Antibiotic prophylaxis for preventing burn wound infection

  • Protocol
  • Intervention

Authors

  • Leticia A Barajas-Nava,

    Corresponding author
    1. IIB Sant Pau, Iberoamerican Cochrane Centre, Barcelona, Barcelona, Spain
    • Leticia A Barajas-Nava, Iberoamerican Cochrane Centre, IIB Sant Pau, C/Sant Antoni Ma Claret 171, Casa de Convalescència, Barcelona, Barcelona, 08041, Spain. leticia.barajas@cochrane.es.

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  • Jesus Lopez-Alcalde,

    1. Agencia Laín Entralgo (Cochrane Collaborating Centre), UETS, Health Technology Assessment Unit, Madrid, Madrid, Spain
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  • Ivan Solà,

    1. IIB Sant Pau, Iberoamerican Cochrane Centre, Barcelona, Barcelona, Spain
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  • Marta Roqué i Figuls,

    1. Institute of Biomedical Research (IIB Sant Pau)., Iberoamerican Cochrane Centre. CIBER Epidemiología y Salud Pública (CIBERESP) Spain, Barcelona, Catalunya, Spain
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  • Xavier Bonfill Cosp

    1. CIBER Epidemiología y Salud Pública (CIBERESP), Spain - Universitat Autònoma de Barcelona, Iberoamerican Cochrane Centre - IIB Sant Pau, Barcelona, Catalonia, Spain
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of antibiotic prophylaxis for preventing burn wound infections.

Background

Description of the condition

The International Society for Burn Injuries (ISBI) define a burn as an injury to the skin or other organic tissue caused by thermal trauma (Latarjet 1995). A skin burn is the destruction of some or all of the different layers of cells in the skin by a hot liquid (scald), a hot solid (contact burns) or a flame (flame burns). Skin injuries due to ultraviolet radiation, radioactivity, electricity or chemicals, as well as respiratory damage resulting from smoke inhalation, are also considered to be burns (Latarjet 1995; Peden 2002; Peden 2008; WHO 2006).

Burn injuries are a major source of morbidity and mortality; they represent a public health problem and a significant burden to the health care system (Church 2006; WHO 2006). More than 300,000 people die each year from fire-related burns, most of them occurring in low and middle-income countries (Mock 2008; Peden 2002).  However, burns also represent one of the main causes of injury-related death in some high-income countries, such as  the USA and some European countries (Church 2006; Hyder 2009; Mathers 2003; Miniño 2006; WHO 2006).  Millions of people suffer permanent disability and disfigurement, which is often stigmatizing; it is estimated that 10 million disability-adjusted life years (DALYs) are lost each year at a worldwide level (Hyder 2009; Mock 2008; Peden 2008). Burns create a heavy economic burden for health services. Treatment costs depend on the type and seriousness of the burn, as well as associated costs such as hospitalization, the need for long-term rehabilitation, the loss of schooling, future unemployment, and social rejection. In spite of this there are actually very few studies that provide evidence of the magnitude and cost of a burn (Mock 2008; Peden 2008).

It can be difficult to decide whether a burn wound is infected . Firstly the inflammation resulting from the injury can mimic infection. Secondly the interpretation of surface cultures is often difficult due to the extensive microbial colonisation of the wound (Ansermino 2004), microorganisms coming from the patient skin or from external sources can rapidly colonize the burn wound (Church 2006; Erol 2004; Wurtz 1995).

The nature and extent of the burn wound, together with the type and amount of colonizing microorganisms can influence the risk of invasive infection. The spectrum of infective agents that can be present in the burn wounds varies. Nowadays, gram-positive bacteria such as Staphylococcus aureus, and gram-negative bacteria such as Pseudomona aeruginosa are the predominant pathogens, however, other microorganisms can be implicated, such as fungi, rickettsias and viruses (Church 2006; Mayhall 2003; Polavarapu 2008; Sharma 2007). It should also be noted that multidrug resistant microorganisms, such as methicillin resistant Staphylococcus aureus (MRSA), have become frequent pathogens identified as present in the burned person (Church 2006; DeSanti 2005; Mayhall 2003; Sharma 2007). 

