Early excision and grafting for burns

Notes

Editorial note

This protocol will not be progressed to review stage.

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the effects of early excision and grafting on scar quality in people with burns of all depths.

Background

Burn injuries are an important health problem. Worldwide it is estimated that each year over 300,000 people die from fire‐related burn injuries and millions more suffer from burn‐related disabilities and disfigurement (World Health Organization 2008). In the United States of America (USA), annually 40,000 people are admitted for burns, including more than 25,000 admissions to hospitals with specialised burn centres (American Burn Association 2007). In the United Kingdom, approximately 13,000 people per year are admitted to hospital for treatment of burns (Hettiaratchy 2004a). In the Netherlands, this number is about 1800 patients per year (Ormel 2010), including 550 to 600 patients in one of the three Dutch burn centres.

Major improvements in burn care in the twentieth century mean that mortality rates from burn injuries have substantially decreased. This has resulted in a shift in attention from mortality towards morbidity, for example, the functional outcome after a burn injury (Van Baar 2006). It is generally understood that superficial burns heal well with few or no functional or aesthetic problems. However, the best treatment for deep partial or full‐thickness burns remains controversial. In the United States, there seems to be consensus on early excision and grafting (Herndon 2007), while in Europe, usually, a more conservative approach is applied. In conservative treatment, surgery is postponed until clinical assessment indicates that surgery is inevitable. Eventually both United States and Europe excise and graft deep partial‐thickness burns, but optimal timing of this intervention is unclear. Timing is important because early excision could reduce length of hospital stay but increases the risk of overzealous excision, while delayed excision reduces the risk of overzealous excision but increases the risk of wound infection and length of hospital stay. Overzealous excision could also increase risk of scarring. Scars usually appear when wound healing takes more than two weeks or after surgical treatment. Therefore, it might be beneficial to postpone surgery until it becomes evident a wound will not heal within two weeks.

Description of the condition

A burn injury of the skin occurs when some or all the different layers of the skin are destroyed by physical energy such as hot liquid, flame, contact burns or ultraviolet/infrared radiation, radioactivity, electricity or chemicals (World Health Organization 2011). In addition to the localisation of a burn and associated injuries, severity of burn wounds is characterised by size and depth. The size of a burn is assessed by the Total Body Surface Area percentage (TBSA%), which is the percentage of the skin surface area burned; the depth of a burn is determined by which layers of the skin are 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 by depth 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 due to the migration of epithelial cells to the surface, with very little or no scarring. 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 layers of the skin and may involve structures underneath, such as muscle and bone, leaving little chance of healing from the epithelial elements in the bottom of the wound. In case of a very small burn, healing might occur by contraction and epithelial cell growth from the wound edges (Herndon 2007). Full‐thickness burns will always result in scarring and often result in hypertrophic scarring.

Burn wound surfaces are sterile immediately following thermal injury, but they are rapidly colonised by a variety of micro‐organisms (Erol 2004; Wysocki 2002). Those micro‐organisms not only originate from the patient’s own skin, respiratory and gastro‐intestinal flora, but also from contact with contaminated external environmental surfaces, 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 2003a; 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 that area. The most common burn wound pathogens are S. aureus and P. aeruginosa (Nagoba 2010). 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).

In addition to local responses, severe burn injuries can also induce systemic responses. The release of inflammatory mediators at the site of injury has a systemic effect once a burn reaches 30% of the total body surface area (Hettiaratchy 2004b). These systemic reactions, besides generating excessive oedema in burns, can further compromise wound healing. 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.

Hypertrophic scarring occurs if the balance between collagen synthesis and breakdown is disrupted (Herndon 2007). The post‐burn hypertrophic scar might present itself as a pink to red, slightly thickened or as a red to purple inelastic mass of skin tissue. Functional impairment can occur, especially if a hypertrophic scar crosses a joint or surrounds openings like eyes. For instance, a contracture of the elbow may result in a limited range of motion and even cause restrictions in daily life activities. Another example are eyes that may not close due to the inelasticity and contraction of the hypertrophic skin. Furthermore, scars can result in discomfort because of itching and sometimes cause neuropathic pain after burn injury (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 if 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 involved with 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 early excision and grafting for burns. In this section we will elaborate on the different surgical interventions and grafting techniques used in burns as well as issues of timing.

