Are Silver Products Safe and Effective for Chronic Wound Management?

1. Are Silver Products Safe and Effective for Chronic Wound Management? 報告者： 林毓珍護理長 J Wound Ostomy Continence Nurs. Published by Lippincott Williams & Wilkins

2. QUESTIONS • Which silver-containing topical modalities are safe foruse in managing pressure ulcers, venous ulcers, or foot ulcers in diabetic patients? 2. Which silver-containing topical modalities have evidence of efficacy in managing pressure ulcers, venous ulcers, or foot ulcers in diabetic patients?

3. Silver exists in three oxidation states, with a single, double,or triple, positive charge. Of these, only Ag+ is solublein water. Wound care modalities contain silver in the following forms from which free silver ions (predominantly Ag+ ions) are released in the presence of wound fluid:

4. (a) ionic silver, the active Ag+form (b) elemental (metallic) silver (Ag0), in the form of nanocrystalline particles or foil (c) inorganic compounds or complexes such as silver nitrate, silver sulphadiazine (d) organic complexes such as colloidal silver or silver protein complexes

5. Silver ions rapidly react with organic • molecules such as proteins or electrolytes • in wound fluid, tissue, or a broad spectrum • of microorganisms including bacteria, • viruses,and fungi. • These interactions interfere with • microbial proliferation by altering DNA and • RNA and cause fatal structural changes in • bacterial cell walls and membranes.

6. This is why microbes rarely develop resistance to silver, unlike antibiotics that usually target one cell function. As reactive silver ions combine with other molecules, more silver ions must be released from the source if silver activity is to be maintained. Table 1 summarizes the form and content of silver in some currently marketed wound products.

8. For more than 40 years, various compounds containing silver have been reported to reduce mortality in severely burned patients. Recent years have seen the advent of many new silver products indicated for topical use on a variety of clinical wounds. There has been considerable in vitro research on silver wound care modalities, but little evidence exists of their safety or efficacy on clinical wounds.

9. Wound professionals are requesting more clinically relevant evidence about silver product safety and efficacy on which to base their care decisions. This Evidence-Based Report Card explores clinical evidence of safety and efficacy of topical products containing silver on pressure ulcers, venous ulcers, and foot ulcers in patients with type 1 or type 2 diabetes mellitus.

10. Methods The National Institute of Health’s National Library of Medicine MEDLINE electronic database was searched from January 1966 through May 2006 for the key word “silver”combined with the search terms: (a) chronic wound, (b) decubitus ulcer, (c) bedsore, (d) pressure ulcer, (e) venous ulcer, (f) ulcus cruris, (g) varicose ulcer, (h) leg ulcer, (i) foot ulcer, (j) diabetic ulcer, (k) neuropathic ulcer.

11. The search was expanded to include relevant additional unique references and abstracts. Facts were verified by contacting authors and product manufacturers or their Web sites using the Internet-based Google search engine.

12. Efficacy data included randomized and nonrandomized clinical studies with outcomes evaluated in a blind and an unblinded fashion along with systematic reviews, metanalyses, and quasi-experimental trials comparing silver products with nonsilver products. For safety data, cohort analyses, sequential case reports,and case series were also included.

13. Question 1: Which Silver-Containing Topical Modalities Are Safe for Use in Managing Pressure Ulcers, Venous Ulcers, or Foot Ulcers in Diabetic Patients?

14. Results No statistically significant differences in adverse effects of silver dressings as compared with the traditional or modern dressings were found on the three chronic wounds explored in this article.

15. In controlled studies (Table 2), the majority of pressure ulcers (n > 26), venous ulcers (n 215), and diabetic foot ulcers (n = 345) managed with silver-containing modalities improved8,9 or healed10-12 as well as or better than same-study control modalities.

17. Case series13-18 and a retrospective chart review19 (Table 3) on a total of 58 pressure ulcers, 213 venous ulcers, and 108 diabetic foot ulcers supported the general conclusion that silver dressings are safe on these chronic wounds. However, these data report effects of only 6 of the silver-containing modalities that were available for wound management.

19. Case series examining silver absorption, antibacterial efficacy, and wound exudate content in venous ulcers dressed with Actisorb 7, Actisorb Silver, AQUACEL Ag Hydrofiber or Contreet Foam silver dressings or 1% silver sulfadiazine cream reported low, inconsistent levels of blood silver that declined on the discontinuation of the silver product.

20. None of the dressings were described as “overly toxic,” and the silver released into the wound bed remained in exudate or wound debris that was to be released for up to 11 weeks after discontinuing the silver application.

21. They reported that silver uptake by an ulcer is related to exudate viscosity and that silver released by a dressing is related to the amount of exudate the dressing absorbs. These venous ulcers did not attain germ- free status, which is consistent with the prior findings that venous ulcers often remain colonized with bacteria until epithelialized.

22. As burns and donor site areas may exceed those of pressure ulcer, venous ulcer, and diabetic ulcer, clinical studies on these indications may be clinically relevant to the Safety of silver-containing modalities.

23. One multicenter prospective randomized clinical study (RCT)23 reported less pain during dressing changes and less burning and stinging up to 21 days wear with fewer procedural medications required using a Hydrofiber containing ionic silver (n = 42) than that of with 1% silver sulfadiazine (SSD) cream impregnated gauze on 5% to 40% body surface area (BSA) with second degree burns.

