CHAPTER 5 Stine Jacobsen, DVM, PhD, Diplomate ECVS Topical treatments have been used in wound care for centuries. Many of the treatments, however, have not – or only to a very limited degree – undergone scientific scrutiny. This is especially true for many of the products that are available over the counter. Determining the contents of many of these products can be difficult, and as a rule of thumb, products without a list of ingredients should not be used on wounds. In contrast, effects of wound cleansers and solutions used for irrigation have been investigated in several studies. Although cleansers and antiseptics had, for some years, fallen out of favor due to their detrimental effects on cells cultured in vitro, current best evidence suggests that they may be of benefit if used judiciously. The negative impact on cell cultures has, in many studies, not been replicated when the products were used in vivo. Use of antiseptics on heavily contaminated or infected wounds seems to enhance healing through a reduction of the wound’s bioburden. Products intended for topical application to wounds with the purpose of supporting and enhancing healing are plentiful in the wound‐care market. Although effects of some products (e.g., wound cleansers and antiseptics) are well characterized and have been investigated in vitro and in vivo in numerous studies, the suggested benefits of other products are based on a much smaller body of evidence. Among the latter are many of the products of herbal origin and products whose purported effects rest on their content of vitamins and minerals, for which the manufacturers’ claims to the efficacy of the products are based on limited scientific data. The same is true for several over‐the‐counter products sold through tack shops, for example the aerosol sprays used extensively by non‐veterinarians for treatment of wounds that are perceived not to need veterinary attention. Using sound judgment and seeking out the best available evidence are, therefore, very important when choosing between the numerous topical wound‐care products available. Topical agents should be applied to wounds to serve a specific purpose; this highlights the importance of a sound knowledge of the properties of the selected product and its proposed effects on the healing tissues. One very common approach is to apply antiseptics to any wound under the “better‐safe‐than‐sorry” principle. This tactic is, however, inadvisable, as antiseptics may exert a negative influence on healing tissues. Antiseptics should thus be used only where necessary, i.e. in high‐risk wounds and in contaminated or infected wounds, where the benefit of reducing wound bioburden outweighs potential negative side‐effects on healing. For technical reasons, it may be impossible to bandage wounds on the body or on the proximal limb of the horse. Consequently, topical wound‐care products may be the only useful means to stimulate healing of wounds in these locations (Figure 5.1). Figure 5.1 Wound on the thigh of a pony. The wound had dehisced partially after suturing. The location of this wound makes bandaging difficult. The simplest means of stimulating healing for such wounds is to apply topical products. The purpose of this chapter is not to provide an exhaustive overview of all available products, as the sheer size of the market precludes such an endeavor. Rather, a selection of the most common products and those whose effects have been investigated in horses is presented, along with the available evidence for the effects of these selected products on healing tissues. Foreign material, necrotic tissue, and microorganisms in the wound impede healing. The actions taken to remove these impediments are cleansing and debridement. Cleansing, also referred to as wound irrigation, involves the use of a fluid to remove loosely attached cellular debris and surface pathogens contained in wound exudate or residue from topically applied wound‐care products, and debridement refers to the use of mechanical or chemical means to remove adherent material from the wound. Every major supplier on the wound‐care market sells a wound cleanser. In addition, a veritable myriad of products, also many over‐the‐counter products, are available from smaller companies. Obtaining information about the contents of different products to ascertain if the beneficial properties declared by the manufacturer hold true may be difficult. Not all wounds need cleansing, and for some wounds, cleansing may traumatize fragile new tissue in the wound and the surrounding skin. For example, cleansing a clean granulating wound unnecessarily traumatizes the fragile granulation tissue. In human medicine, indications for wound cleansing have been described as:1 In wounds that need cleansing, wound cleansers serve important functions, and they thus deserve attention similar to that given dressings and other wound‐care products. Cleansing a wound serves multiple purposes: it removes loose debris and bacteria, provides an optimal environment for healing, and facilitates assessment of the wound by optimizing its inspection. The ideal wound cleanser should be: The selected cleanser should be at body temperature prior to applying it to the wound. Wound temperature influences healing, with optimal healing occurring (in humans) at a temperature between 36 and 38 °C. Delayed healing may occur when the temperature of the wound falls below core body temperature or rises above 42 °C. Using cleansers and other solutions at temperatures lower