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Antibiotics and antiseptics for preventing infection in people receiving primary total joint prostheses

  1. Rabih O Darouiche1,
  2. Michael C Mosier2,
  3. Jeffrey Voigt3,*

Editorial Group: Cochrane Wounds Group

Published Online: 28 FEB 2013

DOI: 10.1002/14651858.CD010363


How to Cite

Darouiche RO, Mosier MC, Voigt J. Antibiotics and antiseptics for preventing infection in people receiving primary total joint prostheses (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD010363. DOI: 10.1002/14651858.CD010363.

Author Information

  1. 1

    Baylor College of Medicine, Center for Prostheses Infection, Houston, Texas, USA

  2. 2

    Washburn University, Topeka, KS, USA

  3. 3

    Ridgewood, New Jersey, USA

*Jeffrey Voigt, 99 Glenwood Rd, Ridgewood, New Jersey, 07450, USA. meddevconsultant@aol.com.

Publication History

  1. Publication Status: New
  2. Published Online: 28 FEB 2013

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This is not the most recent version of the article. View current version (09 JUN 2015)

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Description of the condition

Over 1.5 million primary (first time) total joint prostheses (e.g. hips, knees) are implanted annually worldwide (Sorci Miller 2008). The incidence of infection associated with these types of prostheses has been estimated to be anywhere from 0.39% to 2.5% for primary total knee arthroplasty (Berbari 1998; Hanssen 1998; Peersman 2001; SooHoo 2006); 1% to 2% for primary total hip arthroplasty (Anagnostakos 2009; Berbari 1998; Hanssen 1998; Ong 2009); and 0.7% to 4% for other prostheses (i.e. shoulder, elbow) (Bohsali 2006; Little 2005). In developed countries such as the USA, there has been a close to two-fold increase in the incidence of infection in both hip and knee arthroplasties between 1990 and 2004 (Kurtz 2008). This infection burden is only expected to increase because the number of primary - and revision - procedures is expected to increase dramatically over the next 20 years (Kurtz 2008). Curing these types of infections requires removal of the implant, reimplantation of a revision implant, and long-term therapy with antimicrobial agents.

Not only do primary total joint prosthesis-associated infections increase the costs of health care, they can result in serious disability and mortality. Prosthetic infections have an overall mortality rate of 1% to 2.7% for patients around 65 years of age, increasing to 7% for patients who are over 85 years old (Fisman 2001). These infections require between three to four times the hospital and surgical resources required by (uninfected) primary replacement surgery (Herbert 1996), and costs to treat them stand at, or exceed, USD 50,000 (Jiranek 2006; Sculco 1993; Smith 2004). Infection has been estimated to extend hospital stay by 1.87 times for knee replacements (95% CI 1.85 to 1.88) and 2.21 times for hip replacements (95% CI 2.18 to 2.23) (Kurtz 2008). A conservative estimate of the total annual cost to treat these types of infections stands at USD 750 million (assuming a 1% infection rate of 1.5 million procedures at USD 50,000 per infection) but probably exceeds this number by a significant amount (based on the numbers above).

The development of antibiotic and antiseptic prophylactic guidelines from a systematic review of the literature (along with meta-analysis) may thus help reduce these events and their associated costs. The American Academy of Orthopedic Surgeons has recently identified antimicrobial prophylaxis as a priority for review, but, as yet, has not undertaken a systematic review of the evidence. Additionally, the British Orthopaedic Association cites in its guidelines for knee replacement that, "although there is no specific data relating to knee replacement, we believe that as with hip replacement, all patients should receive an intravenous broad spectrum antibiotic at induction of anaesthesia." (Glasgow 1999) Lastly, while the Scottish Intercollegiate Guidelines Network (SIGN) recently published recommendations for the use of antimicrobial prophylaxis against infection in the management of hip fracture in older people, it did not examine the use of antibiotic prophylaxis for hip implant surgery (SIGN 2009).

