Silver coated endotracheal tubes for prevention of ventilator‐associated pneumonia in critically ill patients
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The main objective of this review is to determine whether silver coated ETTs are effective in reducing the risk of VAP and mortality in comparison with standard non‐coated ETTs.
Our secondary objectives are to ascertain whether silver coated ETTs are effective in reducing the following clinical outcomes.
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Adverse events (authors' definitions).
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Total duration of mechanical ventilation.
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Length of hospital stay.
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Costs.
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Time to VAP onset.
Background
Description of the condition
Ventilator‐associated pneumonia (VAP) is one of the most common nosocomial infections in mechanically ventilated and intubated patients (NNIS 2004; Vincent 1995). Nosocomial infections are hospital‐acquired infections. VAP occurs in 9% to 27% of all intubated patients (Chastra 2002). The etiology of VAP seems to be related to colonization of the aero‐digestive tract with pathogenic bacteria. Endotracheal tubes (ETTs) appear to be an independent risk factor for VAP (Girou 2000; Hubmayr 2002). ETTs are disposable catheters that are used for invasive mechanical ventilation and are inserted into the trachea primarily to maintain and establish a patent airway and to ensure sufficient exchange of oxygen and carbon dioxide. Most ETTs which are used today are made of polyvinyl chloride. Polyvinyl chloride ETT become colonized by bacteria after a few hours of intubation and mechanical ventilation (MV). These bacteria often organize into a thick biofilm, representing a large reservoir of micro‐organisms that can enter the lungs and cause pneumonia (Adair 1999; Costerton 2003; Inglis 1989; Sottile 1986). VAP is also linked with aspiration of contaminated secretions (Kollef 2004; Kollef 2005a). VAP can be divided into early‐onset and late‐onset disease. Early‐onset VAP occurs during the first four days that the patient receives mechanical ventilation and is often caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis or, uncommonly, by anaerobes. In comparison to early‐onset VAP, late‐onset VAP occurs over four days after intubation and is more commonly caused by Pseudomonas aeruginosa, Acinetobacter or Enterobacter species, or methicillin resistant Staphylococcus aureus (MRSA) (Bregeon 2001; Craven 1995; Kollef 1997; Kollef 1999; Mayhall 1997; Trouillet 1998). Moreover, VAP leads to increased healthcare costs, longer hospital stay and a doubling in the risk of mortality (Safdar 2005).
Description of the intervention
Silver has been used both as a prophylactic and a treatment for infectious and other diseases for many centuries. Hippocrates, known as the 'father of medicine', described silver as having healing and anti‐disease properties (Magner 1992). In theory, silver is highly attractive because of its broad spectrum antibiotic activity (Petering 1976). Silver coated ETT contain silver atoms that are slowly released as positively‐charged silver cations (Ag+) (Rello 2010; Thompson 1973). It is these silver ions that appear to have a strong anti‐microbial effect. The silver ions bind to bacterial cell walls causing disruption of the wall and death of the bacteria (Thompson 1973). Silver ions can also bind to bacterial enzymes and can prevent them from performing their function (Thompson 1973). Ionic silver reacts strongly with the thiol groups of vital enzymes in the bacteria thus inactivating the bacteria (Flemming 1990; Liau 1997; Russell 1994). Silver ions could also bind to bacterial deoxyribonucleic acid (DNA) thus interfering with cell division and replication (Feng 2000). Moreover, silver has the ability to reduce bacterial adhesion to devices in vitro (Ahearn 2000; Gabriel 1995) and to block biofilm formation on medical devices in animal models (Berra 2004; Olsen 2002). Recent studies have shown that the use of silver coated ETT to reduce lower lung colonization also reduces the incidence of VAP (Balazs 2004; Berra 2004; Berra 2006; Chaiban 2005; Hartmann 1999; Jones 2003; Olsen 2002; Pacheco‐Flowler 2004; Rello 2006; Rello 2010). Moreover, silver in combination with other anti‐microbials such as chlorhexidine could be another option for coating ETTs. In an animal study, silver with chlorhexidine coated ETTs showed no bacterial growth in comparison with uncoated tubes (Berra 2004); and were associated with less bacterial colonization in bronchial samples and lung parenchyma (Berra 2004). Thus, silver coated ETT may be a valuable intervention to prevent VAP.
How the intervention might work
There are a number of factors which can predispose to VAP. These factors are re‐intubation, nasogastric tubes, aspiration, supine positioning, pooling of subglottic secretions, coma, enteral nutrition, and pH‐altering agents (Collard 2003; Cook 1998b). Intubation and aspiration may bring the pathogenic bacteria into the respiratory tract and cause infection. Silver has a broad‐spectrum anti‐microbial activity in vitro by binding to microbial DNA and thus preventing bacterial replication; and by binding to the sulfhydryl groups of metabolic enzymes of the bacterial electron transport chain, causing their inactivation (Feng 2000; Flemming 1990; Illingworth 1998; Liau 1997; Petering 1976; Russell 1994; Thompson 1973). Because of the bactericidal effects of silver, silver coated ETTs could be an effective intervention against VAP.
