Antimicrobial‐impregnated central venous catheters for prevention of catheter‐related bloodstream infection in newborn infants

Abstract

Background

Central venous catheter‐related bloodstream infection is an important cause of mortality and morbidity in newborn infants cared for in neonatal units. Potential strategies to prevent these infections include the use of central venous catheters impregnated with antimicrobial agents.

Objectives

To determine the effect of antimicrobial‐impregnated central venous catheters in preventing catheter‐related bloodstream infection in newborn infants.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 8), MEDLINE (1966 to September 2015), EMBASE (1980 to September 2015), CINAHL (1982 to September 2015), conference proceedings and previous reviews.

Selection criteria

Randomised or quasi‐randomised controlled trials comparing central venous catheters impregnated or coated with any antibiotic or antiseptic versus central venous catheters without antibiotic or antiseptic coating or impregnation in newborn infants.

Data collection and analysis

We extracted data using the standard methods of the Cochrane Neonatal Group, with independent evaluation of risk of bias and data extraction by two review authors.

Main results

We found only one small trial (N = 98). This trial found that silver zeolite‐impregnated umbilical venous catheters reduced the incidence of bloodstream infection in very preterm infants (risk ratio 0.11, 95% confidence interval 0.01 to 0.87; risk difference ‐0.17, 95% CI ‐0.30 to ‐0.04; number needed to treat for benefit 6, 95% CI 3 to 25].

Authors' conclusions

Although the data from one small trial indicates that antimicrobial‐impregnated central venous catheters might prevent catheter‐related bloodstream infection in newborn infants, the available evidence is insufficient to guide clinical practice. A large, simple and pragmatic randomised controlled trial is needed to resolve on‐going uncertainty.

Plain language summary

Antimicrobial‐impregnated central venous catheters to prevent bloodstream infection in newborn infants

Review question: In newborn infants requiring a central venous catheter (CVC), are antimicrobial‐impregnated CVCs compared to standard CVCs effective in preventing acquired bloodstream infection?

Background: Infection in the bloodstream is a frequent and harmful complication for newborn infants who have a central venous catheter (a cannula that extends several centimetres into the infant's blood vessel). While the catheter may provide a secure route for delivering drugs and nutrition, it may also be a locus for infecting organisms to grow and cause long‐term or more severe infection. One potential method of reducing this serious complication is to use central venous catheters that contain antiseptics or antibiotics to stop organisms from sticking to or growing on the catheter.

Study characteristics: We found only one small randomised controlled trial (with 98 very preterm infants participating) that addressed this question.

Key results: This trial showed that central venous catheters containing antiseptics or antibiotics to stop organisms from sticking to or growing on the catheter could reduce the chance of infants developing a bloodstream infection by about 90%. Becasue the trial was small, however, this finding is not certain.

Conclusions: The trial did provide some evidence that antimicrobial‐impregnated central venous catheters can prevent bloodstream infection in newborn infants, but further, large trials are needed to resolve this question fully.

Background

Description of the condition

Bloodstream infection is the most common serious complication associated with the use of central venous catheters (CVCs). The most commonly used CVCs in neonatal practice are umbilical venous catheters or peripherally‐inserted percutaneous CVCs; these are used to deliver drugs, fluids or parenteral nutrition for newborn infants. Micro‐organisms can gain access through the CVC entry site or, less commonly, via the catheter hub into the lumen or the tract of the CVC (Salzman 1995). Microbial pathogens adhere to the material of the CVC and secrete a protective intraluminal or extraluminal biofilm of extracellular polymeric substances (Machado 2009). Bacteria or fungi proliferating within the biofilm are relatively protected from circulating antimicrobial agents, enabling sustained colonisation (Ramirez de Arellano 1994; Stewart 2001). CVC‐associated thrombosis can act as an additional nidus for infection (Thornburg 2008). It is often necessary to remove the CVC in order to clear the infection (Benjamin 2001).

The reported incidence of CVC‐related bloodstream infection ranges from about 5% to 30%, depending on the precise diagnostic criteria used and the demographics of the population (Trotter 1996a; Trotter 1996b; Cartwright 2004; Van der Zwet 2005; Garland 2008; Hoang 2008; Ohki 2008; Olsen 2009; O'Grady 2011). Very preterm (less than 32 weeks gestation) infants are at the highest risk, but inter‐unit variation in the incidence of CVC‐associated bloodstream infection is not fully explained by case mix, and may relate to care or infection control practices (Wong 2012). Other putative risk factors include prolonged use of parenteral nutrition and insertion of the CVC after the first postnatal week (Mahieu 2001c; Mahieu 2001d).