than the core temperature can cause the temperature in the wound to be below body temperature for up to 40 minutes, and cellular division may take up to 3 hours to recommence.2,3 Cleansers can be applied either manually or by spraying/irrigating the wound (Figure 5.2). Using the former technique, wounds are gently wiped with swabs soaked in the cleanser; with the latter technique, the cleanser is delivered from a spray bottle, a syringe with needle, or another delivery device. When using the latter technique, the cleanser should be delivered with a pressure of no more than 15 pounds per square inch (psi), because a higher pressure tends to drive microorganisms into the wound. Appropriate pressure may be obtained with wound irrigation devices delivering specified pressures (Figure 5.3) or by attaching a 19‐gauge needle to a 60‐mL syringe (Figure 5.2). For more information about wound irrigation techniques, the reader is referred to Chapter 4. A study comparing cleansing of wounds, of humans, healing by second intention, by pressurized irrigation or by swabbing found that wounds cleaned by pressurized irrigation healed faster and that irrigation caused less pain and greater patient satisfaction than did swabbing. The incidence of wound infection in the two groups was similar.4 When using the swabbing technique, the gauze swabs should be non‐woven because woven gauze sheds more fibers into the wound. Figure 5.2 (a) Irrigation of an acute wound using sterile isotonic saline solution. This type of passive gravity fluid flow does not provide sufficient pressure to remove contaminants or overcome the forces with which bacteria adhere to the wound. Photo courtesy of Denis Verwilghen. (b) To achieve an appropriate pressure (10–14 psi) fluid should be firmly expressed from a 60‐mL syringe with a 19‐gauge needle or through devices or spray bottles constructed to deliver the appropriate pressure. (See also Figure 5.3 and Table 5.1.) Table 5.1 Commercially available wound cleansers. *Assessed as the dilution required to maintain viable cells. The larger the number, the more toxic the product (toxicity index of 0: no dilution required; toxicity index of 100: 100‐fold dilution required) **Assessed as time to achieve a 4‐log (99.99%) reduction in colony‐forming units of Staphylococcus aureus at non‐toxic dilution of the cleanser Figure 5.3 Wound irrigation device (Wound flushing unit, Kruuse) constructed to achieve appropriate pressure (10–14 psi) during wound irrigation. Moderate fluid pressure is needed to overcome the adhesion of contaminants and bacteria to the wound. High fluid pressure should be avoided because it may drive bacteria deeper into the wound. Several different solutions can be used for cleansing wounds, such as isotonic saline solution, tap water, Ringer’s solution, or solutions containing active ingredients. Wounds can also be cleansed with solutions containing antimicrobial agents, such as iodine, chlorhexidine, polyhexamethylene biguanide (PHMB), ionized silver, hydrogen peroxide, sodium hypochlorite, acetic acid, alcohol, and octenidine dihydrochloride. Sterile isotonic saline solution is the most appropriate and preferred cleansing solution because it is a widely available, non‐toxic, isotonic solution that does not damage healing tissues. Other isotonic solutions, such as Normosol‐R or lactated Ringer’s solution, are equally well suited for wound cleansing. A systematic review of the effects of cleansing wounds with isotonic saline solution or tap water concluded that the current evidence suggests that irrigation using isotonic saline solution or tap water is ineffective in reducing the bioburden associated with wounds in human patients, and that the use of isotonic saline solution or tap water is not associated with improved wound healing.5 In spite of this, many clinicians still opt to irrigate wounds with isotonic saline solution, for example after surgical debridement. Several studies have been performed to evaluate whether tap water is acceptable for wound cleansing. A systematic review concluded that tap water is acceptable for cleansing acute and chronic wounds, and that using tap water does not seem to increase the risk of infection or cause delayed healing of acute wounds in adult human patients.5 Using either isotonic saline solution, distilled water, or boiled tap water to cleanse open fractures did not produce a statistically significant difference in the number of fractures developing infection.6 Based on these studies, the hypotonicity of tap water or boiled water does not seem to cause injury to the cells in the wound – at least not to a clinically relevant extent. Tap water should not be used as a cleanser in areas where a constant supply of potable drinking water is not available. Under such circumstances, however, distilled or boiled water may be used for wound cleansing.5 One major advantage of using tap water as a cleanser is that it is very cheap, and thus the clinician may be more inclined to use large volumes of tap water compared to the volumes used with other cleansing fluids. In infected wounds, especially those where biofilm has formed, isotonic saline solution and water may not be effective cleansing solutions, because bacteria in biofilms are more resistant to irrigation than are planktonic (free‐floating) bacteria. Biofilms are polymicrobial colonies protected by a matrix, which frequently form in wounds and are characterized by rapid development of resistance to mechanical disruption. The cleansing