Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
ACTICOAT: A Unique Nanocrystalline Silver Delivery System for Burns and Wounds 1 TABLE OF CONTENTS I. HISTORICAL OVERVIEW OF SILVER II. PROPERTIES OF SILVER III. NANOCRYSTALLINE SILVER DELIVERY SYSTEM (ACTICOAT™) IV. ANTIMICROBIAL PROPERTIES OF NANOCRYSTALLINE SILVER (ACTICOAT™) V. PROHEALING PROPERTIES OF NANOCRYSTALLINE SILVER (ACTICOAT™) VI. ANTI-INFLAMMATORY PROPERTIES OF NANOCRYSTALLINE SILVER (ACTICOAT™) VII. AND OTHER SILVER CLINICAL COMPARISON OF ACTICOAT COMPOUNDS IN BURNS VIII. IN DIFFICULT TO HEAL AND CHRONIC USE OF ACTICOAT WOUNDS XI. REFERENCES 2 I. HISTORICAL OVERVIEW OF SILVER Silver has long been used for its antimicrobial properties. However, the delivery systems available, often in the form of a salt, have been the limiting factor to successful biological use of this noble metal. Nanotechnology and the ability to deliver silver from a nanocrystalline structure has and will markedly improve the biologic value of silver. These advances in crystal chemistry will likely have a dramatic impact on the microbiology, as well as biology of wound healing and control of inflammation. We will describe the past, present and future uses of silver in biologic systems focusing on its biological properties on “wounds”. Silver has been used for centuries to prevent and treat a variety of diseases, most notably infections. Silver has extremely potent antimicrobial properties with levels in solutions exceeding 10 parts per million. Silver ions appear to kill micro-organisms instantly by blocking the respiratory enzyme system (energy production), as well as altering microbe DNA and the cell wall, while having no toxic effect on human cells in vivo. Free silver ions, or radicals, are known to be the active antimicrobial agent. In order to achieve a bactericidal effect, silver ions must be available in solution at the bacterial surface. Efficacy depends on the aqueous concentration of these ions. However, crystalline silver is quite insoluble in water and in dilute acids making the available silver cation concentration, inadequate for use as an antimicrobial on a wound surface. Beginning in the 1920’s, a small electrical charge was passed through water and silver crystals in order to obtain an effective silver (electrocolloidal) ion solution to be used topically on wounds. The charged silver solutions (electro-colloidal) were approved in the 1920’s by the FDA for use as an antibacterial agent. These solutions are very unstable and the concentration of silver may be inadequate for an ideal antimicrobial agent. Prior to 1940, pure silver in the colloidal form was being commonly used for wound infection as this period predated the use of antibiotics. After 1940, systemic antibiotics became prevalent. Carl Moyer in 1965 introduced the use of a 0.5% silver nitrate solution for burn wound management. The silver nitrate was a more stable compound and replaced colloidal silver. During the same time period, Dr. Charles Fox developed another silver compound for wounds and burns, silver sulfadiazine. The sulfadiazine is composed of propylene glycol, stearyl alchohol and isopropanolol. This compound was formulated as a water soluble cream to be applied twice a day to a wound surface instead of a continuous soak required of silver nitrate for continued silver delivery. 3 Over the past 40 years silver sulfadiazine has become a very popular anti-microbial silver delivery system. However, both nitrate and sulfadiazine impair fibroblast and epithelial proliferation, impairing healing. Advances in the field of nanotechnology were required before a new form of pure silver was available for use in biological systems. Toxicity of Silver Compounds Silver Sulfadiazine Cream • • • • • Can produce bone marrow suppression Pro-inflammatory response Toxic to fibroblasts Can lead to propylene glycol toxicity Allergic reactions reported Silver Nitrate 0.5% Solution • • • Nitrate can produce oxidant injury Binds chloride Can retard epithelialization Pure Silver • • No local or systemic toxicity described No impairment of healing 4 II. PROPERTIES OF SILVER A) Safety Silver itself is considered to be non-toxic to human cells in vivo. The only reported complication is the cosmetic abnormality argyria caused by precipitation of silver salts in the skin and leading to a blue-gray color. Although not yet defined there remains some concerns about the potential of high tissue levels of silver altering enzyme function. Silver nitrate in vitro has been shown to have a negative impact on fibroblasts, hepatocytes and lymphocytes, but studies on anodically generated silver ions show no impact on mammalian cells in culture. Clinical evaluations carried out by Bador and Coombs et al. found no tissue toxicity. The major complications attributed to silver compounds are due to the complex or anion namely the nitrate and sulfadiazine not the silver itself. Both nitrate and sulfadiazine have been shown to impair fibroblast and epithelial cell proliferation impairing healing allergic reactions to topical silver are rare. Overview of Silver and Wounds •Potent antimicrobial -kills instantly -blocks respiratory enzymes •Non-toxic to human tissue •Pro-healing properties •Anti-inflammatory properties B) Antimicrobial Effects of Silver Silver exerts its antimicrobial effects by interfering with the respiratory chain at the cytochromes (3). Silver ions also interfere with components of the microbial electron transport system, bind DNA and inhibit DNA replication. Silver is effective against a broad range of aerobic, anaerobic, Gram-negative and Gram-positive bacteria, yeast, filamentous fungi and viruses. 5 In order for silver to be biologically active, it must be in a soluble form such as Ag+ or Ag0 clusters. Ag+ is the only form present in silver nitrate, silver sulfadiazine and other ionic silver compounds. Ag0 is the metallic or uncharged form of silver found as one of the silver species in nanocrystalline, silver structures. In solution, the Ag° exists in a sub-crystalline form, less than 8 atoms in size. Silver nitrate and silver sulfadiazine release silver at concentrations up to 3,200 ppm (silver release from silver sulfadiazine is much slower than that from silver nitrate) but most of this is rapidly inactivated through the formation of chemical complexes. Early silver formulations compensated for the rapid loss of silver ions by frequent replacement. Although this was effective, it created problems for healthcare professionals and patients, and resulted in large excesses of silver being delivered to the wound. In burns units, silver sulfadiazine is commonly applied twice a day and silver nitrate up to 12 times a day. Repeated applications increase discomfort and wound trauma. The nature of the solute also affects the biological activity of silver. In complex organic biological fluids, continuous concentrations of silver >50 ppm and as high as 60.5 ppm are needed to kill microbes. Therefore in wound management, quantities of silver ion should be sufficient to provide sustained bactericidal action. Acticoat with nanocrystalline silver also provides the Ag0 form of silver, which is far less rapidly deactivated by chloride or organic matter than the ionic form. In addition to it’s recognized antibacterial properties, silver delivered to a wound, has been reported to also have anti-inflammatory and pro-healing properties. C) Pro-healing Properties Although silver in an electro colloidal form, had been reported to improve the healing of indolent wounds in the early 20th century, that finding disappeared with the use of silver salts and complexes. Recently there have been several reported studies of improved reepithelialization rates across wounds with silver in the nanocrystalline form. The mechanism, although unknown at present, does not appear to be due to silver’s antimicrobial action. Controlling the pro-inflammatory cytokines and proteases may be a factor. 