The most common causes of CVC‐related bloodstream infections in newborn infants are coagulase‐negative staphylococci, Gram‐negative bacilli (mainly enteric bacilli), Gram‐positive cocci (Staphylococcus aureus (S. aureus), enterococci), and fungi (predominantly Candida species) (Makhoul 2002; O'Grady 2002; Stoll 2002; Isaacs 2003; Isaacs 2004; Gordon 2006; De Brito 2010). Newborn infants, particularly very preterm infants, with acquired bloodstream infection have a higher risk of mortality and a range of important morbidities that require intensive care and mechanical ventilation: bronchopulmonary dysplasia, necrotising enterocolitis, retinopathy of prematurity, hepatic dysfunction and prolonged hospitalisation (Saint 2000; Mahieu 2001a; Mahieu 2001b; Chapman 2003; Payne 2004; Adams‐Chapman 2006; Hermans 2007; Lahra 2009). Bloodstream infection is also associated with higher rates of several adverse neurodevelopmental outcomes, long‐term disability, vision and hearing impairment, and cerebral palsy (Stoll 2004; Shah 2008; Bassler 2009).

Various strategies to reduce and prevent CVC‐related bloodstream infections have been introduced, often as care bundles. These include strict aseptic precautions when inserting and accessing the CVC, use of needleless intravascular catheter systems and prompt removal when the CVC is no longer needed (O'Grady 2002; Yébenes 2004; Pronovost 2006; Miller 2010; Sannoh 2010; Vanholder 2010; Wirtschafter 2010; Kaplan 2011; O'Grady 2011; Schulman 2011). Care bundles have been shown to reduce bloodstream infection rates in adult, paediatric and neonatal intensive care studies (Pronovost 2006; Miller 2010; Wirtschafter 2010; Kaplan 2011; Schulman 2011). However, despite these strategies, CVC‐related infections remain a major cause of morbidity and mortality in newborn infants and other interventions are required to reduce the infection rates further.

Description of the intervention

CVCs are vascular cannulae terminating in a large (central) vein. In neonatal practice, the most commonly used CVCs are umbilical venous catheters (usually inserted within the first postnatal day), and peripherally‐inserted percutaneous CVCs (inserted via a peripheral vein). Other CVCs that are commonly used in caring for older children or adults, such as those inserted directly via a central vein (typically the femoral or subclavian vein) and subcutaneously "tunnelled" catheters (usually requiring a surgical procedure to insert), are much less commonly used in neonatal care.

Most commercially available CVCs are made of a silicone or polyurethane (polytetrafluoroethylene) based material. The intervention under study here is the use of CVCs coated with, or manufactured from, materials impregnated with antibiotic or antiseptic agents. Such catheters have been available in adult practice for several years, and emerging evidence supports their clinical and cost‐effectiveness in preventing bloodstream infection (Alonso‐Echanove 2003; Eggimann 2003; Shorr 2003; Casey 2008; Gilbert 2008; Hockenhull 2008; Halton 2009; Walz 2010; Lambert 2012). A US Centre for Disease Control (CDC) expert consensus statement recommends the "use of a chlorhexidine/silver sulphadiazine or minocycline/rifampicin‐impregnated CVCs in [paediatric and adult] patients whose catheter is expected to remain in place for more than 5 days if, after successful implementation of a comprehensive strategy to reduce rates of [CVC‐related bloodstream infection], the [CVC‐related bloodstream infection] rate is not decreasing" (O'Grady 2011).

How the intervention might work

Use of antimicrobial‐impregnated or coated CVCs might reduce micro‐organism adhesion and survival, thus inhibiting intraluminal or extraluminal biofilm formation. Inhibited or abolished biofilm formation would be expected to reduce the incidence of bloodstream infection, reduce the need for CVC removal, and reduce infection‐associated mortality and morbidity (Cicalini 2004).