Burn wound infection is a serious problem: it can delay wound healing, can increase the scarring and can favour the proliferation of microorganisms that may result in invasive infections (Church 2006; Edwards 2004; Singer 2002). Nowadays, after the initial resuscitation of people who have been burned, up to 75% of all deaths are a consequence of infection, rather than osmotic shock and hypovolemia (decreased volume of blood plasma) (Ansermino 2004; Bang 2002; Church 2006; Sharma 2007; Sheridan 2005). Common invasive infections in the burned patient are pulmonary infections, urinary tract infection, bacteraemia and sepsis (Ansermino 2004; Church 2006; Pruitt 1998).

Description of the intervention

Preventing an infection of the burn wound is a team approach that should be an early focus of the care of the burned patient; with particular consideration given to infection-control practices and long-term rehabilitative care (Murray 2008).

Various interventions exist for preventing infections of the burn wound: early removal of full-thickness burned tissue (debridement); early definitive wound closure; strict enforcement of infection-control procedures (hand washing, use of personal protective equipment - i.e. gown, gloves, and masks); and the use of antimicrobial prophylaxis (Church 2006; DeSanti 2005; Murray 2008; Weber 2002; Weber 2004). There is a wide variety of topical antimicrobial agents available for use as prophylaxis for burn wound infections, such as silver nitrate or silver sulfadiazine (Ansermino 2004; Church 2006). Moreover, topical antimicrobials have been used together with systemic antibiotics to prevent and treat infection. There are different antibiotics, and different routes of administration that have been evaluated for the prevention of systemic infection in patients with burn wounds, for example - cephalothin or trimethoprim-sulfamethoxazole (Alexander 1982; Kimura 1998), but in spite of this there is scarce evidence to support the use of systemic antibiotics for the prevention of complications due to infection in burn patients (Kumar 2006; Ugburo 2004). In contrast, it has been shown that selective intestinal decontamination with antibiotics like polymyxin E, tobramycin and amphotericin B decreases bacterial colonization of the wound and the incidence of septic complications in burn patients (Barret 2001; de La Cal 2005).

This review will focus on the evidence for efficacy of antibiotic prophylaxis (oral (PO), intravenous (IV) or topical antimicrobials) for preventing burn wound infections.

How the intervention might work

Improvements in recovery for seriously burned patients have been attributed to medical advances in wound care and infection control practices (Church 2006; DeSanti 2005). Clinical management of these lesions remains complicated due to the diversity of intervening factors. Burn wounds are highly susceptible to infection due to the loss of skin integrity and the reduction of immunity mediated by the cells. Once the physical barrier of the skin has been compromised, a potential for the invasion of microbes into the body has been created (Murray 2008; Sharma 2007). An avascular necrotic tissue (eschar) will replace the skin and will be eventually colonized with microorganisms ( De Macedo 2005; Erol 2004; Sharma 2007). The proliferation of microorganisms in the burn wound may be followed by tissue invasion, giving rise to burn wound infection and invasive infections. Moreover, burn injury has a severe impact on the host’s immune system, resulting in a general impairment of the host defences (Munster 1984; Sharma 2007).

Before the wide adoption of early excision and closure of deep wounds, infection was a frequent occurrence in the burn wound (Sheridan 2005). However, nowadays, the early excision of eschar and avascular tissues improves the perfusion of the burnt tissues, and allows any systemic antibiotics to reach adequate therapeutic levels in the burn wound (Church 2006; Kumar 2006; Mayhall 2003). However, in spite of the fact that local infection such as sepsis is now less frequent, infection in the burn patient continues to be a serious threat (Church 2006; Kumar 2006; Sheridan 2005).

Considering these facts, antibiotic prophylaxis may be useful for protecting the burned person against wound infection and invasive infections.

Why it is important to do this review

The use of prophylactic antibiotics has been considered useful to prevent and treat infections in the burned person (Polavarapu 2008). In some centres, patients with a positive microbiological culture from a burn site were given systemic antibiotic prophylaxis in an attempt to prevent wound infection and sepsis (Atoyebi 1992; Haq 1990; Lee 2009; Onuba 1987). However, this is now controversial (Ansermino 2004). There is a paucity of high quality research evidence to determine the effectiveness and cost-efficiency of antibiotic prophylaxis for preventing burn wound infection (Avni 2010; Lee 2009; Ugburo 2004). Moreover, the use of prophylactic antibiotics may not be safe: it may increase the risk of diarrhoea due to overgrowth of toxigenic strains of Clostridium difficile and other secondary infections, allergic reactions to the drug or bone marrow suppression (Alexander 2009; Church 2006; Ergun 2004; Still 2002). Finally, it may also promote the emergence of resistant strains of micro-organisms, making the treatment of infections even more difficult (Altoparlak 2004; Church 2006; Murphy 2003).