activity of many commercial wound cleansers relies on a surfactant that breaks the bond between foreign bodies/microbes and the wound’s surface, to improve efficacy. The composition of commercially available cleansers can be found in Table 5.1. In vitro studies have shown that many cleansers may be toxic for fibroblasts and keratinocytes.7,8 In particular, cleansers marketed for cleaning intact skin (i.e., shampoos, body wash, and soaps) exhibit toxicity, but many products marketed for use in wounds also exert some negative effect on fibroblasts and keratinocytes in vitro (Table 5.1).7,8 In comparison, wound cleansers containing the surfactant poloxamer 188 (synonym: pluronic F‐68) (Shur‐Clens, SAF‐Clens; both from Convatec; Primaderm Dermal Cleanser, Derma Sciences) have repeatedly been shown to have low toxicity in vitro,7–9 and when SAF‐Clens and Shur‐Clens were applied to full‐thickness skin wounds in guinea pigs, no adverse effects on healing were detected (in contrast to Betadine Surgical Scrub, which significantly slowed healing).10 Poloxamer‐based cleansers mechanically cleanse wounds, but have no antimicrobial effects, and, therefore, the use of these cleansers in wounds that are prone to developing infection should be supplemented with antimicrobial treatment (Table 5.1 and Table 5.2).9 A study comparing the use of isotonic saline solution, povidone–iodine, or Shur‐Clens for cleansing acute wounds in humans prior to suturing, however, failed to demonstrate differences in the incidence of infection among wounds.11 Table 5.2 Indications and contraindications for cleansers with and without antiseptics. MRSA, methicillin‐resistant Staphylococcus aureus; VRE, vancomycin‐resistant enterococci. Several cleansers, most of which are available over‐the‐counter, contain components proposed to promote healing, such as zinc (3 M Wound Cleanser, 3 M; Dermagran, Derma Sciences), Aloe vera (Biolex, Bard Medical; Eclipse Wound Cleanser, PRP Technologies), or vitamins (Dermagran, Derma Sciences). The effects of these compounds on healing are described later in the chapter. Antiseptics are substances that inhibit growth and development of microorganisms. The term is often used for products developed for topical application. Antimicrobial is the umbrella term for agents that kill or prevent the multiplication of microorganisms, e.g. bacteria or fungi. Antimicrobials may be antibiotics, antiseptics or disinfectants. While antibiotics are agents that act selectively against bacteria and usually against a narrow range of bacteria, antiseptics are relatively broad‐acting agents that inhibit multiplication of, or kill, microorganisms. Disinfectants are also relatively non‐selective with multiple sites of action and kill a wide range of microorganisms, but they are generally not suitable for use on body tissues because they are toxic to eukaryotic cells. While development of resistance to antibiotics is an increasing problem, development of resistance to antiseptics is literally unknown in the area of wound care.12 The use of antiseptics in wounds is controversial. Although multiple in vitro studies have shown that antiseptics exert negative effects on cells involved in wound healing, application of antiseptics may be indicated for cleansing and treating severely contaminated and infected wounds. The efficacy of topically applied antiseptics has also been questioned. Some argue that antiseptics are quickly denatured by contact with bodily fluids.13 Sibbald et al. (2000) recommend the use of antiseptics, but only for non‐healing wounds or where the local bacterial burden at the time of presentation is of greater concern than is healing the wound (Figure 5.4).14 A Best Practice document from 2010 summarizes the current understanding of use of antiseptics in wound management by stating that “The use of topical antiseptic/antimicrobial agents is one of the key ways to assist in treating patients with signs of wound infection, and without judicious use of the products, patients may be at risk …. It is equally important to avoid using topical antiseptic/antimicrobial agents on wounds in situations where infection is not present, or where there is no significant clinical risk of infection.”15 Figure 5.4 An acute, severely contaminated degloving injury. This wound is at high risk of developing infection, and will therefore benefit from being irrigated with an antiseptic solution. Photo courtesy of Tinamaria Jensen, Vinding Forlag and Tinamarias Digital Publishing. Choosing the best cleanser or antiseptic for irrigation of a specific wound is not straightforward. The main dilemma is whether to select a product with antimicrobial effects or not, based on the criteria described above. Indications and contraindications for the different cleansers and antiseptics are shown in Table 5.2. Silver has a broad spectrum of antimicrobial activity16 and acts on multiple bacterial sites (it blocks respiratory enzymatic pathways and alters microbial DNA and the cell wall), which may decrease the risk of development of resistance.17 Silver ions have antimicrobial effects against a broad range of Gram‐positive and Gram‐negative wound pathogens, including many antibiotic‐resistant bacteria, such as Staphylococcus aureus, methicillin‐resistant Staphylococcus aureus (MRSA), Enterococcus faecalis, vancomycin‐resistant enterococci, Pseudomonas aeruginosa, and Escherichia coli.18,19 Topical use of silver in infected wounds has been shown repeatedly to reduce bioburden. For example, in