In vitro studies suggest that antiseptic‐ and antibiotic‐impregnated CVCs are equally effective at inhibiting microbial adherence and colonisation (Sampath 2001), but a systematic review of trials with mainly adult participants, found that antibiotic‐impregnated (minocycline/rifampicin) CVCs were more effective than antiseptic‐impregnated (chlorhexidine/silver sulphadiazine) CVCs at preventing catheter‐related bloodstream infections (Casey 2008). Although there is the possibility that prolonged use of antibiotic‐impregnated CVCs might select for antibiotic‐resistant micro‐organisms, evidence exists that if bacteria, including methicillin‐resistant Staphylococcus aureus (S. aureus) and vancomycin‐resistant enterococci, are exposed to antibiotic combinations (rather than a single agent) they are less likely to develop antibiotic resistance (Tambe 2001; Munson 2004; Aslam 2007).

Why it is important to do this review

There are important differences between adults and infants that mean that antimicrobial‐impregnated CVCs might work differently. Firstly, infants’ veins are much smaller and so CVCs need to be narrower, with associated higher flow rates per unit of cross‐sectional area. Secondly, CVCs are often kept in place for much longer in infants and the risk of infection may increase over the time a CVC is in place (Schelonka 2006). Thirdly, there is a higher incidence of infection in newborn infants, especially in very preterm and very low birth weight infants, as their immature immune systems and thin, immature skin increase susceptibility (Borghesi 2008). Finally, the consequences of infection in newborn infants are different and more serious than in older children and adults.

Given the potential for the use of antimicrobial‐impregnated CVCs to affect important outcomes for newborn infants, we will undertake a systematic review to identify, appraise and synthesise the available evidence from randomised controlled trials.

Objectives

To determine the effectiveness of antimicrobial‐impregnated CVCs compared to standard CVCs in preventing acquired bloodstream infection in newborn infants.

Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi‐randomised controlled trials (including cluster randomised trials).

Types of participants

Newborn infants who are to have a CVC placed.

Types of interventions

1. Intervention: CVCs impregnated or coated with any antibiotic or antiseptic agent.

2. Control: any other CVC without antibiotic or antiseptic coating or impregnation.

Trials which assess the effect of antibiotic‐impregnated CVCs as part of a package of infection control measures (care bundle) were eligible for inclusion, but we planned to analyse these separately from trials of discreet interventions.

Types of outcome measures

Primary outcomes

1. Incidence (and rates per 1000 catheter‐days) of laboratory‐confirmed bloodstream infection, where the CVC was in place on the day or the day before the blood sample for microbial culture was obtained. If the CVC was placed on the first postnatal day, then it must have been in place for more than two calendar days on the day that the blood sample for microbial culture was obtained.

Secondary outcomes

1. Mortality due to all causes prior to hospital discharge and at one year corrected age.

2. Neurodevelopmental outcomes assessed after 12 months corrected age using validated tools: neurological evaluations; developmental scores; and classifications of disability, including auditory and visual disability. We will define neurodevelopmental impairment as the presence of one or more of the following: non‐ambulant cerebral palsy; developmental quotient more than two standard deviations below the population mean; and blindness (visual acuity less than 6/60) or deafness (any hearing impairment requiring or unimproved by amplification).

3. Death or neurological impairment assessed after 12 months corrected age.

4. Other morbidity developing after enrolment in trial until discharge from hospital:

   • bronchopulmonary dysplasia (oxygen supplementation at 36 weeks postmenstrual age);

   • necrotising enterocolitis (Bell stage 2 or 3);

   • retinopathy of prematurity, requiring treatment (medical or surgical).

5. Length of index CVC use (days).

6. Incidence of CVC removal for suspected or confirmed CVC infection.

7. Length of stay in the neonatal intensive care and overall hospital stay (days).

8. Proportion of catheters colonised with antibiotic‐resistant organisms at removal.

Search methods for identification of studies

We used the standard search strategy of the Cochrane Neonatal Group.

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library (2015, issue 8), MEDLINE (1966 to September 2015), EMBASE (1980 to September 2015), and CINAHL (1982 to September 2015) using a combination of the following text words and MeSH terms:

[infant, newborn OR infant, premature OR infant, low birth weight OR infan* OR neonat*]

AND

[catheters, Indwelling OR catheterization, central venous OR central near3 cathet* OR central near3 cannul* OR central near3 line OR CVC OR CVL OR PCVC OR PICC OR Umbilical, Veins OR UVC OR UAC OR umbilical near3 cathet* OR umbilical near3 cannul* OR umbilical near3 line OR Broviac OR Hickman OR antibiotic impregnat* OR antimicrobial impregnat* OR antibacterial impregnate* OR antiseptic impregnat* OR antibiotic coat* OR antimicrobial coat* OR antibacterial coat* OR antiseptic coat*]

We limited the search outputs with the relevant search filters for clinical trials as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We did not apply any language restrictions.

