Gentamicin‐impregnated collagen implants for the reduction of surgical site infections

Abstract

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

To evaluate the effects of gentamicin‐impregnated collagen implants for reducing SSIs, in people undergoing all types of surgery.

Background

A surgical site infection (SSI) is an infection of a wound caused by an invasive surgical procedure. These are the most frequent cause of nosocomial (hospital‐acquired) infection in surgical patients, accounting for 38% of all infections (Mangram 1999). Despite advances in perioperative infection control practices, including improved operating room ventilation, sterilisation methods, surgical technique, and availability of antimicrobial prophylaxis, SSIs remain a substantial cause of morbidity and mortality. One study calculated the mortality rate associated with SSI at 3%, with about three‐quarters of deaths being attributable directly to the infection (Awad 2012). Another study reported that over one‐third of postoperative deaths are related ‐ at least in part ‐ to an SSI (Astagneau 2001). An American study found that in over 750,000 episodes of surgical hospitalisation, 1% resulted in an SSI (de Lissovoy 2009), with similar levels found in France (Astagneau 2009). A UK‐wide prevalence survey of over 75,000 patients showed a wide variability in SSI rates ranging from 0.7% after pacemaker surgery to 10.1% after limb amputation (Smyth 2007).

SSI is associated with considerable morbidity, and a reduction in quality of life, as well as increased use of resources and healthcare costs. These infections significantly increase duration and cost of patient hospitalisation, predominantly due to re‐operation, additional nursing care and drug treatment costs (Mangram 1999; Wilson 2004). A case‐controlled USA study of 255 patient pairs found that hospital discharge for patients with SSI was delayed by an average of 6.5 days (95% confidence intervals (CI) 5 to 8 days), with an additional direct cost of USD 3089 per patient (Kirkland 1999). In an another study from Switzerland of 6283 surgical procedures where 187 SSIs were reported and 168 of these were successfully matched with a control patient, the mean additional hospital cost for patients with SSI was SwF 19,638 (95% CI SwF 8492 to SwF 30,784), and the mean additional length of hospitalisation was 16.8 days (95% CI 13 to 20.6 days) (Weber 2008). Other clinical outcomes of SSIs include scars that are cosmetically unacceptable, persistent pain and itching, and increased risk of incisional herniation.

The risk of developing SSI has been shown to be multifactorial. The type of surgical wound is the factor that was first categorised by the National Research Council in 1964. Under this system wounds may be classified as 'clean', 'clean‐contaminated', 'contaminated' and 'dirty' (Berard 1964).

• Clean wounds: surgical wounds in which the bronchi, gastro‐intestinal tract or genitourinary tract were not entered, for example, varicose vein surgery. The incidence of SSI in clean wounds is less than 2% and is most commonly due to endogenous Staphylococcus aureus present on the skin.

• Clean‐contaminated wounds: surgical wounds in which the bronchi, gastro‐intestinal tract or genitourinary tract were breached, but without unusual contamination, for example, elective intestinal resection, or excision of gallbladder. SSI incidence for these procedures is in the range of 4% to 10%.

• Contaminated wounds: fresh traumatic wounds or surgical wounds where there has been a breach in sterile technique or acute, gross spillage from gastrointestinal tract, or nonpurulent inflammation is encountered, for example, bowel resection on unprepared bowel with spillage, or resection of active Crohn's disease. Infection rates in contaminated wounds exceed 10%, even with antibiotic prophylaxis.

• Dirty wounds: old traumatic wounds involving abscesses or perforated viscera, for example, abdominal exploration for acute bacterial peritonitis and intra‐abdominal abscess. There is an SSI risk of up to 25% to 30% for these procedures.