Implant-related infections also impose an emotional burden and suffering for patients who require treatment for them. These infections can often lead to functional impairment, long-lasting disability or even permanent handicap (Poultsides 2010). Curing them requires removal of the implant, followed by six to 18 months of rehabilitation to regain function comparable to the pre-infected state (Hillman 1995), though this state is rarely achieved (Poultsides 2010).

Implanted devices can harbour various micro-organisms within a layer of biofilm (i.e. a thin, resistant layer of micro-organisms such as bacteria, that form on, and coat, implant surfaces) surrounding the device (Donlan 2002). These biofilms develop on more than 25% of devices implanted during hospitalisation (Hazan 2006). These biofilm-embedded pathogens are more resistant to conventional antibiotic agents than their planktonic counterparts (micro-organisms floating or drifting within the circulatory system) (Gilbert 2003). Bacteria form biofilms as a basic survival strategy in any environment in which they proliferate (Donlan 2002). Biofilms protect bacteria from antibacterial chemicals (including natural antibiotics), environmental bacteriophages and phagocytic amoebae (i.e. help protect bacteria from their natural and unnatural predators). Bacteria form biofilms on smooth and rough surfaces with equal ease. Within a biofilm bacteria become encased in a protective polysaccharide matrix (carbohydrates joined by glycosidic bonds) that prevents predators from attacking the bacteria residing within or under it (Donlan 2002).

 

Description of the intervention

Protocols and guidelines have been developed for antibiotic and antiseptic prophylaxis for many different types of surgical procedure (Bratzler 2005; SIGN 2008), but none, to date, relate to primary total joint prostheses (Bratzler 2005; SIGN 2008). Such guidelines generally advocate antibiotic administration an hour prior to initiation of the surgical procedure and discontinuation 24 to 48 hours postoperatively (Bratzler 2005). The types of antibiotics commonly utilised with surgical implants include: cefazolin, vancomycin, cefepime, aztreonam, ciprofloxacin, levofloxacin, trimethoprim/sulfamethoxazole and linezolid (Darouiche 2003). Antiseptics are also generally applied to the incision site as part of skin preparation prior to incision. Commonly used antiseptics include chlorhexidine-alcohol, povidone-iodine, and combinations thereof. These guidelines, however, may not be applicable to primary total joint prostheses due to the potential formation of biofilms on the implant. As noted above, it is important to consider the impact that biofilm formation may play in determining the effect of various antibiotics.

 

How the intervention might work

When properly administered, prophylactic antibiotics significantly reduce the incidence of (non-implant) surgical infection (Classen 1992). The addition of antiseptics to antibiotic prophylaxis may further reduce the incidence of infections associated with primary total joint protheses. Although the Classen 1992 study assessed a patient population undergoing non-implant surgical procedures, the findings from this study indicated that antibiotics administered intravenously, up to one hour prior to the procedure, were most efficacious at reducing surgery-related infections. The findings from this study have become 'standardised' for all types of surgical procedures. This strategy has also been applied to the prevention of perioperative (i.e. occurring around the time of a procedure) infection in primary total joint prostheses (Fletcher 2007). There are, however, several issues regarding the use of antibiotic prophylaxis that remain unanswered.

 

Why it is important to do this review

Although a number of studies have examined the use of antibiotic prophylaxis with primary total joint prostheses, only two meta-analyses of the results (total hip and knee) have been published to date. The first meta-analysis examined primary total hip replacement (Glenny 1999), but ended up also evaluating antibiotic prophylaxis in studies where both total hip and total knee replacement were performed but were not considered separately. The authors of the systematic review did not follow up the authors of studies included in the meta-analysis, or manufacturers, for unpublished data. The review focused primarily on a comparison of the type of antibiotic in order to evaluate superiority; it did not use the 'accepted' criteria for defining a surgical site infection (SSI) (see below under types of outcome measures) (Horan 1992), and it did not examine operator experience, which has been identified as a predictor of infection rates in other types of implants (Mounsey 1994). The second meta-analysis was a review of English language publications only (AlBuhairan 2008), with a restricted definition of infection based on the presence of visible purulent exudate at the surgical site. Additionally, this review only examined primary or revision total hip replacement or total knee replacement, and limited the analysis of local antibiotic administration solely to antibiotic-impregnated cement. The systematic review we are undertaking will examine a number of other comparisons not made in the previous reviews (see Objectives). Furthermore, clinical guidelines have not been published for antibiotic prophylaxis used with primary total joint prostheses by two of the largest orthopaedic associations in the world: the American Academy of Orthopedic Surgeons and the British Orthopaedic Association (as noted above, a guideline has been published by BOA albeit without level 1 evidence).

