Intervention Review

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Topical treatment for facial burns

  1. Cornelis J Hoogewerf1,
  2. Margriet E Van Baar1,*,
  3. M Jenda Hop1,
  4. Marianne K Nieuwenhuis2,
  5. Irma MMH Oen1,
  6. Esther Middelkoop3

Editorial Group: Cochrane Wounds Group

Published Online: 31 JAN 2013

Assessed as up-to-date: 9 NOV 2012

DOI: 10.1002/14651858.CD008058.pub2


How to Cite

Hoogewerf CJ, Van Baar ME, Hop MJ, Nieuwenhuis MK, Oen IMMH, Middelkoop E. Topical treatment for facial burns. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD008058. DOI: 10.1002/14651858.CD008058.pub2.

Author Information

  1. 1

    Association of Dutch Burn Centres, Burn Centre, Maasstad Hospital, Rotterdam, South-Holland, Netherlands

  2. 2

    Association of Dutch Burn Centres, Burn Centre, Martini Hospital, Groningen, Groningen, Netherlands

  3. 3

    Association of Dutch Burn Centres, Burn Centre, Red Cross Hospital, Beverwijk, North-Holland, Netherlands

*Margriet E Van Baar, Burn Centre, Maasstad Hospital, Association of Dutch Burn Centres, PO Box 9100, Rotterdam, South-Holland, 3007 AC, Netherlands. baarm@maasstadziekenhuis.nl.

Publication History

  1. Publication Status: New
  2. Published Online: 31 JAN 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

(We have provided a glossary of some of the terms used in this review in Appendix 1.)

Burn injuries are an important health problem, resulting in 45,000 admissions annually in the United States of America (USA), of which more than 25,000 admissions to hospitals with specialised burn centres (American Burn Association 2011). In the United Kingdom, approximately 13,000 people a year are admitted to hospital for treatment of burns (Hettiaratchy 2004a), while in the Netherlands the annual figure is about 1800 people (Ormel 2010), 550 to 600 of whom are treated in one of the three Dutch burn centres. Mortality rates from burn injuries have substantially decreased because of major improvements in burn care made in the 20th century. This has resulted in a shift in attention towards the functional outcome after a burn injury rather than mortality (Van Baar 2006). The head and neck region is estimated to be the site of burn injury in between 27% (Fatusi 2006) and 60% (Chien 2003; Fraulin 1996) of burn cases. The face is central to our identity and also provides our most expressive means of communication. Appearance, communication and other basic senses and abilities such as hearing, smelling and breathing may be affected as a direct result of a facial burn, or its sequelae (Serghiou 2004). Impaired function and distorted appearance may both induce psychological problems, problems with social reintegration and affect quality of life (Van Loey 2003).

 

Description of the condition

A burn injury to the skin occurs when some, or all, the different layers of skin are destroyed by physical energy delivered via a hot liquid, flame, contact with a hot surface, ultraviolet/infrared radiation, radioactivity, electricity or chemicals (World Health Organization 2011). Severity of burn wounds is characterised by their size and depth as well as their location and associated injuries. The size of a burn is measured by the percentage of Total Body Surface Area affected (% TBSA), which is the percentage of the surface area of the skin burned, while the depth of a burn is determined by the layers of skin destroyed. So far, no consensus has been reached on the exact classifications of burns, especially not in relation to the classification of depth (Klasen 2004). In general, skin burns are classified as either superficial partial-thickness burns, deep partial-thickness burns or full-thickness burns. In superficial partial-thickness burns only the epidermal layer and the superficial part of the dermis is destroyed. Healing generally occurs within two weeks, with very little, or no, scarring, due to the migration of epithelial cells to the surface of the skin. In deep partial-thickness burns, the epidermis and most of the dermis is destroyed, with damage to deeper structures within the skin such as blood vessels, nerves and hair follicles. If re-epithelialisation does not occur within two to three weeks, then hypertrophic scarring may occur (Cubison 2006; Deitch 1983). Finally, full-thickness burns involve all the layers of skin and may involve structures underneath, such as muscle and bone, leaving little chance of healing from the epithelial elements at the bottom of the wound. In the case of a very small burn, healing might occur by contraction and growth of epithelial cell from the wound edges. Full-thickness burns will nearly always result in hypertrophic (raised) scarring. Hypertrophic scarring can be assessed with different tools, but there is still no consensus concerning its definition (Bloemen 2009).

Full-thickness facial burns are rare, since the face's high vascularity rapidly dissipates heat (Choi 2008). Facial burns are often caused by flash burns, which usually cause partial-thickness burns. Nonetheless, full-thickness facial burns do occur, especially in flame and contact burns, and in the event of prolonged exposure to a heating source, for example if the person was unconscious or paralysed at the time of accident. In addition, in some places (e.g. nose and ears) facial skin is very thin, and, therefore, more vulnerable to deep burns. When nose and ears are deeply burned, the anatomical structures can change or disappear.

Immediately after the thermal injury the surfaces of burn wounds are sterile, but they are rapidly colonised by a variety of micro-organisms (Erol 2004; Wysocki 2002). These micro-organisms originate from the patient’s own skin, respiratory and gastro-intestinal flora, and also from contact with contaminated surfaces in the external environment, hands of healthcare workers and even air (Erol 2004; Weber 2004; Wysocki 2002). Burn wounds provide a favourable niche for microbial colonisation and proliferation because of their protein-rich environment and avascular necrotic tissue (Barret 2003; Erol 2004). This avascularity of eschar (necrotic tissue) results in impaired migration of host immune cells and restricts delivery of systemically administered antimicrobial agents to the area. The most common burn wound pathogens are Staphylococcus aureus and Pseudomonas aeruginosa (Nagoba 2010). Microbial colonisation of burn wounds has been associated with delayed wound healing, increased need for surgical interventions and prolonged length of stay at burn centres (Vermeulen 2007).

Once 30% of the total body surface area has been burned there may be systemic (whole body) responses in addition to local responses. This occurs because of the release of inflammatory mediators at the site of injury (Hettiaratchy 2004b). Besides generating excessive oedema in burns, these systemic reactions can further compromise the healing of a burn wound, and so it is important to consider adequate local treatment, as well as systemic management of a burn, as this may influence the final outcome of the injury.

Another possible outcome of a burn injury is hypertrophic scarring, which occurs when the balance between collagen synthesis and breakdown is disrupted (Herndon 2007). The post-burn hypertrophic scar may present itself either as a pink to red in colour and slightly thickened, or as a red to purple inelastic mass of skin tissue. If a hypertrophic scar surrounds openings such as the eyes or mouth, functional impairment of the face can occur. The eyes for instance, may not close, due to the inelasticity and contraction of the hypertrophic skin, and the mouth may not open maximally. Furthermore, these scars can result in discomfort, because of itching, and sometimes cause neuropathic (nerve) pain (Van Loey 2008). The degree of hypertrophic scarring differs among individuals and depends on a variety of factors, one of which is time to wound healing, with hypertrophic scar formation being seen more often when wound healing takes more than 21 days (Cubison 2006). In general, a deeper burn wound results in the formation of more hypertrophic tissue. Other factors that affect hypertrophic scarring are race, age, genetic factors, type of injury, anatomic region and mechanical tension on the wound (Bloemen 2009).

 

Description of the intervention

The focus of this review is topical treatment for facial burns. Topical treatment comprises any remedy, agent, substance, device or skin substitute that is placed on the face as a therapy for burn wounds. This definition excludes invasive surgical intervention, which is another important treatment in burn care. Excluding this intervention is necessary in order to narrow the scope of this review and increase the comparability of outcomes. Numerous dressings and topical ointments are used to treat facial burns. Hansen 2004 conducted a survey on the standards of topical wound care for facial burns among burn centres in the USA. Most burn centres used topical bacitracin for partial-thickness facial burns and silver sulphadiazine (SSD) or bacitracin for full-thickness facial burns, with variations in treatment modalities. A survey of European burn centres reported that most centres agreed that some kind of antibacterial topical agent should be used, particularly for deep facial burns, but there were large variations in practice (De Haas 2005). Before applying topical or surgical treatment, a burn wound surface might need additional preparation in the form of debridement (removal of dead tissue). The debridement of burns is divided in two main approaches, namely:

  • superficial debridement: cleaning the wound surface using a brush, gauze or chemical, and removing the superficial loose wound surface;
  • surgical debridement: the excision of the burn wound, with removal of all non-vital tissue.

In this review only superficial debridement will be considered.

 

How the intervention might work

Interventions used in topical treatment of facial burns can be divided into four main categories: wound preparation agents and antiseptics; wound dressings; antimicrobial agents; and other treatments, including alternative remedies. An elaboration of each category is described below.

 

Wound preparation agents and antiseptics

Antiseptics are topical agents designed to reduce or eliminate micro-organisms in a wound. They can be used to cleanse facial burn surfaces after injury, or to prepare wounds for surgical debridement, or the application of a further topical agent (Ward 1995). Examples of antiseptics include chlorhexidine digluconate and povidone iodine. Other wound-preparation agents include enzymatic debriding agents. These agents prepare the wound by chemical debridement, but their use is controversial for facial burns (Leon-Villapalos 2008).

 

Wound dressings

Wound dressings, including biological dressings and bioengineered skin substitutes, are used to create an optimal environment for epidermal wound healing. For a long time, a moist environment was regarded as optimal (Winter 1962), however, more recently Jonkman 1989 has suggested that epidermal wound healing is best accelerated in an environment "between moist and dry", i.e. a more jelly-like wound exudate environment. Nowadays, several wound dressings have these moist or gel-forming qualities. Occlusive dressings, such as hydrocolloids and hydrogel dressings, form a moist or jelly-like environment by incorporating wound fluids into the dressing. Semi-occlusive dressings (e.g. polyurethane film, foam or a hydrofibre) permit evaporation of excess water and prevent maceration, while maintaining a moist environment. Silicon-coated nylon dressings function primarily as non-adherent dressing layers, and, therefore, reduce potential damage during dressing changes (Walmsley 2002). Simple wound dressings, such as synthetic non-adherent or paraffin gauze dressings, sometimes incorporate medication such as chlorhexidine.