More recently it was thought that this stratification by contamination level was an oversimplification, and other factors such as the physiological status of the patient at operation, and operative variables, were recognised as having an important role to play in the risk of developing an SSI. One system that attempts to quantify the risk of SSI in a more realistic manner is the National Nosocomial Infection Surveillance (NNIS) Risk Index System, developed by the US Centers for Disease Control and Prevention (CDC) (Culver 2001). According to this, operations are assigned a score between 0 and 3 points depending on three factors:

• 1 point awarded if  the operation is classified as either contaminated or dirty

• 1 point awarded if the patient has an American Society of Anaesthesiologists (ASA) pre‐operative assessment score of 3, 4 or 5

• 1 point awarded if the duration of the operation exceeds the 75th percentile of the average duration for a large pool of similar operations recorded in the NNIS survey

In many parts of the world this classification system is largely replacing the older, contamination‐based classification system. Additionally, it permits a degree of standardisation that allows comparison of SSI rates between units, and assessment of the efficacy of interventions that aim to reduce the SSI rate.

Finally, when interpreting reported SSI rates, it should be noted that most studies, particularly the large‐scale epidemiological cohort studies, usually rely on accurate contemporaneous recording of SSI signs and symptoms, and appropriate coding and data entry. As such they are likely to under‐represent the true incidence of this complication significantly. It is becoming widely accepted that the more rigorous a postoperative wound follow‐up programme, the higher the rate of apparent SSI. Recent studies have shown that 40% to 50% of SSIs are diagnosed after the initial discharge from hospital (Smith 2004; Tanner 2009). Therefore the Health Protetection Agency's Surgical Site Infection Surveillance Service (SSISS) developed a system to facilitate post discharge surveillance (PDS) and the comparison of rates incorporating SSIs detected post discharge using a wholly web‐based data handling and reporting system, to improve accurate reporting and data capture.

Surgeons have always strived to reduce their SSI rate. Consequently any intervention that has the potential to reduce the chances of a patient developing an SSI is always welcomed and requires rigorous appraisal of efficacy, acceptability and cost‐effectiveness. National guidelines for the UK concerning the prevention and treatment of SSI were issued in 2007 by the National Institute for Health and Clinical Excellence (NICE 2007). These recommendations were based on systematic reviews of best available evidence, or, when minimal evidence was available, the guideline development group’s opinion of what constituted good practice. Intra‐operative guidance includes the role of hand decontamination, sterile gowns, drapes and antiseptic skin preparation. The intervention of interest in this review ‐ gentamicin‐collagen implants ‐ was explored in the context of sternal wounds prior to closure after cardiac surgery, where the implants appeared to reduce the incidence of SSI, based on a meta‐analysis of two studies from a single centre. No other operative sites or applications were assessed in the guidelines, presumably due to a paucity of published data.

Description of the condition

Surgical site infections can be difficult to define ‐ one review identified 41 different definitions and 13 grading scales for SSI (Bruce 2001). However, the CDC have published the following guidelines defining superficial and deep incisional SSIs (Horan 2008), which are most widely used internationally.

A superficial SSI is defined as: an infection that occurs within 30 days of an operation that only involves the skin and subcutaneous tissue of the incision, and is associated with at least one of the following.

• Purulent (pus) drainage, with or without laboratory confirmation, from the surgical site

• Micro‐organisms isolated from an aseptically‐obtained culture of fluid or tissue from the surgical site

• At least one of the following signs or symptoms of infection: pain or tenderness, localised swelling, redness or heat, and, if the superficial incision is deliberately opened by a surgeon, it is either culture‐positive or not cultured ‐ a culture‐negative finding does not meet this criterion

• Diagnosis of SSI is made by the surgeon or attending physician

A deep incisional SSI is defined as: an infection that occurs within 30 days of an operation if no implant is left in place, or within one year if a permanent implant is left in place; the infection appears to be related to the operative procedure and involves deep soft tissues (e.g. fascial and muscle layers) of the incision associated with one of the following.