experimental burn wounds in rats infected with multi‐drug‐resistant Pseudomonas aeruginosa, 1% silver sulfadiazine and a silver‐coated dressing (Acticoat, Smith & Nephew) reduced bacterial load more than did 3% citric acid and a dressing containing 0.5% chlorhexidine (Bactigras, Smith & Nephew).20 Use of silver‐containing dressings is described in further detail in Chapter 6. Resistance to silver and cross‐resistance between antibiotics and silver are rare.17,21 Two studies investigating silver resistance genes in wound pathogens, including MRSA isolated from humans and horses, detected a low prevalence of silver resistance genes. Moreover, the studies showed that even those bacteria carrying the gene(s) were susceptible to the antimicrobial effects of a silver‐containing hydrofiber dressing.22,23 A wound cleanser containing silver nitrate and menthol is commercially available (Silver‐Stream, Angelini). There are no scientific studies investigating this liquid form of ionic silver, but three conference abstracts (reporting a total of eight cases of difficult‐to‐heal wounds in human patients) suggested that using this product to irrigate infected wounds produced positive effects.24–26 Another type of silver nitrate‐containing product for topical application is the silver nitrate stick, where 75% silver nitrate is combined with potassium nitrate. This product has an entirely different method of action; it is used not as an antiseptic but rather as a chemical caustic agent for removing exuberant granulation tissue (EGT). When the stick/applicator is combined with water, nitric acid is produced, along with an insoluble precipitate, silver hydroxide. Nitric acid (also known as aqua fortis or spirit of niter) is a highly corrosive strong mineral acid, and it is the compound that initiates the biologic caustic action. It induces a chemical burn to the tissues, thereby reducing proliferation of fibroblasts. When used, it should be applied to the wound only, and a skin protectant, such as petrolatum or white paraffin, must be applied to the skin surrounding the wound to minimize harm to healthy tissues. The advancing epithelium and skin should not be touched with the silver nitrate, because to do so delays healing. In humans, silver nitrate is considered to be one of the most successful treatments for hypergranulation and has produced good results in practice.27 Due to its harmful effects, however, cautery with strong silver nitrate should never be considered first‐line therapy and should be used, with great care, for only the most stubborn areas of exuberant granulation. Iodine is a natural element of the halogen group, is an essential nutrient in the body, and has a broad spectrum of antimicrobial activity against Gram‐positive and Gram‐negative organisms. Iodine exerts its antimicrobial effects by penetrating microorganisms and attacking proteins, nucleotides, and fatty acids essential for bacterial survival. Iodine is also antiviral, antifungal, and antiprotozoal. There is no known resistance to iodine. Molecular iodine can be very toxic to tissues and cause skin pain, irritation, and inflammation. Iodophors are iodine carriers or iodine‐releasing agents that act as a reservoir of the active/free iodine. By coupling iodine to these carriers, iodine is released slowly, and its toxicity is reduced. Iodine can be inactivated by blood and serum proteins and by other organic matter. The sustained release of iodine from modern wound‐care products serves to overcome this issue. Two iodophor formulations of iodine are available: povidone–iodine (PI) and cadexomer– (modified starch) iodine (CI). CI products are newer and less toxic than PI. CI is available as a powder and as an ointment (Iodosorb, Smith & Nephew). CI has been shown to accelerate healing by reducing bioburden and by directly stimulating epidermal regeneration and epithelialization.28,29 In clinical studies in humans, the use of CI led to improved wound healing when compared with standard treatments, such as hydrocolloid dressings, paraffin gauze, wet‐to‐dry gauze dressings, zinc paste dressings, saline dressings, enzyme‐based dressings, dextranomer dressings, and non‐adherent dressings.30 A side‐effect of CI has been described as a burning or stinging sensation. Although studies using CI have had consistently positive outcomes, evidence from studies using PI for wound management is conflicting. PI effectively reduces bacterial numbers in infected wounds. Impaired synthesis of collagen, toxic effects on fibroblasts and keratinocytes, and impaired migration of epithelial cells resulting in delayed healing have been observed in animal wound models, but there is no evidence to indicate that PI delays healing of an infected wound.31 In a study using horses, experimental wounds treated with a 10% PI ointment under a bandage healed faster (although not statistically significantly so) than wounds treated with silver sulfadiazine cream (83 and 101 days to healing, respectively).32 A commonly used PI product is Betadine, which is a complex of iodine and polyvinylpyrrolidone (povidone), a synthetic polymer. The most common commercial form is a 10% solution in water yielding 1% available iodine, which is diluted to 0.1–0.2% by adding 10–20 mL of Betadine to 990–980 mL of saline. This dilution increases the availability of free iodine and minimizes cytotoxicity. PI is available as a surgical scrub, a skin cleanser with a detergent, and in other forms, and, according to its formulation, is used to disinfect