We searched ClinicalTrials.gov and Current Controlled Trials for completed or ongoing trials.

Searching other resources

We examined reference lists in previous reviews and included studies. We searched the proceedings of the annual meetings of the Pediatric Academic Societies (1993 to 2015), the European Society for Pediatric Research (1995 to 2014), the Royal College of Paediatrics and Child Health (2000 to 2015), the Perinatal Society of Australia and New Zealand (2000 to 2015), the European Society for Paediatric Infectious Diseases (2005 to 2014), and the Infectious Diseases Society of America (2003 to 2014). Trials reported only as abstracts were eligible if sufficient information was available from the report, or from contact with the authors, to fulfil the inclusion criteria.

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Group.

Selection of studies

We screened the title and abstract of all studies identified by the above search strategy; two review authors independently assessed the full articles for all potentially relevant trials. We excluded those studies that did not meet all of the inclusion criteria and stated the reason for exclusion. We discussed any disagreements until consensus was achieved.

Data extraction and management

Two authors independently extracted data using a data collection form to aid extraction of information on design, methodology, participants, interventions, outcomes and treatment effects from each included study. We discussed any disagreements until we reached consensus. If data from the trial reports were insufficient, we contacted the trialists for further information.

Assessment of risk of bias in included studies

We used the criteria and standard methods of the Cochrane Neonatal Group to assess the methodological quality of any included trials. Two authors conducted the assessment of risk of bias. We resolved disagreements in consultation with a third author. We planned to request additional information from the trial authors to clarify methodology and results if necessary.

We evaluated the following issues in the 'Risk of bias' tables:

Random sequence generation ‐ we categorised the method used to generate the allocation sequence as:

• low risk ‐ any truly random process, e.g. random number table; computer random number generator;

• high risk ‐ any non‐random process, e.g. odd or even date of birth; hospital or clinic record number; and

• unclear risk ‐ no or unclear information provided.

Allocation concealment ‐ we categorised the method used to conceal the allocation sequence as:

• low risk ‐ e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes;

• high risk ‐ open random allocation, e.g. unsealed or non‐opaque envelopes, alternation; date of birth; and

• unclear ‐ no or unclear information provided.

Blinding ‐ we assessed blinding of participants, clinicians and caregivers, and outcome assessors separately for different outcomes and categorised the methods as:

• low risk;

• high risk; and

• unclear.

Incomplete outcome data ‐ we described the completeness of data, including attrition and exclusions from the analysis, for each outcome and any reasons for attrition or exclusion, where reported. We assessed whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we planned to reinstate missing data in the analyses. We categorised completeness as:

• low risk ‐ up to and including10% missing data;

• high risk ‐ more than 10% missing data; and

• unclear risk ‐ no or unclear information provided.

Overall risk of bias ‐ we made explicit judgements about whether studies were at high risk of bias, according to the criteria suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We assessed the likely magnitude and direction of the bias and whether we considered it likely to impact the findings. We planned to explore the impact of the level of bias in sensitivity analyses.

Measures of treatment effect

We analysed the treatment effects in the trial using Review Manager 5.2 (RevMan 2012) and reported risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference (MD) for continuous data, with respective 95% confidence intervals (CIs). We determined the number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH) for analyses with a statistically significant difference in the RD.

Unit of analysis issues

The unit of analysis was the participating infant in individually randomised trials. An infant was considered only once in an analysis. We planned to exclude infants with multiple enrolments unless we obtained data from the report or investigators relating to the first episode of randomisation. If we could not separate data from the first randomisation, we planned to exclude the study as we would not be able to address the unit of analysis issues that arise from multiple enrolments of the same infant.

We intended to conduct intention‐to‐treat analyses. However, if the allocated CVC placement was unsuccessful, the primary outcome (bloodstream infection when the CVC is in place) for that infant may not have been possible to evaluate.

The participating neonatal unit or section of a neonatal unit was the unit of analysis in cluster randomised trials. We planned to analyse these using an estimate of the intra‐cluster correlation coefficient derived from the trial (if possible), or from another source as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

If we identified both cluster randomised trials and individually randomised trials, we planned to only combine the results from both if there was little heterogeneity between the study designs, and the interaction between the effect of intervention and the choice of randomisation unit was considered to be unlikely.