The surgical interventions used in burns can roughly be divided in escharotomy and surgical debridement. Firstly, escharotomy is a surgical procedure used to treat full‐thickness, circumferential burns (Orgill 2009b). In those burns, the combination of a leathery‐like, inelastic burned skin and the swelling of underlying tissue can obstruct circulation and cause cell death in healthy body parts due to ischaemia (e.g. a circumferential full‐thickness burn around the forearm can cause necrosis of the hand with even amputation as a result). In order to prevent cell death and amputation, incisions (escharotomies) are made through the eschar until blood flow to the body part at risk is restored (Herndon 2007). Furthermore, escharotomies to the chest are used to restore respiration and are indicated when burned skin prevents expansion of the chest necessary for respiration (Orgill 2009b). Secondly, surgical debridement is the excision with removal of all non‐vital tissue of the burn wound and can be divided in two main approaches, namely: fascial and tangential excision (Klein 2005). Fascial excision, or avulsion, is only practised in full‐thickness burns and consists of tearing away the burned skin and underlying subcutaneous tissue. This technique will cause body deformities but reduces blood loss compared to tangential excision. Tangential excision is the most commonly used technique in burn surgery and often combined with grafting. With this technique all non‐viable tissue is removed layer by layer, preserving as much viable tissue as possible (Herndon 2007). Nowadays, this procedure can be even more precise with the development of hydro surgery which is especially used in critical functional and aesthetic areas (Klein 2005).

Grafting is the transplantation of skin onto an excised burn wound in order to provide temporary or permanent wound closure. The timing of grafting can be immediate (i.e. in the same procedure as the initial excision) or delayed (i.e. in a subsequent procedure) and the skin transplant can originate from the same individual (autologous), another individual of the same species (homologous) or from a different species (heterologous). There are two different kind of grafts, namely: full‐thickness graft and Split Skin Graft (SSG). A full‐thickness graft consists of the epidermis and all of the dermis, and is more used in reconstructive surgery than primary surgery. A SSG consists of the epidermis and some of the dermis, and is often used in primary surgery. A SSG can be applied as a meshed, unmeshed (Papini 2004) or Meek‐Wall graft. An untreated SSG is unmeshed, but when little incisions are made in the SSG, it can be expanded up to six times its original size and is called a meshed graft (Orgill 2009a). Another technique to increase the surface of a graft even more is the Meek‐Wall technique. With this technique the SSG is divided into little squares, or skin islands, and transplanted on an excised burn wound.

Timing of excision can be divided into early and delayed or late excision, but definitions of these concepts are under debate. Choi 2008 states that "all excision procedures done before the natural separation of the eschar are considered an early excision, and all done afterward are considered delayed excision", while Kirn 1998 defined early excision as operative excision within seven days post‐burn. Herndon 2007 advocates early excision and grafting in major burns without explicitly defining 'early', and in the review by Ong 2006 'early' ranges from < 24 hours to < 144 hours post‐burn. In conclusion, there is no consensus on a cut‐off point between early and delayed excision.