hands, prepare skin for surgery, or irrigate wounds. Chlorhexidine is commonly used in antiseptic solutions. Chlorhexidine is a cationic biguanide that is a strong alkali virtually insoluble in water. In contrast, its salts (chlorhexidine digluconate, chlorhexidine diacetate, and chlorhexidine dihydrochloride) are soluble and used in antiseptic solutions. Chlorhexidine gluconate is the most widely used, as it is highly water soluble. Chlorhexidine binds to the negatively charged bacterial cell wall, thereby altering the cellular osmotic equilibrium. It has activity against Gram‐positive and Gram‐negative bacteria, facultative anaerobes, and aerobes, yeasts including Candida albicans, fungi, and certain viruses. It is, however, important to keep in mind that members of the genus Proteus are invariably insensitive and that Pseudomonas aeruginosa is more resistant to chlorhexidine (and to quaternary ammonium compounds) than are other Gram‐negative organisms.33 Advantages of chlorhexidine are a prolonged residual effect due to its ability to bind to proteins in the stratum corneum and better activity in the presence of blood, pus, and organic debris than PI. It is well tolerated; the most frequently reported adverse reaction is contact dermatitis. Although in vitro studies often suggest that chlorhexidine has adverse effects on cells, effects of topically applied chlorhexidine on in vivo wound healing are less clear. Topical application of two products (a skin cleanser and an aqueous solution) with 4% w/v chlorhexidine was found to have mild inhibitory effects on wound healing in guinea pigs,34 which could have been related to chlorhexidine toxicity to newly formed keratinocytes35 or its suppressive effects on macrophages.36 In contrast, the use of 0.05% chlorhexidine diacetate was found to accelerate healing of full‐thickness wounds on beagles.37 Polyhexamethylene biguanide (PHMB) (also called polyhexanide) is an antiseptic agent that exerts antimicrobial effects by adhering to and disrupting target cell membranes, causing the microorganisms to leak potassium ions and other cytosolic components, leading to cell death. PHMB has several desirable characteristics: it has very good biocompatibility,41 low toxicity, is highly effective against susceptible and resistant strains of common Gram‐positive and Gram‐negative bacteria, as well as fungi found in chronic wounds, and resistance is non‐existent.42 It has been demonstrated, in vivo, to possess direct pro‐healing effects by enhancing the proliferation of normal human keratinocytes43 and promoting epithelialization.44 In humans with chronic leg ulcers, cleansing with PHMB led to statistically significantly faster healing (time to healing 3.3 months) than cleansing with isotonic saline solution or Ringer’s solution (time to healing 4.4 months) and caused 97% of problem wounds to heal within 6 months (compared to 89% of wounds in the control group),45 a difference that was also statistically significant. For irrigation, a solution (Prontosan, B. Braun) containing PHMB in combination with betaine, a detergent/surfactant, is available. The manufacturer describes this product as being efficient in removing biofilm. Betaine has a low surface tension, which is an important factor in the efficacy of Prontosan. Many wounds are coated with denatured proteins, lipoproteins, and lipids from cell membranes and carbohydrates. As these compounds denature, their solubility decreases. The low surface tension of betaine enhances the physical removal of debris and bacteria coating the surface of the wound.45 If the wound is only lightly contaminated, Prontosan should be applied to the wound’s surface directly from the bottle, and the wound thoroughly cleansed. The irrigation solution should not be rinsed off after cleansing. If the wound is heavily contaminated, Prontosan should be applied by saturating a gauze compress with the solution and leaving this compress on the wound for 10–15 minutes. After the compress has been removed, the wound should be wiped lightly to remove loosened debris. The cleansing is completed by irrigating the wound again with Prontosan, which should not be rinsed off the wound. Hydrogen peroxide has been widely used to cleanse wounds. It is, therefore, paradoxical that its effects on wounds have been investigated in only a small number of studies, and, consequently, are not clear. Some studies have shown beneficial effects, but the majority of studies suggest that hydrogen peroxide may be more cytotoxic than bactericidal. There are also no definitive studies demonstrating that it has an antibacterial effect in vivo. Hydrogen peroxide seems ineffective in reducing the bacterial count, but has sporicidal activity.46 One study in horses demonstrated faster healing and improved histology scores (concentrations of neutrophils and bacteria) in experimental, 2‐cm diameter circular excisional wounds on the neck treated with 1% hydrogen peroxide cream (LHP cream, Bioglan Pharma AB) compared to wounds to which petrolatum or no treatment was applied. Time to complete healing in the three groups was 32, 42, and 44 days, respectively. Petrolatum did not impair wound healing in this study, but it induced the formation of EGT, perhaps because the occlusive properties of petrolatum resulted in lower oxygen tension in the wound; petrolatum‐treated wounds also accumulated significantly more bacteria.47 Hydrogen peroxide may best serve as a chemical debriding agent. Hydrogen peroxide rapidly decomposes into