Why it is important to do this review
The increase in length of hospital stay, healthcare costs and infection with multidrug‐resistant pathogens due to VAP is a major concern in the intensive care unit (ICU) (Cook 1998a; Kollef 2005a; Kollef 2005b; Rello 2002a). The prevention strategies aimed at reducing VAP often focus on modifiable risk factors for colonization and aspiration (Babcock 2004). However, there is no single strategy which completely eliminates VAP. Therefore, nowadays the prevention strategies are composed of a combination of several effective interventions on multiple modifiable risk factors, which in total reduce infections. These combinations are also known as care bundles. Unfortunately, the compliance to such bundles may be hindered by costs and lack of education of the personnel, resources and leadership (Cook 2000; Craven 2006; Rello 2002b). The benefits may diminish if the initiatives for education of the personnel are not continually reinforced or monitored (Zack 2002). Moreover, the claims of silver coated endotracheal tubes having antiseptic qualities, reducing the incidence of ventilator‐associated pneumonia, bacterial airway colonization and biofilm formation, have been promoted to a high degree in recent years. This may have led, or may lead, to an increase in the use of such devices. However, we know little of the costs, effectiveness and benefits of silver coated endotracheal tubes. It is therefore necessary to review the literature on this topic and investigate the claims from an evidence‐based perspective.
Objectives
The main objective of this review is to determine whether silver coated ETTs are effective in reducing the risk of VAP and mortality in comparison with standard non‐coated ETTs.
Our secondary objectives are to ascertain whether silver coated ETTs are effective in reducing the following clinical outcomes.
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Adverse events (authors' definitions).
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Total duration of mechanical ventilation.
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Length of hospital stay.
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Costs.
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Time to VAP onset.
Methods
Criteria for considering studies for this review
Types of studies
We will include all randomized controlled trials (RCTs) and quasi‐randomized trials which have evaluated the effects of silver coated ETTs.
Types of participants
We will include studies investigating mechanical ventilated, critically ill patients. Due to the variety of criteria for admission to adult ICUs, we will use authors' definitions of critically ill. We will exclude studies investigating children under 16 years, patients who are re‐intubated or patients requiring planned short‐term ventilation (less than 24 hours).
Types of interventions
We will include trials that compare silver coated ETTs or a combination of silver with any anti‐microbial coated ETTs with standard non‐coated ETTs or with other anti‐microbial coated ETTs such as chlorhexidine coated ETTs. We will exclude studies in which silver coated ETTs are not studied in the intervention group or control group.
Types of outcome measures
Primary outcomes
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The risk rate of VAP;
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Mortality (defined as early (< 30 days) or late (> 30 days)).
Secondary outcomes
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Adverse events (authors' definitions);
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Cost effectiveness of the silver coated ETTs (authors' definitions);
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Length of hospital stay;
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Total duration of mechanical ventilation;
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Time to VAP onset.
Search methods for identification of studies
Electronic searches
We will search the current issue of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), see Appendix 1; Ovid MEDLINE (1950 to present), see Appendix 2; Ovid EMBASE (1980 to present), see Appendix 3; and EBSCO CINAHL (1982 to present), see Appendix 4. We will not impose any restrictions on the basis of date of publication or language. We will contact experts in the field for information on unpublished studies which are finished but not yet published.
We will conduct a search for unpublished studies and clinical trials using the following site:
Searching other resources
We will search the reference lists of identified RCT reports and relevant systematic reviews for additional articles, contact companies and expert informants for further details of unpublished and ongoing trials, and check conference proceedings for any relevant trials. We will also contact experts in the field of VAP and silver technology to identify additional studies and information. Moreover, we will contact corresponding authors of all relevant studies for detail clarification, where necessary.
Data collection and analysis
Selection of studies
Two authors (GT, PK) will independently assess the titles and abstracts of studies identified in terms of their relevance and design. We will obtain full versions of the articles if they appear to meet the inclusion criteria in the initial assessment. A third author (SZ) will evaluate any discrepant judgments.
Data extraction and management
One review author (GT) will extract the data and summarize study details from all included studies using the specially designed data extraction form shown in Appendix 5; and will enter the data into Review Manager 5.1 (RevMan 5.1) for statistical analysis. Another review author (SZ) will check the study details from all included studies by randomly checking a sample and will independently check all quantitative data. In case of any disagreement on the details or quantitative data between GT and SZ, a third review author (HV) will be consulted as a referee. We will extract data from any papers in languages not known to the review authors with help from appropriate translators, wherever possible. We will also contact study authors through an open‐ended request in order to obtain missing information or for clarification, if necessary.
