Chakrapani Vasudevan1, William McGuire2
Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs
1University of Leeds, Leeds, UK
2Centre for Reviews and Dissemination, Hull York Medical School, University of York, York, UK
Citation example: Vasudevan C, McGuire W. Early removal versus expectant management of central venous catheters in neonates with bloodstream infection. Cochrane Database of Systematic Reviews 2011, Issue 8. Art. No.: CD008436. DOI: 10.1002/14651858.CD008436.pub2.
Centre for Reviews and Dissemination, Hull York Medical School
University of York
York
Y010 5DD
UK
E-mail: William.McGuire@hyms.ac.uk
| Assessed as Up-to-date: | 14 February 2011 |
|---|---|
| Date of Search: | 14 February 2011 |
| Next Stage Expected: | 14 February 2013 |
| Protocol First Published: | Issue 3, 2010 |
| Review First Published: | Issue 8, 2011 |
| Last Citation Issue: | Issue 8, 2011 |
Uncertainty exists regarding the management of central venous catheters (CVCs) in neonates with bloodstream infections. Early CVC removal may reduce the risk of persistent or complicated infection and its associated morbidity and mortality. However, since CVCs provide secure vascular access to deliver nutrition and medications, the possible harms of early removal versus expectant management need to be considered.
To determine the effect of early removal versus expectant management of CVCs on morbidity and mortality in neonates with bloodstream infections..
We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials ((CENTRAL), The Cochrane Library, 2011, Issue 1), MEDLINE (1966 to January 2011), EMBASE (1980 to January 2011), CINAHL (1982 to January 2011), conference proceedings, and previous reviews.
Randomised and quasi-randomised controlled trials that compared early removal versus expectant management of CVCs in neonates with bloodstream infections.
There are no trial data to guide practice regarding early removal versus expectant management of CVCs in neonates with bloodstream infections. While observational data generally indicate that early removal is associated with a lower incidence of persistent or complicated infection, caution should be exercised in applying these findings to practice because of inherent biases in the study design. A simple and pragmatic randomised controlled trial is needed to resolve the uncertainty about optimal management in this common and important clinical scenario.
Infection in the bloodstream is a frequent and potentially harmful complication for newborn infants who have a central venous catheter (a cannula that extends several centimetres into the infant's blood vessels). When such infants develop a bloodstream infection, clinicians need to decide whether or not to remove the catheter. 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. We did not find any randomised controlled trials the addressed this question. Because of the potential for benefit and harm related to this common clinical scenario, such a trial is warranted.
Bloodstream infection is the most common serious complication associated with the use of central venous catheters (CVCs) including percutaneous central venous catheters (PCVCs), umbilical catheters, and subcutaneously-tunnelled catheters in neonates. Between 5% to 30% of neonates with a CVC in situ develop a bloodstream infection (Trotter 1996a; Trotter 1996b; Mahieu 2001; Cartwright 2004; van der Zwet 2005; Garland 2008; Hoang 2008; Ohki 2008; Olsen 2009). The reported incidences vary with the case-definition and with the demographic characteristics of the populations studied. The incidence of bloodstream infection is generally estimated to be higher than 25% in very preterm and very low birth weight (VLBW) infants reflecting their level and duration of exposure to invasive procedures and intensive care (Pandit 1999; Makhoul 2002; Stoll 2002; Stoll 2003). Nosocomial (acquired in hospital) bloodstream infection is more strongly associated with PCVC and subcutaneously-tunnelled catheter use than umbilical catheter use even after accounting for infant characteristics and illness severity (Chien 2002). However, it is not certain to what extent CVC use is an independent risk factor for a bloodstream infection or whether an association exists because infants who are smaller, less mature, sicker and receiving more intensive and invasive support are also more likely to have a CVC in situ. A Cochrane review of randomised controlled trials of PCVCs versus peripheral cannulae for delivering parenteral nutrition to neonates did not find any evidence of an effect on invasive infection rates (Ainsworth 2007).