6 D) Anti-inflammatory Properties Increased wound inflammation not only accentuates pain but markedly impairs healing. Several heavy metals have been reported to decrease surface inflammation, the most recognized being gold. Wound surface inflammation has been reported to be decreased with the use of nanocrystalline silver. Excess metalloproteinases (MMP) are known to increase inflammation by both increasing inflammatory cell exudates and also leading to a non-healing chronic wound. A characteristic of this type of wound is excess surface MMP activity, decreased inhibitory MMP activity and degradation of growth factors by the MMP’s. Nanocrystalline silver has been shown both in vitro and in vivo to decrease but not totally prevent MMP activity as some activity is needed to remove devitalized tissue. The mechanism for this action also remains unknown. Decreasing the necessary zinc activity required for MMP’s is one possibility. The other is an effect on the expression or release of pro-inflammatory cytokines. Silver in the nanocrystal form also decreases wound release of TNFα. III. NANOCRYSTALLINE SILVER DELIVERY SYSTEM (ACTICOAT™) A) Nanotechnology The property of matter depends on size and many of the chemical and physical characteristics change significantly when matter is reduced in size. Nanotechnology is a general term that refers to a relatively new frontier of scientific endeavor. The prefix “nano” signifies one-billionth. Therefore, a nanometer is one-billionth of a meter, a nanogram is one billionth of a gram. Ten hydrogen atoms placed side by side measures one nanometer in length. Silver crystals sputtered under normal vapor deposit conditions result in tightly adherent crystals of 100-900nm in diameter. Decreasing crystal volume by nanotechnology markedly increases the exposed surface area of the crystal which increases the available surface for chemical reactions to take place over a shorter time period. Decreasing the particle size will also, in general, change the physical/chemical properties of the material. Examples of changed properties resulting from nano-sized metals, include increased superconductivity and increased optical and electrical properties. Nanosizing can also lead to a more economical utilization of expensive materials-meaning that can use less material because the reactions are more efficient. Although not yet specifically defined, it is clear that some of the properties of silver in a nanocrystal are quite different than the typical crystal. A large portion of the silver is available as grain or interphase boundaries, considered by some to be a new form of matter. Orientation relationships are very different for the silver. Also some of the silver appears to be in an oxidized form. Increasing the variety of oxidized silver species would be expected to increase solubility and lead to a much higher overall reactivity. 7 Nanotechnology •Nanometer (one billionth) •Nanosilvercrystals (10 -20 nm) •Huge surface area •Crystal properties very different -much more reactive -higher energized state -increasing silver penetration •Burrell R. An electrochemical analysis of thin silver films produced by reactive sputtering. Electrochem Soc 2001:148; 791. •OvingtonL. Nanocrystalline silver; where the old and familiar meets a new frontier. Wounds 2001:13; 5. Normal Silver Crystals Normal crystallization is shown micron sized particles closely adherent, decreases surface area for water exposure and silver release. Nanocrystalline Silver The structure of the silver system Acticoat is evident using scanning electron microscopy. The silver coating consists of nonacrystals, which allow for rapid exposure to water and subsequent silver ion and silver radical release. There is a marked increase in surface area for water to reaction with silver in the nanocrystalline form. In addition, other reactive silver species are released from the more unstable nanocrystal. 8 B) Physical Properties Of Acticoat™ Nanocrystalline Silver Delivery System The method of making the nanocrystalline material on Acticoat is called physical vapour deposition. Argon gas is introduced into a vacuum chamber that contains a silver cathode, the chamber acting as the anode. When an electric current is passed through the gas, positive argon ions are created which accelerate towards the negatively charged silver cathode. On impact, the argon ions knock out silver atoms that travel towards the substrate to be coated where they deposit and develop into nanocrystals when energy inputs are limited. These are only about 15 nanometres across, which is between 30 a 50 atoms. Thus a nanocrystalline structure is created with a significant grain-boundary component and increased surface area. These changes to the physical properties of the crystal lattice result in a meta-stable, high-energy form of elemental silver. Normal silver placed in water will not dissolve, but nanocrystalline silver dissolves to provide a continuous concentration in solution of around 70 ppm. Both Ag+ and Ag0 are released: it is thought that Ag0 does not react with chloride as quickly as Ag+ and does not require a carrier. As the ions in solution are depleted, the equilibrium shifts and more Ag+ and Ag0 ions are released. By contrast, silver nitrate provides a huge immediate concentration of silver ions which, two hours after application, have virtually all been chemically consumed by chloride. 9 C) Silver Nanocrystalline Delivery Dressing (ACTICOAT™) The silver delivery dressing developed by Dr. Burrell is a 3 layer wound dressing consisting of an absorbent rayon/polyester core laminated between an upper and lower layer of silver coated high density polyethylene mesh. The laminations are held in place with ultrasound welds. The silver coating, which consists of 0.25±0.4 mg silver per mg high-density polyethylene, is a binary allow of silver and oxygen with negligible contaminants (content is 99.99% silver). The coatings are highly porous and consist of nanocrystals organized into coarse columnar structures. This unique physical structure, in combination with the oxygen atoms/molecules that are trapped in the crystal lattice, contribute to the enhanced solubility of the films which continue to release silver until the concentration in solution reached 66mg/L a level that is 50 to 100 times higher than is expected from typical bulk pieces of silver metal. The silver crystals coat both sides of the product with a polyester core between the sheets to maintain the moisture needed for silver release. Either side of the silver dressing can be placed onto the wound surface. The silver coating when wet with sterile water, produces a continual release of Ag+ and likely other silver radicals for days. The delivery system readily olds to the wound producing wound occlusion as well as maintaining a wound surface moisture layer. Current published data indicates that this silver release product produces a rapid and complete killing of essentially all pathogens found on a wound. The silver delivery system is represented. Both silver layers release the silver ion exposure to water. 10 REACTIVE SPECIES OF SILVER RELEASED FROM SILVER PRODUCTS Medical Name Initial forms of Silver Species in Silver Solution Nanocrystal Silver Metallic Ag Ag+AgOH Delivery Nanocrystal Ag° clusters 1% SSD Ag+ Ag+ (0.5%) Silver Nitrate Arglaes Ag+ Ag+ AgKzPO4 Ag+ Note the different silver species released by the nanocrystals, ACTICOAT™ System Note: the release of silver with the nanocrystalline pure silver delivery system is constant for over 48 hours when exposed to water. The silver concentration on the wound surface is 20-30 times greater than the concentration required to kill microbes. (The concentration of Ag+ required to kill pseudomonas is comparable to that required for killing of other microbes. This constant silver release is unique and quite different from the initial pulse release of silver Ag+ from other products. 