How the intervention might work

Early excision and immediate or delayed grafting for burns provides an early wound closure or coverage which might have beneficial effects on infection, survival and scarring. In particular, a reduced infection rate seems evident because early wound closure limits the time a wound is exposed to possible invading pathogens colonising the wound. Colonised burn wounds have been associated with delayed wound healing, increased need for surgical interventions and prolonged length of stay at burn centres (Vermeulen 2007). The effects on survival might be a result of early excision of eschar. Removal of eschar is thought to decrease the release of inflammatory mediators which could cause systemic effects (Barret 2003b; Hettiaratchy 2004b). Systemic effects, like systemic inflammatory response syndrome (SIRS), sepsis and multi‐organ failure, compromise wound healing and can cause death. Effects of early excision and grafting on scarring could be beneficial or harmful, depending on the depth of the burn wound. In full‐thickness and deep partial‐thickness burns there will be scarring regardless of intervention, but early excision and grafting provides early wound closure and could reduce the severity of scarring (Cubison 2006). Superficial partial‐thickness burns, on the other hand, could heal without scarring when conservative treatment is applied, while surgical treatment will always leave scars. Often the depth of a burn is not either superficial partial‐thickness or deep partial‐thickness but a mix of those depths. In these cases, early excision and grafting could be overzealously executed and cause scarring in areas that would have been able to reepithelialise without surgical intervention. Conservative treatment could give the superficial partial‐thickness areas time to reepithelialise with little or no scarring, but postponing excision of the deep partial‐thickness areas too long will cause more extensive scars (Cubison 2006).

Why it is important to do this review

Surgical procedures are an important intervention in burns, but there is no consensus on the best timing of surgical intervention. One review states that "early excision of burns reduces mortality in patients without inhalational injury, increases blood transfusion requirements and reduces the length of hospital stay in patients" (Ong 2006), but this review is non‐systematic and not up‐to‐date. Several systematic reviews have been published in the field of wound care, but most of them focus on wound dressings (Wasiak 2008) and other topical treatments (Storm‐Versloot 2010; Vermeulen 2007) instead of surgical procedures. Despite these reviews, 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, concerning the treatment of burns and scalds in primary care (New Zealand Guidelines Group 2007). Systematic reviews are necessary to increase the body of underlying evidence for these guidelines. In conclusion, published reviews do not address the effectiveness of early excision and grafting in burns.

We have provided a glossary of some of the terms used in this protocol in Appendix 1.

Objectives

To assess the effects of early excision and grafting on scar quality in people with burns of all depths.

Methods

Criteria for considering studies for this review

Types of studies

We will consider all randomised controlled trials (RCTs), both published and unpublished, evaluating the effects of early excision and grafting in people with burns. We will only consider quasi‐randomised controlled trials in the absence of RCTs.

Types of participants

We will consider studies including people of any age with burns of any degree in any care setting. Any type of burn injury will be eligible (flame, scald, chemical etc).

Types of interventions

We will consider studies for inclusion if early excision and grafting is applied and compared with any comparator intervention. Whilst there is no clear consensus on the definition of 'early' we have defined early excision as excision within 144 hours post‐burn (within a week post‐burn)(Ong 2006). We will consider any kind of graft. Comparator interventions can include any other intervention (e.g. different excision technique or grafts, ointments), no intervention or a placebo intervention on condition that timing of excision is different compared to the intervention. The timing or type of grafting will not form part of the selection process.

Types of outcome measures

Study outcome will not form part of the selection process.

Primary outcomes

Three outcome measures are considered primary outcomes. These primary outcomes consist of one positive and two negative outcomes. The positive primary outcome is the following:

• scar quality: observed and self reported (any definition of scar quality is accepted).

The negative primary outcomes are the following:

• wound infection (any definition);

• mortality.

Secondary outcomes

Eight outcome measures are considered secondary outcomes. These outcomes are the following:

• proportion of burns requiring reconstructive surgery;

• pain;

• time to complete wound healing;

• length of hospital stay;

• adverse effects;

• patient satisfaction;

• quality of life;

• costs of treatment.

Search methods for identification of studies

Electronic searches

We will search the following electronic databases:

• Cochrane Wounds Group Specialised Register (most recent);

• the Cochrane Central Register of Controlled Trials (CENTRAL) ‐ The Cochrane Library (latest issue);

• Ovid MEDLINE ‐1950 to date;

• Ovid MEDLINE ‐ In‐process & Other Non‐Indexed Citations (most recent);

• Ovid EMBASE ‐ 1980 to date;

• EBSCO CINAHL ‐ 1982 to date.