A review of primary total joint prostheses (hip and knee) is needed for the following reasons: no one has performed a systematic review of the literature and meta-analysis on antibiotic prophylaxis for primary total joint prostheses; no evidence-based guidelines for preventing infections during these types of procedures have been published by leading medical associations; and development of specific guidelines (a potential result of this review) may help to reduce the incidence of these events and their implications and costs.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

To determine whether perioperative systemic (whole body) or local antibiotic prophylaxis, or a combination of the two, combined with local antiseptics are effective in reducing the rates of SSI when compared with placebo or with no antibiotic prophylaxis in patients undergoing primary total hip or knee implants.
To determine whether the perioperative timing of antibiotics has an effect on the infection rate.
To determine whether the route of antibiotics (oral, systemic intravenous (IV), local) has an effect on the infection rate.
To determine whether the type of antiseptic has an effect on the infection rate (if all else is equal).

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled trials (RCTs) that determine the effect on SSIs of perioperative antibiotic prophylaxis (local or systemic) during primary total joint (hip or knee) prostheses implantation will be eligible for inclusion. We will consider quasi-randomised trials, defined as those trials where participants were allocated via the following schemes: allocation by date of birth, day of the week, medical record number, month of  the year, or the order in which participants are included in the study (e.g. alternation), only in the absence of RCTs.

 

Types of participants

Any person undergoing primary (first time) implantation of a joint prostheses (total knee or total hip), cemented or non-cemented.

 

Types of interventions

Any regimen of systemic administration or local antibiotic prophylaxis, or both, administered at or around the time of surgical implantation of a primary total joint prothesis (i.e. peri-procedural). Systemic antibiotic administration is defined as intravenous or oral perioperative antibiotic administration. Local antibiotic administration is defined as intra-operative antibiotic administration at the open surgical site. Local antibiotic prophylaxis is typically administered in antibiotic-loaded bone cement (with a cemented prosthesis). The following are likely comparisons (assuming that all included trials include local antiseptic administration):

  • systemic antibiotics alone compared to placebo or local antibiotic or another systemic antibiotic;
  • systemic antibiotics plus local antibiotics compared with systemic antibiotics or placebo;
  • comparison of one local antibiotic to another;
  • local antibiotics plus local antiseptics compared with no antibiotics or placebo ;
  • administration of antibiotics with different durations or dose, at different time points (e.g. preoperative versus perioperative), via different routes.

 

Types of outcome measures

 