11 Silver Delivery Systems (ACTICOAT) Nanocrystal Silver Delivery System (ACTICOAT) A three ply dressing consisting of inner rayon/polyester core between two layers of silver coated mesh •Nanocrystalline silver placed onto a bilayer of polyethylene for controlled release •Ionic silver and silver radicals released in ideal concentrations when exposed to wate •Active silver release up to 7 days •Maintains moisture layer for healing betwe wound and silver membrane Highly bacteriocidal fungicidal •Nanocrystal coating contains 0.841.34mg silver/cm2 Silver concentration in current silver products • Silver Nitrate 0.5% solution -Silver concentration 3180 µg Ag+/mL water -Ag+ availability 318µ g Ag+/mL water -Immediate release • Silver sulfadiazine 1% cream Silver concentration 3030Ag+/gram -Silver availability 3030 µg Ag+/gram -Release over 12-24 hours • Silver delivery (Nanocrystals) -Silver concentrations 13% -Silver availability 100 µg Ag+/mL water -Stable release for at least 48 hours Although the nanocrystal silver delivery membrane has less total silver, a more rapid and sustained release appears to occur due to the nanocrystalline structure. This process markedly increases the surface area of the silver when exposed to the wound. This physical property may explain its more rapid bacteriocidal action. Less total silver (Ag+) released by the nanocrystals should decrease any potential toxicity. 12 The large sheets of Acticoat™ nanocrystal silver is shown form fitting to a large wound One side of the sheet is typically darker than the other, but both sides actively release silver when water is added. The Acticoat 7 dressing releases silver for 7 days and comes in a variety of sizes to fit different wound pages 13 IV. ANTIMICROBIAL PROPERTIES OF NANOCRYSTALLINE SILVER As can be seen in Table 3 of Nanocrystal Silver, the aqueous concentration of silver ions released from the nanocrystalline film is approximately 3% of that released from a 0.5% silver nitrate or a 1% silver sulfadiazine cream. However, the biological properties of the silver released from nanocrystals are much greater. Silver resistance has been reported in the literature and is mediated through one of two pathways. Either the silver is tied up in the cell wall and membranes, or it is actively transported out of the cell. Bacterial organisms that have either one of these resistance mechanisms, which are effective up to 1000 g/mL Ag+.have been tested against the nanocrystalline silver coated dressing. These tests showed that these organisms were susceptible to the silver produced by the nanocrystals but not to Ag+ from silver nitrate. These findings, as will be described, strongly suggest that other species of silver besides Ag+ are released from the nanocrystals. (ACTICOAT™). MRSA death curve comparing different silver compounds. Note increased killing with Acticoat silver. 14 VRE death curve comparing different silver compounds. Note increased killing with Acticoat silver. The lower amount Ag+ released should also decrease the potential of silver toxicity to cells, if it exists, by a substantial margin when compared to the other silver agents. In another study nanocrystalline silver was extracted from the silver delivery system Acticoat by incubating the dressing in pure water at 37°C in a shaking incubator, and silver concentrations were measured using atomic absorption spectrophotometry. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined using five bacterial isolates of clinical interest, and results were compared for nanocrystal silver, silver nitrate and silver sulfadiazine, based upon total silver. Nanocrystalline silver had similar MIC and MBC values when compared to three silver containing agents. Kill kinetics were also studied, using 2.0 cm x 2.0 cm of pieces of silver dressing, and the same sized pieced of dressing impregnated with either silver nitrate or silver sulfadiazine. Bacterial survival was measured using a plate counting technique. Nanocrystal silver demonstrated the fastest kill times for the five bacteria used. In most instances with Nanocrystal silver, bacterial survival was undetectable 30 minutes after inoculation, whereas at least 2-4 hours elapsed before no viable cells were detected with silver nitrate or silver sulfadiazine. These findings strongly suggest that silver species in addition to Ag+, released from the nanocrystalline film are responsible for the more potent antimicrobial properties. To date the nanocrystalline silver system kills all microbes found in a wound including fungi and all current antibiotic resistant organisms such as Vancomycin resistant enterococcus (VRE) and methicillin resistant staphylococcus aureus (MRSA). 15 The susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) to a range of silver preparations: silver sulfadiazine, silver nitrate, silver calcium phosphate (Arglaes™ dressing; Medline Industries Inc., IL, USA), metallic silver film (Silverlon®; Argentum Medical, IL, USA) and nanocrystalline silver (Acticoat™) was tested. After 30 minutes, nanocrystalline silver had reduced the number of viable bacteria to very low levels (102CFU/mL) while after 2 hours the other dressings had still not reduced the levels to below 105CFU/mL. Similar results are seen with vancomycin-resistant enterococcus (VRE). The Acticoat™ dressing has been shown to inhibit the growth of Pseudomonas aeruginosa and S.aureus for a minimum of nine days while a silver film dressing was only able to inhibit the growth of P. aeruginosa for four days of repetitive challenge, and S. aureus for one day. This may be due to the presence of phosphate in the film dressing which is known to reduce the bactericidal properties of silver. Sustained release of silver is important in reducing bacterial burden. Silver nitrate has to be applied every two hours to be effective, and the cream base in silver sulfadiazine reacts with serous exudates to form a pseudo-eschar that must be removed before the cream can be re-applied. Acticoat™ can be left in place for up to seven days, meaning that the wound does not have to be manipulated during this period, which may cause trauma to the new epithelial growth and may spread bacteria into the blood stream. Resistance to silver is rare, but not unknown. There are two forms of resistance: silver can be bound by cells in the form of an intracellular complex: and it can also be excreted from microbes using cellular efflux systems. Resistance can be induced using low concentrations of silver. Exposure of various E. coli strains to silver nitrate started at half the minimum inhibitory concentration (MIC) value (2-4 mg Ag+/L) produced resistance which increased with each generation. Bactericidal levels of silver do not produce resistance as dead cells cannot mutate, but MIC and sub-MIC levels can result in the development of resistance. Resistant cells appear to have reduced permeability of the outer membrane to silver combined with an ability to pump silver out of the cell – an active efflux mechanism. This emphasizes the importance of using clinically relevant levels of silver particularly as a range of silver dressings are now in widespread use. Non-controlled use of silver 16 (sub-lethal levels) may result in bacteria developing resistance in the way that antibiotic and biocide-resistant bacteria have emerged. V. PROHEALING PROPERTIES OF NANOCRYSTALLINE SILVER ACTICOAT Past observations and recent studies using a pure silver delivery system have demonstrated an increased rate of healing in wounds and