Local warming therapy for treating chronic wounds

Abstract

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

To undertake a systematic review of all randomised controlled trials (RCTs) investigating the effects of LWT on chronic wounds (pressure ulcers, venous ulcers, arterial ulcers and diabetic foot ulcers).

Background

Description of the condition

A chronic wound is any interruption in the continuity of the body's surface that does not pass through an orderly and timely repair process. The most common types of chronic wounds include venous leg ulcers, arterial leg ulcers, diabetic foot ulcers and pressure ulcers (Doughty 2012; Gray 2001). Orderly healing follows a sequence of metabolic activity, namely: inflammation; collagen and fibroblast deposition (scar tissue formation); angiogenesis (new blood vessel formation); wound contraction and scar remodeling. The timeliness of healing is subjective, but refers to healing within a timeframe that could reasonably be expected with conventional treatment (Jull 2013). Chronic wounds are more commonly encountered in the elderly and those with multiple health problems (Dealey 2012; Lauterbach 2010).

Wound types

Pressure ulcers

Pressure ulcers, also known as bedsores or pressure sores, are regions of localised damage to the skin sometimes involving deeper tissue layers such as muscle, tendon and bone (Reddy 2008; Whitney 2006; Zhang 2013). They are caused by unrelieved pressure, or pressure in combination with shear, usually over bony prominences (sacrum (tailbone), back, buttocks, heels, back of the head and elbows) (Torpy 2003; Zeller 2006). Pressure ulcer prevalence and incidence figures differ according to the method used to collect data and the classification used. A review of the international literature suggested that prevalence in the UK ranged from 4.4% in community settings to 37% in a palliative care setting (Kaltenthaler 2001). The UK incidence of pressure ulcers ranged from 2.2 per 100 new admissions per year in a hospital setting to 66% over 18 months for hospitalised older patients with hip fractures (Kaltenthaler 2001). In the USA and Canada prevalence ranged from 4.7% for hospitalised patients to 33% for community‐based spinal cord injured patients (Kaltenthaler 2001). The USA/Canada incidence rates ranged from 0% for community settings over a six‐month period to 65.6% over five years for patients with spinal injuries (Kaltenthaler 2001).Pressure ulcers are generally categorised according to grades numbered from one to four, according to the European Pressure Ulcer Advisory Panel and National Pressure Ulcer Advisory Panel (EPUAP/NPUAP 2009) (see Appendix 1).

Venous leg ulcers

Venous leg ulcers (also known as stasis ulcers, varicose ulcers, or ulcus cruris) are thought to occur as a result of improper functioning of venous valves. Venous leg valves consist of two flaps that converge in order to keep the blood moving in one direction i.e. towards the heart. Damage to valves results in venous reflux (venous insufficiency) causing high venous pressure. It is reported that the prevalence of venous leg ulcers ranges between 1.5 and 3 per 1000 population, and 1% to 2% of people will suffer from a venous ulcer at least once in their life (Amsler 2009; Kranke 2004). It has been estimated that Western healthcare systems spend around 1% to 2% of their budget on treatment, need for intensive nursing, and in some cases social care, for people with venous ulcers (Gallenkemper 2008; Gloviczki 2009; Purwins 2010; Ragnarson 2005). In the United States, treatment cost for venous ulcers in more than six million patients is approaching USD 2.5 billion (GBP 1.6 billion; EUR 1.8 billion), and two million work days are lost annually because of venous ulcer disease (van Gent 2010).

Arterial leg ulcers

Arterial ulcers, also referred to as ischaemic ulcers, result from an inadequate arterial blood supply. The wounds are typically very painful, especially at night. The ulcers are characterised by well‐defined, even wound margins that give the wound a 'punched‐out' look. Risk factors for the development of arterial ulcers include age, smoking, peripheral vascular disease (commonly referred to as peripheral arterial disease or peripheral arterial occlusive disease), diabetes mellitus, hypertension, dyslipidaemia (abnormal amount of lipids (e.g. cholesterol or fat, or both) in the blood), family history, obesity, and a sedentary lifestyle (Hess 2010). Noninvasive diagnostic options for arterial assessment include manual palpation of pulses, ankle brachial pressure index (ABPI; the ratio of the blood pressure in the lower legs to the blood pressure in the arms), and Doppler examination (mechanical evaluation of the arterial blood flow in the body) (Holloway 1996; Perceau 2012).

