The use of silver sulfadiazine should be discouraged for burn wounds

数十年来，含银抗菌剂一直作为非全层皮肤烧伤患者的标准局部疗法使用。尤其是磺胺嘧啶银（SSD）被普遍用于治疗烧伤。然而，其疗效一直不明确。最近发表的两篇系统评述[1, 2]文章揭示了含银敷料和局部治疗药物治疗烧伤缺乏有效证据。

Silver-containing antibiotics have been applied as standard topical therapy for patients with partial-thickness burns for decades. Silver sulfadiazine (SSD or SD-Ag) in particular is commonly used to manage burns. However, evidence of their effectiveness remains poorly defined. Two recently published systematic reviews [1, 2] suggested the lack of evidence of effectiveness for silver-containing dressings and topical agents in burns.

第一篇系统评述[1]是在英国外科杂志上发表的，Brölmann等人筛选了Cochrane创伤与外周血管疾病组截止到2011年6月发表的所有Cochrane系统评述文章[3]。他们鉴别和审阅了包含109条基于证据的结论的共44篇相关评述。在其文章表2中列出了数条与烧伤有关的证据，包括“其他纤维敷料和含银抗菌剂可能没有效果或甚至延缓了愈合”，“与SSD相比，局部负压治疗5天时烧伤伤口面积缩小”以及“使用SSD霜增加或减少感染率证据有限，相互矛盾。没有证据表明在创伤愈合和伤口感染时局部使用银制剂有效”，同时在对急性创伤（含烧伤）的总结中得出结论“由于多个临床试验显示延缓创伤愈合和增加疼痛及感染率的趋势，磺胺嘧啶银不宜用于烧伤”。而且，在其表8中他们建议“在急性创伤中不要使用磺胺嘧啶银作为局部治疗药物”。

In the first article, published on British Journal of Surgery [1], Brölmann et al. have screened all Cochrane systematic reviews [3] up to June 2011 published by the Cochrane Wounds and Peripheral Vascular Diseases Groups. They identified and reviewed 44 relevant reviews containing 109 evidence based conclusions. Several evidences regarding burns were listed in table 2 of their article, including “Other fibre dressings and antimicrobial (silver) dressings may have no effect on, or even prolong, healing”, “A reduction in burn size at day 5 was seen when TNP (topical negative pressure) was compared with SSD” and “Contradictory limited evidence of increased and decreased infection rates when using SSD cream. No evidence for effectiveness of topical silver for preventing wound infection in terms of wound healing and wound infection”, and they concluded that “For burn wounds the use of silver sulfadiazine should be discouraged, as several trials showed a trend towards wound healing delay and increased pain and infection rates” in their results for acute wounds. Furthermore, they recommended that “In acute wounds do not use silver sulfadiazine as topical agent” in table 8 of their article.

Brölmann引用的一篇系统评述[4]总结了来自治疗浅表烧伤和非全层皮肤烧伤的26项随机对照临床试验的最好证据，结果显示烧伤敷料用水凝胶、硅衣敷料、生物合成敷料和抗菌敷料要比用SSD或洗必泰药纱敷料伤口愈合的更快。这篇评述还发现，虽然在所有相关研究中没有统计意义上的差别，但是有个一致的趋势，就是与SSD或洗必泰敷料相比，使用其他所有干预敷料时病人经受的疼痛更少。

One systematic review [4] cited by Brölmann summarized the best available evidence from a total of 26 included randomised controlled trials (RCTs) relating to the effects of dressings used to treat adults with superficial or partial thickness burns, and the results indicated that burn wounds dressed with hydrogels, silicon coated dressings, biosesynthetic dressings and anti microbial dressings healed more rapidly than those dressed with SSD or chlorhexidine impregnated gauze dressings. Also in this review, there was a finding, not statistically significant in all studies but was consistent for all intervention dressings, that the pain experienced by patients appeared to be reduced with the use of the intervention dressing when compared against SSD or chlorhexidine dressings.

