkins LM, Watson SR, Prosky SF, et al: Development of a bilayered living skin construct for clinical applications. -8iotechnoiogy and Bioengineering 43:747, 1994 Winter GD. Formation of scab and the rate of epithelialization of superficial wounds in the skin of young domestic pigs. Nature (London) 193:293, 1962 Wiseman DM, Rover DT, Alvarez OM: Wound dressings: Design and use. In Cohen IK, Diegelmann RF, Lindblad WJ (eds): Wound Healing: Biochemical and Clinical Aspects. Philadelphia, WB Saunders, 1992, p 562 Witkowski JA, Parish L C Debridement of cutaneous ulcers: Medical and surgical aspects. Clin Dermatol 9:585, 1992 Woodley D, Peterson H, Herzog S, et al: Burn wounds resurfaced by cultured epidermal autografts show abnormal reconstruction of anchoring fibrils. J Am Acad Dermatol259:2566, 1988 Address reprint requests to Hugo J. Degreef, MD Department of Dermatology U.Z. Sint-Rafael Kapucijnenvoer 33 8-3000 Leuven, Belgium