We will combine the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE; sensitivity‐ and precision‐maximising version (2008 revision); Ovid format. This filter is published in the Cochrane Handbook for Systematic Reviews of Interventions ('Cochrane Handbook') (Lefebvre 2011). We will combine the EMBASE and CINAHL searches with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2010). We will not apply date or language restrictions.

We will use the following CENTRAL search strategy:

#1 MeSH descriptor Debridement explode all trees
#2 (surg* OR excis* OR tangenti* OR debrid* OR avul* OR fascial):ti,ab,kw
#3 (necrotomy OR escharotomy OR nettoyage OR hydrosurgery):ti,ab,kw
#4 (#1 OR #2 OR #3)
#5 MeSH descriptor Skin Transplantation explode all trees
#6 MeSH descriptor Transplantation, Autologous explode all trees
#7 MeSH descriptor Transplantation, Heterologous explode all trees
#8 MeSH descriptor Transplantation, Homologous explode all trees
#9 MeSH descriptor Transplantation, Heterotopic explode all trees
#10 (skin NEAR/5 (graft* or transplant*)):ti,ab,kw
#11(meek OR SSG OR FTG):ti,ab,kw
#12 ((mesh* OR unmesh* OR "full thickness" OR "split thickness" OR "full‐thickness" OR "split‐thickness" OR "split skin") NEAR/5 graft*):ti,ab,kw
#13 (autograft* OR homograft* OR allograft* OR xenograft*):ti,ab,kw
#14 (#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13)
#15 MeSH descriptor Burns explode all trees
#16 (burn OR burns OR burned OR scald*):ti,ab,kw
#17 (thermal NEXT injur*):ti,ab,kw
#18 (#15 OR #16 OR #17)
#19 (#4 AND #14 AND #18)

In addition we will search the International Clinical Trials Registry Platform Search Portal (http://apps.who.int/trialsearch/).

Searching other resources

We will check citation lists within all reports of included studies and major review articles in an effort to identify any additional relevant studies. Furthermore we will contact authors of included trials for information about any ongoing trial or unpublished study.

Data collection and analysis

Selection of studies

Two review authors (CH and JH) will independently assess the titles and abstracts of studies identified from the search in terms of their relevance and design. We will obtain full versions of articles if they match the inclusion criteria from this initial assessment. These review authors will also carry out the final selection of trials to be included. Another review author (MvB) will evaluate any discrepancies and will advise in case of disagreement. There will be no restrictions on the inclusion of reports based on language of publication or publication status.

Data extraction and management

Two review authors, working independently, will extract and summarise details of trials using a data extraction sheet. They will extract data on the following items:

• characteristics of the trial: method of randomisation, setting, location of care, country, source of funding;

• participants baseline information: number, age, gender, types of burns, percentage total body surface area (TBSA) burned, burn depth, inhalation injury, concurrent illness;

• intervention: time elapsed before treatment, percentage TBSA grafted, types of excision, types of grafting, concurrent interventions;

• comparator intervention (see above);

• outcomes: types of outcomes measured, timing of outcomes;

• results.

We will resolve any discrepancies by discussion with a third review author (MvB). We will contact the trial authors to obtain missing information if data are missing from reports, or clarification is needed. We will include data from trials published in duplicate only once, but will maximally extract data.

Assessment of risk of bias in included studies

Two review authors (CH and JH) will make systematic and independent assessments of the risk of bias of each trial using the Cochrane 'Risk of bias' criteria (Higgins 2011a). The criteria are as follows:

• sequence generation;

• allocation concealment;

• blinding of participants and care providers;

• blinding of outcome assessors;

• incomplete outcome data: assessment 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 and trial sponsorship.