water and oxygen when it combines with organic tissue or blood. During this breakdown, hydrogen peroxide produces effervescence that mechanically cleanses wounds and removes tissue debris via the release of oxygen. Dakin’s solution is dilute household bleach, or sodium hypochlorite. Its antimicrobial effects were discovered by biochemist Henry Drysdale Dakin at the beginning of the 1900s, and the solution gained popularity during World War I as part of the Carrel–Dakin technique based on a concept of thorough wound cleansing (developed by the renowned French doctor Alexis Carrel) combined with irrigation with sodium hypochlorite. This technique helped save lives and mobility of numerous soldiers in the camp hospitals of World War I.48 Sodium hypochlorite kills bacteria and liquefies necrotic tissue by driving chlorine and oxygen into tissues. It is effective against a broad spectrum of aerobic and anaerobic organisms, as well as fungi, and it has an aggressive debriding action.48 Dakin’s solution is available commercially in multiple dilutions ranging from “full strength” (0.5% solution, where household bleach comes as a 5% solution) and 1/40 strength (0.0125% solution). The term “full strength” refers to the highest concentration tolerable to the intact skin. Studies have shown that full‐strength Dakin’s solution has a negative impact on migration and viability of neutrophils, fibroblasts, and endothelial cells in vitro, and for this reason Dakin’s solution fell out of favor for years. A recent in vitro study investigating the effects of antiseptics toward different fungi, however, demonstrated that in a comparison between Dakin’s solution, mafenide acetate, and amphotericin B, Dakin’s solution most consistently met the balance between toxicity and efficacy. A 0.00025% Dakin’s solution appeared to optimize the efficacy:toxicity index,49 thus necessitating dilution of the commercially available 0.0125% Dakin’s solution 50‐fold. Whether or not Dakin’s solution applied to wounds at this dilution has in vivo antimicrobial activity towards bacteria is, however, not clear. Dakin’s solution may not penetrate deep complex wounds or deeply into tissue. The original method of applying Dakin’s solution therefore entailed frequent or continuous infusion into the wound through fenestrated tubes.48,49 Hypochlorous acid is produced when sodium hypochlorite is added to water and also endogenously during the respiratory burst of neutrophils. When neutrophils are activated, hydrogen peroxide is generated and converted to hypochlorous acid by the enzyme myeloperoxidase released from the granules of the neutrophils. Hypochlorous acid induces cellular death via numerous pathways, including oxidation of sulfhydryl enzymes and amino acids, ring chlorination of amino acids, oxidation of respiratory components, decreased production of adenosine triphosphate, breaks in DNA, and depressed synthesis of DNA. There are certain advantages of using hypochlorous acid over Dakin’s solution. The amount of hypochlorous acid released from bleach (sodium hypochlorite) is pH dependent. Therefore electrolyzing water to make hypochlorous acid solution, as described below, ensures a product with a more consistent content of the active agent. Hypochlorous acid has been suggested to have an antimicrobial effect around 80–100 times stronger than the hypochlorite ion.50 Hypochlorous acid solution has the added advantages of not forming the irritant chlorine gas, being more stable and not possessing the corrosive and alkaline properties of bleach. Hypochlorous acid is highly active against all Gram‐positive and Gram‐negative bacterial, viral and fungal human pathogens, including drug‐resistant staphylococci; a small amount of hypochlorous acid can kill spore‐forming and non‐spore‐forming bacteria in a short time.51,52 It may also disrupt biofilm.8 Several products containing hypochlorous acid are available commercially. Neutrophase (Novabay Pharmaceuticals) is a pure solution of hypochlorous acid (0.01%) in isotonic saline solution. A solution containing electrolyzed water (99.97%), sodium chloride 0.023%, sodium hypochlorite 0.004%, and hypochlorous acid 0.003% is marketed by Oculus Innovative Sciences under a number of brand names, including Dermacyn, Puracyn, Oxum, Microdacyn60, Innovacyn, and Vetricyn/Vetericyn – with the latter intended for the veterinary wound‐care market. Vetericyn is made by electrochemical treatment of dilute saline solution. A pH neutral solution of hypochlorous acid, and its salt, sodium hypochlorite, is generated (Figure 5.5). Figure 5.5 Hypochlorous acid made through electrochemical treatment of dilute saline solution, whereby a pH‐neutral solution of hypochlorous acid, and its salt, sodium hypochlorite, is generated (Vetericyn, Oculus Innovative Sciences). Hypochlorous acid is highly active against all Gram‐positive and Gram‐negative bacterial, viral and fungal pathogens, including drug‐resistant staphylococci; moreover, it combines rapid bacterial kill with low cytotoxicity in vitro. These desirable characteristics make hypochlorous acid very useful for wound cleansing. A study by Rani et al. (2014)8 showed that the products based on hypochlorous acid demonstrated a very desirable combination of rapid bacterial kill and low cytotoxicity. Consequently, hypochlorous acid seems to be an ideal antiseptic.51 A recent study showed that a homemade solution with extremely low concentration of hypochlorous acid, made by mixing 1.5 mL of “concentrated” bleach