Biological dressings (e.g. cadaver allografts (skin from corpses) and porcine (pig) skin xenografts) can be used to treat partial-thickness burns. These provide temporary wound coverage until full healing can be achieved, or until autografting (skin graft(s) using the patient's own skin) can take place. Their use is limited due to their lack of availability, acceptability, and the possibility of disease transfer (Pham 2007). Another biological dressing, amnion (derived from the membranous sac that surrounds the developing embryo), has recently been proposed as a wound dressing for burn treatment (Kesting 2008). In addition, bioengineered skin substitutes can be used as "smart dressings" in topical therapy; these not only provide immediate wound cover, but are also available in large quantities, with a negligible possibility of disease transfer. Unfortunately, most skin substitutes are expensive and considerable expertise is required to select the appropriate material for the situation (Pham 2007).

 

Antimicrobial agents

Topical antimicrobial agents are used with the aim of controlling and limiting infection, and they are central to topical burn therapy. The ideal topical prophylactic antimicrobial agent would have a broad spectrum of activity with a long duration of action, low toxicity and the ability to penetrate eschar (necrotic tissue) without being absorbed by the body (Monafo 1990). Ideal topical antimicrobials do not hamper epithelial outgrowth and deliver a high concentration of active ingredients to devitalised, devascularised and potentially necrotic wounds, helping to provide a favourable wound healing environment. Use of topical antimicrobials may help to minimise wound deepening, and the need for extensive debridement and subsequent grafting. This is fundamentally important for facial wounds, where overzealous debridement may affect function and appearance (Leon-Villapalos 2008).

The antimicrobial agents used in burn care include silver preparations. Silver sulphadiazine (SSD), in particular, is widely used and acts on burn eschar to limit the extent of non-viable tissue in situations where surgery is either not possible, or would not be the immediate first option - as in facial burns (Leon-Villapalos 2008). Cerium nitrate is another antimicrobial agent which penetrates burned tissue and has a broad spectrum of activity against Gram-positive and Gram-negative bacteria, and fungal species, especially in combination with SSD. Cerium nitrate also has a hardening effect on burn eschar, which is thought to prevent bacterial ingress and helps maintain a moist wound. Furthermore, cerium is supposed to bind and denature the lipid-protein complex released from burned skin responsible for the profound immunosuppression associated with major cutaneous burns (Allgöwer 2008; Garner 2005). Despite their popularity and widespread use, silver-based modalities are not without complications, including frequently observed delayed wound healing, which might be due to the retardation of sloughing in partial-thickness burns. In addition, increased hypertrophic scarring has been described with SSD; while skin irritation, black staining of the skin and the possibility of systemic absorption of silver have also been reported (Atiyeh 2007; Pham 2007). Furhermore, a Cochrane systematic review concluded that "there is insufficient evidence to establish whether silver-containing dressings or topical agents promote wound healing or prevent wound infection; some poor quality evidence for SSD suggests the opposite" (Storm-Versloot 2010).

Other antimicrobial agents include natrium fusidate and nitrofuran. It has been reported that some antimicrobial medications might delay proper healing mechanisms of the wound (Le Duc 2007; Teepe 1993), and that improper use can contribute to the emergence of resistant microbes (Nagoba 2010). In this review, simple wound dressings will be included in this antimicrobial category when they contain an antimicrobial medication.

 

Other treatments, including alternative remedies

Several additional forms of topical therapy are available, including alternative remedies such as honey and Aloe vera. Honey is said to prevent bacterial growth, form a physical barrier, act as an enzymatic debrider and promote epithelialisation and angiogenesis (formation of new blood vessels). Aloe vera could accelerate the wound healing process and rate of re-epithelialisation in partial-thickness burns (Maenthaisong 2007; Somboonwong 2000). Other alternative remedies, such as covering with banana or cabbage leaves, or potato skins, are sometimes used in places where treatment resources are limited. Any other topical treatment for facial burns which does not fall into one of the main groups above will be included in this category of alternative remedies.

 

Why it is important to do this review

Treatment of facial burns is more demanding than treatment of burns on other parts of the body, not only because of the location of vital sensory and communication organs but also because the face is highly vascular. This high vascularisation increases the self-healing potential of facial burns and, therefore, justifies a conservative approach to treatment, though this may require intensive daily care. There is uncertainty about which treatment is the most effective for facial burns, and, consequently, there are large variations in practice (De Haas 2005; Leon-Villapalos 2008). Since treatment contributes to outcome - which is especially important for facial burns in terms of both physical and psychological functioning - it is important to consider the most effective treatment.

Existing guidelines to support clinical decision making in burn care are predominantly practice-based or are concerned with the general treatment of burns. For example, an evidence-based guideline was published on treatment of burns and scalds in primary care (New Zealand Guidelines Group 2007). In addition, several systematic reviews have been published in the field of wound care; in 2008 a review on dressings for superficial and partial-thickness burns was published (Wasiak 2008), and in the same year the use of honey as a topical treatment for wounds was systematically reviewed (Jull 2008 ), however neither review specifically considered facial burns. Another systemic review by Vermeulen 2007 reviewed the use of topical silver for treating infected wounds, and Storm-Versloot 2010 recently reviewed the effects of topical silver for prevention of wound infection. In conclusion, current published reviews do not address the effectiveness of topical treatment for facial burns.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

To evaluate the effects of topical interventions on wound healing in people with facial burns of any depth.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We considered all randomised controlled trials (RCTs) that evaluated the effects of topical treatments for facial burns. We decided to consider controlled clinical trials (CCTs) only in the absence of RCTs.

 

Types of participants

We considered studies that included people of any age with a facial burn wound of any degree in any care setting. Any type of burn injury was eligible (flame, scald, chemical etc).

 

Types of interventions

Studies were considered for inclusion if topical therapy was applied and compared with any comparator intervention. We defined topical therapy as any remedy, agent, substance, device or skin substitute (biological or bioengineered) that was applied to the surface of the facial wound in the acute phase with the aim of treating the burn. We defined the acute phase as the period of wound healing that occurs up to wound closure (epithelialisation). We divided the topical interventions considered for inclusion into the following four categories:

  • wound preparation agents and antiseptics;
  • wound dressings, e.g. occlusive and semi-occlusive dressings, biological and bioengineered dressings;
  • antimicrobial agents;
  • other treatments, including alternative remedies.

The previously stated definition of topical therapy excluded surgical debridement as an index intervention in this review. Comparator interventions could include any other intervention, no intervention or a placebo intervention.

 

Types of outcome measures

Study outcomes did not form part of the selection process. We divided outcomes into primary and secondary outcomes; these are listed below.

 

Primary outcomes

  • Time to complete wound healing.
  • Change in wound surface area over time, or the proportion of the burn wound surface area that had healed within a specified time period.
  • Wound infection (as defined by the trial authors).

We accepted any definition of change in wound surface area over time, or proportion of wound surface area healed in a specified time period. In addition, we accepted any definition of wound infection. All primary outcomes were assessed as short-term endpoints (i.e. three months).

 

Secondary outcomes

  • Proportion of facial burns requiring (reconstructive) surgery.
  • Scar quality: observed and self-reported (any definition of scar quality was accepted).
  • Pain.
  • Patient satisfaction.
  • Adverse effects: classified as: diagnosed by a clinician, diagnosed by laboratory results or patient-reported symptoms.
  • Quality of life.
  • Length of hospital stay (LOS).

Because we anticipated that primary studies would report and analyse secondary outcomes at different time points, we prespecified time points as either short-term or long-term. The short-term endpoints (i.e. up to three months post burn) included the outcomes: pain, patient satisfaction, adverse effects and length of hospital stay; the long-term endpoints (i.e. after 3 months and up to 12 months post burn) included the outcomes: proportion of facial burns requiring (reconstructive) surgery, scar quality and quality of life.

 

Search methods for identification of studies

 

Electronic searches

We searched the following electronic databases for reports of randomized controlled trials:

  • Cochrane Wounds Group Specialized Register (Searched 12 November 2012);
  • the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10);
  • Ovid MEDLINE (1950 to November Week 1 2012);
  • Ovid MEDLINE (In-Process & Other Non-Indexed Citations, searched November 12 2012);
  • Ovid EMBASE (1980 to 2012 Week 45);
  • EBSCO CINAHL (1982 to 9 November 2012).

The search strategies for Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL can be found in Appendix 2, Appendix 3 and Appendix 4 respectively. The Ovid MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximizing version (2008 revision) (Lefebvre 2011). The EMBASE and CINAHL searches were combined with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2009). No date or language restrictions were applied.