Coagulase-negative staphylococci cause about half of all CVC-related bloodstream infections in neonates (Isaacs 2003). Other pathogens include Gram-negative bacilli (mainly enteric bacilli), Gram-positive cocci (Staphylococcus aureus, enterococci), and fungi (predominantly Candida species) (Stoll 2002; Isaacs 2004; Gordon 2006). Neonates, particularly VLBW infants, with nosocomial bloodstream infections have a higher risk of mortality and a range of important morbidities including the need for intensive care and mechanical ventilation, bronchopulmonary dysplasia, necrotising enterocolitis, retinopathy of prematurity, and prolonged hospitalisation (Stoll 2002; Chapman 2003; Adams-Chapman 2006; Bassler 2009). These higher rates of mortality and serious morbidity are usually associated with Gram-negative enteric bacillus or fungal infection. Coagulase-negative staphylococcal infection, although common, is associated with a more benign clinical course. Meningitis and other deep-seated involvement is rare and attributable mortality is much lower than with infection from other organisms. However, even 'low-grade' coagulase-negative staphylococcal bloodstream infections may generate inflammatory cascades associated with both acute morbidity (e.g. metabolic, respiratory or thermal instability, thrombocytopenia) and long-term white matter and other brain damage that may result in neurodevelopmental disability (Stoll 2004; Khashu 2006).
A clinical management dilemma exists when a neonate with a CVC in situ develops signs consistent with a bloodstream infection. There is substantial uncertainty among clinicians about whether early CVC removal versus retention and expectant management is the better option (Karlowicz 2002; Rubin 2002). The CVC provides secure vascular access that allows continued provision of fluids, nutrition and medications, including anti-infective agents. If the CVC is removed then an alternative route for drug and fluid administration, either a peripheral cannula or and new CVC, may be required. However, the CVC, or an associated thrombus, may act as a nidus (locus) for micro-organisms thus decreasing the effectiveness of anti-infective agents and perpetuating the invasive infection, inflammatory cascades, and end-organ damage (Thornburg 2008). The decision whether to retain or to remove the CVC depends on the perceived balance between these potential benefits and risks and may be affected by additional factors including the infant's clinical status, level of need for continued vascular access, and the ease with which replacement vascular access can be secured.
Surveys of practice suggest that clinicians generally elect to retain an existing CVC in situ in neonates with 'suspected' bloodstream infection; that is, a possible infection treated empirically with antibiotics but not yet confirmed by microbiological culture from blood (Benjamin 2001; Rubin 2002). Furthermore, many clinicians opt for expectant CVC management in neonates and young infants with a confirmed bloodstream infection due to coagulase-negative staphylococci. However, some clinicians elect to remove the CVC at an early stage whenever infection is suspected because the early clinical features of a bloodstream infection due to Gram-negative bacilli or fungi can be similar to those due to a coagulase-negative staphylococcal infection (Benjamin 2000).
Several additional factors need to be considered when deciding whether to remove or retain a CVC in neonates with bloodstream infections. Clinical signs of bloodstream infections in neonates, especially very preterm and VLBW infants, are generally non-specific. Similarly, laboratory measures (biomarkers) have low predictive value for bloodstream infections (Fowlie 1998; Malik 2003). Most neonates who have a suspected bloodstream infection and who undergo 'sepsis evaluation' do not have the infection confirmed subsequently (Buttery 2002). Since clinical signs and laboratory markers are generally unreliable predictors of a true bloodstream infection, a policy of early CVC removal when the infection is suspected would inevitably result in many unnecessary interventions. Even in situations where an infection has been confirmed by microbiological culture from blood this may represent contamination from skin commensals, particularly coagulase-negative staphylococci (Isaacs 2003). Conversely, culture of blood samples that are of insufficient volume may give falsely reassuring negative results (Jawaheer 1997; Connell 2007).
Early removal of a CVC in neonates with nosocomial bloodstream infections may hasten microbiological clearance and thereby reduce the incidence of end-organ involvement and damage including that due to inflammatory cascades (Chapman 2003). Observational studies have provided some evidence that prompt CVC removal following a confirmed bloodstream infection due to Staphylococcus aureus, enterococci, Gram-negative bacilli or Candida species reduces the likelihood of persistent or complicated bacteraemia or fungaemia with end-organ involvement (Eppes 1989; Karlowicz 2000; Benjamin 2001; Nazemi 2003). Data from retrospective cohort studies also suggest that early CVC removal in neonates with a confirmed coagulase-negative staphylococcal infection is associated with a reduced risk of persistent bacteraemia and end-organ involvement and that infants with persistent coagulase-negative staphylococcal bacteraemia only achieve microbiological cure when the CVC is removed (Benjamin 2001; Karlowicz 2002). However, these observational studies need to be interpreted cautiously since their findings may be due to confounding factors such as clinicians electing to delay CVC removal in smaller, less mature, or sicker infants.