Several measures are used to help distinguish between venous and arterial ulcers. Venous ulcers usually occur between the knee and the ankle, and arterial ulcers usually occur below the ankle. However, 'mixed aetiology' (mixed cause) ulceration (where the ulcer has both a venous and arterial component) can occur above the ankle. Arterial ulcers are more painful than venous ulcers when lying down. Venous leg ulcers are frequently described as 'throbbing', 'burning' and 'itchy', while arterial ulcer pain tends to be described as 'sharp' and 'hurting' (Closs 2008). An ABPI between 0.5 and 0.8 suggests that ulcers may be caused by a mixture of venous and arterial disease. An ABPI value of less than 0.5 indicates arterial ulcers, while an ABPI greater than 0.8 is considered to indicate that ulcers are venous in aetiology (Vowden 2001).

Diabetic foot ulcers

Diabetic foot ulcers are a major health risk for people with diabetes mellitus, and can result in limb loss and mortality. Since 1996 the number of people diagnosed with diabetes has increased from 1.4 million to 2.9 million in the UK (Diabetes UK 2012). By 2025 it is estimated that five million people will have diabetes (Diabetes UK 2012).Global projections suggest that the worldwide prevalence of diabetes is expected to rise to 4.4% by 2030, meaning that approximately 366 million people will be affected (Wild 2004). About 25% of diabetic patients are at risk of developing a foot ulcer (Palestro 2009), and 7% of them might be at risk of amputation in the next 10 years (Margolis 2005). The Wagner wound classification system is well established and widely used for grading diabetic foot ulcers (Wagner 1981). However, newer grading systems, such as the University of Texas Wound Classification System (Oyibo 2001), PEDIS system (Perfusion, Extent/size, Depth/tissue loss, Infection and Sensation) (Schaper 2004), and SINBAD system (Site, Ischemia, Neuropathy, Bacterial infection, And Depth score) are also deployed (Ince 2008).

Description of the intervention

Local warming therapy (LWT) has been used for treatment of chronic wounds for about 1260 years in China according to the China Association of Traditional Chinese Medicine (CATCM 2009), and for about 30 years in the USA (Rabkin 1987). Different types of LWT are available for wound management. These include non‐contact wound warming units, wound dressings with a removable heating element and moxibustion.

Non‐contact wound warming units are designed to apply radiant heat to a wound. The objective is to raise the wound temperature in order to increase blood flow and transport of oxygen to the local area. However, practitioners need to be very careful to control the level of heat so that the patient's skin is not burned (Rabkin 1987).

Certain technological advances have resulted in a specifically designed wound dressing with a removable heating element capable of delivering radiant heat emitted at 38°C to affect local wound warming. Under this circumstance, both the temperature and heating episode can be controlled by the heating element (Robinson 1998).

Moxibustion is a traditional Chinese therapeutic method that uses the heat generated by burning moxa sticks (usually made from herbal preparations containing Artemisia vulgaris (mugwort)) near an acupoint (location on the body used in acupuncture and other traditional Chinese therapies) to cause warming (Cardini 1998; Ewies 2002; WHO 2007). It has been used throughout Asia for thousands of years; in fact, the actual Chinese character for acupuncture, when translated literally, means 'acupuncture‐moxibustion'. The purpose of moxibustion, as with most forms of traditional Chinese medicine, is to strengthen the blood, stimulate the flow of 'qi' (the natural energy, or life force, that is believed to be part of every living thing in traditional Chinese medicine (Deng 2003)), and maintain general health. In addition, it is typically a cheap therapy that can be self‐administered at home (Cardini 1998).