burns compared to other wound care products. The direct healing effect of pure silver has yet to be defined. Silver has a number of effects which would indirectly increase healing, namely controlling infection, decreasing excess inflammation, maintaining moist healing and decreasing wound surface mechanical trauma caused by frequent dressing changes. Mechanisms for Pro-Healing Effect of Nanocrystalline Silver . • • • • • Direct effect in wound biology Controlling surface microbes Moist wound healing maintained Decreasing mechanical trauma during dressing changes Decreasing excess wound inflammation A) Direct Effect of Silver on Healing Silver has a number of biological effects on the wound surface. It remains to be determined whether any of these effects produces a healing stimulus. Several studies comparing silver released from a silver nanocrystal delivery system with other topical antibiotics have demonstrated increased re-epithelialization of partial thickness wounds and meshed skin grafts. A comparison was made of the rate of reepithelialization of 2:1 meshed skin grafts on excised burn wounds. The nanocrystal silver group re-epithelialized at a significantly faster rate. No infection was noted in either group, both using moist wound healing. 17 Re-epithelialization rate of Meshed Skin graft. Typical meshed skin graft (2:1) studied (Acticoat vs. Neosporin). Treatment with Acticoat in one group. Comparison with meshed graft continuously moistened with Neosporin solution. Methods 20 burn patients with bilateral extremity burns Excised and covered mesh graft (2:1) One group skin graft covered with Acticoat Other group skin graft kept moist using Neosporin solution 18 The meshed graft re-epithelialized much faster using topical silver (Acticoat) compared to neomycin solution. (Demling R., et al, The rate of re-epithelialization across meshed skin graft is increased with exposure to silver, Burns 2002:28; 264) B) Controlling Surface Microbes Increasing evidence has demonstrated that wound colonization can result in a bacterial burden to healing. The concept that one needs 105 organisms per gram of tissue to be deleterious is no longer considered accurate. Certainly 105 organisms or greater is destructive to healing but fewer bacteria can also impede healing as the immune defenses of a wound and of a patient vary considerably, e.g. the elderly diabetic versus the healthy young adult. Improved antimicrobial activity should therefore assist healing independent of any direct healing property of silver. C) Maintaining Moist Wound Healing Numerous studies followed which demonstrated that wound occlusion and moisture improved all phases of healing. The data demonstrating that a moist wound surface increases re-epithelialization and all other components of wound healing, is now well established. Any surface desiccation leads the risk of further tissue damage. 19 Problems of Surface Dessication • • • • • Increased depth of surface tissue necrosis Impediment to surface epithelial cell migration Decreased surface oxygen available for healing and bacterial killing Impaired nutrient flow to surface Increased infection risk In general, research has shown that a moist wound environment is associated with less severe and prolonged inflammation; more rapid keratinocyte proliferation and migration; earlier differentiation of keratinocytes to restore surface barrier function; more rapid fibroblast proliferation, increase in collagen synthesis; earlier, angiogenesis; and earlier full-thickness wound contraction. A more rapid decrease in wound volume and surface area has also been well documented with moisture. This use of a moist healing environment has not routinely been used in burns because of the concern for infection. Also the antibiotic creams do not produce a moist healing environment. In fact, the creams silver sulfadiazine and sulfamylon, will extract water from the wound surface as a result of the hyperosmolarity of the cream, especially with drying of the cream. Advantages of a Moist Wound Surface • • • • • • • • Reduction in wound surface conversion Decrease in surface desiccation and eschar formation Increase in local growth factor production Activation of surface proteases to remove devitalized tissue Decreased surface inflammation Enhanced wound surface immune defenses Increased rate of angiogenesis and fibroblast proliferation Increased proliferation and migration of epithelial cells along thin water layer Silver nitrate solution maintains a moist surface but this approach is not very popular because of increased nursing care demands as the dressings must be constantly moistened. The nanocrystal silver delivery system maintains a moisture layer between the wound surface and the inner silver membrane. This moisture layer is also a potent antimicrobial silver solution on the wound surface. Moisture is maintained on a deep burn by wetting the surface of the Acticoat™. Moisture on a partial thickness wound is provided by the wound itself under the Acticoat, which is covered with a secondary dressing. 20 The ability to maintain both a moist healing environment and an antimicrobial environment is a unique property of this silver system, especially beneficial for burns and wounds. Clean Wound Bed Addition of Nanocrystalline silver delivery maintains moisture layer on wound surface. Use of silver cream results in a pseudo eschar and can withdraw fluid from this wound surface. 21 Acticoat on Burn (Day 3). Note moisture layer and lack of exudates when silver dressing is peeled back. D) Decreasing Mechanical Trauma Frequent dressing change and wound manipulation create not only systemic toxicity but also local wound trauma. The high rates of bacteremias with wound manipulation have been well described as has the typical pyrogen release and post-dressing change hyperthermia. Also wound surface manipulation especially on the re-epithelializing wound will injure new tissue formation Mechanical removal of creams, ointments and dressings will all cause local trauma. The nanocrystalline silver dressing can remain in place for days and if wetted prior to removal, mechanical trauma is minimal. In addition, the exudates beneath is usually minimal and there is no film or byproduct, which requires mechanical removal. 22 VI. ANTI-INFLAMMATORY PROPERTIES OF NANOCRYSTALLINE SILVER ) (ACTICOAT Some inflammation is needed for wound healing. However, excess inflammation on a wound surface will retard healing by several mechanisms. A) Problem of excess neutrophils and byproducts By products of dead and dying neutrophils releasing toxins damaging to local cells impair the healing process Typically when neutrophils die, in the process of necrosis or exudates formation, proteases and oxidants are released. The controlled cell death known as APOPTOSIS occurs without cell rupture. Increasing the process of apoptosis in neutrophils would be a protective advantage to the wound bed. B) What are Metalloproteases (MMP’s) and How do they alter Healing? The metalloproteases are a family of proteases (enzymes which break down tissue) characterized by: a. dependence of the metal zinc for activation b. present in wounds where their role is to break down damaged tissue, denatured protein and matrix, in order to make way for new tissue initiated by growth factors c. high sulfur content including sulfhydryl and disulfide bonds d. present in highest concentration on the wound surface and in matrix e. can inactivate growth factors The wound healing process is recognized to be a dynamic balance between growth factors, or the synthetic aspects, and proteases, which produce tissue breakdown and remodeling. These proteases therefore break down the elements of a wound namely collagen, elastin, and matrix. In addition, these proteases will inactivate growth factors if present in excess as in a chronic wound or an acute burn wound. There is present a counteraction system to maintain optimum balance in the wound called endogenous tissue inhibitors of MMP’s or TIMP’s. There are a number of TIMP’s, released by macrophages and fibroblasts, in response to MMP production which protect tissue from protease breakdown by a competitive binding to tissue protease sites. This system is limited to a finite production, which can be overwhelmed by the greater potential for protease production with inflammation. At present, considerable research is underway to increase TIMP’s activity. Presently, there are no clinically available protease inhibitors. 