Dealing with missing data

We requested additional data from the trial investigators if data on important outcomes were missing or reported unclearly. Where data were still missing, we examined the impact on effect size estimates in sensitivity analyses.

Assessment of heterogeneity

As only one study was included in any analysis tests for heterogeneity were not applicable.

Assessment of reporting biases

Where we suspected reporting bias, we contacted trial investigators asking them to provide missing outcome data. Where this was not possible, and the missing data were thought to introduce serious bias, we planned to explore the impact of including such trials in the overall assessment of results in a sensitivity analysis.

Data synthesis

We planned to use the fixed‐effect model in Review Manager 5.2 (RevMan 2012) for meta‐analyses (as per Cochrane Neonatal Group recommendations). Where substantial heterogeneity existed, we planned to examine the potential causes in subgroup and sensitivity analyses.

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses.

• Very preterm (less than 32 weeks) infants (versus infants born at or later than 32 weeks).

• Type of CVC (umbilical venous catheters versus peripherally‐inserted CVCs versus surgically‐placed or tunnelled central lines, and antimicrobial versus antiseptic impregnation or coating).

Sensitivity analysis

We planned sensitivity analyses to determine if findings were affected by including only studies of adequate methodology (low risk of bias), defined as adequate randomisation and allocation concealment, blinding of intervention and measurement, and up to and including a 10% loss to follow‐up.

Results

Description of studies

See the Characteristics of included studies and Characteristics of excluded studies sections.

Characteristics of ongoing studies: PREVAIL

Results of the search

We identified 31 records, for four of which we assessed full‐text articles for eligibility. Only one trial met all of our inclusion criteria (Bertini 2013).

Included studies

We identified one randomised controlled trial (N = 98) that met the inclusion criteria (Bertini 2013).

Excluded studies

We excluded three reports (see Characteristics of excluded studies).

Risk of bias in included studies

We included only one trial (Bertini 2013).

Allocation

The report states that allocation was contained in sealed opaque envelopes.

Blinding

The trial was unblinded.

Incomplete outcome data

Of the 98 infants who were randomised, 12 died within the first week. These 12 infants were not included in the mortality analysis in the primary report.

Effects of interventions

Antimicrobial‐impregnated bloodstream infection (Comparison 1)

Primary outcomes

1. Catheter‐related bloodstream infection (Analysis 1.1):Bertini 2013 found that a statistically significant reduced incidence in infants allocated to the intervention (RR 0.11, 95% CI 0.01 to 0.87; RD ‐0.17, 95% CI ‐0.30 to ‐0.04; NNTB 6, 95% CI 3 to 25; Figure 1).

1.1. Analysis.

Comparison 1 Antimicrobial‐impregnated CVC vs. non‐impregnated CVC, Outcome 1 Catheter‐related bloodstream infection.

1.

Forest plot of comparison: 1 Antimicrobial‐impregnated CVC vs. non‐impregnated CVC, outcome: 1.1 Catheter‐related bloodstream infection.

Secondary outcomes

1. Mortality due to all causes prior to hospital discharge (Analysis 1.2):Bertini 2013 did not find a statistically significant difference (RR 0.73, 95% CI 0.21 to 2.53; RD ‐0.03, 95% CI ‐0.16 to 0.10; Figure 2).

2. Neurodevelopmental outcomes: Not reported.

3. Death or neurological impairment assessed after 12 months corrected age: Not reported.

4. Other morbidity developing after enrolment in trial until discharge from hospital:

   1. Bronchopulmonary dysplasia (oxygen supplementation at 36 weeks postmenstrual age; Analysis 1.3): Bertini 2013 did not find a statistically significant difference (RR 0.80, 95% CI 0.45 to 1.42; RD ‐0.08, 95% CI ‐0.28 to 0.12; Figure 3).

   2. Necrotising enterocolitis (Bell stage 2 or 3; Analysis 1.4): Bertini 2013 reported the incidence of "necrotising enterocolitis [defined] by Bell's criteria" and did not find a statistically significant difference (RR 0.46, 95% CI 0.04 to 4.84; RD ‐0.03, 95% CI ‐0.11 to 0.05; Figure 4). It is unclear if this analysis included infants with Bell stage 1 disease (as well as Bell stage 2 or 3).

