The use of silver sulfadiazine should be discouraged for burn wounds

數(shù)十年來(lái)，含銀抗菌劑一直作為非全層皮膚燒傷患者的標(biāo)準(zhǔn)局部療法使用。尤其是磺胺嘧啶銀（SSD）被普遍用于治療燒傷。然而，其療效一直不明確。最近發(fā)表的兩篇系統(tǒng)評(píng)述[1, 2]文章揭示了含銀敷料和局部治療藥物治療燒傷缺乏有效證據(jù)。

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.

第一篇系統(tǒng)評(píng)述[1]是在英國(guó)外科雜志上發(fā)表的，Brölmann等人篩選了Cochrane創(chuàng)傷與外周血管疾病組截止到2011年6月發(fā)表的所有Cochrane系統(tǒng)評(píng)述文章[3]。他們鑒別和審閱了包含109條基于證據(jù)的結(jié)論的共44篇相關(guān)評(píng)述。在其文章表2中列出了數(shù)條與燒傷有關(guān)的證據(jù)，包括“其他纖維敷料和含銀抗菌劑可能沒(méi)有效果或甚至延緩了愈合”，“與SSD相比，局部負(fù)壓治療5天時(shí)燒傷傷口面積縮小”以及“使用SSD霜增加或減少感染率證據(jù)有限，相互矛盾。沒(méi)有證據(jù)表明在創(chuàng)傷愈合和傷口感染時(shí)局部使用銀制劑有效”，同時(shí)在對(duì)急性創(chuàng)傷（含燒傷）的總結(jié)中得出結(jié)論“由于多個(gè)臨床試驗(yàn)顯示延緩創(chuàng)傷愈合和增加疼痛及感染率的趨勢(shì)，磺胺嘧啶銀不宜用于燒傷”。而且，在其表8中他們建議“在急性創(chuàng)傷中不要使用磺胺嘧啶銀作為局部治療藥物”。

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引用的一篇系統(tǒng)評(píng)述[4]總結(jié)了來(lái)自治療淺表燒傷和非全層皮膚燒傷的26項(xiàng)隨機(jī)對(duì)照臨床試驗(yàn)的最好證據(jù)，結(jié)果顯示燒傷敷料用水凝膠、硅衣敷料、生物合成敷料和抗菌敷料要比用SSD或洗必泰藥紗敷料傷口愈合的更快。這篇評(píng)述還發(fā)現(xiàn)，雖然在所有相關(guān)研究中沒(méi)有統(tǒng)計(jì)意義上的差別，但是有個(gè)一致的趨勢(shì)，就是與SSD或洗必泰敷料相比，使用其他所有干預(yù)敷料時(shí)病人經(jīng)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, biosynthetic 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引用的系統(tǒng)評(píng)述[5]中，鑒別出26項(xiàng)隨機(jī)對(duì)照臨床試驗(yàn)（共計(jì)2066患者）。由于治療方法和效果的異質(zhì)性，沒(méi)有做薈萃分析，而是按創(chuàng)傷類(lèi)型和銀制劑將結(jié)果分組總結(jié)。而在感染率、傷口愈合率、疼痛和費(fèi)用方面的比較研究都得出明顯不利于SSD的結(jié)果，其相關(guān)結(jié)論為“沒(méi)有證據(jù)支持使用SSD預(yù)防非全層皮膚燒傷患者的傷口感染。與其他含銀及非銀敷料相比，沒(méi)有臨床試驗(yàn)表明SSD在其他療效上有益。而且，有證據(jù)表明SSD可能延緩傷口愈合，花費(fèi)更貴以及用于燒傷時(shí)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.”