There is considerable debate concerning the use of antibiotic prophylaxis for the prevention of the burn wound infection and therefore a systematic review of the evidence is warranted.

Objectives

To assess the effects of antibiotic prophylaxis for preventing burn wound infections.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs), published or unpublished, with allocation to interventions at the individual (Patient-RCT) or at the group level (Cluster-RCT), testing the efficacy and safety of antibiotic prophylaxis for the prevention of burn wound infections. Quasi-randomised studies will be excluded.

Types of participants

Studies involving people of any age or gender, with any type of burn injury to the epidermis, dermis, subcutaneous tissues, vessels, nerve, tendons, or bone admitted to any unit in the hospital setting or treated in an outpatient setting.

We will include studies regardless of the severity of the burn (determined by either clinical evaluation or objective assessment, or both) or the method of burn injury (e.g., chemical, scald, or flame burns). We will not exclude studies depending on the presence of inhalation injury as a co-morbidity. We will exclude studies that include mixed population, i.e. people with already infected wounds in addition to those without an infection unless the data can be presented separately.

Types of interventions

We will assess antibiotic prophylaxis compared with placebo, no treatment, usual care or an alternative intervention (for example: non pharmacological - isolation of the burn patient, surgical excision; or pharmacological, such as another antibiotic regimen (trials comparing different antibiotics or different antibiotic dosages, routes of administration, timings or duration of administration)).

Prophylaxis is defined as the administration of antibiotics to patients without a documented infection, regardless of the signs of systemic inflammation, with the intention of preventing infection in the wound and invasive infection, including systemic antibiotics given intravenously, orally, or by intramuscular injection, oral nonabsorbables antibiotics, or topical antibiotics (dressings, ointments, or by inhalation). Antibiotics can be given at any moment after admission ("general") or can be specifically connected to a surgical procedure ("perioperative"). We will not consider a minimum duration of the intervention or of the follow-up as an inclusion criteria.

Studies evaluating antibiotic impregnated catheters will be excluded, as will evaluations of ointments or dressings that contain antimicrobials (iodine, chlorhexidine), non-antibiotics or antifungals. Dressings for superficial burns with partial thickness have been evaluated in a previous review by Wasiak 2008, but the principal objective of that study was not the evaluation of antibiotic prophylaxis.

Types of outcome measures

Primary outcomes
  1. Burn wound infection: Studies must report an objective measure of burn wound infection in order to be included in the review. Diagnosis should rely on clinical examination (burn wound appearance) and culture data, if possible. However, burn wound infections diagnosed only by clinical examination will be also eligible.

  2. Infections in the burned patient: such as pneumonia, urinary tract infection, bacteremia or blood infection (sepsis), or central venous catheter-associated bloodstream infections. We will admit any metric for quantifying infections, such as incidence rate or incidence density rate.

  3. Infection-related mortality: for example, mortality due to burn wound infection, sepsis, or another infection complication.

  4. Adverse events: as considered by the study investigators to be related to the antibiotic prophylaxis, such as toxicity, allergies, antibiotic-associated diarrhoea due to the overgrowth of toxigenic strains of Clostridium difficile, etc.

Secondary outcomes
  1. Objective measures of wound healing rate: such as time to complete healing; proportion of wounds completely healed within a trial period; proportion of participants with completely healed wounds; or proportion of wounds partly healed in a specified time period.

  2. Antibiotic resistance: defined as clinical infection or colonization caused by bacteria resistant to one or more of the antibiotics included in the prophylactic regimen (proportion or rate of isolates of a specific pathogen ).

  3. All-cause mortality: We will try to analyse this outcome according to longest common time point of assessment among the included studies.

  4. Length of hospital stay (LOS).

Studies will be eligible for inclusion even if they only report secondary outcomes, as these outcomes are relevant to patients.

Search methods for identification of studies

Electronic searches

We will search the following electronic databases for potentially relevant studies (without any language or date of publication restriction):

  • Cochrane Wounds Group Specialised Register

  • The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library latest Issue).