   3. Retinopathy of prematurity, requiring treatment (medical or surgical; Analysis 1.5): Bertini 2013 reported the incidence of retinopathy of prematurity as not statistically significantly different (RR 0.46, 95% CI 0.12 to 1.70; RD ‐0.08, 95% CI ‐0.21 to 0.05; Figure 5). It is unclear if this analysis included infants with retinopathy that did not require treatment (as well as those who did).

5. Length of index CVC use (days; Analysis 1.6):Bertini 2013 found that a statistically significant increase in duration of UVC (days) in infants allocated to the intervention (MD 2.3, 95% CI 0.38 to 4.22; Figure 6).

6. Incidence of CVC removal for suspected or confirmed CVC infection: Not reported.

7. Length of stay in the neonatal intensive care and overall hospital stay (Analysis 1.7):Bertini 2013 did not report data on length of stay in neonatal intensive care. Bertini 2013 found a statistically significant shorter duration of stay in hospital for infants allocated to the intervention (MD ‐15.00 days, 95% CI ‐29.41 to ‐0.59; Figure 7).

8. Proportion of catheters colonised with antibiotic‐resistant organisms at removal: Stated as "similar" between groups but data not presented.

1.2. Analysis.

Comparison 1 Antimicrobial‐impregnated CVC vs. non‐impregnated CVC, Outcome 2 Mortality prior to hospital discharge.

2.

Forest plot of comparison: 1 Antimicrobial‐impregnated CVC vs. non‐impregnated CVC, outcome: 1.2 Mortality prior to hospital discharge.

1.3. Analysis.

Comparison 1 Antimicrobial‐impregnated CVC vs. non‐impregnated CVC, Outcome 3 Bronchopulmonary dysplasia.

3.

Forest plot of comparison: 1 Antimicrobial‐impregnated CVC vs. non‐impregnated CVC, outcome: 1.3 Bronchopulmonary dysplasia.

1.4. Analysis.

Comparison 1 Antimicrobial‐impregnated CVC vs. non‐impregnated CVC, Outcome 4 Necrotising enterocolitis.

4.

Forest plot of comparison: 1 Antimicrobial‐impregnated CVC vs. non‐impregnated CVC, outcome: 1.4 Necrotising enterocolitis.

1.5. Analysis.

Comparison 1 Antimicrobial‐impregnated CVC vs. non‐impregnated CVC, Outcome 5 Retinopathy of prematurity.

5.

Forest plot of comparison: 1 Antimicrobial‐impregnated CVC vs. non‐impregnated CVC, outcome: 1.5 Retinopathy of prematurity.

1.6. Analysis.

Comparison 1 Antimicrobial‐impregnated CVC vs. non‐impregnated CVC, Outcome 6 Length of index CVC use.

6.

Forest plot of comparison: 1 Antimicrobial‐impregnated CVC vs. non‐impregnated CVC, outcome: 1.6 Length of index CVC use.

1.7. Analysis.

Comparison 1 Antimicrobial‐impregnated CVC vs. non‐impregnated CVC, Outcome 7 Length of hospital stay.

7.

Forest plot of comparison: 1 Antimicrobial‐impregnated CVC vs. non‐impregnated CVC, outcome: 1.7 Length of hospital stay.

Subgroup analyses

• Very preterm (less than 32 weeks) infants (versus infants born at or later than 32 weeks): All participants were less than 31 weeks' gestation at birth.

• Type of CVC (umbilical venous catheters versus peripherally‐inserted CVCs versus surgically‐placed or tunnelled central lines, and antibiotic‐ versus antiseptic‐impregnation or coating): Bertini 2013 only assessed silver zeolite‐impregnated umbilical venous catheters.

Discussion

Summary of main results

We found only one trial for inclusion in this review. This trial had various methodological limitations, including lack of blinding and incomplete inclusion of all randomised participants. The trial reported a statistically significant reduction in the incidence of catheter‐related bloodstream infection, a statistically significant increase in the length of duration of use of the CVC, and a borderline statistically significant reduction in total length of stay in hospital. There was no evidence of an effect on mortality.