23 Excess wound matrix metalloproteinases (MMP’s) have also been shown to impede healing by breaking down growth factors and new cells. These MMP’s are activated and produced in excess as a result of pro-inflammatory cytokines and the other activators of excess inflammation. There are several types of wounds where there is a recognized MMP imbalance. Infected wound logically because bacterial promotes inflammation The acute burn wound likely due to the massive tissue insult (mostly seen in the partial thickness burn) The chronic non-healing wound where excess inflammation is known to be the cause of the lack of healing There are many documented mechanisms for the excess MMP’s produced by: • increased tissue neutrophils • increased neutrophil, macrophage and fibroblast gene expression for MMP’s • oxidant and other mediator induced increase in MMP production by all wound cell types • increase in pro-inflammatory cytokines Metalloprotease Profile MMP’s involved in Wounds Characteristics of MMP’s • Collagenase (MMP-1, MMP-8 • Breakdown collagen, elastin and matrix • Gelatinases (MMP-2, MMP-9) • Should be in balance with natural inhibitors and with Growth Factors • Elastase (MMP-13) • Can degrade growth factors and also wound tissue if in excess • Dependent on zinc to activate • Need sulfhydryl bonds 24 Exudate buildup on wound surface increases local neutrophils & byproducts. Excess MMP’s breakdown new collagen and denature new growth factors and can increase the depth of the wound (conversion). Burn Wound Immediately after initial cleaning Wound Conversion Presence of inflammation induced pseudo eschar. 25 C) Anti-inflammatory Properties of Silver Released from Nanocrystals (Acticoat™) Silver from Acticoat, has been shown to decrease wound surface inflammation by at least two known mechanisms. The first is by a decrease in excess surface MMP’s. The nanocrystal silver has been shown to decrease MMP activity in an in vitro model as well as on the surface of non-healing wounds (in animals and man). In the first five days after wounding, the wounds were dressed daily and the dressing materials from each of the experimental groups and the controls were collected and the wound fluid extracted for analysis. The wounds covered with inactive control and silvernitrate-soaked dressings (4 to 6) reached high levels of MMP activity from day 3 onwards which were maintained throughout the duration of the experiment. The woundfluid samples were assayed for total MMP activity. The Acticoat™ wound MMP levels of activity remained steady. More rapid healing and reduced inflammation was also noted. The levels of total proteases mirrored those of the MMP’s. Of particular importance was the observation that MMP levels in wounds dressed with the Acticoat™ nanocrystalline silver dressings were normalized but did not fall to zero. Total inhibition of MMP activity might delay healing. 26 Protease release from wounds in swine. Note: Decreased wound MMP’s using Acticoat silver in swine model. 27 Patient with chronic wound treated with nanocrystalline silver. 28 In addition to MMP suppression the Acticoat silver was shown to increase wound surface neutrophil apoptosis. Apoptosis is a programmed form of cell death in which cells are fragmented into membrane-bound particles that are then eliminated through phagocytosis, avoiding the necrotic pathway and reducing inflammation. This response of silver would also protect the wound from damage by excess neutrophil products. Overall, the reduced inflammation in the wounds treated with Acticoat™ contributed to more rapid healing. This was demonstrated by the marked decrease in time to develop granulation tissue. Increased healing rate in an experimental wound using the Acticoat silver. 29 VII. CLINICAL COMPARISON OF ACTICOAT™ AND OTHER SILVER COMPOUNDS IN BURNS A. Antimicrobial Effects and Infection Control A number of clinical trials have been performed comparing antibacterial efficacy of the nanocrystal silver delivery system. Tredget et al performed a randomized prospective trial in burns comparing nanocrystal silver delivery versus silver nitrate 0.5%. The nanocrystal silver significantly decreased wound colonization. In addition, there was a significant decrease in burn wound infection (> 105 organisms per gram tissue) and bacteremias. Stephens et al compared nanocrystal silver delivery and silver sulphadiazine on deep burns in 20 patients. There was no evidence of infections in either group but nanocrystalline silver (Acticoat) was reported to produce less pain, and nursing time due to less frequent dressing changes, i.e. twice a day versus every three days. In a study reported by Honori et.al., randomized prospective trial, nanocrystal delivery use resulted in a 0% infection rate compared to 5.2% with the use of silver sulfadiazine on donor sites in burn patients. Another study on superficial partial thickness burns reported a 50% decrease in local infections with the use of nanocrystal silver versus xeroform gauze, a common treatment for superficial burns. A study in toxic epidermal necrolysis patients reported nanocrystal silver to be as effective as silver nitrate in controlling infection. There was much less pain and less nursing time required with the silver membrane.(34) In summary to date, clinical studies on burns have demonstrated that use of the nanocrystal silver delivery system is either better or at least as effective an antimicrobial as the currently used silver compounds. However, every study demonstrated less patient pain and considerably less nursing time with use of the silver membrane. B. Improved Healing Several clinical trials have identified that nanocrystal silver delivery improves healing of partial thickness wounds. These wounds include donor sites, partial thickness skin slough disorders and re-epithelialization of meshed skin grafts. 30 Table 14: Efficacy Studies on Nanocrystal Silver Use (Increased Re-epithelialization Rate) Donor Sites Acticoat vs Xeroform -Increased healing with nanocrystal silver Acticoat vs SSD+ -improved healing with nanocrystal silver Skin Slough Acticoat vs Silver Nitrate (TENS) -improved healing Meshed Grafts Acticoat vs Neosporin Solution -30% reduction with Acticoat in time to re-epithelialization + silver sulfadiazine * nanocrystal silver The donor site studies comparing nanocrystal silver versus xeroform also compared, a moist healing used with the silver dressing with a dry environment seen with xeroform making it difficult to determine what component of the silver or the moisture was responsible. The study, by Demling, et.al., on mesh graft re-epithelialization compared the silver moist healing environment with that of a standard diluted Neosporin solution. In this study, the only difference in the wound environment was the presence of the nanocrystalline release of silver. The study was performed on the rate of re-epithelialization across a standard meshed graft on an excised wound, both approaches being used on the same patient. The significant increase in healing with pure silver more clearly reflects silver healing properties. The mechanisms are yet to be defined. C. Versatility Because of the potent antimicrobial pro-healing properties and ease of use, the nanocrystal silver delivery system has been effectively used on a variety of burns with success. 