The following CENTRAL search strategy was used:
#1 MeSH descriptor Anti-Bacterial Agents explode all trees
#2 MeSH descriptor Administration, Topical explode all trees
#3 (#1 AND #2)
#4 (topical NEAR/3 antibiotic*):ti,ab,kw
#5 MeSH descriptor Anti-Infective Agents, Local explode all trees
#6 (topical NEAR/3 antiseptic*):ti,ab,kw
#7 MeSH descriptor Anti-Inflammatory Agents explode all trees
#8 MeSH descriptor Glucocorticoids explode all trees
#9 (#7 OR #8)
#10 (#2 AND #9)
#11 (topical NEAR/3 (steroid* or corticosteroid* or glucocorticoid*)):ti,ab,kw
#12 MeSH descriptor Estrogens explode all trees
#13 (#2 AND #12)
#14 (oestrogen or estrogen):ti,ab,kw
#15 MeSH descriptor Enzymes explode all trees
#16 (#2 AND #15)
#17 enzym*:ti,ab,kw
#18 MeSH descriptor Growth Substances explode all trees
#19 (#2 AND #18)
#20 (growth NEXT factor*):ti,ab,kw
#21 MeSH descriptor Collagen explode all trees
#22 collagen*:ti,ab,kw
#23 MeSH descriptor Silver explode all trees
#24 MeSH descriptor Silver Sulfadiazine explode all trees
#25 silver*:ti,ab,kw
#26 cerium nitrate:ti,ab.kw
#27 MeSH descriptor Complementary Therapies explode all trees
#28 MeSH descriptor Honey explode all trees
#29 honey:ti,ab.kw
#30 MeSH descriptor Aloe explode all trees
#31 aloe:ti,ab,kw
#32 MeSH descriptor Ointments explode all trees
#33 (ointment* or lotion* or cream* or gel* or solution*):ti,ab,kw
#34 topical:ti,ab,kw
#35 MeSH descriptor Bandages explode all trees
#36 MeSH descriptor Alginates explode all trees
#37 MeSH descriptor Hydrogel explode all trees
#38 MeSH descriptor Skin, Artificial explode all trees
#39 (dressing* or pad or pads or gauze or tulle or film or bead or foam* or non-adherent or "non adherent" or hydrocolloid* or hydrofibre* or hydrogel* or alginate* or plaster* or compress or absorb* or dextra* or silicon* or amnion*):ti,ab,kw
#40 (#3 OR #4 OR #5 OR #6 OR #10 OR #11 OR #13 OR #14 OR #16 OR #17 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39)
#41 MeSH descriptor Burns explode all trees
#42 (burn or burns or burned or scald*):ti,ab,kw
#43 (thermal NEXT injur*):ti,ab,kw
#44 (#41 OR #42 OR #43)
#45 MeSH descriptor Face explode all trees
#46 MeSH descriptor Facial Injuries explode all trees
#47 MeSH descriptor Ear explode all trees
#48 (face or facial or mouth* or nose* or "ear" or "ears"):ti,ab,kw
#49 (#45 OR #46 OR #47 OR #48)
#50 (#40 AND #44 AND #49)

In addition, we searched the International Clinical Trials Registry Platform Search Portal (www.who.int/trialsearch) (Searched 19 November 2012).

 

Searching other resources

We checked reference lists within all studies and major review articles retrieved in an effort to identify any additional relevant studies. We sent emails to all authors of included studies requesting information on unpublished data and ongoing studies.

 

Data collection and analysis

 

Selection of studies

Without restrictions on language of publication or publication status, two review authors (CH and JH) independently assessed the titles and abstracts of studies identified from the search in terms of their relevance and design. We obtained full versions of articles if they matched the inclusion criteria from this initial assessment. The review authors independently assessed full text articles and determined a final selection of trials eligible for this review. Another review author (MvB) evaluated any discrepancies and advised in case of disagreement.

 

Data extraction and management

Two review authors (CH and JH), working independently, extracted and summarised details of trials using a data extraction sheet. They extracted data on the following items:

  • Characteristics of the trial: method of randomisation, setting, location of care, country, source of funding.
  • Participants: number, age, gender, type of burn, percentage Total Body Surface Area (TBSA) burned, burn depth, concurrent illnesses.
  • Intervention topical agents: type of dressing, dose used, frequency of dressing changes, time elapsed before treatment, concurrent interventions.
  • Comparator intervention: see above.
  • Outcomes: types of outcomes measured, timing of outcomes.
  • Results.

The authors resolved any discrepancies by discussion with a third review author (MvB), and contacted the trial authors when information was missing from published reports or clarification was needed. Data from trials published in duplicate were included only once, but were maximally data extracted.

 

Assessment of risk of bias in included studies

Two review authors (CH and JH) made systematic and independent assessments of the risk of bias of each trial, using the Cochrane Risk of Bias criteria (Higgins 2011). The criteria relate to the following issues:

  • sequence generation;
  • allocation concealment;
  • blinding of participants, care providers and outcome assessors;
  • incomplete outcome data: assessment of drop-out rate and intention-to-treat analysis;
  • selective outcome reporting;
  • other sources of bias: baseline similarity, co-interventions, compliance, similar timing of outcome assessment.

Risk of bias increases with each criterion that is judged to be negative. A detailed description of criteria for a judgement of 'low risk of bias', 'high risk of bias' or 'unclear risk of bias' is available (see Appendix 5). Any discrepancies in judgement between the two review authors was resolved by discussion with a third review author (MvB). Final assessment of risk of bias was presented in a risk of bias summary figure, which presents all of the judgements in a cross-tabulation of study by entry. This display of internal validity indicates the weight the reader may give to the results of each study.

 

Measures of treatment effect

Data analysis was performed according to the guidelines of the Cochrane Collaboration (Deeks 2011). One review author (CH) entered quantitative data into RevMan, this was checked by another review author (JH), and analysed using the Cochrane Collaboration's associated software (RevMan). For each outcome, summary estimates of treatment effect (with 95% confidence intervals (CI)) were calculated for every comparison. Dichotomous outcomes were presented as risk ratios (RR) (also called relative risks) (see Handbook 9.2.2, Deeks 2011) with 95% CI, and continuous outcomes were presented as mean differences (MD) with 95% CI. We intended to use standardised mean differences (SMD) on occasions when studies assessed the same outcome (e.g. quality of life) but measured the outcome in different ways. Time to wound healing would be analysed as a survival (time-to-event) outcome if possible, using an appropriate analytical method (i.e. hazard ratio, Cochrane Reviewers handbook 9.2.6 Deeks 2011).

 

Unit of analysis issues

We addressed the level at which randomisation occurred in our analysis. In general, the unit of randomisation and measurement was expected to be the patient. Any deviations were described and addressed in the analysis.

 

Dealing with missing data

We contacted the original investigators to request missing data whenever possible.

 

Assessment of heterogeneity

We planned to explore both clinical and statistical heterogeneity. Clinical heterogeneity was assessed using information on type of dressing, dose used and frequency of dressing changes. We planned to test statistical heterogeneity using the chi squared test and estimate the amount of heterogeneity using I2 (with 95% CI) (Higgins 2003; Deeks 2011), which examines the percentage of total variation across studies due to heterogeneity rather than to chance.

 

Assessment of reporting biases

We planned to measure publication bias by the Begg funnel plot (Begg 1994) and the Egger test (Egger 1997), if the included studies were homogeneous and sufficient in number.

 

Data synthesis

We planned to perform a meta-analysis for each primary outcome if clinical and statistical homogeneity indicated this would be appropriate (Higgins 2003), and calculate summary estimates of treatment effect for every comparison. We planned to conduct a narrative overview, structured by the type of comparison, when statistical meta-analyses was inappropriate.

 

Subgroup analysis and investigation of heterogeneity

We planned to investigate heterogeneity through subgroup and sensitivity analysis (Deeks 2011), when there was a sufficient number of studies in the meta-analysis (i.e. more than 10). We planned to conduct subgroup analysis for:

  • Partial-thickness burns compared with full-thickness burns, as the effects of topical interventions were expected to differ between patient groups with different burn depths.
  • Adequate concealment of allocation (low risk of bias versus unclear, or high risk of bias).

 

Sensitivity analysis

If there were a sufficient number of studies in the meta-analysis, we planned to perform a sensitivity analysis showing how conclusions might be affected if studies at high risk of bias were excluded from the analyses. We planned to explore the effect of excluding studies with unclear and inadequate sequence generation and unclear and inadequate allocation concealment within the sensitivity analysis.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies.

See: Characteristics of included studies; Characteristics of excluded studies.

 

Results of the search

The search identified, after initial de-duplication, 416 articles. Two review authors (CH and JH) independently assessed the titles and abstracts of these articles and judged 20 citations to be potentially eligible for the review. Two citations appeared to be duplicates, decreasing the number of unique articles to 18. Full texts of the eligible articles were obtained and assessed by the same two review authors. They completed data extraction forms and the risk of bias table, and screened the references in the articles for additional eligible studies. No additional studies were identified with this "snowballing" method. The full text of two articles (Li 2005; Liang 2007) was published only in Chinese and were assessed by Chinese speakers who decided that they were not RCTs. An additional search in the International Clinical Trials Registry Platform Search Portal (www.who.int/trialsearch) resulted in one additional, potentially eligible trial (Lehna 2012).

 

Included studies

Assessment of the 18 potentially eligible articles (20 citations) resulted in the inclusion of five studies (six citations) (Ang 2000; Demling 1999; Demling 2002; Desai 1991; Horch 2005). The characteristics of these studies are described in the Characteristics of included studies and are summarised below. Four studies (Hindy 2009; Jiaao 2011; Mabrouk 2012; Oen 2012) have been added to the Characteristics of studies awaiting classification and will be assessed in the next update of this review. The details of the trial retrieved from the International Clinical Trials Registry Platform Search Portal (Lehna 2012) has been added to the Characteristics of ongoing studies while we keep in contact with the trialists regarding the progress of the trial.

 

Health care settings

All five RCTs took place in burn centres; three in the USA (Desai 1991; Demling 1999; Demling 2002); one in Singapore (Ang 2000) and one in Germany (Horch 2005).

 

Participants

A total of 119 participants (55 intervention, 64 control) were recruited to the five included studies (range of sample size 10 to 39), although it is possible that this number might be lower due to a possible overlap of participants between two studies (Demling 1999; Demling 2002), which potentially would decrease the total to 98. Age and percentage TBSA burned of the included participants are summarised below. The mean age and standard deviation (SD) or standard error (SE) were reported in three studies (Demling 1999; Demling 2002; Desai 1991), and one study reported median age only (34.3 years), and range (24 to 67 years) of the whole study population (Horch 2005). In Desai 1991, the mean age was 11.4 years (SE 1.2 years) in the intervention group and 9.5 years (SE 1.6 years) in the control group. In Demling 1999 and Demling 2002, the mean age varied from 29 years (SD 7 years) to 44 years (SD 10 years). Percentage TBSA burned was reported in four studies (Ang 2000; Demling 1999; Demling 2002; Desai 1991) and varied from 1.56% (SE 0.18) in the control group in Ang 2000, to 50% (SE 6) in the control group in Desai 1991. Horch 2005 did not provide information about the percentage TBSA burned.