• Purulent drainage from the deep incision, but not from the organ/space component of the surgical site

• Spontaneous dehiscence (opening up) of the incision, or the incision is deliberately opened by the surgeon and is either culture‐positive or not cultured when the patient has at least one of the following symptoms: fever, localised pain, or tenderness

• An abscess, or other evidence of infection involving the deep incision is found on direct examination, during re‐operation, or by histopathologic or radiologic examination

• Diagnosis of a deep incisional SSI is made by a surgeon or attending physician

Other systems have been used to diagnose or classify SSI (including the ASEPSIS system, in which points are given for the need for Additional treatment, the presence of Serous discharge, Erythema, Purulent exudate, and Separation of the deep tissues, the Isolation of bacteria, and the duration of inpatient Stay [ASEPSIS]) and, when predominantly based upon a clinical diagnosis of SSI, these will be included in this review. Purely bacteriological definitions of SSI will be excluded because the current clinical guidelines specify definitions of SSI based predominantly on clinical signs (Mangram 1999; NICE 2007), and because it is difficult to differentiate infection from contamination when interpreting the positive results of swab cultures (Gurevich 1995; Peel 1991).

Description of the intervention

Systemic antibiotic therapy may be associated with a risk of allergic reactions, development of antibiotic‐resistant bacteria and Clostridium difficile diarrhoea. The intervention of interest is a lyophilised (freeze‐dried) collagen implant impregnated with the antibiotic gentamicin. The process of lyophilisation dries the collagen implant without altering its physical properties, and allows the uniformly‐incorporated gentamicin in the collagen matrix to provide a uniform dose per cm² once in the body (Delfosse 2011). These implants can be applied to surgical wounds to provide high local concentrations of gentamicin, thus avoiding the deleterious effect on kidneys (nephrotoxicity) that is associated with high systemic concentrations of gentamicin when they are administered intravenously. Gentamicin implants are available as biodegradable collagen fleeces, which are either placed under the skin before closure of the wound, or placed between muscle layers. These implants have been used in various types of surgery, including cardio‐thoracic, orthopaedic, abdominal, perineal and vascular surgery, which have a high risk of infection and in which SSI can lead to severe complications. Many randomised controlled trials published in recent years have studied the effectiveness of these implants for prevention or reduction of SSI.

How the intervention might work

The use of antibiotic‐eluting (antibiotic‐releasing) products provides high local concentrations of the drug, thereby avoiding any potential systemic (whole body) complications such as nephrotoxicity. Moreover, with the higher maximum inhibitory concentrations obtained with these implants, the levels of gentamicin eluted locally is reported to be highly effective in treating even gentamicin‐resistant bacteria. These bio‐absorbable implants may improve epithelialisation and granulation at the wound site, and so accelerate wound healing through their interaction with platelets, fibroblasts and macrophages. They may also help with local tissue haemostasis (clotting) in areas with a high risk of SSI.

Why it is important to do this review

SSIs increase postoperative morbidity and lead to prolonged hospitalisation or readmission, accompanied by greater utilisation of the limited resources available to healthcare systems. Therefore, the area of SSI is of heightened interest to both patients and healthcare providers: reduction of treatment expenses and overall costs is desirable. SSIs are relative easy to diagnose, and most (if not all) SSIs are avoidable. Therefore, we aim to establish whether the use of gentamicin‐impregnated collagen implants is associated with decreased incidence of SSI‐related postoperative morbidity and length of hospital stay in patients undergoing surgery.

Objectives

To evaluate the effects of gentamicin‐impregnated collagen implants for reducing SSIs, in people undergoing all types of surgery.

Methods

Criteria for considering studies for this review

Types of studies

Published or unpublished randomised controlled trials (RCTs) studying the effects of gentamicin‐impregnated collagen implants for reducing SSIs. We will include any RCT where the use of gentamicin‐impregnated collagen implants is the only systematic difference between trial arms.

Types of participants

All adults aged 18 years and above who have undergone any surgical procedure that used gentamicin implants for wound closure.