solution (8.25% sodium hypochlorite) and 1 L of distilled water (resulting in a concentration of 99.988% water and 0.012% hypochlorous acid), was as efficient as Vetericyn in inhibiting growth of Staphylococcus aureus and Escherichia coli in vitro. The homemade solution retained its antibacterial effect for at least 1 week.53 Dilute acetic acid is used for the treatment of chronic wounds. It has moderate bactericidal activity against many Gram‐positive and Gram‐negative organisms, especially Pseudomonas aeruginosa. Clinical antibacterial efficacy requires a concentration of at least 0.5%,54 but solutions up to a concentration of 5% have been used for irrigation. A study evaluating the effects of a 3% solution of acetic acid on bacteria commonly found in burn wounds showed “excellent bactericidal effect of acetic acid, particularly with problematic Gram‐negative bacteria, such as [….] P. aeruginosa.”55 Antibiotic‐resistant strains of Pseudomonas aeruginosa are also susceptible to the effects of 3% acetic acid.54 Effects of acetic acid on healing tissues are not entirely clear, because negative as well as positive effects on wound healing have been demonstrated. Wilson et al. (2005) investigated the toxicity of numerous wound cleansers towards keratinocytes and fibroblasts and found that 0.25% acetic acid had low toxicity (toxicity index of 10) compared to 3% hydrogen peroxide or 10% PI (both of which had toxicity indices of 1000).7 Based on current best evidence, it seems that acetic acid may be indicated for cleansing wounds infected with Pseudomonas aeruginosa. Other acids, e.g. 3% boric acid, 2–3% citric acid, 2% ascorbic acid and 0.5–2% salicylic acid, may also be applied topically to treat Pseudomonas aeruginosa infections.54 Octenidine is a bispyridinamine that exhibits a broad spectrum of antimicrobial efficacy against Gram‐positive and Gram‐negative bacteria and fungi. Its efficacy is not adversely affected by interfering substances, such as blood and mucus. Octenidine has strong residual activity on skin, which can still be observed 24 hours after application. When cytotoxicity of octenidine at a concentration producing a 3 log10 reduction of Escherichia coli and Staphylococcus aureus was compared to the cytotoxicity of other antiseptics (benzalkonium chloride, cetylpyridinium chloride, chlorhexidine digluconate, mild silver protein, PHMB, PI, silver nitrate, silver sulfadiazine, and triclosan), octenidine and PHMB were the only tested products with a biocompatibility index greater than 1, meaning that these substances were the only antiseptics more toxic to the microorganisms than to murine fibroblasts.41 A recent review emphasized that octenidine and PHMB are the most effective, as well as best tolerated, antiseptics used in wound management today.56
Topical Wound Treatments and Wound‐Care Products
Summary
Introduction
Wound cleansers and irrigation solutions
Product name
Supplier
Contents
Delivery
Fibroblast toxicity index* (Rani et al. 2014)8
Time to bacterial kill** (Rani et al. 2014)8
Shur‐Clens
Convatec
Poloxamer 188 (synonym: Pluronic F‐68)
Pour‐on/squeeze bottle
0
>24 h
Neutrophase
Novabay Pharmaceuticals
Hypochlorous acid
Pump
10
<1 min
Vetericyn
Innovacyn Inc.
Hypochlorous acid, electrolyzed water
Pump or spray bottle
10 (the study tested Puracyn, which is the equivalent product on the human wound‐care market)
30 min
3 M Wound Cleanser
3 M
Dextrose, sodium chloride, “nutrients” (pyridoxine, zinc). Does not contain surfactant or antimicrobial agents
Squeeze bottle (8.5 psi)
10
<24 h
EquineVet Acemannan Wound Cleanser
Carrington Labs
Acemannan hydrogel, sodium lauryl sulphate, dibasic sodium phosphate
Spray bottle
10
>24 h
Biolex
Bard Medical
Aloe vera, proprietary non‐ionic surfactant
Spray bottle
10
>24 h
SAF‐Clens AF Dermal Wound Cleanser
Convatec
Poloxamer 188 (synonym: Pluronic F‐68)
Spray bottle
100
24 h
Prontosan Wound Cleanser
B. Braun
Polyhexanide, betaine
Nozzled bottle (7 psi) or 40 mL single use ampoule
100
>24 h
Dermal Wound Cleanser
Smith & Nephew
Benzethonium chloride, Polysorbate 20
Spray bottle
1000
>24 h
UltraKlenz
Carrington Labs
Glycine, sucrose, benzoic acid, imidazolium compounds, dodecanoic (lauric) acid, mannitol
Spray bottle
Not assessed
Not assessed
MicroKlenz
Carrington Labs
Benzethonium chloride 0.1%, citric acid, cocamidopropyl betaine, dibasic sodium phosphate
Spray bottle
Not assessed
Not assessed
Sea‐Clens
Coloplast
Saline‐based
Spray bottle (7.6 psi)
Not assessed
Not assessed
Isotonic saline solution
Tap water
Commercial wound cleansers
Solution
Indication
Contraindication
Comments
Saline/tap water
Acute and chronic clean or minimally contaminated wounds
Saline and tap water are not effective for cleansing contaminated, necrotic, dirty or infected wounds
Commercial cleansers with surfactant
Effective for wounds with adherent cellular debris and wounds with necrotic tissue. The presence of a surfactant means that less fluid pressure is required to remove bacteria and cellular debris
Infected wounds, as antimicrobial activity is minimal
Cleansers based on poloxamer 188 (synonym: pluronic F‐68) seem to have the least toxicity, while cleansers marketed for intact skin (soaps, body washes and shampoos) the highest. See Table 5.1 for further detail
Antiseptics: silver
Wounds infected with Gram‐positive and Gram‐negative wound pathogens, including anaerobes and many antibiotic‐resistant bacteria (MRSA, VRE), Pseudomonas aeruginosa, Serratia marcescens, fungi and yeasts (Aspergillus and Candida spp.)