31 Currently Acticoat has been reported to be effective and efficient in managing the wounds described below. Uses of nanocrystalline silver delivery in burns • Deep dermal to full thickness: prior to and after excision • Partial thickness burns - usually large with a potential for infection • Large skin sloughs (TENS) • Donor sites • Meshed skin grafts The ability to use one effective silver product from admission of a deep burn to coverage of meshed grafts and donor sites has many clinical uses and cost effective advantages. The data on antimicrobial efficacy in deep burns has been described. The data on donor sites indicates decreased infections as well as decreased pain with Acticoat, especially compared to xeroform gauze. The data on use over meshed skin grafts indicates a prohealing as well as antimicrobial effect. One wound which deserves special attention is the partial thickness skin slough wound as seen, e.g. in Toxic Epidermal Necrolysis (TENS). Typically, the wounds are partial thickness but very large in size and extremely painful. In addition, these wounds are often present in immunocompromised patients and therefore require antimicrobial coverage. The major problems in these patients are control of severe pain, infection and healing. The standard use of antimicrobials with frequent dressing changes typically leads to not only severe pain and high narcotic needs but wound manipulation induced endotoxemia, bacteremia, increased inflammation and immense nursing resources. Less pain, fewer wound related side effects, and negative effects of narcotics have been well documented with nanocrystal silver use. Increased rate of reepithelialization has also been reported likely due to the ability to maintain an undisturbed optimum healing environment. 32 to cover meshed skin graft Use of Acticoat Acticoat in place day 3 Note excellent comformability TENS Patient Wound Coverage with Acticoat 33 changed every Acticoat 3-5 days. D) Patient Comfort and Decreased Toxicity The major cause of pain in the burn patient is the dressing change. This problem is of less concern with deep burns. However, wound manipulation does lead to increased bacteremias, cytokine release and an inevitable pyrogen response in the post-dressing change period. The increased body temperature also corresponds with lethargy, hemodynamic instability and increased oxygen demands. Increased CO2 production also occurs. A number of studies have demonstrated less pain with dressing changes compared to the use of other products. Honari et.al., compared the pain of a donor site treated with nanocrystal silver dressing versus SSD and noted a significant decrease in pain using the silver dressing. Stephens et.al., reported a significant decrease in pain in deep burns using the silver delivery system compared to silver sulfadiazine SSD. Tredget et al, reported a similar decrease in pain with dressing changes in burn wounds with nanocrystal silver delivery versus silver nitrate solution. A decrease in pain has been reported in TENS patients using the silver delivery membrane compared to silver nitrate solution. It is quite evident that wetting the outer surface of the silver dressing is much less painful than removal and replacement of SSD or use of silver nitrate in burns or xeroform in donor sites. Decreasing the toxicity of wound manipulation is another significant benefit of the nanocrystalline silver delivery system, where wound manipulation is minimal. Demling et.al., recently reported a study comparing the burn care response of nanocrystalline silver versus SSD in deep burns. A randomized prospective study was undertaking looking at pain, cost effectiveness and wound care side effects of silver delivery compared to SSD. 34 Clinical Response to Dressing Changes+ SSD (n=25) Silver Delivery Burn Dressing Increased T°° Size Changes (> 101 F°) 25±8% 42±10 100% 28±9% 36±9 10%* Hemodynamic Changes BP Pulse 20% 5%* 100% 40%* * significantly different from silver delivery + time period from onset to 3 hrs post dressing A significant decrease in wound care related complications were noted using the nanocrystalline silver. E) Cost Effectiveness Several clinical studies on burns and skin sloughs have demonstrated a significant decrease in cost using the nanocrystal silver delivery system. Demling, et.al.(67) recently reported a significant decrease in actual cost (not charges) for deep burn wound care due mainly to the marked decrease in nursing care and pain medication required. Cost Comparison SSD versus Nanocrystal Silver Delivery per week in Major Burns (a randomized prospective trial) Nursing Times/w k Nursing cost Supplies Medication Cost++ Pain/ sedation Total SSD+ (n=25) 20±2 $760±50 $720±40 $1800±290 Acticoat (n=26) 7±2* $280±40* $650±50* $1275±30* $350±40 $1050±240* *significant decrease in wound care costs compared to SSD 35 Other studies have reported a similar cost effectiveness due mainly to at least a 60% decrease in nursing time for wound care. The decrease in wound manipulation also markedly decreases pain, pain medications and narcotic induced morbidity.The studies include the management of skin slough disorders, deep burns. All studies demonstrated cost effectiveness with a cost saving of 15-25% compared to standard of care. CASE 1 Patient is a 40year old male injured in a plane crash. He suffered deep burns to 60% of TBS plus a fractured pelvis. He weighed 350 pounds and any turning was very difficult for him and the staff. After initial resuscitation, all burns were covered with ACTICOAT until excision and grafting could be performed. Initial assessment of back and buttock burns was that of a deep dermal burn which may require grafting. Back and buttock care was markedly simplified by the use of ACTICOAT and buried catheters to rewet. The wound beneath the ACTICOAT was clean and moist with minimal exudates. Of interest was the fact that the back did not require excision but healed in 21 days. Bacterial count was always scant growth. Burn Admission Note: burn is deep dermal to full thickness. Burn Day 3 Note: adherence presence of moisture layer and lack of exudates. 36 Burn Day 21 Burn completely re-epithelialized With return of pigment Case 2 Patient is a 12 month old boy suffering deep dermal burns to chest, neck, arms in addition to smoke inhalation. Burn wounds were managed with Acticoat™ changed every 3-4 days. Wounds were healed by 14 days. Pain management was much easier with the decrease in need for wound manipulation. Admission burn Burn at 10 days Note nice adherence of the Acticoat to the burn wound. 