 

Interventions

One study compared two different antimicrobial agents: Moist Exposed Burn Ointment (MEBO) and silver sulphadiazine (SSD) (Ang 2000). Another study compared routine care plus an antimicrobial agent (i.e. 1% gentamicin cream) administered via iontophoresis (use of an electric current to move a drug through the skin to a deep site) with routine care alone (Desai 1991). The routine care comprised of the application of mafenide acetate (another antimicrobial substance) every six hours.

The remaining three studies compared skin substitutes with antimicrobial agents. In Demling 1999 and Demling 2002, the intervention group received bio-engineered skin substitutes (TransCyte®) and the control group received standard care with topical antibiotics. TransCyte® is a bilayered, biologically-active, temporary skin substitute with an outer flexible knitted-nylon layer permeable to water vapour but impermeable to bacteria that decreases environmental insults. The inner layer is impregnated with human fibronectin and collagen Type I. In Demling 1999, the standard care consisted of application of bacitracin two to three times a day in mid-dermal burns, while this procedure was preceded by the application of SSD in the first one to two days in deeper burns. Demling 2002 did not provide additional information about the topical antibiotic used in standard care. In Horch 2005, the biological skin substitute used was an allograft (glycerolised cadaver skin), and the topical antimicrobial ointment was SSD. In both groups the application of treatment followed superficial debridement. No studies investigated wound preparation agents and antiseptics or other treatment, including alternative remedies.

 

Outcomes

Four studies included time to complete wound healing as an outcome of interest, but differed in their definition of this outcome, measuring it as number of days to complete wound healing (Ang 2000), number of days to complete re-epithelialisation (Horch 2005), time in days to more than 90% re-epithelialisation (Demling 1999), and time in days to more than 95% re-epithelialisation (Demling 2002). In addition, Ang 2000 reported the number of participants healed at 10 days. Wound infection was a pre-specified outcome in three studies (Demling 1999; Demling 2002; Desai 1991), and another study reported this outcome although it had not be pre-specified in the methods section (Horch 2005). Demling 2002 determined wound infection with quantitative swab cultures, using a cut-off value of 105 organisms/g. Demling 1999 and Desai 1991 determined wound infection with qualitative outcome measures, which included increased exudate and surrounding cellulitis (Demling 1999), and the appearance of chondritis (Desai 1991). The Horch 2005 trial did not describe how infection was measured.

Secondary outcomes reported in the five studies included the need for (reconstructive) surgery, hypertrophic scarring, pain, length of hospital stay and adverse effects. Ang 2000 and Desai 1991 examined the need for (reconstructive) surgery with a follow-up of six months post-burn. Hypertrophic scarring was an outcome in one study (Horch 2005), but a measurement instrument was not described. Pain was reported as an outcome of interest only in the Demling studies (Demling 1999; Demling 2002). Both studies used a 10-point scale to assess pain (0 for no pain and 10 for worst pain). Two studies reported the length of hospital stay (Demling 1999; Desai 1991), and additional adverse effects were reported in Horch 2005 and Desai 1991.

 

Sponsorship

One study explicitly stated that none of the authors had commercial associations or financial interests that might pose a conflict of interest (Ang 2000), while Horch 2005 and Desai 1991 provided no information about sponsorship. In Demling 1999 and Demling 2002 the intervention was an explicitly mentioned brand, but it was not stated whether this application was sponsored or purchased.

 

Excluded studies

Nine studies (10 citations) were excluded because they were not RCTs (Branski 2008; Covey 1987; Hartmann 2007; Lansdown 2004; Li 2005; Liang 2007; Papp 1990), or because the focus of the study was not on facial burns (Ang 2001; Rege 1999).

 

Risk of bias in included studies

Two review authors (CH and JH) independently assessed risk of bias in the five included studies and initially disagreed on 14 judgements. Thirteen disagreements were resolved by discussion, and one disagreement was presented to a third review author (MvB) for final judgement. This one disagreement was related to the avoidance or similarity of co-interventions in Demling 1999. Most of the other disagreements were related to blinding of the outcome assessor, which sometimes differed between short-term and long-term follow-up. Details of the risk of bias judgements for the five studies are presented in separate risk of bias tables (part of Characteristics of included studies), a summary figure (Figure 1), and are described below.

 FigureFigure 1. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

For risk of bias assessment the term "allocation" included sequence generation and allocation concealment, which both had to be considered.

 

Sequence generation

Of the five included studies, only Ang 2000 described the method of sequence generation adequately. Ang 2000 described the method as: "Randomly alternating permuted sub-blocks of size 4 and 6, with equal numbers per treatment within each sub-block, were used to obtain an overall block size of 10". The other four studies stated only that participants were randomised, but did not describe the method of sequence generation (Demling 1999; Demling 2002; Desai 1991; Horch 2005).

 

Allocation concealment

Of the five included studies, only Ang 2000 described the method of allocation concealment employed adequately, stating that allocation was determined by means of telephone calls to a research unit during office hours or by sealed envelopes after office hours. The other four studies did not describe the method of allocation concealment (Demling 1999; Demling 2002; Desai 1991; Horch 2005).

 

Blinding

Review authors had to judge the blinding of participants, care providers and outcome assessors. None of the five studies reported blinding of participants or care providers, and so, because the nature of treatments made it impossible to blind them, the reviewers made a judgement of "no" rather than one of "unclear". Blinding of outcome assessors was reported in one study (Ang 2000); two studies clearly did not undertake blinded outcome assessment (Demling 1999; Demling 2002), and in two studies it was unclear whether the outcome assessor was blinded (Desai 1991; Horch 2005).

 

Incomplete outcome data

The item "incomplete outcome data" consisted of two topics: drop-out rate and intention-to-treat analysis (ITT). The drop-out rate was described and acceptable (i.e.did not exceed 20% for short-term follow-up and 30% for long-term follow-up and does not lead to substantial bias) in three studies (Ang 2000; Demling 2002; Horch 2005), while two studies did not report it or make it evident in the outcome assessment (Demling 1999; Desai 1991). ITT-analysis was performed in one study (Demling 2002); another study did not report ITT-analysis specifically, but it appeared likely when the study was assessed (Horch 2005). One study stated that ITT-analysis was performed, but assessment of the study showed clearly that it had not (Ang 2000). The final two studies were unclear on this point (Demling 1999; Desai 1991).

 

Selective reporting

Four studies were classified as free of suggestion of selective outcome reporting (Ang 2000; Demling 1999; Demling 2002; Horch 2005), but one was not (Desai 1991). In Demling 1999, the pre-specified outcome of length of hospital stay was not reported for major burns, because other non-facial burns interfered with this outcome and prolonged hospital stay. Desai 1991 listed wound healing as an outcome of interest but did not report it in the results section.

 

Other potential sources of bias

Review authors considered four other potential sources of bias (i.e. baseline characteristics, co-interventions, compliance and timing of outcome assessment). The baseline characteristics between intervention and control group were similar in three studies (Demling 1999; Demling 2002; Horch 2005). In Ang 2000, the description of baseline characteristics was limited to only one important prognostic indicator (i.e. % TBSA burned), which was insufficient to make a judgement of low risk of bias for baseline similarity. In Desai 1991 the percentage TBSA burned in both groups was not similar and no information was provided about etiology. Co-interventions were avoided, or similar, in one study (Demling 1999); cleaning procedures were different in one study (Ang 2000); no information was provided about co-interventions in two studies (Desai 1991; Horch 2005); and one study stated "subsequent care in the intervention group when needed", but did not report whether this care was applied (Demling 2002). Compliance with the intervention was acceptable in all five studies (Ang 2000; Demling 1999; Demling 2002; Desai 1991; Horch 2005). The timing of the outcome assessment was similar in all groups in all five studies (Ang 2000; Demling 1999; Demling 2002; Desai 1991; Horch 2005).

 

Effects of interventions

Heterogeneity of studies with regard to interventions and outcomes prevented assessment of reporting biases and limited data synthesis to a narrative overview, structured by the type of comparison. Because meta-analysis was inappropriate, no subgroup and sensitivity analyses were performed. The effects of interventions are presented in  Table 1 and summarised below.

 

Comparison: antimicrobial agents compared with other antimicrobial agents

Two studies compared antimicrobial agents with another antimicrobial agent in 54 people (Ang 2000; Desai 1991).

 

Primary outcomes

 
Time to complete wound healing

One study reported time to complete wound healing (Ang 2000). A study by Ang 2000 compared Moist Exposed Burn Ointment (MEBO) with silver sulphadiazine (SSD) in 39 people with partial thickness facial burns. Although time to complete wound healing was an outcome of interest in this study, the authors reported only the range of this outcome for the intervention group (2-35 days) and stated that MEBO resulted in healing rates similar to those seen with SSD dressings. After adjusting for initial percentage Body Surface Area (BSA) burned of the face wound, the hazard ratio for healing was 0.84 (95% CI 0.38 to 1.85) (no statistically significant difference).

 
Proportion completely healed in specified time period

Ang 2000 also reported the proportion of participants who were completely healed at 10 days (14 out of 17 participants in the MEBO group and 17 out of 22 participants in the SSD group); risk ratio (RR) 1.07 (95% CI 0.78 to 1.46;  Analysis 1.1) (no statistically significant difference).

 
Wound infection

Desai 1991 compared routine care (application of mafenide acetate cream dressings every six hours) plus an antimicrobial agent (gentamicin) administered via iontophoresis with routine care alone in 15 participants with ear burns. Three participants in the intervention group and four participants in the control group developed infection and chondritis (inflammation of cartilage), RR 0.86 (95% CI 0.29 to 2.58;  Analysis 2.1) (no statistically significant difference).