Chronic wound care has made great progress in the last few decades, which will help patients achieve good outcomes. Standard wound care can promote speedier wound healing, help lower morbidity, and improve quality of life (Patricia 2012), so it is often used as comparator in clinical studies (Suissa 2011). The components of standard wound care should include (WHS 2007):

• application of dressings to maintain a moist wound environment;

• debridement of necrotic tissue, if present;

• cleansing of the wound initially, and at each dressing change, using a neutral, nonirritating and nontoxic solution;

• evaluation of, and provision for, adequate nutritional status; and

• documentation of evaluation, care, and wound measurements by a licensed medical professional.

How the intervention might work

Chronic wounds are often hypoxic (i.e. have inadequate oxygen supply) (Hopf 2000). The usual surface temperature of ulcers is about 33°C (Hellgren 1977); this temperature limits the movement and growth of tissue (Jensen 1981; Yang 1995). Increasing the temperature of chronic wounds to 38°C may help to induce healing by increasing blood flow, and improving the availability of oxygen (Ikeda 1998; Rabkin 1987). LWT may also decrease incidence of wound infection (Melling 2001), and may eradicate established methicillin‐resistant Staphylococcus aureus (MRSA) infection in pressure sores (Ellis 2003).

Why it is important to do this review

Although the application of warmth to wounds is a commonly‐used ancient practice, there is uncertainty about its effects (Jun 2010). The evidence for the use of LWT for chronic wounds has not previously been summarised.

Objectives

To undertake a systematic review of all randomised controlled trials (RCTs) investigating the effects of LWT on chronic wounds (pressure ulcers, venous ulcers, arterial ulcers and diabetic foot ulcers).

Methods

Criteria for considering studies for this review

Types of studies

RCTs published or unpublished, in any language, will be included.

Types of participants

We will include trials recruiting people with chronic wound/s (pressure ulcers, venous leg ulcers, arterial ulcers and diabetic foot ulcers). As the method of diagnosis of different types of chronic wounds may vary, we will accept definitions as used in the RCTs.

Types of interventions

Trials comparing the effects of LWT (via moxibustion, radiant heat dressing, and other local warming interventions) with standard wound care or other wound‐healing interventions will be included. Trials that compare different types of LWT will also be considered for inclusion.

Types of outcome measures

Primary outcomes

The following primary outcomes will be measured:

• time to healing assessed using appropriate survival analysis (i.e. based on censored data);

• proportion of people with diabetic foot ulcers undergoing amputation of the lower limb at any level, including single toes;

• proportion of wounds with complete healing.

Secondary outcomes

The following secondary outcomes will be measured:

• change in wound size, with change expressed as absolute change (e.g. surface area change in cm² since baseline) or relative change (e.g. percentage change in area relative to baseline);

• healing rate per day, week or other unit of time;

• quality of life measured by a validated scale, either generic (such as EQ‐5D, SF‐36, SF‐12 or SF‐6) or disease‐specific;

• treatment costs (as reported by the trial author);

• recurrence rate (as reported by the trial author);

• pain from wound (measured using survey/questionnaire/data capture process or visual analogue scale);

• adverse events (for example, infection).

RCTs that evaluate any of these outcomes will be included, irrespective of the scale(s) used for assessment. If possible, outcomes will be evaluated at one week, one month, and up to three months after treatment has finished.

Search methods for identification of studies

Details of the search strategy for this review are available as follows:

Electronic searches

We will search the following electronic databases for RCTs that evaluate the use of LWT for chronic wounds:

• The Cochrane Wounds Group Specialised Register;

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

• Ovid MEDLINE (1946 to present);

• Ovid EMBASE (1974 to present);

• EBSCO CINAHL (1982 to present);

• Chinese Biomedical Literature Database (1980 to present) (Chinese Database);

• China National Knowledge Infrastructure (1980 to present) (Chinese Database);

• VIP Information (1980 to present) (Chinese Database); and

• Wanfang Data (1980 to present) (Chinese Database).