37 Burn at 14 days Note: re-epithelialization Summary is beneficial for the Nanocrystalline silver delivery by Acticoat management of : Partial and Full Thickness burn Donor sites Excised and grafted wounds The mechanism is likely multifactorial: Eliminating toxic complexes Decreasing bacteria and inflammation Moist wound healing Decreased mechanical trauma Direct healing effect of nanocrystal silver 38 VIII Use of Acticoat in Difficult to Heal and in Chronic Wounds A. Overview There are several types of wounds which characteristically are much more difficult to heal than the acute traumatic wounds. The major reasons are the typical presence of impaired perfusion as seen, e.g. with venous hypertension or diabetes and an underlying disorder such as immobility as seen in the population with pressure ulcers. Typically, these wounds begin healing by the normal acute healing process, with the process simply being prolonged into months instead of weeks. There is also an increased risk of wound complications due to the underlying impediments to healing. These wounds are also at high risk for evolving into a chronic wound, which fit into the difficult to heal category are a diabetic, venous stasis and pressure ulcer. Difficult to heal wounds Diabetic Ulcer Venous Stasis Ulcer Pressure Ulcer Each have distinct properties which make them difficult to heal. All of them share the characteristics of impaired perfusion and increased risk of infection, increased bacterial burden and inflammation. Chronic wounds differ substantially from an acute wound. The wound no longer follows the normal healing processes. The term “non-healing wound” is often used to describe the chronic wound. Characteristics are presented. However, the exact distinction between acute and chronic is still somewhat arbitrary and often based on the cause of the wound and physical status of the patient. Chronic Wound Characteristics Wound which fails the normal healing process Lack of any significant healing over a 3 month period despite good local care Excess wound inflammation is present Wound surface often contains necrotic tissue and increased exudates Colonization with bacteria is usually present Increased levels of wound metalloproteases which can damage any new tissue formation Decreased protease inhibitors Decreased surface growth factors 39 The time period most commonly used to define a chronic wound is usually 3 months of lack of healing. The most common chronic wounds are pressure ulcers, diabetic ulcers and venous stasis ulcers. The 3 categories account for 70% of chronic wounds. However, any acute wound, which fails to follow the normal healing process can become a chronic wound. It is important that criteria for determining when an acute wound becomes a chronic wound be met before calling a wound “chronic”. For example, a pressure ulcer characteristically heals slower than an acute surgical wound but a pressure ulcer can progressively heal by the normal healing process. It only becomes a chronic wound if there is failure of the normal healing process. Successful treatment of the chronic wound depends on a thorough understanding of the pathophysiologic mechanisms underlying the failure of the normal wound healing process. Common Types of Chronic Wounds Pressure Ulcers Vascular Insufficiency: Chronic Venous Hypertension, Arterial Insufficiency Metabolic: Diabetes Mellitus, Gout Infection: Vasculitis Malignant Cutaneous Wounds RadiationBurns These wounds cause a major disability due to the chronicity and frequent recurrence and therefore negatively impact quality of life in addition to producing an enormous health care cost (3billion/yr in the U.S.). B. Etiology A number of etiologic factors have been identified which impede the normal healing process allowing a chronic wound to develop. Systemic factors such as malnutrition and chronic illness prevent the acute wound from healing due to inadequate protein synthesis needed for new tissue development. Other factors such as impaired perfusion, hypoxia, do not allow healing to occur because of inadequate oxygen. Other systemic factors such as infection, diabetes and corticosteroids directly impede healing. The most common local factors which allow a chronic wound to develop are continued mechanical trauma to the wound and/or the use of wound care products toxic to the cells of the wound bed. Repeated loss of the new tissue synthesis will eventually lead to a chronically inflamed wound. Etiologic Factors Leading to Chronic Wounds Malnutrition (protein-calorie) especially with involuntary weight loss Micronutrient deficiency Tissue hypoxia Infection Diabetes Mellitus Chronic disability: elderly, chronic disease Use of toxic wound care products Inadequate care of the acute wound Mechanical Injury (repetitive): pressure, shear force, friction Radiation Therapy 40 C. Treatment of the Difficult to Heal and Chronic Wounds with Acticoat There is increasing evidence that nanocrystalline silver Acticoat is very effective in the management of difficult to heal and chronic wounds. Difficult to Heal and Chronic Wounds 1. Sibbald R. Screening evaluation of an ionized nanocrystalline silver dressing in chronic wound care. Ostomy Wound Management 2001:47;38. 2. Dousett C. An overview of Acticoat dressing in wound management. Br. J Nurs 2003:12;44 3. Fromantin I. Use of nanocrystalline silver in cancer wounds. Soins 2003:678;31 The nanocrystalline silver is very effective at: Decreasing bacterial burden Controlling excess inflammation Decreasing excess MMP activity Maintaining moist healing environment 41 The Chronic Wound 42 Management of Difficult to heal ulcers with a new silver dressing: A clinical evaluation. (Poster presentation, EWMA, Grenada, 2002) Romanelli M, et al (Dept Dermatology, University Hospital of Pisa, Italy) Venous Leg Ulcer Treated with Acticoat, results after 4 weeks. Case Study: The Use of Acticoat on an infected thigh stump (EVEAN Thiuszorg, Wondevrepleegkundige, Netherlands) An infected thigh stump in a patient with vascular disease Infected amputation site with massive fat necrosis. Wound dressed with Acticoat and covered with an absorbent secondary dressing. 43 Heavily exuding wound during first few days. At 7 days P. aeruginosa, S. aureus, and Streptococci colonization was reduced. After 12 days wound swabs were clear. Wound healed in 7 weeks. Case Study: / Acticoat 7 on infected ulcers of the foot and lower The use of Acticoat leg (Dr. Huuk, Kath. Krankenhaus gem. GmbH (Catholic Hospital,non-profit limited company) Dr. Winkelhoff, Head of the hospital surgical department. St.JohnnesHospital Infected ulcers on the anterior and posterior aspects of both legs. 44 1. Treatment with Acticoat 2. Acticoat used in conjunction with a secondary dressing 3. Acticoat and secondary dressing are under the compression dressing After 64 days the ulcers had clearly improved with treatment. 45 Case Study: 7 on an acutely infected leg ulcer The use of Acticoat Stephen Cook, Tissue Viability Nurse, The Queen Elizabeth Hospital, Norfolk,UK Patient was an 82 year old admitted with a fracture of the left distal femur, suspected DVT (deep vein thrombosis) and cellulitis. Pictured is his extremely inflamed and painful right leg. On exam, infection was seen tracking up the leg. Systemic antibiotics were begun, and Acticoat 7 was used to dress the wound. The wound had greatly improved by day 7 and the patient was now pain free. Some over-granulation was noted, Acticoat 7 treatment continued in combination with a secondary pressure dressing. The over-granulation was stopped and the wound had healed by 95%. The combined effect of systemic antibiotics and Acticoat 7 had a dramatic effect on the ulcer by controlling infection and improving healing. 