Overall completeness and applicability of evidence

We identified only one small trial (N = 98) for inclusion in this review. This trial provided some evidence that use of antiseptic‐impregnated umbilical venous catheters reduced the risk of bloodstream infection in very preterm infants. The control events rate (20% incidence of catheter‐related bloodstream infection) is comparable to other published studies and the findings are likely to be generally applicable to healthcare settings in high‐income and middle‐income countries with similar populations and care practices (Van der Zwet 2005; Olsen 2009; Wong 2012).

The available data are insufficient to exclude plausible and important effects on important secondary outcomes. For example, for mortality, wide 95% confidence interval bounds included a five‐fold reduced risk and a more than two‐fold increased risk. Long‐term (post discharge) data have not been reported in this trial.

Quality of the evidence

Although allocation was concealed, the trial intervention was not blinded to caregivers and investigators, and surveillance bias may have influenced the assessment of some outcomes, including bloodstream infection. Clinicians' subjective assessment of when to investigate for infection may have been affected by the perceived clinical efficacy of antimicrobial impregnated CVCs. The unblinded design may also have influenced care practices. For example, a perception that antimicrobial‐impregnated CVCs prevent infection may influence healthcare staff's adherence to other infection control practices. Lack of blinding may also influence the timing of the decision to remove the CVC, which may be reflected in the longer duration of use of antibiotic‐impregnated CVCs reported in the trial.

Intention‐to‐treat analysis for mortality

Of the 98 infants who were randomised, 12 died within the first week. These infants were not included in the mortality analysis in the primary report. The reason for exclusion from analysis after randomisation is not clear. We have contacted the principal investigator seeking these data (not yet obtained) which can be included in an intention‐to‐treat re‐analysis in an update of this review.

Potential biases in the review process

We found only one trial for inclusion in this review. Although we conducted a comprehensive search, including conference proceedings, we cannot exclude fully the possibility of publication bias since do not know whether other published (but not indexed) or unpublished trials exist.

Definition of catheter‐related bloodstream infection

Our protocol defined catheter‐related bloodstream infection as culture of a micro‐organism from blood obtained when the "CVC was in place on the day or the day before the blood sample for microbial culture was obtained". The included trial's protocol defined catheter‐related bloodstream infection as culture of a micro‐organism from blood "concordant with organism colonising the UVC tip" obtained "when the UVC is in place or within 48 hours of central line removal". We made a post hoc, pragmatic, consensus decision to accept this definition of the primary outcome since (i) it was very similar to our a priori definition (allowing a 48 hours rather than 24 hours window post CVC removal for obtaining blood cultures), and (ii) it was unlikely to be possible to obtain trial data revised to fit our review definition.

Agreements and disagreements with other studies or reviews

The current evidence from studies in which adults participated suggests that antimicrobial‐impregnated CVCs are clinically effective and cost‐effective in preventing bloodstream infection (Alonso‐Echanove 2003; Eggimann 2003; Shorr 2003; Casey 2008; Gilbert 2008; Hockenhull 2008; Halton 2009; Walz 2010; Lambert 2012). In the paediatric population, there are more limited and inconsistent data available (Lenz 2010, Weber 2012).

Other antimicrobial‐impregnated or coated devices for newborn infants, including ventriculoperitoneal shunts, external ventricular drain catheters, and tympanostomy tubes, have been studied and assessed in randomised controlled trials. The limited data currently available do not provide consistent or definite evidence of benefit or harm (Licameli 2008; Muttaiyah 2010; Demetriades 2011; Kandasamy 2011; Thomas 2012).

Authors' conclusions

Implications for practice.

The available data from one, methodologically‐weak trial, although indicating that antimicrobial‐impregnated umbilical venous catheters might reduce the incidence of bloodstream infections in very preterm infants, are insufficient to guide clinical practice.

Implications for research.

Further trials are required to assess the effectiveness of antimicrobial‐impregnated CVCs for preventing bloodstream infections in newborn infants. The trials should be large, simple and pragmatic, and ideally should blind caregivers and investigators to the intervention to avoid introducing bias. Trials might compare either antibiotic‐ or antiseptic‐impregnated CVCs with non‐impregnated standard CVCs. Participants may include any newborn infants cared for in neonatal care centres who require CVC placement, or may be restricted to infants who are at a very high risk of catheter‐related bloodstream infection, such as very, or extremely, preterm infants. As well as assessing the impact on the incidence of bloodstream infection and mortality, trials should be powered to detect plausible effects on important secondary outcomes, including acute neonatal morbidity, duration of hospital admission, and neurodevelopmental outcomes. There are theoretical concerns about potential harm due to emergence of resistant strains of bacteria and drug toxicity, which could be assessed within and between trials. Given the costs associated with this intervention, it is also important to embed a health economics assessment within any trial design.