The following provisional search strategy will be used in the Cochrane Central Register of Controlled Trials (CENTRAL):

#1 MeSH descriptor: [Chronic Disease] explode all trees #2 MeSH descriptor: [Wound Healing] explode all trees #3 #1 and #2 #4 MeSH descriptor: [Skin Ulcer] explode all trees #5 MeSH descriptor: [Diabetic Foot] explode all trees #6 ((skin next ulcer*) or (foot next ulcer*) or (diabetic next foot) or (leg next ulcer*) or (varicose next ulcer*) or (venous next ulcer*) or (stasis next ulcer*) or (arterial next ulcer*) or "ulcus cruris" or "ulcer cruris"):ti,ab,kw #7 ((ischaemic or ischemic) next (wound* or ulcer*)):ti,ab,kw #8 (bedsore) or (bed‐sore) or (bed next sore*) or (pressure next sore*) or (pressure next ulcer*) or (decubitus next ulcer*):ti,ab,kw #9 (chronic next wound*):ti,ab,kw #10 (chronic next ulcer*):ti,ab,kw #11 {or #3‐#10} #12 ((local or topical) near/3 warming):ti,ab,kw #13 (radiant next heat*) or (heat next dressing*):ti,ab,kw #14 (wound next warm*):ti,ab,kw #15 MeSH descriptor: [Moxibustion] explode all trees #16 (moxibustion or moxa):ti,ab,kw #17 {or #12‐#16} #18 #11 and #17

We will adapt this strategy to search Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL. We will combine the Ovid MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity‐ and precision‐maximising version (2008 revision) (Lefebvre 2011). We will combine the EMBASE search with the Ovid EMBASE filter developed by the UK Cochrane Centre (Lefebvre 2011). We will combine the CINAHL searches with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2011). We will not restrict studies with respect to language, date of publication or study setting.

We will search the following clinical trials registries:

• ClinicalTrials.gov (http://www.clinicaltrials.gov/)

• WHO International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/Default.aspx)

• EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/)

Searching other resources

We will search for grey literature/unpublished work by accessing Sciencepaper online (an open‐access website in China http://www.paper.edu.cn/en). This source indexes material that may be unavailable from other electronic databases. Relevant manufactures of local warming devices will be contacted to request details about any further studies. For example, we will contact Beijing Muyuan Jiaxing Technology Development Limited Company, the manufacturers of moxibustion sticks and devices, for information about unpublished or ongoing trials.

Data collection and analysis

Selection of studies

Two review authors (JHY and QHZ) will independently screen the title and abstract of each potentially relevant study identified from the electronic searches. We will use pre‐determined eligibility criteria to identify the potentially relevant trials for which full reports should be retrieved. Disagreements among authors will be resolved by discussion with a third review author (ZRS) when necessary. This process of screening will be repeated for the full texts retrieved which will result in a decision on studies eligible for inclusion in the review.

Data extraction and management

Independently, two review authors (QHZ and ZRS) will extract data using a data extraction sheet.

We will extract the following data:

• authors;

• year of publication;

• country of origin;

• trial setting;

• type of wound;

• inclusion criteria for participants;

• baseline characteristics of participants;

• number of participants randomised to each trial arm;

• details of the intervention (treatment and comparator);

• setting of treatment;

• duration of treatment;

• duration of follow‐up;

• outcome data for primary and secondary outcomes;

• number of participants completing;

• number of withdrawals;

• reasons for participant withdrawal;

• statistical methods used in the analysis;

• adverse events.

Assessment of risk of bias in included studies

For this review two review authors will independently assess each included study using the Cochrane Collaboration tool for assessing risk of bias (Higgins 2011a). This tool addresses the following domains: sequence generation, allocation concealment, blinding of participants, blinding of outcome assessors, incomplete outcome data, selective outcome reporting and other sources of bias, which for this review may include baseline imbalance (see Appendix 2 for details of criteria on which the judgement will be based). In addition, blinding will be assessed separately for participants, care providers and outcome assessors. Regarding selective outcome reporting, where possible, we intend to seek trial protocols in order to determine whether all pre‐specified outcomes were reported adequately. If trial protocols are unavailable, we will make a judgement based on whether all expected outcomes are reported, with reference to those described in the methods sections of RCT reports. We will complete a risk of bias table for each eligible study. We will discuss any disagreement amongst all review authors to achieve a consensus.