 

Secondary outcomes

 
Need for further surgery

The need for further surgery was reported by Ang 2000. At six months post-burn no participant in either the MEBO group (n = 17) or the SSD group (n = 20) received surgery. Desai 1991 reported that the mean number of surgical procedures in the intervention group was 1.2 (SE 0.1) and 1.0 (SE 0) in the control group. This difference was statistically significant (P < 0.05) in favour of the control group.

 
Adverse effects of treatment

The adverse effects of treatment were reported in one study (Desai 1991). Desai 1991 documented the appearance of gentamicin-resistant organisms in 29% of the participants in the group receiving gentamicin via iontophoresis, and in 0% of the participants in the control group, resulting in a RR of 5.63 (95% CI 0.31 to 100.52;  Analysis 2.2) (no statistically significant difference).

 
Length of stay (LOS)

In Desai 1991, the mean LOS was significantly shorter in the intervention group, 26 days (SD 2.6 days), compared with 38 days (SD 8.5 days) in the control group (mean difference -12.00, 95% CI -18.20 to -5.80;  Analysis 2.3), but there was no significant difference in LOS after adjusting for burn size.

Scar quality, pain, patient satisfaction and quality of life were not reported in these trials.

 

Comparison: wound dressings (skin substitutes) compared with antimicrobials

Three studies compared a skin substitute (a bio-engineered skin substitute (Demling 1999; Demling 2002) or allograft (Horch 2005)) with an antimicrobial (either bacitracin (Demling 1999) or SSD (Horch 2005) or an unspecified antibacterial ointment (Demling 2002)) in 65 people.

 

Primary outcomes

 
Time to complete wound healing

Three studies reported time to complete wound healing (Demling 1999; Demling 2002; Horch 2005) but as they did not use the appropriate statistical method for their analyses these data were not plotted graphically. Time to healing is a form of time to event data, more correctly analysed using survival methods which can account for censoring (i.e., just for the time that people were observed so it takes account of when they dropped out), it is inappropriate to report and analyse time to wound healing as if it were a continuous variable unless everyone healed and there was no loss to follow up. Demling 1999 divided 21 participants into two groups for minor and major burns. Wounds in the minor burns skin substitute group had a mean healing time of eight days (SD 1 day), which was significantly less than the mean healing time of 12 days (SD 3 days) in the bacitracin group (P value < 0.05). Similar results were reported for major burns where the skin substitute group had a mean healing time of eight days (SD 2 days), which was significantly less than the mean healing time of 14 days (SD 4 days) in the bacitracin group (P < 0.05). In Demling 2002, wounds in the skin substitute group had a mean healing time of nine days (SD 4 days; n = 16), which was significantly less than the mean healing time of 15 days (SD 4 days; n = 18) in the antibacterial ointment group (P < 0.05). Horch 2005 reported the median time to re-epithelialisation, which was significantly less in the allograft group (10.5 days; n = 5) compared to the SSD group (12.4 days; n = 5) (P < 0.05).

 
Wound infection

Three studies reported wound infection as an outcome. In Demling 1999 and Demling 2002 none of the participants in the intervention or the control groups showed signs of infection. In Horch 2005 none of the participants in the intervention group showed local infections, while there was no information about wound infection in the control group.

 

Secondary outcomes

 
Scar quality

Scar quality was a reported outcome in Horch 2005. Scar quality was defined as the incidence of hypertrophic scar formation six months post-burn. At that point none of the participants in the intervention group (n = 5) and two participants in the control group (n = 5) had hypertrophic scar formation, resulting in a non-significant risk ratio (RR) of 0.20 (95% CI 0.01 to 3.35;  Analysis 4.1). Horch 2005 did not report a measurement tool or provide a definition used to classify scars as hypertrophic.

 
Pain

Pain was an outcome of interest in both studies by Demling (Demling 1999; Demling 2002), which used a 10-point scale to measure it (0 for no pain and 10 for worst pain). Pain measurements were made during, and between, facial care. Demling 1999 divided the participants into two groups for minor and major burns. In the minor burn group, the mean pain score during facial care in the intervention group was 2 (SD 1) and 5 (SD 1) in the control group (mean difference -3.00, 95% CI -4.24 to -1.76;  Analysis 3.1); while the mean pain between facial care in the intervention group was 1 (SD 0.5) and 3 (SD 2) in the control group (mean difference -2.00, 95% CI -3.81 to -0.19;  Analysis 3.2). In the major burns group, the mean pain during facial care in the intervention group was 2 (SD 1) and 5 (SD 1) in the control group (mean difference -3.00, 95% CI -4.19 to -1.81;  Analysis 3.3); while the mean pain between facial care in the intervention group was 2 (SD 1) and 4 (SD 2) in the control group (mean difference -2.00, 95% CI -3.82 to -0.18;  Analysis 3.4). All the above mean differences were statistically significant (P < 0.05).

In Demling 2002, the mean pain during facial care in the intervention group was 3 (SD 1) and 7 (SD 2) in the control group (mean difference -4.00, 95% CI -5.05 to -2.95;  Analysis 3.5); while the mean pain between facial care in the intervention group was 2 (SD 1) and 4 (SD 2) in the control group (mean difference -2.00, 95% CI -3.05 to -0.95;  Analysis 3.6). Both mean differences were statistically significant (P < 0.05).

 
Adverse effects of treatment

Adverse effects of treatment was reported in one study (Horch 2005). In Horch 2005, one participant in the intervention group suffered a localised integration of the biological dressing, which was removed by two repeated dermabrasion manoeuvres. After these manoeuvres, no more visible allograft remnants remained.

 
Length of stay (LOS)

Length of stay (LOS) was reported by Demling 1999, for the minor burns group only where the mean LOS was significantly less in the intervention group at 1 day (SD 0.5 days), compared with 3 days (SD 1 day) for the control group (mean difference -2.00, 95% CI -2.98 to -1.02;  Analysis 3.7).

Need for (reconstructive) surgery, patient satisfaction and quality of life were not reported in these trials.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Summary of main results

We included five randomised controlled trials in this review that evaluated the effect of a variety of topical interventions for facial burns. Three studies compared skin substitutes with different antimicrobial agents whilst two studies compared two different antimicrobial agents. None of the studies investigated wound preparation agents, antiseptics or other treatments, including alternative remedies. The variety of topical interventions evaluated and differences in outcome measures between studies made pooling of data inappropriate, therefore, the results have been presented in a narrative overview by comparison. This summary of main results is divided in two primary outcomes (i.e. wound healing and wound infection) and all secondary outcomes have been combined.

 

Wound healing

Wound healing was variously measured and reported as: time to complete wound healing, average proportion of wound completely healed within a specified time period, change in wounds and percentage of wound healed during follow up. Time to complete wound healing was reported in four studies, but only Ang 2000 used survival methods (the appropriate approach to statistical analysis of time to event data). This study compared two antimicrobial agents (MEBO and silver sulphadiazine) in 39 participants and found a similar risk of healing with both interventions (hazard ratio 0.84, 95% CI 0.38 to 1.85) (Ang 2000). The other three studies compared a wound dressing (i.e. skin substitute (Transcyte® and allograft)) with an antimicrobial agent. The difference in mean time to complete wound healing in days was significantly reduced with the skin substitutes in two of the studies (Demling 1999; Demling 2002). The third study reported a statistically significant reduction in median days to complete wound healing, which also favoured the skin substitutes (i.e. intervention group 10.5 days, control group 12.4 days) (Horch 2005). Thus, the results of all three studies of skin substitutes compared with antimicrobial agents favoured the skin substitutes. A cautious conclusion might be that the time to complete wound healing is shorter with the application of skin substitutes compared with topical antimicrobials. A reason for our caution is that none of the three studies used the appropriate statistical method - survival analysis - for these analyses (Demling 1999; Demling 2002; Horch 2005) and if not all participants were completely healed or if there were withdrawals during the study this estimate will be biased. The proportion of the wound that was completely healed in a specified time period was reported in Ang 2000, where the results did not show a statistically significant difference. Consequently we can only confidently conclude that there is no high quality evidence of a difference in facial burn wound healing between the antimicrobials studied and either alternative antimicrobials or skin substitutes.

 

Wound infection

Four studies addressed wound infection as a negative outcome. Demling 1999 and Demling 2002 reported no occurrence of wound infection in any group; Horch 2005 reported no occurrence of wound infection in the intervention group, but did not provide information about the control group; Desai 1991 reported three cases of chondritis in the intervention group and four cases in the control group. These data were insufficient to support any definite conclusions.

 

Secondary outcomes

Except for patient satisfaction and quality of life, all other secondary outcomes (need for (reconstructive) surgery, scar quality, pain, adverse effects of treatment and length of stay) were addressed by at least one study. One study addressed the number of surgical procedures required (Desai 1991), which significantly favoured the control group. One study addressed the need for reconstructive surgery (Ang 2000); none of the participants needed any in the follow-up period. The follow-up period in this study was six months post-burn, which might be too short for a full assessment of the need for reconstructive surgery. Reconstructive surgery can be divided into urgent, essential and desirable procedures. The urgent and essential procedures might be performed within a six-month follow-up period, but the desirable procedure is usually postponed until scars have fully matured. This maturation can take a year or longer (Barret 2004). Therefore, differences in the need for reconstructive surgery between intervention and control group might appear in a later phase.

An adverse effect of treatment that consisted of a localised integration of the biological dressing (removed by two dermabrasion manoeuvres) was reported in Horch 2005. Another adverse effect of treatment was reported in Desai 1991 where gentamicin-resistant micro-organisms appeared in the intervention group. The only study that assessed scar quality did not find a significant treatment effect (Horch 2005). Both studies that assessed pain found significantly better results for the groups receiving skin substitutes (Demling 1999; Demling 2002). The results showed a greater mean difference in pain levels during facial care sessions, which scored 3 to 4 points on the pain scale compared to pain experienced between facial care sessions, which scored 2 points. This finding might not be surprising because the intervention group had hardly any wound dressing sessions: after the application of a skin substitute, facial care was usually restricted to the first day, although the control group received facial care two or three times a day. The two studies that addressed length of stay did report a statistically significant difference (Demling 1999; Desai 1991), but only in the minor burns sub-group (n = 10) (Demling 1999), or before adjusting for burn size (Desai 1991). After adjusting for burn size in Desai 1991 no difference could be determined between the intervention and control groups for length of hospital stay. All secondary outcomes should be interpreted with caution due to wide 95% confidence intervals and lack of sufficient data.