Primary outcomes

  • Rates of SSI defined as (Horan 1992):
    • Superficial (within 30 days of the operation and infection involves only skin or subcutaneous tissue of the incision and at least one of the following):
      • Visible purulent exudate at surgical site (with or without laboratory confirmation).
      • Organisms isolated from an aseptically obtained culture of fluid or tissue from the superficial incision.
      • At least one of the following signs or symptoms of infection: pain or tenderness, localised swelling, redness, or heat and superficial incision is deliberately opened by surgeon, unless incision is culture-negative.
      • Diagnosis of superficial incisional SSI by the surgeon or attending physician.
    • Deep incisional SSI (within one year of insertion of implant if implant is in place and the infection appears to be related to the operation and infection involves deep soft tissues of the incision and at least one of the following) (Horan 1992):
      • Purulent drainage from the deep incision but not from the organ/space component of the surgical site.
      • A deep incision spontaneously dehisces (i.e. bursts open) or is deliberately opened by a surgeon when the patient has at least one of the following signs or symptoms: fever (temperature exceeds 38oC), localised pain, or tenderness, unless site is culture negative.
      • An abscess or other evidence of infection involving the deep incision is found on direct examination, during reoperation, or by histopathologic or radiologic examination.
      • Diagnosis of a deep incisional SSI by a surgeon or attending physician.
    • Organ or space SSI (within one year of insertion of implant if implant is in place and the infection appears to be related to the operation and infection involves any part of the anatomy (i.e. organ or spaces), other than the incision, which was opened or manipulated during an operation and at least one of the following) (Horan 1992):
      • Purulent drainage from a drain that is placed through a stab wound into the organ or space.
      • Organisms isolated from an aseptically-obtained culture of fluid or tissue in the organ or space.
      • An abscess or other evidence of infection involving the organ or space that is found on direct examination, during reoperation, or by histopathologic or radiologic examination.
      • Diagnosis of an organ or space SSI by a surgeon or attending physician.
  • Adverse events (e.g. allergic reaction, microbial resistance to antibiotic).

 

Secondary outcomes

  • All healthcare costs in direct treatment of infections (includes in hospital, out of hospital and consumer out-of-pocket costs).
  • Non out-of-pocket costs to the patient or consumer - including lost time from work.
  • Quality of life.

 

Search methods for identification of studies

 

Electronic searches

We will search the following electronic databases:

  • 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)
  • Network Digital Library of Theses and Dissertations (NDLTD).

We will search the Cochrane Central Register of Controlled Trials (CENTRAL) using the following exploded MeSH headings and keywords:

#1 MeSH descriptor Vancomycin explode all trees
#2 MeSH descriptor Cephalosporins explode all trees
#3 MeSH descriptor Ciprofloxacin explode all trees
#4 MeSH descriptor Ofloxacin explode all trees
#5 MeSH descriptor Aztreonam explode all trees
#6 MeSH descriptor Trimethoprim-Sulfamethoxazole Combination explode all trees
#7 MeSH descriptor Oxazolidinones explode all trees
#8 (antibiotic* or antibacterial* or antimicrobial* or cefazolin or cefepime or vancomycin or aztreonam or ciprofloxacin or levaquin or trimethoprim or linezolid):ti,ab,kw
#9 MeSH descriptor Anti-Infective Agents, Local explode all trees
#10 antiseptic*:ti,ab,kw
#11 MeSH descriptor Iodophors explode all trees
#12 MeSH descriptor Chlorhexidine explode all trees
#13 MeSH descriptor Povidone-Iodine explode all trees
#14 MeSH descriptor Alcohols explode all trees
#15 (iodophor* or povidone or iodine or chlorhexidine or betadine or alcohol*):ti,ab,kw
#16 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15)
#17 MeSH descriptor Surgical Wound Infection explode all trees
#18 MeSH descriptor Surgical Wound Dehiscence explode all trees
#19 (surg* NEAR/5 infect*):ti,ab,kw
#20 (surg* NEAR/5 wound*):ti,ab,kw
#21 (surg* NEAR/5 site*):ti,ab,kw
#22 (surg* NEAR/5 incision*):ti,ab,kw
#23 ((post-operative or postoperative) NEXT (wound NEXT infection*)):ti,ab,kw
#24 (#17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23)
#25 MeSH descriptor Replacement, Arthroplasty explode all trees

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 and CINAHL searches with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2010). There will be no restrictions on the basis of date or language of publication.

 

Searching other resources

We will contact corresponding authors of included trials in addition to the manufacturers and distributors of antibiotics (linezolid, quinupristin/dalfopristin, daptomycin, tigecycline, telavancin and other anti-staphylococcal agents and antiseptics). We will make further searches of the US Food and Drug Administration (FDA) briefing documents used in the licensing of antistaphylococcal agents. We will check the citation lists of papers identified by the above strategies for further reports of eligible studies. We will undertake handsearches of the following journals:

  • Journal of Bone and Joint Surgery (American volume) (most recent six months);
  • Journal of Bone and Joint Surgery (British volume) (most recent six months);
  • Clinical Orthopedics & Related Research (most recent six months); and
  • Journal of Antimicrobial & Chemotherapy (most recent six months).