Types of interventions

People in whom gentamicin‐impregnated collagen implants were used at sites of surgical wound closure will be compared with people who had standard wound closure (i.e. did not have any implants placed in their surgical wounds).

Types of outcome measures

Primary outcomes

• Incidence of SSIs as defined by the trial authors, or using any standard definition of postoperative SSI based on clinical findings (e.g. CDC criteria). We will not differentiate between superficial, deep‐incisional and organ space infection

• Adverse events relating to use of gentamicin‐impregnated collagen implants, including wound contamination, wound complications, and bacteriological outcomes, as defined and categorised in individual studies

Secondary outcomes

• Postoperative pain, measured using survey/questionnaire/data capture process or visual analogue scale in individual studies. The postoperative pain scores will be analysed where the scores were obtained during the primary hospital stay

• Time to wound healing, measured using methods of survival analysis

• Health‐related quality of life, measured using a standardised generic questionnaire such as EQ‐5D, SF‐36, SF‐12 or SF‐6 or disease‐specific questionnaire. We will not include ad hoc measures of quality of life that are likely not to be validated and will not be common to multiple trials

• Overall costs, including measures of resource use such as duration of hospital stay, operation duration, use of antibiotic or analgesic drugs, dressing costs and nursing time

• Mortality rates

Search methods for identification of studies

The search will include publications in all languages with no restrictions regarding publication dates. Relevant studies will be identified using standard search terms for individual databases. The bibliography of all included RCTs will be reviewed to identify any trials missed during the initial database search. The Cochrane Wounds Group's Trials Search Co‐ordinator will perform an independent search using the search strategy, and the search results will be cross‐checked for any missing studies.

Electronic searches

We will search the following electronic databases to identify reports of relevant randomised clinical trials:

• 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)

The following search string will be used to search the Cochrane Central Register of Controlled Trials (CENTRAL): #1 MeSH descriptor Gentamicins explode all trees #2 MeSH descriptor Surgical Sponges explode all trees #3 (#1 AND #2) #4 MeSH descriptor Collagen explode all trees #5 (#1 AND #4) #6 (gentamicin* NEAR/5 collagen*):ti,ab,kw #7 (#3 OR #5 OR #6) #8 MeSH descriptor Surgical Wound Infection explode all trees #9 MeSH descriptor Surgical Wound Dehiscence explode all trees #10 (surg* NEAR/5 infect*):ti,ab,kw #11 (surg* NEAR/5 wound*):ti,ab,kw #12 (surg* NEAR/5 site*):ti,ab,kw #13 (surg* NEAR/5 incision*):ti,ab,kw #14 (surg* NEAR/5 dehisc*):ti,ab,kw #15 (wound* NEAR/5 dehisc*):ti,ab,kw #16 (wound NEAR/5 complication*):ti,ab,kw #17 (#8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16) #18 (#7 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 2013). We will not restrict studies with respect to language, date of publication or study setting.

We will search the following clinical trials registries:

• Current Controlled Trials Register (http://www.controlledtrials.com/isrctn)

• clinical trials registry (http://clinicaltrials.gov/)

• clinical trials register (www.clinicaltrialsregister.eu)

• www.who.int/trialsearch

Searching other resources

Bibliographies of RCTs, meta‐analyses, and systematic reviews will be handsearched for studies not captured by the initial electronic search. We will review the 'related articles' feature of PubMed and consult experts in the subject to ensure that no published or unpublished work has been missed. We will contact manufacturers of gentamicin‐impregnated collagen implants for details of unpublished studies.

We will also search the abstracts of conference proceedings or meetings for the last three years from:

• The American Society of Colon and Rectal Surgeons (ASCRS),

• The Association of Coloproctology of Great Britain and Ireland (ACPGBI),

• The Association of Surgeons of Great Britain and Ireland (ASGBI),

• The British Society of Gastroenterology (BSG),

• The Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS), and

• The British Thoracic Society (BTS).