46 D. Diabetic Ulcers Incidence: Approximately 15-20% of the estimated 16 million diabetics in the United States will be hospitalized for a foot complication, usually an ulcer, during the course of their disease. Progression of these ulcers are the leading cause of foot amputations. Etiology Impaired perfusion leading to ischemia Foot neuropathy High risk of infection Characteristics Full thickness wound usually surrounded by a rim of callous caused by compression of soft tissues against bony prominences: feet are most common Presence of diabetic neuropathy High risk of infection Characteristics: The ulcer is usually full thickness, therefore extracellular matrix components are initially absent. The most common site is on the foot, especially over bony prominences and on the heel. The ulcers are typically full thickness and difficult to heal, often becoming chronic wounds. An adequate description of ulcer characteristics is necessary for selection of appropriate treatment. Description includes size, depth, appearance and location. In addition, it must be determined whether the ulcer is the result of neuropathy, ischemia or typically both. Gentle probing with a blunt sterile probe will detect the presence of an undermining ulcer and the presence of sinus tracts. One classification system uses wound color as a marker of wound status. Red wounds are usually the healthiest and need wound coverage for protection and to maintain moisture. Yellow wounds indicate the presence of non-viable but moist tissue. Wounds need to be debrided to remove necrotic tissue and reduce the bacterial load. Frank infection does not need to be present to retard healing, simply an increased bacterial burden which overwhelms the wounds defenses. Black wounds indicate dead, dehydrated tissue or eschar on the wound surface. The eschar needs to be removed to be able to assess the wound, prevent infection and promote healing. Treatment: The primary goal of treatment is to obtain wound closure. Treatment is multifaceted due to the complex nature of the wound. Relief of pressure on the ulcer is critical to the wound healing process. This endpoint often requires pressure relieving interventions. Total contact casting reapplied weekly is the optimum management of pressure offloading. Treatment of any underlying ischemia is required. Distal vascular reconstruction may be required to restore pulsatile flow to the foot. When infection is present, 47 appropriate aerobic and anaerobic antibiotic therapy is necessary. Adequate insulin availability to the wound is needed to stimulate healing. Also, blood sugar control is important for healing. Debridement of all necrotic tissue and callous is also required. Debridement should be performed to bleeding tissue. Moist wound healing should then be initiated along with protection from external contamination. Nanocrystalline silver (Acticoat) should improve healing by: 1. Decreasing bacteria 2. Decreasing inflammation 3. Providing a moist healing environment Treatment of Diabetic Ulcer Relief of pressure on the ulcer Correction of ischemia, if possible Debridement of necrotic tissue Control of bacterial burden and infection Maintain moist wound healing Adequate insulin therapy, control of blood glucose and increase anabolic activity Modulate excess inflammation Generally infections can be detected by the presence of surrounding cellulitis. Cultures should be obtained from purulent drainage or curetted material from the wound bed. Palpation of foot pulses should be performed as well as non-invasive Doppler blood flow studies. Radiographs of extensive ulcers should be performed to assess for underlying osteomyelitis. Evidence of Excessive Bacterial Content: 1. 2. 3. 4. Wound not healing despite appropriate optimum care Increased wound drainage Increase in very friable granulation tissue Increasing pain, edema, peri-wound redness 48 Case Study: The use of Acticoat on a diabetic ulcer Patient is an 80 year old diabetic with an ulcer on his left heel present for 1 year. Wound dimensions were 6cm wide, 7 cm long and 1 cm deep. Note the periwound redness, maceration and edema, with exudates and malordor. The wound was covered with Acticoat 7 and an absorbant secondary dressing applied. After 4 weeks, the wound had significantly reduced in size to 0.8cm wide, 3.7cm long and 0.2cm deep, a reduction of 93%. The patient no longer experienced pain and the wound was free of signs of infection. The patient had approximately 12 months of conventional treatment for his diabetic ulcer, and the ulcer remained unhealed, at a cost of $14,500.00. A 4 piece course of Acticoat 7 resulted in an ulcer reduced in size within 4 weeks at a cost of $1,700.00. Conclusion: The nanocrystalline silver improved healing while decreasing cost. 49 in treating Venous Stasis Ulcer E. Experience with Acticoat Definition and Etiology Venous stasis ulcer is a partial or full thickness wound on the lower extremities often over the malleolus caused by venous insufficiency, local stasis, edema and resulting ischemia. Venous ulcers occur when the superficial leg veins become dilated from inadequate valve function leading to stasis and venous hypertension. There are several theories as to the etiology and the difficulty of healing. 1. Calf venous pump failure 2. Peri-capillary fibrin cuffs which impair oxygen diffusion to the wound 3. Macromolecules like fibrinogen leak into the dermis, due to venous hypertension, and trap Growth Factors and Matrix Proteins making them unavailable for the repair process. 4. Decrease in nutritive skin capillary blood flow 5. Combination of the above Incidence: Venous ulcers account for over 70% of chronic leg ulcers with the incidence increasing with age. The prevalence in the adult population either active or healed is about 1-2%. Characteristics: The classic presentation is an irregularly shaped wound with well defined borders surrounded by erythematous or hyper-pigmented skin. A yellow to white exudates is commonly observed. The lower leg is typically edematous. Varicosities are often present, and a dilated vein may be near the base of the ulcer. The surrounding skin change is known as lypodermatosclerosis. This process is caused by chronic changes in the soft tissue from edema and inflammation. The skin is often tender and can be mistaken for infection. Characteristics of Venous Ulcers Irregularly shaped wound with well defined borders Found on the lower leg often over the medial malleolus Yellowish exudates often at base Lower leg and foot edema usually present Surrounding skin brawny, erythematous or hyper-pigmented Lower leg venous hypertension 50 Treatment: The treatment goals for venous ulcers are first and foremeost to decrease tissue edema with compression therapy, followed by healing of the ulcer, control of pain and prevention of recurrence, the latter by controlling edema. Local care to the ulcer includes optimizing the healing environment. Initiation of moist wound healing while minimizing infection risk, and environmental insults is the standard of care. Controlling excess inflammation and MMP would also be very advantageous for healing. As with any tissue ulcer, debridement of necrotic tissue along with control of exudates is necessary. A variety of hydrogels and alginates are used inckuding a nanocrystalline silver alginate, in addition to the Acticoat. Treatment of Venous Ulcers Control of tissue edema with compression therapy Correction of any ischemia Debridement of necrotic tissue Control infection Maintain moist wound healing Control inflammation Case Study: Patient is a 45 year old international businessman with a non healing venous stasis ulcer for 2 years, despite compression therapy. Edema management was made difficult by traveling. The ulcer was 4cm x 6cm prior to treatment with Acticoat 7 (Figure 1). Initial cultures grew 2+ staph Aureus. He was then managed with Acticoat 7 followed by a soft moist gauze, followed by compression. The dressing was changed weekly (Figure 2). Figure 1 Figure 2 51 The ulcer healed by 50% in 4 weeks and by 85% 8 weeks (Figure 3, 4). The ulcer was healed by 12 weeks. Figure 3 Figure 4 Wound is 85% healed The use of Acticoat 7 on a venous leg ulcer present for 13 months (Kerrie Coleman, Clinical Nurse Specialist, Outpatient Services, Royal Brisbane Hospital, Australia) The patient was 74 years old with a longstanding history of leg ulceration and deep venous disease. The ulcer was heavily exuding, malodorous and composed of slough and granulating tissue. 52 At day 6 the wound was responding quickly to the treatment, which consisted of a moistened. Acticoat 7 and a multi layer compression bandage. Initially, the dressings were change twice weekly for exudates management. Note continued improvement of the ulcer, after 6 weeks. The ulcer had improved further and by 8 weeks the ulcers were close to healing. 53 X. References: 54 55 56 57