24. This US-based study reported a comparable incidence of adverse events (45%-47%) and study burn infections(15%-19%) in the 2 groups.

25. A noncomparative open-labeled prospective European multicenter 4-week study reported safety on 41 patients hospitalized with second degree burns of up to 500 cm2 in area dressed with a SSD lipidocolloid wound dressing.No secondary infections,one adverse event, and one episode of obstructed wound healing were reported.

26. A nonadherent dressing coated with nanocrystalline silver retarded re- epithelialization of clinical skin graft donor sites as compared with a foam dressing.

27. After systematically examining potential causesof the delayed healing, the author concluded that “Acticoat significantly delays re-epithelialization. The reason for this is not clear, but we believe that it may be related to the concentration of silver on the wound surface and we believe that this possibility should be examined more closely. It has not been determined whether this effect generalizes to the re-epithelialization in chronic wounds.

28. The permissible limit of elemental or soluble silver exposure is 0.01mg/m3 as recommended by the Occupational Safety and Health Administration and the Mine Safety and Health Administration. The adverse effects of chronic excessive exposure to silver are a bluish-gray Discoloration of the skin (argyria) and/or the eyes (argyrosis).

29. These symptoms have not been reported in the literature for Individuals taking a commercially available oral “health supplement” containing 10 ppm (0.001%) colloidal silver.However, a more concentrated“Sporicidal Strength” solution did not affect microbial growth,so insufficient silver may be released for this formulation to be an exposure benchmark for silver safety.

30. Current occupational exposure limits may not reflect differences in the absorption of different silver compounds or risk levels for metabolically or endocrinologically challenged patients.

31. Wound exposure may approach permissible exposure levels during the repeated use of some silver-containing modalities over large or highly exuding wounds. However, no studies were identified that reported the amount of silver released daily into pressure ulcer, venous ulcer, or diabetic ulcer.

32. Systemic silver absorption from wound management products is higher through wounded skin than through intact skin and is related to silver content, formulation,mode, and frequency of application of the product.

33. 20 Absorption increases with the increase of wound area,depth, and quantity of exudates and becomes significant through wounds involving more than 5% of the total body surface area.

34. For example, patients with extensive burnshave experienced silver deposition in tissue after the use of topical silver sulfadiazine, and argyria-like symptoms were reported in a 17-year-old boy with 30% body surface areaburns dressed for 1 week with Acticoat.

35. Such wound areas are rarely attained by pressure ulcers, venous ulcers, or diabetic foot ulcers. At present, there is insufficient evidence to draw conclusions regarding systemic absorption from all silver modalities. However, clinical evidence supports Safety on these chronic ulcers for the 6 modalities containing silver listed in Tables 2 and 3.

36. Question 2: Which Silver-Containing Topical Modalities Have Evidence of Efficacy in Managing Pressure Ulcers, Venous Ulcers,or Foot Ulcers in Diabetic Patients?

37. Munter and colleagues8 reported that 26 pressure ulcers dressed with a silver foam showed significantly faster reduction in ulcer area than those managed with “local bestpractice”including gauze and other silver dressings (mainly Acticoat) (Table 2).

38. The lack of a specific control protocol and an inclusion of other silver modalities in the Control group prevent a clear conclusion regarding the effects of silver on the pressure ulcer healing. In a Cochrane systematic review of wound cleansing for pressure ulcers, Moore and Cowman30 found one study in which a saline spray containing Aloe vera, silver chloride, and decyl glucoside used to cleanse pressure ulcers improved Pressure Sore Status Tool scores more than the saline alone spray.

39. However, it is not clear which of the three ingredients caused this effect. Results of this meta-analysis suggest that the level of silver in this cleanser is safe, but does not support a conclusion that silver chloride is the cleansing component that improved the pressure ulcer healing.

40. Venous Ulcer Healing More venous ulcers healed after 4 weeks of dressing with a silver-foam dressing as compared with a nonsilver hydrocellular foam dressing (Table 2). This result was Reinforced by Munter and colleagues8 who reported that venous ulcers dressed with the same silver-foam dressing healed significantly faster, with less pain and discomfort than Those dressed in the“local best practice”described above.

41. Though healing measures and control products differed, consistent,significant positive effects on healing of a total of 215 venous ulcers support the conclusion that at least one silver dressing improves venous ulcer healing.

42. Diabetic Foot Ulcer Healing In a Cochrane systematic review of silver- based wound dressings and topical agents for treating diabetic foot ulcers(last updated November 16, 2005), Bergin and Wraight concluded that there were no randomized or Controlled clinical trials evaluating clinical effectiveness or costeffectiveness of silver- containing products for these ulcers.

43. However, our search found 3 multicenter trials (Table 2)presented or published after the Cochrane review was updated.Significantly faster depth reduction was reported in diabetic foot ulcers dressed with a silver Hydrofiber dressing than those dressed with a nonsilver alginate (as shown in one European study) and with a saline-moistened gauze (as shown in one North American study).

44. Clinical infection rates and other healing parameters were comparable for the test and control modalities. The only other controlled study by Munter and colleagues8 reported Significantly less slough, maceration, and odor in diabetic foot ulcer dressed with a silver- foam dressing than with other“local best care”for diabetic ulcers, including gauze and other silver dressings, mainly those containing nanocrystalline silver.

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