The above journals will be handsearched because of the time lag between their publication and availability on electronic indexes.

 

Data collection and analysis

 

Selection of studies

Two review authors will screen the titles and abstracts of all studies identified by the search independently. Upon agreement by both review authors, we will obtain full text versions of all studies identified as potentially relevant and two review authors will assess them independently against the inclusion criteria. Any disagreement(s) between the two review authors will be resolved by discussion or adjudicated by a third party.

 

Data extraction and management

A data extraction form has been developed. One review author will independently extract the data and a second review author will validate the extracted data. If more than one publication arises from the same study, we will consider all versions to maximise data extraction and identify the primary publication along with the secondary references.

 

Assessment of risk of bias in included studies

Two review authors will independently assess each included study using the Cochrane Collaboration tool for assessing risk of bias (Higgins 2011). This tool addresses six specific domains, namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other issues (e.g. extreme baseline imbalance) (see Appendix 1 for details of the criteria on which judgements will be based). We will assess blinding and completeness of outcome data for each outcome separately. We will complete a 'Risk of bias' table for each eligible study. Any disagreement(s) amongst all review authors will be discussed to achieve a consensus.

We will evaluate an 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 will indicate the weight the reader may give the results of each study.

We will assess studies other than RCTs (i.e. quasi-randomised controlled trials) using the same criteria. We will incorporate the results of the risk of bias assessment into the review through systematic narrative description and commentary about each of the domains, leading to an overall assessment of the risk of bias of the included studies and a judgement about the internal validity of the results.

 

Measures of treatment effect

Each study will be reported separately. We will summarise the results of binary outcomes descriptively (e.g. infection) as percentages, and present treatment comparisons as risk ratios (RR) with corresponding 95% confidence intervals (CI). For continuous data, we will use the mean difference (MD) where trials measured outcomes in the same way, and the standardised mean difference (SMD) where trials used different methods to measure the same outcomes.

 

Unit of analysis issues

Where clustering exists and study comparisons do not account for clustering during analysis, we will attempt to re-analyse this, where possible, by calculating an effective sample size. In the unlikely event that the intra-class correlation coefficient (ICC) for clustering is reported, this will be used to estimate the effective sample size. Otherwise, we will make an attempt to estimate the ICC using external sources. If re-analysed,we will annotate the P value as 're-analysed'.

If trials include multiple intervention groups (e.g. different antibiotics), we will split the shared control group into two or more groups with smaller sample sizes, depending upon the number of interventions, and include two or more comparisons.

 

Dealing with missing data

We will deal with missing data for binary primary outcome variables as follows:

  • Where possible, we will contact the original investigators to request the missing data.
  • If it is not possible to obtain the missing data from the original investigators, we will make explicit the assumption of the method used to cope with the missing data: e.g. that the data are missing at random or are not missing at random. If the data are not missing at random, we will impute the missing data with replacement values, and treat these as if observed.
  • A sensitivity analysis will be performed to assess how sensitive the results are to including, and excluding, the imputed values.
  • We will address the potential impact of missing data on the findings of the review in the Discussion section.

Secondly, it is possible that information about study design characteristics that are needed for subgroup analyses will be missing. Also, this may be the case for missing data related to secondary outcomes such as cost. In such cases, we will attempt to contact authors where data are missing. We will also address the impact of missing data in the Discussion section.

In the case of trials for which we can only identify an abstract, we will attempt to contact authors to see whether a paper has been published in a peer-reviewed journal or is available from the author as an unpublished draft.