  • Ovid MEDLINE - 1950 to present

  • Ovid EMBASE - 1980 to present

  • EBSCO CINAHL - 1982 to present

The Cochrane Central Register of Controlled Trials (CENTRAL) will be searched using the following exploded MeSH headings and keywords:

#1 MeSH descriptor Burns explode all trees
#2 (burn or burns or burned or scald*):ti,ab,kw
#3 (thermal NEXT injur*):ti,ab,kw
#4 (#1 OR #2 OR #3)
#5 MeSH descriptor Anti-Bacterial Agents explode all trees
#6 MeSH descriptor Anti-Infective Agents, Local explode all trees
#7 (antibiotic* or amoxicillin or ampicillin* or bacitracin or cephalothin or cefazolin or  cefotaxime or cefoperazone or ceftazidime or ceftriaxone or cefuroxime or chloramphenicol or ciprofloxacin or clarithromycin or clindamycin or cloxacillin or colistin or colymycin or erythromycin or flucloxacillin or furazolidone or "fusidic acid" or gentamicin or  gramicidin or imipenem or "mafenide acetate"  or mupirocin or natamycin or neomycin or  nitrofurazone or oxacillin or penicillin or piperacillin or polymyxin or rifam* or "silver  nitrate" or "silver sulfadiazine"  or "sulfacetamide sodium" or tobramycin or amphotericin  or tazocin or teicoplanin or tetracylcin or (trimethopri* NEXT sulfamethoxazole) or vancomycin):ti,ab,kw
#8 (#5 OR #6 OR #7)
#9 (#4 AND #8)

This strategy will be adapted to search Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL. The Ovid MEDLINE search will be combined with the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity- and precision-maximizing version (2008 revision) (Lefebvre 2009). The EMBASE and CINAHL searches will be combined with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN 2009).

Websites such as www.controlled-trials.com or www.clinicaltrials.gov will be searched in order to find additional ongoing clinical trials.

Searching other resources

The references of all identified studies will be searched in order to find any further relevant trials.

Data collection and analysis

Selection of studies

At least two review authors (LB, CJ) will independently screen all titles and abstracts of studies identified by the search strategy to assess for eligibility. If a reliable decision cannot be made based on this information, the full text version will be obtained for further assessment.

The full text versions of all potentially eligible studies will be retrieved and at least one pair of review authors will assess the eligibility of each study against the inclusion criteria. We will detail in the table of excluded studies all studies that appear initially to meet our inclusion criteria, but on closer examination fail to, and we will document the reasons for exclusion. The two review authors will resolve any disagreement by discussion, if there is no consensus; they will consult a third review author.

Data extraction and management

Two review authors (LB, CJ) will independently extract data from included studies using a predefined data form. We will extract details of participants, setting, methods, intervention and control, outcome data, risk of bias and results. Any discrepancy will be resolved by consensus. If there is no consensus a third review author or the editorial base of the Cochrane Wounds Group will settle the discrepancies. When information regarding any of the above is unclear, we will attempt to contact authors of the original trial reports to provide further details.

Assessment of risk of bias in included studies

At least two review authors will independently assess the risk of bias of each included study. We will use the risk of bias tool designed by the Cochrane Collaboration (Higgins 2009a).

We will consider the following domains:

  1. Sequence generation - we will describe for each included study the methods used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups. 

  2. Allocation concealment - we will describe for each included study the method used to conceal the allocation sequence in sufficient detail and determine whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.  

  3. Blinding - we will describe for each included study all the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Where blinding is not possible, we will assess whether the lack of blinding was likely to have introduced bias. Blinding will be assessed separately for different outcomes or classes of outcomes. We will also describe if the outcome assessors are blind to intervention. Note: In some situations there may be partial blinding e.g. where outcomes are self-reported by unblinded participants but they are recorded by blinded personnel without knowledge of group assignment. 

  4. Incomplete outcome data - we will assess the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomized participants), reasons for attrition/exclusions where reported, and any re inclusions in analyses performed by the review authors.

  5. Selective outcome reporting - where possible we will assess whether study reports are free of any suggestion of selective outcome reporting.

  6. Additional sources of bias - for cluster-randomised trials, we will assess these additional sources of bias: recruitment bias; baseline imbalance in either clusters or individuals (patient); loss of clusters and incorrect analysis (Higgins 2009b, Section 16.3.2). For the trials where the unit of randomisation is the patient we will also assess the existence of additional sources of bias: Were baseline characteristics similar?

Assessments will be made for each main outcome (or class of outcomes). We will label each criterion as 'Yes' (meaning low risk of bias), 'No' (high risk of bias) or 'Unclear'. See Appendix 1 for details of criteria on which the judgements will be based. We will try to obtain this information from the trial reports but, if there is not enough information to make a judgement, we will write to the trial authors for clarification. Disagreements will be resolved by discussion and consensus, and by consulting a third review author (JLA or IS if necessary).