第二篇系統(tǒng)評(píng)述是Aziz等人[2]在國(guó)際燒傷學(xué)會(huì)的燒傷雜志上發(fā)表的，他們想通過(guò)對(duì)已有證據(jù)的薈萃分析，評(píng)價(jià)在燒傷中含銀的敷料和局部藥物對(duì)于預(yù)防感染和促進(jìn)愈合的作用效果。他們鑒別出14項(xiàng)隨機(jī)對(duì)照臨床試驗(yàn)，涉及877名患者。其結(jié)果表明“與非銀組相比，局部銀制劑顯示出明顯更差的愈合時(shí)間，并且沒(méi)有顯示出有效預(yù)防傷口感染的證據(jù)”。他們的評(píng)述揭示了“含銀敷料和局部銀制劑比對(duì)照敷料在預(yù)防燒傷感染和促進(jìn)燒傷愈合上更差或者不會(huì)更好”。

In the second systematic review article, published on Burns[2], Aziz et al. aimed to evaluate 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對(duì)皮膚細(xì)胞有毒[6]，傾向于粘附在傷口表明并且需要經(jīng)常換藥因而損傷新生上皮延緩傷口愈合[6]。有確鑿證據(jù)表明，應(yīng)用了含銀藥物制劑后銀離子被吸收入體循環(huán)并從尿中排泄。研究表明磺胺嘧啶銀中釋放的銀離子在角化細(xì)胞、肝細(xì)胞、中性粒細(xì)胞、白細(xì)胞以及成纖維細(xì)胞中是有毒性的并與細(xì)胞特征的喪失有關(guān)[8, 9]。受損的人角化細(xì)胞表現(xiàn)出的退行性病變可能導(dǎo)致創(chuàng)傷處上皮再生的延遲。而且，長(zhǎng)期暴露于銀離子的細(xì)菌產(chǎn)生了對(duì)銀的抗藥性。依據(jù)細(xì)菌對(duì)抗菌劑的性質(zhì)，在選擇壓力下增殖的細(xì)菌可能出現(xiàn)固有的和獲得性的抗藥機(jī)制。臨床證據(jù)已發(fā)現(xiàn)死于感染的患者的燒傷部位具有銀抵抗的菌株。

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.

對(duì)PubMed就“磺胺嘧啶銀對(duì)燒傷之效果的系統(tǒng)評(píng)述”進(jìn)行快速搜索，獲得兩篇相關(guān)的文章，結(jié)果都不利于SSD。 其中Wasiak等人[11]的評(píng)述觀點(diǎn)是“SSD霜可能無(wú)效或有害”以及“相比于其他治療，SSD霜可能延長(zhǎng)愈合時(shí)間并增加疼痛”。另一篇Andrew等人[12]的文章只鑒別出了7個(gè)動(dòng)物實(shí)驗(yàn)且結(jié)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.

總的來(lái)說(shuō)，鑒于沒(méi)有強(qiáng)有效的臨床證據(jù)支持SSD在燒傷的應(yīng)用以及“業(yè)界的利潤(rùn)增長(zhǎng)通常來(lái)自加強(qiáng)廣告宣傳而非更強(qiáng)的療效證據(jù)” [13]，Brölmann等人在英國(guó)外科雜志上的系統(tǒng)評(píng)述里做出的結(jié)論“磺胺嘧啶銀不宜用于治療燒傷”和建議“在急性創(chuàng)傷中不要使用磺胺嘧啶銀作為局部治療藥物”是確實(shí)可信的。他們的研究
幫助闡明了沒(méi)有證據(jù)表明含銀敷料和制劑，尤其是SSD，對(duì)類(lèi)似燒傷的某些類(lèi)型創(chuàng)傷的治療有效，這暗示著目前的臨床實(shí)踐不是基于證據(jù)的，為了獲得最佳治療效果需要改變。正如Palfreyman對(duì)Brölmann等人所做的評(píng)論[13]，“他們的評(píng)述會(huì)幫助臨床醫(yī)生和決策者們?cè)谧鰶Q定時(shí)是根據(jù)臨床證據(jù)，而不是根據(jù)傳統(tǒng)或?qū)＜乙庖?jiàn)。這在創(chuàng)傷治理領(lǐng)域尤其重要，因?yàn)檫@個(gè)領(lǐng)域常常缺少高質(zhì)量的臨床證據(jù)，而系統(tǒng)評(píng)述可能僅是一種借以合理推斷和減少選擇的途徑”。

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”.

北京榮祥再生醫(yī)學(xué)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. Evaluation 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.
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[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