 

Assessment of heterogeneity

We will make assessment of statistical heterogeneity using the I2 statistic in order to determine appropriateness for meta-analysis. If the I2 statistic is at or below 60%, we will consider statistical heterogeneity to be moderate and pooling will be considered, if appropriate. If the value is greater than 60%, we will undertake sensitivity analyses in an attempt to identify which studies are most likely to be causing the problem. If there are only a few such studies, and they can be identified, we will explore the reasons for their difference and determine the appropriateness of removing these studies. When appropriate, we will perform the meta-analysis excluding any such studies (Higgins 2011). Likely variables that may represent important clinical differences include: type of implant (cemented versus non-cemented); timing of antibiotic administration; route of antibiotic administration; and dosing of antibiotics.

 

Assessment of reporting biases

We will use a funnel plot to assess reporting bias. Each primary outcome will be reported separately. Furthermore, we will make an assessment of publication bias (including a review of unpublished studies); location bias (types of journals) and language bias. We will examine whether the results of trials were favourable or not, with the assumption that favourable results demonstrate a positive effect of antibiotic prophylaxis in lowering the infection rate and thus are published (versus not published) (Song 2010). Location bias refers to more significant results being published in less-respected/low impact factor journals (Higgins 2011).

 

Data synthesis

Where possible we will group studies that are similar together. In the absence of heterogeneity (I2 statistic equal to 0%) or in the presence of low heterogeneity (I2 statistic less than 40%) we will use a fixed-effect model. If heterogeneity is moderate (I2 statistic greater than 40% and less than or equal to 60%) we will use a random-effects model. For high levels of heterogeneity (I2 over 60%) pooling may not be appropriate. We will undertake a sensitivity analysis, however, as described above under assessment of heterogeneity, to identify the studies that are causing the problem and determine the appropriateness of removing them.

 

Subgroup analysis and investigation of heterogeneity

Where possible, we will perform subgroup analyses by grouping studies based on categorical characteristics and investigate for heterogeneity including: type of implant (e.g. cemented versus non-cemented with cemented resulting in a potentially higher infection rate due to the longer length of the procedure), effect of systemic versus local administration, and timing of perioperative administration. In order to minimise the risk of a type 1 error (rejecting a null hypothesis when it is true - i.e. a false positive) we will only combine studies for subgroup analysis that have larger (100+) sample sizes.

 

Sensitivity analysis

We will perform a sensitivity analysis to determine the effect of risk of bias on the results. We will classify studies as low risk of bias if the randomisation sequence was generated appropriately, the allocation was concealed, if bias due to non-blinding was unlikely (with blinding of the assessor outcome evaluated only), and if incompleteness of outcome data was addressed.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

The authors would like to thank the contribution of the peer referees: Wounds Group Editors, Susan O’Meara, Joan Webster and Gill Worthy and referees Joel W Beam, Jane Burch and Amy Zelmer. The protocol was copy edited by Elizabeth Royle.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Appendix 1. Risk of bias assessment form

 

Criteria for a judgment of yes for the sources 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 non­opaque 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

Either 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

Either of the following:

  • Insufficient reporting of attrition or 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 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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Rabih Darouiche and Michael Mosier: conceived the review question, developed the protocol and performed part of writing or editing of the protocol. Made an intellectual contribution to the protocol and approved final version of the protocol prior to submission.
Jeffrey Voigt: conceived the review question, developed the protocol, co-ordinated the protocol development and completed the first draft of the protocol. Made an intellectual contribution to the protocol and approved final version of the protocol prior to submission.
All authors are guarantors of the work.

 

Contributions of editorial base

Nicky Cullum: edited the protocol; advised on methodology, interpretation and protocol content. Commented on the final protocol prior to submission.
Joan Webster, Editor: approved the final protocol prior to submission.
Sally Bell-Syer: co-ordinated 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.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Rabih Darouiche: received educational and research funds from CareFusion which manufactures chlorhexidine-alcohol skin antiseptic preparations.
Michael Mosier: none to declare.
Jeffrey Voigt: works as a consultant for medical technology companies and for insurers on evidence-based assessment and health technology assessment, but has not worked for any medical technology company (in the past or currently) that would seek to lose or gain from the results of this review.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Internal sources

  • Jeffrey Voigt, USA.
    Use of self paid access to reference databases, computer, printer

 

External sources

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

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
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