Assessment of risk of bias in included studies
Two authors (GT, SZ) will independently assess and rate the methodological quality of each trial using the Cochrane Collaboration tool for assessing risk of bias (Higgins 2011). We will judge the quality of the studies by evaluating the studies for the six domains found in Appendix 6. The six domains are as follows:
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Random sequence generation;
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Allocation concealment;
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Blinding of participants and personnel;
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Blinding of outcome assessment;
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Blinding of outcome assessment;
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Incomplete outcome data.
We will evaluate each study and assess separately for these domains. We will judge each explicitly as follows:
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Low risk of bias;
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High risk of bias;
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Unclear risk (lack of information or uncertainty over the potential for bias).
We will enter data on what was reported to have happened in the study in the ’risk of bias' table in Review Manager 5 (RevMan 5.1). We will obtain further information from the study authors if clarification is required. We will present a summary figure of the ’risk of bias in included studies’ in the review. This will provide a context for discussing the reliability of the results. We will resolve any disagreement by referring to a third author (HV) to reach a consensus. If there is still any disagreement, a discussion amongst all authors will be held to achieve consensus.
Measures of treatment effect
We will calculate summary estimates of treatment effect (with 95% confidence intervals (CI)) for each comparison. We will present mean differences (MD) for continuous outcomes. For dichotomous outcomes we will present the absolute risk reduction, that is the risk difference (RD). This is an absolute effect measure that expresses the difference between the experimental and the control event rates and allows calculation of the number needed to treat (NNT). We will analyse time to event data and the risk rate of VAP as risk ratios.
Unit of analysis issues
We will not include studies with cross‐over designs because these study designs are not appropriate designs for this research question.
Dealing with missing data
Whenever possible, we will contact the trial authors to request missing data. We will extract data regarding intention to treat (ITT). If study authors did not perform ITT analysis and participants lost to follow up are less than 20% of the total, but sufficient raw data are available, we will conduct an ITT analysis prior to data entry into RevMan 5.1. If more than 20% of the data are missing from the study, we will exclude the study from the meta‐analysis and perform an available case analysis. If possible, we will calculate missing statistics (such as standard deviations or correlation coefficients) from other statistics (such as standard error or CI ). We will perform sensitivity analysis to assess the impact of changing the assumptions made.
Assessment of heterogeneity
We will analyse the amount of heterogeneity using the I² statistic. If we detect statistical heterogeneity, we will explore the sources by considering differences in study design or definitions of outcome measures in the trials. If there is sufficient homogeneity in populations, study design and outcome measures (Higgins 2003), we will pool results following assessment for statistical heterogeneity. If the outcome of the heterogeneity is low, as indicated by an I² < 30%, we will use the fixed‐effect model to synthesize the results. If heterogeneity is moderate or high, as indicated by an I² > 30% but below 60%, we will use the random‐effects model to synthesize the results. We will refrain from pooling and restrict the analysis to a qualitative overview when I² values are above 60%.
Assessment of reporting biases
We will assess reporting bias through careful attention to quality assessment, particularly methodology. We will use funnel plot analysis to assess publication bias when there are greater than 10 studies included in the meta‐analysis. We will also use the Egger test (Egger 1997) to assess funnel plot asymmetry. A thorough search for unpublished studies through grey literature searches and contact with known experts in the field will also assist in reducing the risk of publication bias.
Data synthesis
We will carry out statistical analysis using the Review Manager software. The entry of data into Review Manager 5 (RevMan 5.1) will be done by one author (GT) and checked for accuracy by a second review author (HV). We will use fixed‐effect inverse variance meta‐analysis for combining data where trials examine the same intervention and the trials’ populations and methods are judged sufficiently similar. Where there is clinical or methodological heterogeneity between studies that is sufficient to suggest that treatment effects may differ between trials we will consider using a random‐effects meta‐analysis or not combining the data.
Subgroup analysis and investigation of heterogeneity
We will investigate heterogeneity by performing the following relevant subgroup analysis: length of intubation, that is patients intubated for 24 hours or more versus patients intubated for less than 24 hours.
Sensitivity analysis
We will perform sensitivity analyses to identify the effects of unpublished studies, small studies, allocation concealment, assessor blinding, and loss to follow up on the results. We will perform sensitivity analyses in order to explore the influence of the following factors on effect size:
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Including or excluding unpublished studies;
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Including or excluding studies judged as presenting high‐risk of bias;
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Sensitivity to ITT or per protocol (PP) data analysis assumptions;
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Including or excluding studies with industry funding.
Summary of findings table
We will use the principles of the GRADE system (Guyatt 2008) to assess the quality of the body of evidence associated with specific outcomes in our review and construct a summary of findings (SoF) table using the GRADE software. The specific outcomes which will be included in the SoF are as follows:
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Risk rate of VAP;
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Mortality (defined as early (< 30 days) or late (> 30 days));
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Adverse events (authors' definitions);
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Time to VAP onset.
The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. The assessment of the quality of a body of evidence considers within study risk of bias (methodologic quality), the directness of the evidence, heterogeneity of the data, precision of effect estimates and risk of publication bias.