Data collection and analysis

Selection of studies

Two review authors (KV, TDP) will examine all citations and abstracts derived from the electronic search. Full text articles of potentially relevant trials will be reviewed for eligibility according to the selection criteria. Any disagreements will be resolved by discussion and, where required, the input of a third review author. Studies published in duplicate will be included once, but the maximum amount of data will be extracted from the papers. We will complete a PRISMA flowchart to indicate the results of the search strategy and selection of studies for the review (Liberati 2009).

Data extraction and management

Data will be extracted independently by two review authors (KV, TDP) using a standardised data extraction form. Disagreements will be resolved through consensus involving other review authors (DNL, AGA).

The following data will be extracted:

• country of origin of trial

• type of surgery

• classification of surgical contamination

• eligibility criteria and baseline participant data

• details of the protector/treatment regimen received by each group and any co‐interventions

• primary and secondary outcome(s) (with definitions)

• outcome data for primary and secondary outcomes (by intervention group)

• duration of follow‐up

• number of withdrawals (by intervention group)

• source of funding for trial

Assessment of risk of bias in included studies

Two review authors will independently assess each included study using the Cochrane Colloboration tool for assessing risk of bias (Higgins 2011). This tool addresses seven specific domains, namely sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective outcome reporting and other issues (e.g. extreme baseline imbalance) (see Appendix 1 for details of criteria on which the judgement will be based). Blinding and completeness of outcome data will be assessed for each outcome separately. 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 our 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 (Higgins 2011).

Measures of treatment effect

We will use risk ratio (RR) with 95% confidence intervals (CI) for the summary statistic for dichotomous variables, such as number of patients with SSI; for continuous outcomes we will use mean difference (MD), or standardised mean difference (SMD) when the trials measured the units of outcome differently, for example hours versus days, as appropriate.

Unit of analysis issues

We anticipate that individual participants will form the unit of randomisation and analysis in the included studies. If we include any studies that have used a different design, for example cluster RCTs, we will adjust for this in our analysis if necessary and possible.

Dealing with missing data

The trial authors of RCTs will be contacted to obtain missing data, as appropriate. When data are unavailable, we will perform an available‐case analysis. However, missing standard deviations will be calculated from the standard errors or confidence intervals (Higgins 2011), or from ranges or interquartile ranges (Hozo 2005).

Assessment of heterogeneity

We will explore both clinical and statistical heterogeneity. We will consider clinical heterogeneity (i.e. the degree to which RCTs appear similar in terms of participants, intervention type and outcome type) and explore it using subgroup analyses as described below. Statistical heterogeneity will be assessed using the Chi² test (a significance level of P value less than 0.1 will be considered to indicate heterogeneity), and the I² test (Higgins 2011). The I² test examines the percentage of total variation across studies due to heterogeneity rather than to chance. The importance of the observed value of I² depends on (i) magnitude and direction of effects and (ii) strength of evidence for heterogeneity (e.g. P value from the Chi² test, or a confidence interval for I²) (Deeks 2011). Values of I² over 50% may represent substantial heterogeneity (Higgins 2011). In the absence of clinical heterogeneity, and in the presence of statistical heterogeneity (I² over 50%), we will use a random‐effects model, if pooling is appropriate. Where there is no clinical or statistical heterogeneity, we will use a fixed‐effect model to pool trials.

Assessment of reporting biases

We will analyse studies for evidence of reporting biases, and, where suspected (where the protocol or abstract mentioned outcomes that were not reported in the final publication), we will contact the trial authors and ask them to supply the missing data. We will seek clarification about whether the missing outcome measures were collected or analysed and request the missing data. A study‐level approach will be used for assessment for risk of bias due to selective reporting. Evidence of publication bias and time‐lag bias, if suspected, will be addressed using the GRADE approach. If more than 10 trials are included in the review, assessment of publication bias and other small study effects will include a qualitative, funnel plot analysis for asymmetry using weighted linear regression of effect estimates on the standard error (Egger 1997).