 

Overall completeness and applicability of evidence

The objective of this review was to assess the effectiveness of topical interventions on wound healing in people with facial burns of any depth. All topical interventions were eligible for inclusion, but only seven different interventions were identified. Furthermore, four of the included studies investigated only partial-thickness burns, and one did not specify the depth(s) of the facial burns of its participants (Desai 1991). None of the included studies addressed the outcomes of patient satisfaction or quality of life. Therefore, overall completeness has clearly not been achieved. The included studies were heterogeneous, so we could not assess publication bias with a Begg funnel plot or an Egger test. In addition, applicability of evidence might be restricted to specialised burn centres in developed countries, because of the relatively high costs of skin substitutes.

 

Quality of the evidence

The evidence combined in this review was of insufficient quality to allow definite conclusions to be drawn. In particular, the methodological quality of the included studies was relatively low: all five studies had small sample sizes, ranging from 10 to 39, which increase the spread of confidence intervals and decrease validity of results. While pooling data from small trials could increase statistical power and give a more precise overall estimate of effect size, the studies in this review did not compare similar interventions and had different outcome measures, which prevented pooling. Most of the included studies had other shortcomings regarding sequence generation, allocation concealment, blinding and intention-to-treat (ITT) analysis. Only one study described sequence generation and allocation concealment adequately (Ang 2000); the other four studies only stated that participants were randomised. Blinding of participants and care providers is not easy in studies that compare topical interventions, but outcome assessors could have been blinded. Despite this possibility, only one study reported blinding of outcome assessors for all outcomes (Ang 2000). Intention-to-treat analysis was reported and confirmed in only one study (Demling 2002). Another study did not report ITT-analysis, but it appeared likely when the study was assessed (Horch 2005). The other three studies did not perform ITT-analysis (Ang 2000), or did not report this clearly (Demling 1999; Desai 1991), possibly introducing bias. As a result of all these deficiencies, evidence from the included studies should be interpreted with caution.

 

Potential biases in the review process

Potential bias in the review process might have arisen as a result of the minimal response to our queries from authors of the eligible studies. The review authors tried to contact study authors by email in an attempt to retrieve all possible data to assess the studies thoroughly. Despite issuing a reminder, we received only one reply from Branski 2008 with answers to our questions. As a result of those answers, we excluded this study as sequence generation and allocation concealment were inadequate and therefore judged not to be a randomised controlled trial. Four other studies scored unclear on these items, but as additional information was not provided, they were included. Another potential bias might have occurred due to a possible patient overlap between Demling 1999 and Demling 2002. Both studies were performed in the same hospital, and did not provide inclusion periods. Therefore, we were unable to confirm whether there was a patient overlap, or determine how one might alter our conclusions.

 

Agreements and disagreements with other studies or reviews

In general, the results of this review are in accordance with the results of the included studies, but some conclusions in the studies are slightly premature. None of the studies provided firm evidence, so conclusions should be cautious. This review agrees with the statement in Horch 2005 that "it would be worthwhile to perform more clinical studies with a larger number of patients to further evaluate the effect and function of allogenic skin for facial burns", and shows this statement is applicable for skin substitutes in general. Furthermore, the small number of included studies in this review is in accordance with a Cochrane review on a similar topic with a broader search (Wasiak 2008). In that review, burns of all types - except hand burns - were eligible, resulting in 26 included studies. In this review only facial burns were eligible, resulting in five included studies. Another review investigated the methodological quality of randomised controlled trials in burn care (Danilla 2009). Danilla 2009 included 257 eligible studies (from OVID Medline 1950 to January 2008) and concluded that "the reporting standards of RCTs are highly variable and less than optimal in most cases". Furthermore, their results showed an increase in RCTs over time without a significant improvement in methodological quality. These findings are in line with our results, as four out of the five included RCTs were performed in the last decade, but included no studies of high methodological quality. In summary, the number of studies in burn care is growing, but the body of evidence is still hampered due to an insufficient number of studies that follow appropriate evidence-based standards.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

 

Implications for practice

There is insufficient high quality research and evidence to enable conclusions to be drawn about the effects of topical interventions on wound healing in people with facial burns.

 
Implications for research

In order to improve the quality of the evidence, future studies should be designed in conjunction with a trials expert and a statistician and include a sample size calculation. An appropriate sequence generation and allocation concealment should be used in order to reduce risk of bias, and blinding should be attempted. Although it is difficult to blind participants and care providers, it is possible to blind outcome assessors. A sample size calculation should be used in order to increase statistical power and give a more precise overall estimate of effect size. Furthermore, future trialists might add patient satisfaction and quality of life to their outcomes of interest, as these outcomes are especially important for patients. In addition, future trialists might give some extra thought to the outcome wound healing, as this outcome can be reported in numerous ways and it is not always analysed correctly (i.e. survival analyses). Ideally, all trialists should use the same measurement for wound healing, and as a result, allow comparisons to be made. We suggest a clinical important measurement, for instance time to 95% wound healing, that could be considered as the percentage of wound healing necessary for discharge to outpatient management. This subjective wound assessment, performed by an experienced observer, is found to be a reliable (Bloemen 2011) and valid tool (Bloemen 2012). Topical interventions are numerous, so future research should focus on those interventions most likely to benefit patients.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

The review authors would like to thank Johannes van der Wouden for his advice on methodology and the people who refereed the protocol and/or review: Wounds Group Editors Andrew Jull, Liz McInnes, Dirk Ubbink, Methodologist: Lois Orton, Statistician: Gill Worthy and Peer referees: Heather Cleland, Mary Mondozzi and Jane Nadel for their comments. Furthermore, we would like to thank Mingming Zhang for assessing two Chinese articles and Elizabeth Royle for copy editing the review.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
Download statistical data

 
Comparison 1. MEBO vs silver sulphadiazine (SSD)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Proportion completely healed in 10 days1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 2. Gentamicin iontophoresis vs routine care

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Chondritis1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Gentamicin-resistant micro-organisms1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 3 Length of hospital stay in days1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 
Comparison 3. Bioengineered skin substitute vs topical antibiotic

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pain in minor burns during facial care1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 2 Pain in minor burns between facial care1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 3 Pain in major burns during facial care1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 4 Pain in major burns between facial care1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 5 Pain during facial care1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 6 Pain between facial care1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 7 Length of hospital stay in days1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 
Comparison 4. Biological skin substitute vs SSD

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Hypertrophic scar formation1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Appendix 1. Glossary

Allografting: transplantation of tissue/organs between individuals of the same species.
Amnion: the innermost membranous sac that surrounds and protects the developing embryo, bathed in amniotic fluid.
Angiogenesis: the development of new blood vessels.
Autografting: transplantation of an individual’s own tissue from one site to another site.
Avascular: not associated with, or supplied by, blood vessels.
Bioengineered skin substitute: an artificially-manufactured replacement for skin.
Biological dressings: human or animal tissue used as temporary wound coverings.
CCT: Controlled Clinical Trial.
Debridement: usually surgical removal of lacerated, devitalised, or contaminated tissue.
Dermis: the deep inner layer of the skin, beneath the epidermis, containing connective tissue, blood vessels and fat.
Epidermal: related to the outer epithelial layer of the skin.
Eschar: a scab or dry crust that results from trauma, such as a thermal or chemical burn, infection, or excoriating skin disease.
Flash burn: a lesion caused by exposure to an extremely intense source of radiant energy or heat.
Gastro-intestinal flora: micro-organisms living in both stomach and intestine.
Hypertrophic scar: an elevated scar, resembling a keloid, but which does not spread into surrounding tissues. It is formed by enlargement and overgrowth of scar tissue and regresses spontaneously.
Immunosuppression: deliberate prevention or diminution of the host’s immune response.
Iontophoresis: the introduction of an ionised substance (as a drug) through intact skin by the application of a direct electric current.
MD: Mean Difference.
Necrosis: the pathological process that occurs in cells dying from irreparable injuries. It is caused by the progressive, uncontrolled action of degradative enzymes, leading to mitochondrial swelling, nuclear flocculation and cell lysis (breakdown). Distinguished from apoptosis (programmed cell death), which is a normal, regulated cellular process.
Occlusive dressing: material, usually gauze or absorbent cotton, used to cover and protect wounds, to seal them from contact with air or bacteria.
Ointment: semisolid preparation used topically for protective emollient effects, or as a vehicle for local administration of medications.
PB: post-burn.
Prophylactic: guarding from, or preventing, the spread or occurrence of disease or infection.
RCT: Randomised Controlled Trial.
Re-epithelialisation: healing by the growth of epithelium over a denuded surface.
Scald: burn caused by a hot liquid, or a hot, moist vapour.
SD: Standard Deviation.
SE: Standard Error.
SMD: Standardised Mean Difference.
Sloughing: process of separating necrotic tissue from viable portions of the body.
SSD: silver sulphadiazine.
Systemic response: reaction related  to the whole body rather than to a localized area or regional part of the body.
TBSA: Total Body Surface Area.
Vascular: relating to the vessels in the body, which circulate fluid, such as blood.
Wound exudate: the material composed of serum, fibrin, and white blood cells that escapes from blood vessels into a superficial lesion.
Xenografting: transplantation of tissue/organs between animals of different species.