Two figures will be also included in the review: a ‘Risk of bias graph figure’ and a ‘Risk of bias summary figure’. We will assess the overall risk of bias for each outcome (or class of similar outcomes) within each study. Each outcome (or class of outcomes) will be defined as having a ‘low risk of bias’ only if it is at low risk of bias for all the domains; at ‘high risk of bias’ if it demonstrates high risk of bias for one or more of the domains; or at ‘unclear risk of bias’ if it demonstrates unclear risk of bias for at least one key domain without any of the other domains being described as ‘high risk of bias’.

Finally, we will incorporate the results of the risk of bias assessment into the review through systematic narrative description and commentary and we will explore the effect of the risk of bias in the meta-analysis by carrying out sensitivity analysis as detailed below.

Measures of treatment effect

We will report study results, organised by type of intervention and study design. Analyses will be stratified by antibiotic mode and intervention: systemic antibiotic prophylaxis (general); systemic antibiotic prophylaxis (perioperative); non-absorbable antibiotics, and  topical antibiotics. Regimens including both systemic and non-absorbable or topical antibiotics will be included in the systemic category. All outcome effects will be shown with their associated 95% confidence intervals (CI). We will report, when possible, the risk ratio (RR) for dichotomous data (for example, incidence of patients with infection);  for continuous data (for example, length of hospital stay) we will report mean difference (MD) and for time-to-event date (for example, time to healing) we will report hazard ratios (HR).

Dealing with missing data

Missing outcome data will be assessed for the included studies and reported. We will contact the authors of the primary studies for missing data and clarification of issues. If we do not obtain this data, it will be clearly documented on the data extraction form and the narrative of the review. We will explore the impact in the overall treatment effect of including studies with high levels of missing data (>20%) using a sensitivity analysis.

As far as possible, we will carry out analyses on an intention-to-treat basis for all dichotomous outcomes; i.e. we will attempt to include all participants randomised to each group in the analyses, irrespective of what happened subsequently, assuming that missing participants experienced a negative outcome. We will explore the impact of this assumption using a sensitivity analysis.

Assessment of heterogeneity

Where possible we will display graphically the results of clinically and methodologically comparable studies and will assess heterogeneity visually. We will also use the I² statistic (Higgins 2003) which describes the percentage total variation across studies that is due to heterogeneity rather than chance. We will judge the importance of the observed value of I² depending on the magnitude and direction of effects and the strength of evidence for heterogeneity (moderate to high heterogeneity will be defined as I² ≥ 50%) (Deeks 2009).

Assessment of reporting biases

If sufficient studies are found, we will assess publication bias by means of a funnel plot for each outcome (a simple scatter plot of the intervention effect estimates from individual studies against some measure of each study’s size or precision (Sterne 2009)). Funnel plot asymmetry will be assessed statistically. If there is evidence of asymmetry, publication bias will be considered as only one of a number of possible explanations.

Data synthesis

The outcome measures from the individual trials will be combined in a meta-analysis to provide a pooled effect estimate if there are enough studies and if these studies are sufficiently similar.

Cluster-randomised trials will be combined with individually randomised trials in the same meta-analysis only if unit of analysis errors are not detected. If the data analysis is determined to have been performed incorrectly and sufficient information is available, an 'approximately correct analysis' will be performed for each cluster-RCT. If it is not possible, the results of the study will be reported as point estimates of the intervention effect without presentation of any statistical analysis (P values) or confidence intervals and they will not be included in the meta-analysis (Higgins 2009b). 'Unit of analysis error' is defined as taking place when in some studies individuals are assigned in groups, rather than in an individual manner (i.e., by healthcare centre, hospital, or community). When this is done, often the assignment unit is different from the analysis unit, i.e., if subjects are assigned by group but analysed individually (Whiting-O'Keefe 1984).

We will use a random-effects model to pool data, although we will assess in the sensitivity analysis the influence of a fixed-effect model. In the event that relevant statistical heterogeneity is detected (I² ≥50%) or if the meta-analysis is inappropriate for any other reason, we will present a narrative analysis of eligible studies, providing a descriptive presentation of the results, grouped by intervention and study design, with supporting tables.

We will perform the analyses using Review Manager 5 (RevMan 2008) a statistical package provided by the Cochrane Collaboration and we will present the results with 95% confidence intervals (CI).