在另一篇Brölmann引用的系统评述[5]中，鉴别出26项随机对照临床试验（共计2066患者）。由于治疗方法和效果的异质性，没有做荟萃分析，而是按创伤类型和银制剂将结果分组总结。而在感染率、伤口愈合率、疼痛和费用方面的比较研究都得出明显不利于SSD的结果，其相关结论为“没有证据支持使用SSD预防非全层皮肤烧伤患者的伤口感染。与其他含银及非银敷料相比，没有临床试验表明SSD在其他疗效上有益。而且，有证据表明SSD可能延缓伤口愈合，花费更贵以及用于烧伤时病人更疼痛”。

In another systematic review [5] cited by Brölmann, 26 RCTs (2066 patients) were identified. Due to the heterogeneity of treatments and outcomes precluded meta-analysis, they grouped results according to wound type and silver preparation. The comparisons in terms of infection rate, wound healing rate, pain, and costs showed statistically significant differences in favour of non-silver dressing against SSD with conclusions that “ there was no evidence to support the use of silver sulphadiazine (SSD) for prevention of wound infection in patients with partial-thickness burns. None of the trials indicated a beneficial effect for SSD for other outcomes when compared with other silver-containing or non-silver dressings. Furthermore, there was evidence that SSD may delay wound healing, may be more expensive, and may be more painful when applied to burns.”

第二篇系统评述是Aziz等人[2]在国际烧伤学会的烧伤杂志上发表的，他们想通过对已有证据的荟萃分析，评价在烧伤中含银的敷料和局部药物对于预防感染和促进愈合的作用效果。他们鉴别出14项随机对照临床试验，涉及877名患者。其结果表明“与非银组相比，局部银制剂显示出明显更差的愈合时间，并且没有显示出有效预防伤口感染的证据”。他们的评述揭示了“含银敷料和局部银制剂比对照敷料在预防烧伤感染和促进烧伤愈合上更差或者不会更好”。

In the second systematic review article, published on Burns[2], Aziz et al. aimed to evalsuate the effectiveness of silver containing dressings and topical silver for preventing infection and promoting healing in burns wounds through a meta-analysis of the available evidence. They identified 14 RCTs involving 877 participants. Their results indicated that “topical silver showed significantly worse healing time compared to the non-silver group and showed no evidence of effectiveness in preventing wounds infection”. Their review suggests that “silver-containing dressings and topical silver were either no better or worse than control dressings in preventing wound infection and promoting healing of burn wounds”. 

另外，SSD对皮肤细胞有毒[6]，倾向于粘附在伤口表明并且需要经常换药因而损伤新生上皮延缓伤口愈合[6]。有确凿证据表明，应用了含银药物制剂后银离子被吸收入体循环并从尿中排泄。研究表明磺胺嘧啶银中释放的银离子在角化细胞、肝细胞、中性粒细胞、白细胞以及成纤维细胞中是有毒性的并与细胞特征的丧失有关[8, 9]。受损的人角化细胞表现出的退行性病变可能导致创伤处上皮再生的延迟。而且，长期暴露于银离子的细菌产生了对银的抗药性。依据细菌对抗菌剂的性质，在选择压力下增殖的细菌可能出现固有的和获得性的抗药机制。临床证据已发现死于感染的患者的烧伤部位具有银抵抗的菌株。

In addition, SSD has toxic effect on skin cells [6] and tends to adhere to wound surface and requires frequent dressing changes which would hurt newly generated epithelium and delayed wound healing [7]. Irrefutable evidence has shown that silver is absorbed into the systemic circulation and excreted in urine after application of silver-containing pharmaceutical preparation. Study has shown that silver released from SSD was toxic in keratinocyte, hepatocyte, neutrophils, leucocyte and fibroblast and was association with a loss in cellular identity [8, 9]. One of the possible outcome of human keratiocytes is degenerative changes which lead to actual "delay" of wound re-epithelialisation. Furthermore, one consideration has been implicated in bacteria after long time exposure to silver, the consequential bacterial resistance to silver [10] .
According to the nature of bacteria toward antimicrobial agent, intrinsic and acquired mechanism may emerge as bacteria proliferate under selective pressure. Clinical evidence has found patients who died from infection contained silver resistant strain of bacteria at their burn wound.

对PubMed就“磺胺嘧啶银对烧伤之效果的系统评述”进行快速搜索，获得两篇相关的文章，结果都不利于SSD。 其中Wasiak等人[11]的评述观点是“SSD霜可能无效或有害”以及“相比于其他治疗，SSD霜可能延长愈合时间并增加疼痛”。另一篇Andrew等人[12]的文章只鉴别出了7个动物实验且结果相互矛盾。

A quick search in PubMed for “systematic review on the effectiveness of silver sulphadiazine on burns” retrieved two relevant articles, both of which are not in favor of SSD. The review by Wasiak et al. [11] got the view of “ likely to be ineffective or harmful” for SSD cream and that “Silver sulfadiazine cream may prolong healing times and increase pain compared with other treatments”. The other article by Andrew et al. [12] identified only 7 animal studies providing conflicting results.