 

Appendix 2. Ovid MEDLINE search strategy

1 exp Burns/
2 (burn or burns or burned or scald$).ti,ab.
3 thermal injur$.ti,ab.
4 1 or 2 or 3
5 exp Face/
6 exp Facial Injuries/
7 exp Ear/
8 (face or facial or nose$1 or mouth$1 or ear$1).ti,ab.
9 or/5-8
10 4 and 9
11 exp Anti-Bacterial Agents/
12 exp Administration, Topical/
13 11 and 12
14 (topical adj3 antibiotic$).ti,ab.
15 (topical adj3 antimicrobial$).ti,ab.
16 exp Anti-Infective Agents, Local/
17 (antiseptic$ or eusol or furagin or sodium hypochlorite or furaltadon).ti,ab.
18 exp Anti-Inflammatory Agents/
19 exp Glucocorticoids/
20 18 or 19
21 12 and 20
22 (topical adj3 (steroid$ or corticosteroid$ or glucocorticoid$)).ti,ab.
23 exp Estrogens/
24 12 and 23
25 (oestrogen$ or estrogen$).ti,ab.
26 exp Enzymes/
27 12 and 26
28 enzym$.ti,ab.
29 exp Growth Substances/
30 12 and 29
31 growth factor$.ti,ab.
32 exp Collagen/
33 collagen$.ti,ab.
34 exp Silver/
35 exp Silver Sulfadiazine/
36 silver$.ti,ab. (14809)
37 cerium nitrate.ti,ab. (42)
38 exp Complementary Therapies/
39 exp Honey/
40 honey$.ti,ab.
41 exp Aloe/
42 aloe.ti,ab.
43 exp Ointments/
44 (ointment$ or lotion$ or cream$ or gel$ or solution$).ti,ab.
45 topical.ti,ab.
46 exp Bandages/
47 exp Alginates/
48 exp Hydrogel/
49 exp Skin, Artificial/
50 exp Hemostatics/
51 (dressing$ or pad or pads or gauze or tulle or film or bead or foam$ or non-adherent or non adherent or hydrocolloid$ or hydrofibre$ or hydrogel$ or alginate$ or plaster$ or compress or absorb$ or dextra$ or silicon$ or amnion$).ti,ab.
52 or/13-17,21-22,24-25,27-28,30-51
53 10 and 52

 

Appendix 3. Ovid EMBASE search strategy

1 exp Burns/
2 (burn or burns or burned or scald$).ti,ab.
3 thermal injur$.ti,ab.
4 1 or 2 or 3
5 exp Face/
6 exp Facial Injuries/
7 exp Ear/
8 (face or facial or nose$1 or mouth$1 or ear$1).ti,ab.
9 or/5-8
10 4 and 9
11 exp Anti-Bacterial Agents/
12 exp Administration, Topical/
13 11 and 12
14 (topical adj3 antibiotic$).ti,ab.
15 (topical adj3 antimicrobial$).ti,ab.
16 exp Anti-Infective Agents, Local/
17 (antiseptic$ or eusol or furagin or sodium hypochlorite or furaltadon).ti,ab.
18 exp Anti-Inflammatory Agents/
19 exp Glucocorticoids/
20 18 or 19
21 12 and 20
22 (topical adj3 (steroid$ or corticosteroid$ or glucocorticoid$)).ti,ab.
23 exp Estrogens/
24 12 and 23
25 (oestrogen$ or estrogen$).ti,ab.
26 exp Enzymes/
27 12 and 26
28 enzym$.ti,ab.
29 exp Growth Substances/
30 12 and 29
31 growth factor$.ti,ab.
32 exp Collagen/
33 collagen$.ti,ab.
34 exp Silver/
35 exp Silver Sulfadiazine/
36 silver$.ti,ab.
37 cerium nitrate.ti,ab.
38 exp Complementary Therapies/
39 exp Honey/
40 honey$.ti,ab.
41 exp Aloe/
42 aloe.ti,ab.
43 exp Ointments/
44 (ointment$ or lotion$ or cream$ or gel$ or solution$).ti,ab.
45 topical.ti,ab.
46 exp Bandages/
47 exp Alginates/
48 exp Hydrogel/
49 exp Skin, Artificial/
50 exp Hemostatics/
51 (dressing$ or pad or pads or gauze or tulle or film or bead or foam$ or non-adherent or non adherent or hydrocolloid$ or hydrofibre$ or hydrogel$ or alginate$ or plaster$ or compress or absorb$ or dextra$ or silicon$ or amnion$).ti,ab.
52 or/13-17,21-22,24-25,27-28,30-51
53 10 and 52

 

Appendix 4. EBSCO CINAHL search strategy

S48 S4 and S8 and S47
S47 S11 or S12 or S13 or S14 or S15 or S16 or S17 or S18 or S20 or S21 or S23 or S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33 or S34 or S35 or S36 or S37 or S38 or S39 or S40 or S41 or S42 or S43 or S44 or S45 or S46
S46 AB dressing* or pad or pads or gauze or tulle or film or bead or foam* or non-adherent or non adherent or hydrocolloid* or hydrofibre* or hydrogel* or alginate* or plaster* or compress or absorb* or dextra* or silicon* or amnion*
S45 TI dressing* or pad or pads or gauze or tulle or film or bead or foam* or non-adherent or non adherent or hydrocolloid* or hydrofibre* or hydrogel* or alginate* or plaster* or compress or absorb* or dextra* or silicon* or amnion*
S44 (MH "Skin, Artificial")
S43 (MH "Alginates")
S42 (MH "Bandages and Dressings+")
S41 TI topical or AB topical
S40 TI ( ointment* or lotion* or cream* or gel* or solution*) or AB ( ointment* or lotion* or cream* or gel* or solution*)
S39 (MH "Creams")
S38 (MH "Ointments")
S37 TI aloe or AB aloe
S36 (MH "Aloe")
S35 TI honey or AB honey
S34 (MH "Honey")
S33 TI cerium nitrate or AB cerium nitrate
S32 TI silver or AB silver
S31 (MH "Silver Sulfadiazine")
S30 (MH "Ionic Silver Dressings")
S29 (MH "Silver")
S28 TI collagen* or AB collagen*
S27 (MH "Collagen")
S26 TI growth factor* or AB growth factor*
S25 (MH "Growth Substances+")
S24 TI enzyme* or AB enzyme*
S23 S10 and S22
S22 (MH "Enzymes+")
S21 TI ( oestrogen* or estrogen* ) or AB ( oestrogen* or estrogen* )
S20 (S10 and S19)
S19 (MH "Estrogens+")
S18 TI ( topical N3 steroid* or topical N3 corticosteroid* or topical N3 glucocorticoid* ) or AB ( topical N3 steroid* or topical N3 corticosteroid* or topical N3 glucocorticoid* )
S17 (MH "Glucocorticoids, Topical+")
S16 (MH "Antiinflammatory Agents, Topical+")
S15 TI ( antiseptic* or eusol or furagin or sodium hypochlorite or furaltadon ) or AB ( antiseptic* or eusol or furagin or sodium hypochlorite or furaltadon )
S14 (MH "Antiinfective Agents, Local+")
S13 TI topical N3 antimicrobial* or AB topical N3 antimicrobial*
S12 TI topical N3 antibiotic* or AB topical N3 antibiotic*
S11 S9 and S10
S10 (MH "Administration, Topical+")
S9 (MH "Antibiotics+")
S8 S5 or S6 or S7
S7 TI ( face or facial ) or AB ( face or facial )
S6 (MH "Facial Injuries+")
S5 (MH "Face+")
S4 S1 or S2 or S3
S3 TI thermal* injur* or AB thermal* injur*
S2 TI ( burn or burns or burned or scald* ) or AB ( burn or burns or burned or scald* )
S1 (MH "Burns+")

 

Appendix 5. Assessing risk of bias

 

1.  Was the allocation sequence randomly generated?

 
Low risk of bias

The investigators describe a random component in the sequence generation process such as: referring to a random number table; using a computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots.

 
High risk of bias

The investigators describe a non-random component in the sequence generation process. Usually, the description would involve some systematic, non-random approach, for example: sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number.

 
Unclear

Insufficient information about the sequence generation process to permit judgement of low or high risk of bias.

 

2.  Was the treatment allocation adequately concealed?

 
Low risk of bias

Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web-based and pharmacy-controlled randomisation); sequentially-numbered drug containers of identical appearance; sequentially-numbered, opaque, sealed envelopes.

 
High risk of bias

Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

 
Unclear

Insufficient information to permit judgement of low or high risk of bias. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement, for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed.

 

3.  Blinding - was knowledge of the allocated interventions adequately prevented during the study?

 
Low risk of bias

Any one of the following.

  • No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding.
  • Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
  • Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non-blinding of others unlikely to introduce bias.

 
High risk of bias

Any one of the following.

  • No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding.
  • Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken.
  • Either participants or some key study personnel were not blinded, and the non-blinding of others likely to introduce bias.

 
Unclear

Any one of the following.

  • Insufficient information to permit judgement of low or high risk of bias.
  • The study did not address this outcome.

 

4. Were incomplete outcome data adequately addressed?

 
Low risk of bias

Any one of the following.

  • No missing outcome data.
  • Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias).
  • Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups.
  • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate.
  • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size.
  • Missing data have been imputed using appropriate methods.

 
High risk of bias

Any one of the following.

  • Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups.
  • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate.
  • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size.
  • ‘As-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation.
  • Potentially inappropriate application of simple imputation.

 
Unclear

Any one of the following.

  • Insufficient reporting of attrition/exclusions to permit judgement of low or high risk of bias (e.g. number randomised not stated, no reasons for missing data provided).
  • The study did not address this outcome.

 

5. Are reports of the study free of suggestion of selective outcome reporting?

 
Low risk of bias

Any of the following.

  • The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way.
  • The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon)

 
High risk of bias

Any one of the following.

  • Not all of the study’s pre-specified primary outcomes have been reported.
  • One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified.
  • One or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect).
  • One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis.
  • The study report fails to include results for a key outcome that would be expected to have been reported for such a study.