A detailed description of criteria for a judgement of 'low risk', 'high risk' or 'unclear risk' of bias is available (see Appendix 2). We will resolve any discrepancies by discussion with a third review author (MvB). We will present assessment of risk of bias using 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

We will perform data analysis according to the guidelines of the Cochrane Collaboration (Deeks 2011). One review author (CH) will enter quantitative data into RevMan, it will be checked by another review author (JH) and analysed using the Cochrane Collaboration's associated software (RevMan 2011). For each outcome, we will calculate summary estimates of treatment effect (with 95% confidence intervals (CI)) for every comparison. We will analyse time to wound healing as survival (time‐to‐event) outcomes, using an appropriate analytical method (i.e. hazard ratio, Cochrane Handbook 9.2.6 Deeks 2011). We will present dichotomous outcomes as risk ratios (RR) (see Cochrane Handbook 9.2.2, Deeks 2011) with 95% CI. When appropriate, we will present mean differences (MD) or standardised mean differences (SMD) for continuous outcomes. We will use SMD when studies assess the same outcome but measure it in a variety of ways.

Unit of analysis issues

We will address in our analysis the level at which randomisation occurred. In general, the unit of randomisation and measurement is likely to be the person. We will describe and address deviations in the analysis.

Dealing with missing data

In the case of missing data, we will contact the original trial investigators to request missing data whenever possible. If necessary, we will perform data imputation according to the principles from the Cochrane Handbook (Higgins 2011b). We will explicitly describe our assumptions in case of imputing missing data. In addition, we will perform sensitivity analyses to assess how sensitive results are to changes in the assumptions that are made. Also, we will address the potential impact of missing data on the findings of the review in the Discussion section.

Assessment of heterogeneity

We will explore both clinical and statistical heterogeneity. We will assess clinical heterogeneity using information on type of early excision, timing of early excision and body part burned. We will test statistical heterogeneity using the Chi² test and estimate the amount of heterogeneity using the I² statistic with 95% CI (Deeks 2011; Higgins 2003). The I² statisticexamines the percentage of total variation across studies due to heterogeneity rather than to chance.

Assessment of reporting biases

We will present the overall risk of bias in a 'Risk of bias' summary per primary or secondary outcome (Higgins 2011a). We will measure publication bias by the Begg funnel plot (Begg 1994) and the Egger test (Egger 1997). We will analyse study reports on reported biases, using the results of the 'Risk of bias' assessment for the selective reporting domain.

Data synthesis

We will perform a meta‐analysis for each primary outcome, if assessment of clinical and statistical heterogeneity indicates this would be appropriate (Higgins 2003), and we will calculate summary estimates of treatment effect for every comparison. We will focus on direct comparisons between surgical interventions. No totals will be calculated if trial heterogeneity is considerable (I² statistic greater than 75%). If pooling is appropriate (I² statistic less than 75%) we will use both a fixed‐effect and a random‐effects model. The fixed‐effect model ignores heterogeneity and gives an estimate of the intervention effect, assuming a single intervention effect. A random‐effects model incorporates heterogeneity amongst studies (Deeks 2011; Ioannidis 2007).

Subgroup analysis and investigation of heterogeneity

Where there are sufficient studies in the meta‐analysis (N > 10), we will investigate heterogeneity through subgroup and sensitivity analysis (Deeks 2011). We will conduct subgroup analysis for the following groups, where data permit:

• % TBSA burned (<20% TBSA versus 20% or more TBSA);

• age (<5 years versus 5 to 60 years versus 60 years and older);

• adequate concealment of allocation (low risk of bias versus unclear or high risk of bias).

Sensitivity analysis

Where there is a sufficient number of studies in the meta‐analyses, we will perform a sensitivity analysis showing how conclusions might be affected if only studies at low risk of bias are included in analyses. Studies will be judged to be at overall low risk of bias if they adequately generate the randomisation sequence and adequately conceal allocation.

What's new

Date	Event	Description
27 June 2022	Amended	Published note added to indicate that this protocol will not be progressed to review stage.

History

Protocol first published: Issue 3, 2012

Date	Event	Description
8 August 2008	Amended	Converted to new review format.