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 the results of each study.

Measures of treatment effect

Dichotomous data

For dichotomous data (e.g. wounds healed, amputations, ulcer recurrence, adverse events), we will calculate the risk ratio (RR) with 95% confidence interval (CI).

Continuous data

For continuous outcomes (e.g. change in wound size, quality of life), we will extract the difference between means with 95% CI.

Time to event data

For time to event data (time to complete wound healing), we plan to plot (and, if appropriate, pool) estimates of hazard ratios and 95% CIs as presented in the RCT reports using the generic inverse variance method in RevMan 5.3. We will only consider mean or median time to healing without survival analysis as a valid outcome if reports specify that all wounds healed (i.e. if the trial authors regarded time to healing as a continuous measure as there is no censoring).

Unit of analysis issues

Healing of multiple wounds on the same patient cannot be considered as independent events. We will note whether RCT reports specified participants, limbs or ulcers as the units of allocation and analysis. When multiple limbs or ulcers on the same individual are studied, we will note whether the trialists’ analysis was appropriate (i.e. correctly taking account of highly correlated data) or inappropriate (i.e. considering outcomes for multiple ulcers on the same participant as independent). Where the number of wounds appears to equal the number of participants, we will assume that the participant was the unit of analysis, unless otherwise stated. Wherever possible, measures of effect will be based on the individual patient (as opposed to wound or limbs).

Dealing with missing data

Outcome data may be 'missing at random' or 'not missing at random' (Higgins 2011b) but in practice it is often difficult to categorise missing data in this way with any certainty. If outcome data are missing from reports, we will make attempts to contact the study authors to obtain missing information. If this is not successful, we will employ the following strategy. Where RCTs report dichotomous complete healing outcomes for only those participants completing the RCT (i.e. participants withdrawing and lost to follow up are excluded from the analysis), we will regard the participants not included in the analysis as if their wound did not heal (that is, they will be included in the denominator but not the numerator for healing outcomes). Where results are reported for participants who completed the RCT without specifying the numbers that were randomised per group initially, we will present only complete case data. For other outcomes we will present data for all participants randomised, where reported; otherwise we will base estimates on complete cases only.

Assessment of heterogeneity

We will consider both clinical and statistical heterogeneity. Consideration of clinical heterogeneity involves assessment of the degree of similarity between trials in terms of the clinical status of participants (e.g. wound type), intervention type, duration of intervention and type of outcome. We will investigate statistical heterogeneity using the Chi² test. We will interpret a Chi² test resulting in a P value of equal to or less than 0.10 as being indicative of significant statistical heterogeneity. We will measure the quantity of heterogeneity using the I² statistic (Higgins 2003). Thresholds for the interpretation of the I² statistic can be misleading. A rough guide to interpretation is as follows:

• 0% to 30%:may represent low heterogeneity;

• 31% to 59%: may represent moderate heterogeneity;

• 60% to 100%: considerable heterogeneity.

When interpreting the I² statistic, we will take factors such as clinical and methodological heterogeneity, along with whether the heterogeneity is in the magnitude of effect or in the direction of effect, into account, particularly where confidence intervals overlap.

Where appropriate we will pool data using meta‐analysis (conducted using RevMan 5.3 (RevMan 2014). Where there is no or low levels of heterogeneity we will use a fixed effects model, where there is moderate heterogeneity we will use a random effects model. Where clinical heterogeneity is evident or where statistical heterogeneity is substantial we will not pool but present the results only in narrative form.

Assessment of reporting biases

In order to assess the likely presence of publication bias, funnel plots will be constructed if at least 10 studies are available for meta‐analysis of a primary outcome.