 
Unclear

Insufficient information to permit judgement of low or high risk of bias. It is likely that the majority of studies will fall into this category.

 

6. Other sources of potential bias

 
Low risk of bias

The study appears to be free of other sources of bias.

 
High risk of bias

There is at least one important risk of bias. For example, the study:

  • had a potential source of bias related to the specific study design used; or
  • has been claimed to have been fraudulent; or
  • had some other problem.

 
Unclear

There may be a risk of bias, but there is either:

  • insufficient information to assess whether an important risk of bias exists; or
  • insufficient rationale or evidence that an identified problem will introduce bias.

 

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

Cornelis J. Hoogewerf coordinated the review, extracted and interpreted data, checked the quality of data extraction, undertook quality assessment, performed and checked quality of statistical analysis, completed the first draft of the review, edited the review, made an intellectual contribution, approved final review prior to submission, and wrote to authors/experts/companies.
Magriet E. Van Baar conceived, designed and coordinated the review, checked quality of data extraction, undertook quality assessment, interpreted data, checked quality of statistical analysis, completed first draft of the review, edited the review, made an intellectual contribution,  approved final review prior to submission, advised, secured funding, performed previous work that was the foundation for the current review, and is guarantor for the review.
Jenda M. Hop extracted data, checked quality of data extraction, undertook quality assessment, interpreted data, completed first draft of the review, performed part of the writing or editing, made an intellectual contribution, approved final review prior to submission and advised on the review.
Irma MMH Oen conceived and designed the review, interpreted data, completed the first draft of the review, performed part of the writing or editing, made an intellectual contribution, approved final review prior to submission, advised on the review and performed previous work that was the foundation of the current review.
Ester Middelkoop conceived and designed the review, interpreted data, completed first draft of the review, edited the review, made an intellectual contribution, approved final review prior to submission, advised on the review, secured funding and performed previous work that was the foundation of the current review.
Marianne K. Nieuwenhuis conceived and designed the review, interpreted data, checked quality of statistical analysis, completed first draft, performed part of the writing or editing, made an intellectual contribution, approved final review prior to submission, advised, and performed previous work that was the foundation of the review.

 

Contributions of editorial base:

Nicky Cullum: edited the protocol; advised on methodology, interpretation and protocol content, approved the final protocol and review prior to submission.
Sally Bell-Syer: coordinated the editorial process, advised on methodology, interpretation and content, edited the protocol and review.
Ruth Foxlee: designed the search strategy, ran the searches and edited the search methods section.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

Magriet van Baar, Irma Oen, Esther Middelkoop and Marianne Nieuwenhuis were involved in a trial (Oen 2012) which has been added to the Characteristics of studies awaiting classification and may be eligible for inclusion in future updates of this review.
No other conflicts of interest are declared.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

Internal sources

  • The Association of Dutch Burn Centres, Netherlands.

 

External sources

  • NIHR/Department of Health (England), (Cochrane Wounds Group), UK.

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

There are four significant differences between protocol and review. Firstly, two authors were added to the review (CH and JH). Secondly, the electronic search strategy was revised. We expanded the search string and added an extra database (i.e. Ovid MEDLINE - In-Process). Another database changed platform from Ovid CINAHL to EBSCO CINAHL. Thirdly, we changed one question on our data extraction sheet. The question concerning sponsorship was changed from, "Was the trial sponsored by a manufacturer who potentially had an interest in the results?" to, "Was the trial guarded from sponsoring by a manufacturer who potentially had an interest in the results?". In the former question, an affirmative answer (yes) would have a negative meaning (sponsorship). This flaw was detected in a pilot study performed by two review authors (CH and JH), and the question was changed in the latter in order to give an affirmative answer a positive meaning (guarded from sponsorship). Finally, we could not perform all analyses described in the protocol. It was not possible to analyse time to wound healing as survival outcome due to insufficient data. Furthermore, none of the studies assessed the same outcome with the same definition (e.g. 90% or 95% re-epithelialisation for complete wound healing), so no standardised mean differences were used. For the same reason, no meta-analyses or associated analyses were performed.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. References to ongoing studies
  21. Additional references
Ang 2000 {published data only (unpublished sought but not used)}
  • Ang ES, Lee ST, Gan CS, See P, Chan YH, Ng LH, et al. The role of alternative therapy in the management of partial thickness burns of the face - experience with the use of moist exposed burn ointment (MEBO) compared with silver sulphadiazine. Annals of the Academy of Medicine 2000;29(1):7-10.
Demling 1999 {published data only (unpublished sought but not used)}
  • Demling RH, DeSanti L. Management of partial thickness facial burns (comparison of topical antibiotics and bio-engineered skin substitutes). Burns 1999;25(3):256-61.
Demling 2002 {published data only (unpublished sought but not used)}
  • Demling RH, DeSanti L. Closure of partial-thickness facial burns with a bioactive skin substitute in the major burn population decreases the cost of care and improve outcome. Ostomy/Wound Management 2002;48(8):52.
  • Demling RH, DeSanti L. Closure of partial-thickness facial burns with a bioactive skin substitute in the major burn population decreases the cost of care and improves outcome. Wounds: A Compendium of Clinical Research and Practice 2002;14(6):230-4.
Desai 1991 {published data only (unpublished sought but not used)}
  • Desai MH, Rutan RL, Heggers JP, Alvarado MI, McElroy K, Herndon DN. The role of gentamicin iontophoresis in the treatment of burned ears. Journal of Burn Care and Rehabilitation 1991;12(6):521-4.
Horch 2005 {published data only (unpublished sought but not used)}
  • Horch RE, Jeschke MG, Spilker G, Herndon DN, Kopp J. Treatment of second degree facial burns with allografts - preliminary results. Burns 2005;31(5):597-602. [DOI: 10.1016/j.burns.2005.01.011]

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. References to ongoing studies
  21. Additional references
Ang 2001 {published data only}
  • Ang E S-W, Lee S-T, Gan CS-G, See PG-J, Chan Y-H, Ng L-H, et al. Evaluating the role of alternative therapy in burn wound management: randomized trial comparing moist exposed burn ointment with conventional methods in the management of patients with second-degree burns. Medscape/General Medicine 2001;3(12):3-18.
Branski 2008 {published and unpublished data}
  • Branski LK, Herndon DN, Celis MM, Norbury WB, Masters OE, Jeschke MG. Amnion in the treatment of pediatric partial-thickness facial burns. Burns 2008;34(3):393-9. [DOI: 10.1016/j.burns.2007.06.007]
  • Branski LK, Herndon DN, Norbury WB, Celis M, Masters OE, Jeschke MG. Amnion in the treatment of pediatric facial partial-thickness burns... American Burn Association 39th annual meeting, March 20-23, 2007, Manchester Grand Hyatt, San Diego, California. Journal of Burn Care and Research 2007;28(2):S106.
Covey 1987 {published data only}
  • Covey MH, Prestigiacomo MJ, Engrav LH. Management of face burns. Topics in Acute Care and Trauma Rehabilitation 1987;1(4):40-9.
Hartmann 2007 {published data only}
  • Hartmann B, Ekkernkamp A, Johnen C, Gerlach JC, Belfekroun C, Küntscher MV. Sprayed cultured epithelial autografts for deep dermal burns of the face and neck. Annals of Plastic Surgery 2007;58(1):70-3. [DOI: 10.1097/01.sap.0000250647.39784.bb]
Lansdown 2004 {published data only}
  • Lansdown ABG, Williams A. How safe is silver in wound care?. Journal of Wound Care 2004;13(4):131-6.
Li 2005 {published data only}
  • Li H-M, Liang Z-Q, Meng C-Y. Comparison of repaired effect of recombinant human epidermal growth factor for the facial burn wounds of degree II. Chinese Journal of Clinical Rehabilitation 2005;9(34):110-1.
Liang 2007 {published data only}
  • Liang ZQ, Li HM, Meng CY. Repair of second degree facial burns in children using recombinant human epidermal growth factor. Journal of Clinical Rehabilitative Tissue Engineering Research 2007;11(10):1974-5.
Papp 1990 {published data only}
  • Papp T, Ménesi L, Szalai I. Experiences in the Ebrimycin® gel treatment of burns. Therapia Hungarica (English edition) 1990;38(3):125-8.
Rege 1999 {published data only}
  • Rege NN, Dahanukar SA, Ginde VK, Thatte UM, Bapat RD. Safety and efficacy of Azadirachta indica in patients with second degree burns. The Indian Practitioner 1999;52(4):240-8.

References to studies awaiting assessment

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. References to ongoing studies
  21. Additional references
Hindy 2009 {published data only}
  • Hindy A. Comparitive study between sodium carboxymethyl-cellulose silver, moist exposed burn ointment, and saline-soaked dressing for treatment of facial burns. Annals of Burns and Fire Disasters 2009;22(3):131-7.
Jiaao 2011 {published data only}
  • Jiaao Y, Kai S, Hua JZ, Chun ZJ, Hai NZ, Jing LH, et al. Treatment of deep second-degree facial burns in pediatric population with recombinant human GM-CSF hydrogel. Wound Repair and Regeneration 2011;19(2):A29.
Mabrouk 2012 {published data only}
  • Mabrouk A, Boughdadi NS, Helal HA, Zaki BM, Maher A. Moist occlusive dressing (Aquacel Ag) versus moist open dressing (MEBO) in the management of partial-thickness facial burns: a comparative study in Ain Shams University. Burns 2012;38(3):396-403.
Oen 2012 {published data only}
  • Oen IM, van Baar ME, Middelkoop E, Nieuwenhuis MK, and Facial Burns Group. Effectiveness of cerium nitrate-silver sulfadiazine in the treatment of facial burns: a multicenter, randomized, controlled trial. Plastic and Reconstructive Surgery 2012; Vol. 130, issue 2:274e-83e.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. References to ongoing studies
  21. Additional references
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