Appendices

Appendix 1. Glossary

Autologous graft: Skin transplant originates from same individual.
Avascular: Not associated with or supplied by blood vessels.
Avulsion: See fascial excision.
CI: Confidence interval.
Debridement: The removal of foreign material and dead or damaged tissue from a wound.
Deep partial‐thickness burn: A burn that involves the epidermis and most of the dermis with damage to deeper structures within the skin such as blood vessels, nerves and hair follicles.
Dermis: The deep inner layer of the skin, beneath the epidermis, containing connective tissue, blood vessels and fat.
Edema: Swelling. An abnormal accumulation of fluid beneath the skin, or in one or more of the cavities of the body.
Epidermis: The outer layer of the skin, made up of flattened, dead, epithelial cells.
Eschar: A scab or dry crust that results from trauma, such as a thermal or chemical burn, infection, or excoriating skin disease.
Escharotomy: A surgical incision into necrotic tissue resulting from a severe burn. The procedure is sometimes necessary to prevent oedema from generating sufficient interstitial pressure to impair capillary filling, causing eschemia.
Fascial excision: Surgical technique used to remove skin and underlying tissue by tearing away the damaged structures until the fascia is reached.
Full‐thickness burn: A burn that involves all layers of the skin and may involve structures underneath, such as muscle and bone.
Gastro‐intestinal flora: Micro‐organisms living in both stomach and intestine.
Heterogeneity: A state of having different characteristics and qualities.
Heterologous graft: Skin transplant originates from a different species.
Homogeneity: A state of having similar characteristics and qualities.
Homologous graft: Skin transplant originates from another individual of the same species.
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.
Necrosis: The pathological process occurring in cells that are dying from irreparable injuries. It is caused by the progressive, uncontrolled action of degradative enzymes, leading to mitochondrial swelling, nuclear flocculation and cell lysis. Distinguish it from apoptosis which is a normal, regulated cellular process.
Overzealous: Excessive.
RCT: Randomised controlled trial
Re‐epithelialisation: Healing by the growth of epithelium over a denuded surface.
RR: Risk ratios or relative risks.
Scald: Burn caused by a hot liquid or a hot, moist vapour.
SIRS: Systemic Inflammatory Response Syndrome.
SMD: Standardised mean difference.
SSG: Split Skin Graft
Superficial partial‐thickness burn: A burn that involves only the epidermal layer and the superficial part of the dermis.
Systemic response: Reaction related to the whole body rather than to a localised area or regional part of the body.
Tangential excision: Surgical technique used to remove non‐viable tissue layer by layer.
TBSA: Total Body Surface Area.

Appendix 2. Assessing risk of bias form

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

• had extreme baseline imbalance; 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

Cornelis Hoogewerf: developed and co‐ordinated the protocol; conceived the review question; designed the search strategy; advised on and completed the first draft of the protocol; made an intellectual contribution to the protocol; approved the final version of the protocol prior to submission and is guarantor of the work.
Jenda Hop: advised on and developed the protocol; completed and edited the first draft of the protocol; made an intellectual contribution to the protocol and approved the final version of the protocol prior to submission.
Marianne Nieuwenhuis: advised on and developed the protocol; completed and edited the first draft of the protocol; made an intellectual contribution to the protocol and approved the final version of the protocol prior to submission.
Esther Middelkoop: secured funding; advised on and developed the protocol; completed and edited the first draft of the protocol; made an intellectual contribution to the protocol and approved the final version of the protocol prior to submission.
Margriet van Baar: advised on and developed the protocol; conceived the review question; completed and edited the first draft of the protocol; made an intellectual contribution to the protocol and approved the final version of the protocol prior to submission

Contributions of editorial base:

Nicky Cullum: edited the protocol; advised on methodology, interpretation and protocol content. Approved the final protocol prior to submission.
Sally Bell‐Syer: coordinated the editorial process. Advised on methodology, interpretation and content. Edited and copy edited the protocol.
Ruth Foxlee: designed the search strategy and edited the search methods section.

Sources of support

Internal sources

• The Association of Dutch Burn Centres, Netherlands

External sources

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

Declarations of interest

No conflict of interest.

Edited (no change to conclusions)