Data synthesis

We will combine studies using a narrative overview with meta‐analysis of outcome data where appropriate using Review Manager (version 5.3) software (RevMan 2014). The decision to include studies in a meta‐analysis will depend on the availability of treatment effect data and assessment of heterogeneity. Where feasible (i.e. where data are available, and where studies are similar enough) data will be pooled. We will present the summary estimate as a risk ratio (RR) with 95% CI for dichotomous outcomes and difference between means with 95% CI for continuous outcomes. Where a group of RCTs has assessed the same concept with a continuous outcome but used different scales (e.g. quality of life) we will consider using standardised mean difference (SMD) as the summary measure of effect. For time to event data, we will plot and pool available hazard ratio estimations using the generic inverse variance method in RevMan (RevMan 2014).

'Summary of findings' tables

We will present the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2011a). The 'Summary of findings' tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach. The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2011b). We plan to present the following outcomes in the 'Summary of findings' tables:

• time to healing assessed using appropriate survival analysis (i.e. based on censored data);

• proportion of people with diabetic foot ulcers undergoing amputation of the lower limb at any level, including single toes;

• proportion of wounds with complete healing.

Subgroup analysis and investigation of heterogeneity

We will make the following analyses, according to subgroup, to investigate for possible sources of heterogeneity:

• type of wounds; or

• type of interventions (e.g. moxibustion versus control intervention; wound warming unit versus control intervention).

Sensitivity analysis

If a sufficient number of trials are found, sensitivity analysis will be conducted to assess the robustness of the treatment effect as follows:

• removing studies with inadequate concealment of allocation.

• removing studies in which outcome evaluation is not blinded.

Appendices

Appendix 1. NPUAP/EPUAP pressure ulcer classification

Introductory statements

This classification starts from the premise that the use of the terms 'stage' and 'grade' imply a natural progression from stage/grade 1 through to 4, which is not generally the case. The use of the term 'category' is intended to be a neutral term. However, it is recognised that in the United States it may be more difficult to change from the use of 'stages' to 'categories' because of some regulations and legislation.

Category I: Nonblanchable redness of intact skin

Intact skin with non‐blanchable erythema (redness) of a localised area usually over a bony prominence. Discoloration of the skin, warmth, oedema, hardness, or pain may also be present. Darkly pigmented skin may not have visible blanching.

Further description

The area may be painful, firm, soft, warmer, or cooler compared to adjacent tissue. Category I may be difficult to detect in individuals with dark skin tones. Presence may indicate 'at risk' persons.

Category II: Partial‐thickness skin loss or blister

Partial‐thickness loss of dermis (skin) presenting as a shallow open ulcer with a red‐pink wound bed, without slough. May also present as an intact or open/ruptured serum‐filled or serosanguineous‐filled blister.

Further description

Presents as a shiny, or dry, shallow ulcer without slough or bruising. This category should not be used to describe skin tears, tape burns, incontinence‐associated dermatitis, maceration (skin breakdown under moist conditions), or excoriation (skin loss due to scratching, abrasion or a burn).

Category III: Full‐thickness skin loss (fat visible)

Full‐thickness tissue loss in which subcutaneous fat may be visible but bone, tendon, or muscle are not exposed. Some slough may be present. May include undermining and tunnelling.

Further description

The depth of a Category III pressure ulcer varies according to its anatomical location. The bridge of the nose, ear, occiput (back part of the head or skull), and malleolus do not have (adipose) subcutaneous tissue, so in these locations Category III ulcers can be shallow. In contrast, areas with significant adiposity can develop extremely deep Category III pressure ulcers. Bone/tendon is not visible or directly palpable.

Category IV: Full‐thickness tissue loss (muscle/bone visible)

Full‐thickness tissue loss with exposed bone, tendon, or muscle. Slough or eschar (dead skin) may be present. Often includes undermining and tunnelling.

Further description

The depth of a Category IV pressure ulcer varies according to its anatomical location. The bridge of the nose, ear, occiput, and malleolus do not have (adipose) subcutaneous tissue and so Category IV ulcers in these locations can be shallow. Category IV ulcers can extend into muscle or supporting structures (e.g., fascia, tendon, or joint capsule), or both, making osteomyelitis or osteitis likely to occur. Exposed bone/muscle is visible or directly palpable.