Data synthesis

The data from individual studies will be grouped as either dichotomous or continuous data and synthesised using Review Manager version 5.2 (RevMan 2013). Pooled analyses will be performed using either the random‐effects model, according to DerSimonian and Laird, in the presence of statistical heterogeneity, or the fixed‐effects model when there is no statistical heterogeneity. Time to complete wound healing will be summarised using methods of survival analysis and the intervention effect expressed as a hazard ratio. Time‐to‐event data incorrectly presented as continuous data will not be analysed but presented in a narrative form in the review. If meta‐analysis is performed, the results of this review will be presented according to outcome measures; if meta‐analysis is not performed, the results will be presented narratively, first according to outcome measures and then according to type of surgery.

Subgroup analysis and investigation of heterogeneity

All eligible RCTs will be analysed for overall treatment effect for individual outcomes for all types of surgery. A separate subgroup analysis will be performed for each type of surgery (example: abdominal, pelvic or cardio‐thoracic surgery etc). The Chi² test of subgroup differences will be used to identify differences in the effect estimates in the subgroups. The GRADE approach will be used to assess the strength of evidence for each type of surgery and also for all types of surgery.

Sensitivity analysis

We will undertake a sensitivity analysis to investigate the effects of removing studies assessed as being at high risk of bias from the analysis. The studies classified as being at high risk of bias will be those that do not define random sequence generation, allocation concealment methods and blinding of outcome assessor adequately.

'Summary of findings' table

The primary findings of the review will be presented in a 'Summary of findings' table (GRADEpro).

The important outcomes that will be included will include:

• SSI

• adverse events

The strength of evidence for these outcomes will be analysed using 'GRADEpro' software. The principle of the GRADE system is to assess the quality of evidence for the reported effect estimates of study outcomes, carefully considering the studies' methodological quality, directness of the evidence, heterogeneity, precision of the effect estimates and the risk of bias; the quality of evidence is then reported as being 'very low', 'low', 'moderate' or 'high'.

Appendices

Appendix 1. Risk of bias criteria

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 is provided 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 provided 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? (Participants, personnel and outcome assessors)

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 is likely to introduce bias.

Unclear

Either of the following.

• Insufficient information provided 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 are unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias).

• Missing outcome data are 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 is 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 is 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 is 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 is 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

Either 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

Either 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 provided 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.

What's new

Date	Event	Description
10 June 2019	Amended	This protocol has been withdrawn from publication due to lack of progress with the review.

Contributions of authors

Krishna Varadhan: conceived the review question, and developed, wrote, edited and coordinated the protocol. Is a guarantor or the protocol. Thomas Pinkney: conceived the review question, and developed, wrote, edited and coordinated the protocol. Is a guarantor or the protocol. Keith Neal: conceived the review question and developed the protocol. Edited and advised on the protocol. Dileep Lobo: conceived the review question and developed the protocol. Edited and advised on part of the protocol. Approved final version of the protocol prior to submission. Austin Acheson: conceived the review question, and developed and coordinated the protocol development. Made an intellectual contribution to the protocol, edited the protocol, advised on the protocol and approved final version of the protocol prior to submission. Is a guarantor of the protocol.

Contributions of editorial base:

Kurinchi Gurusamy: 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. Rachel Richardson: edited the protocol. Ruth Foxlee: designed the search strategy and edited the search methods section.

Sources of support

Internal sources

• No sources of support supplied

External sources

• The National Institute for Health Research (NIHR) is the sole funder of the Cochrane Wounds Group, UK.

Declarations of interest

Krishna K Varadhan: nothing to declare Thomas D Pinkney: nothing to declare Keith Neal: nothing to declare Dileep Lobo: Potential conflicts of interest for unrelated work declared, but no conflict of interests to declare for the subject of this review. Austin G Acheson: nothing to declare

Notes

This protocol has been withdrawn from publication due to lack of progress with the review.

Withdrawn from publication for reasons stated in the review