总的来说，鉴于没有强有效的临床证据支持SSD在烧伤的应用以及“业界的利润增长通常来自加强广告宣传而非更强的疗效证据” [13]，Brölmann等人在英国外科杂志上的系统评述里做出的结论“磺胺嘧啶银不宜用于治疗烧伤”和建议“在急性创伤中不要使用磺胺嘧啶银作为局部治疗药物”是确实可信的。他们的研究
帮助阐明了没有证据表明含银敷料和制剂，尤其是SSD，对类似烧伤的某些类型创伤的治疗有效，这暗示着目前的临床实践不是基于证据的，为了获得最佳治疗效果需要改变。正如Palfreyman对Brölmann等人所做的评论[13]，“他们的评述会帮助临床医生和决策者们在做决定时是根据临床证据，而不是根据传统或专家意见。这在创伤治理领域尤其重要，因为这个领域常常缺少高质量的临床证据，而系统评述可能仅是一种借以合理推断和减少选择的途径”。

In summary, since there is no strong clinical evidence supporting the use of SSD in burns and that “The explosion in profits for industry has more often than not been based on high levels of advertising rather than high levels of evidence of effectiveness” [13], the conclusion “For burn wounds the use of silver sulfadiazine should be discouraged ” and recommendation “In acute wounds do not use silver sulfadiazine as topical agent”, made by Brölmann et al. in their newly published systematic review on British Journal of Surgery, are reliable. Their study helps to illuminate the lack of evidence for silver containing dressings and agents, in particular SSD, for certain types of wound like burns, which may imply that current practice is not evidence-based and needs to change in order to ensure best quality care. As stated by Palfreyman [13], “Their review will help clinicians and policy-makers to make decisions regarding treatment based on evidence rather than tradition or expert opinion. This can be especially important within the area of wound care where high-quality evidence is often lacking and systematic reviews may be portrayed as merely a means of rationing access and reducing choice”.

北京荣祥再生医学研究所，北京 100020
Beijing Rongxiang Institute of Regenerative Medicine, Beijing 100020

Corresponding email:tao_939@usc.edu

References

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[2] Aziz Z, Abu SF, Chong NJ.  A systematic review of silver-containing dressings and topical silver agents (used with dressings) for burn wounds. Burns. 2012, 38(3):307-18.

[3] Petticrew M, Wilson P, Wright K, Song F. Quality of Cochrane reviews. Quality of Cochrane reviews is better than that of non-Cochrane reviews. Brit Med Journal, 2002, 324: 545.

[4] Wasiak J, Cleland H, Campell F. Dressings for superficial and partial thickness burns. Cochrane Database Syst Rev, 2008, article (4)CD002106.

[5] Storm-Versloot MN, Vos CG, Ubbink DT, et al. Topical silver for preventing wound infection. Cochrane Database Syst Rev, 2010, (3)CD006478.

[6] Hussain S, Ferguson C. Silver sulphadiazine cream in burns. Emerg Med J. 2006, 23:929–32.

[7] Thomas S, Lawrence J, Thomas A. evalsuation of hydrocolloids and topical medication in minor burns. J Wound Care, 1995, 4:218–20.

[8] Lansdown AB, Silver. 2: Toxicity in mammals and how its products aid wound repair. J Wound Care, 2002, 11(5):173-7.

[9] Atiyeh BS, Costagliola M, Hayek SN, et al.  Effect of silver on burn wound infection control and healing: review of the literature. Burns, 2007, 3(2):139-48.

[10] Percival SL, Bowler PG, Russell D. Bacterial resistance to silver in wound care.
J Hosp Infect. 2005, 60(1):1-7.

[11] Wasiak J, Cleland H., Burns (minor thermal). Clin Evid (Online). 2009 Oct 27; 2009. pii: 1903.

[12] Miller AC, Rashid RM, Falzon L, et al. Silver sulfadiazine for the treatment of partial-thickness burns and venous stasis ulcers. J Am Acad Dermatol. 2012, 66(5):e159-65. 

[13] (S. Palfreyman, Evidence-based decisions for local and systemic wound care (Br J Surg 2012; 99: 1172–1183).  British Journal of Surgery 2012; 99: 1184