Subgroup analysis and investigation of heterogeneity

Analyses will be conducted separately for the following groups:

  1. Patient age: children (ages between 0 and 18 years) compared with adults (>18 years).

  2. Severity of the burn: burns involving less than 20% total burned body surface area (TBSA) versus burns involving greater than 20% TBSA.

Sensitivity analysis

If there are sufficient studies the following sensitivity analyses will be undertaken:

  1. We will repeat the meta-analysis to assess the effect of including only studies with allocation to interventions at the group level ('cluster designs').

  2. We will assess the effect of including studies with high or unclear risk of bias (as defined above), excluding these trials in the sensitivity analysis.

  3. We will assess the effect of missing data, excluding studies with high levels of missing data (>20%) in the sensitivity analysis.

  4. We will assess the impact of imputation of missing data performing a sensitivity analysis without imputation (i.e. analyzing available data on the included papers).

  5. We will assess the effect of the statistical model chosen, using a fixed-effect model in the sensitivity analysis.

  6. We will do sensitivity analyses restricted to studies including patients with specific co morbidities (i.e. diabetes mellitus, respiratory or kidney failure).

Acknowledgements

Leticia A. Barajas-Nava is a doctoral candidate at the Pediatrics, Obstetrics and Gynecology and Preventive Medicine Department, Universitat Autònoma de Barcelona, Barcelona, Spain. The Iberoamerican Cochrane Center, Barcelona, Spain and Hospital Sant Pau for its locations. The Consejo Nacional de Ciencia y Tecnología (CONACYT) México for it's support. The authors would like to acknowledge the contribution of the referees (Roy Buffery, Fiona Campbell, Rachel Richardson and Mary Mondozzi) and Wounds Group Editors (Joan Webster, Susan O'Meara and Gill Worthy)

Appendices

Appendix 1. Risk of bias judgement criteria for RCT studies

1.  Was the allocation sequence randomly generated?

Yes, 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.

No, 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 ‘Yes’ or ‘No’.

2.  Was the treatment allocation adequately concealed?

Yes, 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.

No, 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 ‘Yes’ or ‘No’. 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?

Yes, 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.

No, high risk of bias

Any one of the following:

  • No blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding.

  • Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken.

  • Either participants or some key study personnel were not blinded, and the non-blinding of others likely to introduce bias.

Unclear

Any one of the following:

  • Insufficient information to permit judgement of ‘Yes’ or ‘No’.

  • The study did not address this outcome.

 4.  Were incomplete outcome data adequately addressed?

Yes, 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.

No, 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 standardized 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 ‘Yes’ or ‘No’ (e.g. number randomized 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?

Yes, 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)

No, 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 ‘Yes’ or ‘No’. It is likely that the majority of studies will fall into this category.

 6.  Other sources of potential bias:

Yes, low risk of bias

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

No, 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

  • Stopped early due to some data-dependent process (including a formal-stopping rule); 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.

History

Protocol first published: Issue 10, 2010

Contributions of authors

Leticia Barajas: Conceiving, designing, drafting and writing the protocol. Identifying references for the protocol background. Organising retrieval of papers. Statistical analysis and interpretation. Providing a methodological, clinical and policy perspective to the manuscript. Approval of the final draft document.
Jesús López Alcalde: Support in designing, drafting and writing the protocol.  Support in organising retrieval of papers. Providing a methodological, clinical and policy perspective to the manuscript. Approval of the final draft document.
Ivan Solá: Advice on the search strategy and review of the protocol text.
Marta Roqué: Will be responsible for the statistical analysis and interpretation of results.
Xavier Bonfill: Critically commenting on the intellectual content of the protocol. Approval of the final draft document.

Contributions of editorial base:

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

Declarations of interest

Leticia Andrea Barajas Nava: None known.
Jesús López Alcalde: None known. 
Ivan Solà Arnau: None known. 
Marta Roqué: None known.                                                                                                                                          
Xavier Bonfill Cosp: None known.

Sources of support

Internal sources

  • Iberoamerican Cochrane Centre. IIB Sant Pau. Barcelona, Spain.

  • Department of Pediatrics, Obstetrics and Gynecology and Preventive Medicine. Universitat Autònoma de Barcelona, Spain.

External sources

  • Agencia de Calidad del Sistema Nacional de Salud. CIBERESP. Ministerio de Sanidad y Política Social, Spain.

  • Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico.

Ancillary