Data and analyses

Comparison 1. Antimicrobial‐impregnated CVC vs. non‐impregnated CVC.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Catheter‐related bloodstream infection	1	86	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.01, 0.87]
2 Mortality prior to hospital discharge	1	86	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.21, 2.53]
3 Bronchopulmonary dysplasia	1	86	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.45, 1.42]
4 Necrotising enterocolitis	1	86	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.04, 4.84]
5 Retinopathy of prematurity	1	86	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.12, 1.70]
6 Length of index CVC use	1	86	Mean Difference (IV, Fixed, 95% CI)	2.30 [0.38, 4.22]
7 Length of hospital stay	1	86	Mean Difference (IV, Fixed, 95% CI)	‐13.00 [‐29.41, ‐0.59]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bertini 2013.

Methods	Randomised controlled trial
Participants	Preterm newborn infants (< 31 weeks' gestation) who needed an umbilical venous catheter (UVC) for parenteral nutrition, therapy, or both during the first week after birth.
Interventions	1. Silver zeolite‐impregnated UVC (Vygon Lifecath PICC ExpertTM), 4 to 5 French gauge (Fr). 2. Another polyurethane UVC (ArgyleTM), 3.5 to 5 Fr.
Outcomes	Incidence of "definite" catheter‐related bloodstream infection: micro‐organism grown on peripheral, percutaneously‐obtained blood culture concordant with organism colonising the UVC tip in infants with clinical manifestation of infection, with a UVC in place or within 48 hours of central line removal, and without other apparent sources of bloodstream infection.
Notes	Location: Tertiary Neonatal Unit, Florence, Italy (2007 to 2009).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described.
Allocation concealment (selection bias)	Low risk	Allocation contained in sealed opaque envelopes.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Unblinded.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Unblinded.
Incomplete outcome data (attrition bias) All outcomes	High risk	Of the 98 infants who were randomised, 12 died within the first week. These 12 infants were not included in the mortality analysis in the primary report ‐ we have sought (but not yet obtained) this information from the investigators (email to cdani@unifi.it on 07/05/14)

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Seidler 2006	In vitro study.
Stevens 2011	In vitro study.
Venkatesh 2009	Study of catheter‐lock solutions.

Characteristics of ongoing studies [ordered by study ID]

PREVAIL.

Trial name or title	PREVAIL
Methods	Randomised controlled trial
Participants	Infants in neonatal units for whom placement of a 1 French percutaneously‐inserted CVC is planned
Interventions	CVC with rifampicin and miconazole coating or identical catheter without antimicrobial coating
Outcomes	Time to first positive blood culture taken 24 after randomisation and up to 48 hours after CVC removal
Starting date	June 2015
Contact information	sam.oddie@bthft.nhs.uk
Notes

Differences between protocol and review

Definition of catheter‐related bloodstream infection

Our protocol defined catheter‐related bloodstream infection as culture of a micro‐organism from blood obtained when the "CVC was in place on the day or the day before the blood sample for microbial culture was obtained". The included trial's protocol defined catheter‐related bloodstream infection as culture of a micro‐organism from blood "concordant with organism colonising the UVC tip" obtained "when the UVC is in place or within 48 hours of central line removal". We made a post hoc, pragmatic, consensus decision to accept this definition of the primary outcome since (i) it was very similar to our a priori definition (allowing a 48 hours rather than 24 hours window post CVC removal for obtaining blood cultures), and (ii) it was unlikely to be possible to obtain trial data revised to fit out review definition.

Contributions of authors

All authors contributed to the development of the protocol and production of the review..

Sources of support

Internal sources

• NIHR Cochrane Programme Grant, UK.

External sources

• Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA.

  Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C

• National Institute for Health Research, UK.

  This report is independent research funded by a UK National Institute of Health Research Grant (NIHR) Cochrane Programme Grant (13/89/12). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the UK Department of Health.

Declarations of interest

Drs Sam Oddie and William McGuire are co‐investigators in a UK multi‐centre trial of antimicrobial‐impregnated CVC in preterm infants (PREVAIL).

Dr Munisha Balain does not have any conflicts of interest.

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