Wounds that are not high risk, wounds that are not critically colonized or infected
Antiseptics: iodine
Wounds infected with Gram‐positive and Gram‐negative organisms, fungi, and protozoa. Iodine is active against dermatophyte fungal infections (Microsporum and Trichophyton spp.) and has some sporicidal and virucidal activity, especially with increased exposure time
Wounds that are not high risk, wounds that are not critically colonized or infected
Cadexomer–iodine is more consistently beneficial than is povidone–iodine
Antiseptics: chlorhexidine
Wounds infected with Gram‐positive bacteria and many Gram‐negative bacteria, facultative anaerobes, and aerobes, yeasts, and fungi
Wounds that are not high risk, wounds that are not critically colonized or infected. Wounds infected with Proteus, Serratia and Pseudomonas spp., as these organisms are inherently resistant or very insensitive to the effects of chlorhexidine. Chlorhexidine has limited virucidal activity and no sporicidal activity
Antiseptics: polyhexamethylene biguanide (PHMB)
Wounds infected with Gram‐positive and Gram‐negative wound pathogens, including many antibiotic‐resistant bacteria, atypical organisms (e.g., Chlamydia and Mycoplasma spp.), and bacteria that form plaques and biofilms. PHMB is fungicidal against Candida and Aspergillus spp.
Wounds that are not high risk, wounds that are not critically colonized or infected. PHMB has little or no antiviral activity
Among the best antiseptics currently on the market. PHMB combines rapid and broad‐spectrum antimicrobial activity with low cytotoxicity in vitro
Antiseptics: hydrogen peroxide
Hydrogen peroxide is mainly useful as a debriding agent: upon contact with organic matter hydrogen peroxide produces effervescence that mechanically cleanses wounds. It has sporicidal activity, but low bactericidal activity against vegetative forms of Gram‐positive and Gram‐negative bacteria
Hydrogen peroxide is cytotoxic and has limited bactericidal activity, therefore generally not indicated for wound cleansing
Antiseptic activity is reduced by the presence of blood. Hydrogen peroxide is cytotoxic at the efficacious concentrations (3%)
Antiseptics: sodium hypochlorite/Dakin’s solution
Wounds infected with a broad spectrum of aerobic and anaerobic organisms including Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, group D Enterococcus, and Bacteroides fragilis, as well as fungi. At higher concentrations (0.025%, which also has some cytotoxicity) Dakin’s solution is effective against MRSA, Staphylococcus epidermidis, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, and Proteus mirabilis
Wounds that are not high risk, wounds that are not critically colonized or infected. Dakin’s solution has limited penetration and is therefore not suited for deep complex wounds
Conflicting cytotoxicity data, but 0.0125–0.00025% solutions seem safe
Antiseptics: hypochlorous acid
Wounds infected with very broad range of microorganisms, hypochlorous acid is active against all Gram‐positive and Gram‐negative bacterial, viral and fungal human pathogens, including drug‐resistant staphylococci
Wounds that are not high risk, wounds that are not critically colonized or infected
Among the best antiseptics currently on the market. Hypochlorous acid combines rapid and broad‐spectrum antimicrobial activity with low cytotoxicity in vitro
Antiseptics: acetic acid
Wounds infected with Pseudomonas spp.
Acetic acid is cytotoxic and has limited bactericidal activity, it is generally not recommended for wound cleansing
Limited studies are available on the cytotoxicity of acetic acid, but those available indicate that its cytotoxicity may surpass its bactericidal effects
Antiseptics: octenidine
Wounds infected with Gram‐positive and Gram‐negative bacteria, MRSA, plaque‐forming organisms such as Actinomyces and Streptococcus spp., atypical organisms such as Chlamydia and Mycoplasma spp., fungi, some viruses
Wounds that are not high risk, wounds that are not critically colonized or infected. Octenidine has no activity against spores and protozoa
Among the best antiseptics currently on the market. Octenidine combines rapid and broad‐spectrum antimicrobial activity with low cytotoxicity in vitro
Antiseptics: cetylpyridinium chloride
Wounds infected with Gram‐positive bacteria and yeasts
Wounds that are not high risk, wounds that are not critically colonized or infected. Cetylpyridinium chloride is relatively ineffective against Gram‐negative bacteria
Antiseptics: tris‐ethylenediamine tetra‐acetic acid (tris‐EDTA)
Wounds infected with Gram‐negative bacteria, including Escherichia coli, Pseudomonas aeruginosa, and Proteus vulgaris
Wounds that are not high risk, wounds that are not critically colonized or infected. Tris‐EDTA has little effect on Gram‐positive bacteria and yeasts
Mainly useful in combination with other antiseptics (or antibiotics), because a main effect of tris‐EDTA is to damage the bacterial cell membrane and increase its permeability to antimicrobial substances
Antiseptics
Silver
Iodine compounds
Chlorhexidine
Polyhexamethylene biguanide
Hydrogen peroxide
Dakin’s solution
Hypochlorous acid
Acetic acid
Octenidine dihydrochloride
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