Additional Categories for the United States

Unstageable/Unclassified: Full‐thickness skin or tissue loss ‐ depth unknown

Full‐thickness tissue loss in which actual depth of the ulcer is completely obscured by slough (yellow, tan, grey, green, or brown) and/or eschar (tan, brown, or black) in the wound bed.

Further description

Until enough slough or eschar, or both, are removed to expose the base of the wound, the true depth cannot be determined; but it will be either a Category III or IV ulcer. Stable (dry, adherent, intact without erythema or fluctuance (an indication of the presence of pus in a bacterial infection)) eschar on the heels serves as 'the body's natural (biological) cover' and should not be removed.

Suspected deep tissue injury

Purple or maroon localised area of discoloured intact skin or blood‐filled blister due to damage of underlying soft tissue from pressure or shear, or both.

Further description

The area may be preceded by tissue that is painful, firm, mushy, boggy, warmer, or cooler than adjacent tissue. Deep tissue injury may be difficult to detect in individuals with dark skin tones. Evolution may include a thin blister over a dark wound bed. The wound may evolve further and become covered by thin eschar. Evolution may be rapid, exposing additional layers of tissue even with treatment.

Source

National Pressure Ulcer Advisory Panel/European Pressure Ulcer Advisory Panel. Clinical Practice Guidelines for the Prevention and Treatment of Pressure Ulcers (EPUAP/NPUAP 2009).

Appendix 2. The Cochrane Collaboration's tool for 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 of participants / care providers / outcome assessors

Low risk of bias

Explicit statement that participants / care givers / outcome assessors were blind or inclusion of any information in the trial report suggests that participants / care givers / outcome assessors were not aware of treatment allocation.

High risk of bias

Explicit statement indicates that participants / care givers / outcome assessors were not blind to treatment allocation.

Unclear

Terms such as 'open' or 'double‐blind' are used with no further explanation or with no reference at all to blinding of participants / care givers / outcome assessors.

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. Comparability at baseline

Low risk of bias

Groups appeared to be similar at baseline for ulcer infection status, ulcer duration and wound surface area (with median values and interquartile ranges reported for duration and area); or differences were observed but were adjusted for in the analysis.

High risk of bias

Group imbalance was observed at baseline for ulcer infection status, ulcer duration or wound surface area, and no adjustment was made.

Unclear

Information on one or more predictive variables was not provided, or the information was difficult to interpret (e.g. only mean values provided for ulcer area/duration).

7. 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.

What's new

Date	Event	Description
3 July 2017	Amended	This protocol has been withdrawn.

Contributions of authors

Jinhuan Yue: conceived the review question and developed the protocol; secured funding; performed part of writing the protocol; advised on the protocol; and approved the final version of the protocol prior to submission. Zongren Sun: conceived the review question and developed the protocol; performed part of writing the protocol; advised on the protocol; and approved the final version of the protocol prior to submission. Qinhong Zhang: conceived the review question; developed and co‐ordinated the protocol; secured funding; performed part of writing the protocol and edited the protocol; advised on the protocol; approved the final version of the protocol prior to submission; and is the guarantor of the protocol.

Contributions of editorial base:

Susan O'Meara, Editor: 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 the protocol. Gill Rizzello: coordinated the final editorial stages prior to publication.

Sources of support

Internal sources

• This work was partly supported by the National Natural Science Foundation of China (Grant No. 81303045), Foundation of Outstanding Innovative Talents Support Plan of Heilongjiang University of Chinese Medicine (Grant No. 2012RCQ64; 2012RCL01), Natural Science Foundation of Heilongjiang Province (Grant No. ZD201315), Foundation of Graduate Innovative Plan of Heilongjiang Province (Grant No. YJSCX2012‐357HLJ), China.

External sources

• This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Wounds. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health, UK.

Declarations of interest

Zhang QH: none known Yue JH: none known Sun ZR: none known

Notes

This protocol has been withdrawn.

Withdrawn from publication for reasons stated in the review