Uncertainty exists about the balance between the putative benefits and harms associated with early removal versus expectant management of CVC in neonates with bloodstream infections. This intervention has the potential to affect several major outcomes for this population. Because observational data may be subject to various biases that limit validity and utility to inform practice, an attempt to detect, appraise, and synthesise evidence from randomised controlled trials is needed.
To determine the effect of early removal versus expectant management of CVCs in neonates with nosocomial bloodstream infections.
Randomised or quasi-randomised controlled trials including cluster randomised trials.
Newborn infants (including preterm infants up to 44 weeks postmenstrual age) with suspected or confirmed bloodstream infections who have a CVC in situ.
Since infants may experience more than one episode of a bloodstream infection, eligible trials should have enrolled participants on one occasion only with management of subsequent infections determined by clinician preference.
1. Mortality from study entry (due to all causes):
2. Neurodevelopmental outcomes assessed after 12 months postmenstrual 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 delay (developmental quotient > two standard deviations below population mean), blindness (visual acuity less than 6/60) or deafness (any hearing impairment requiring or unimproved by amplification).
1. Persistent or recurrent infection; proportion of neonates with:
2. Other morbidity developing after enrolment in trial:
3. Parenteral nutrient input from trial enrolment until establishment of full enteral feeding:
4. Number of cannulae/catheters per infant during trial period.
5. Growth from trial enrolment until establishment of full enteral feeding:
We used the standard search strategy of the Cochrane Neonatal Review Group.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2011, Issue 1), MEDLINE (1966 to Jan 2011), EMBASE (1980 to Jan 2011), and CINAHL (1982 to Jan 2011) 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/adverse effects 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]. We limited the search outputs with the relevant search filters for clinical trials as recommended in the Cochrane Handbook. We did not apply any language restrictions.
We searched ClinicalTrials.gov and Current Controlled Trials for completed or ongoing trials.
We examined the references in studies identified as potentially relevant.
We also searched the abstracts from the annual meetings of the Pediatric Academic Societies (1993 to 2010), the European Society for Pediatric Research (1995 to 2010), the UK Royal College of Paediatrics and Child Health (2000 to 2010), and the Perinatal Society of Australia and New Zealand (2000 to 2010).
We considered trials reported only as abstracts to be eligible if sufficient information was available from the report, or from contact with the authors, to fulfil the inclusion criteria.
We planned to use the standard methods of the Cochrane Neonatal Review Group.
Both authors planned to independently screen the title and abstract of all studies identified by the above search strategy and assess the full articles for all potentially relevant trials. We planned to exclude any studies that did not meet all of the inclusion criteria and to state the reason for exclusion. We intended to discuss any disagreements until we reached a consensus.
If we had identified any eligible studies, we planned to independently extract 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 intended to discuss any disagreements until we reached a consensus. If data from the trial reports were insufficient, we planned to contact the trialists for further information.
We planned to use the criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of any included trials. We intended to evaluate and describe the following issues using a 3-category scale: yes, no, unsure. We planned to resolve any disagreements by discussion. If required, we planned to request additional information from the trial authors to clarify methodology and results.
We planned to calculate risk ratio (RR) and risk difference (RD) for dichotomous data and weighted mean difference (WMD) for continuous data, with respective 95% confidence intervals (CI). We planned to determine the number needed to treat to benefit (NNTB) or to harm (NNTH) for a statistically significant reduction in the RD.
We planned that the unit of analysis would be the participating infant in individually randomised trials and the neonatal unit (or sub-unit) for cluster randomised trials.
More than one episode of a bloodstream infection can occur in the same infant with a CVC. We planned to include only one episode per infant to avoid a unit-of-analysis problem.
We planned to examine the treatment effects of individual trials and heterogeneity between trial results by inspecting the forest plots. We planned to calculate the I² statistic for each analysis to quantify inconsistency across studies and to describe the percentage of variability in effect estimates that may be due to heterogeneity rather than sampling error.
If there were data from more than five trials included in a meta-analysis, we intended to conduct a funnel-plot analysis.
We pre-specified separate comparisons for infants with:
For confirmed infection, we planned to perform subgroup analyses by infecting organism:
If sufficient data were available, we would have performed further subgroup analyses by:
If substantial (I² > 50%) heterogeneity had been detected, we planned to explore the possible causes (for example, differences in study design, participants, interventions, or completeness of outcome assessments) in sensitivity analyses.
Given that nosocomial bloodstream infection in neonates with a CVC in situ is a common and important clinical problem and that substantial uncertainty and variation in practice exists with regard to early CVC removal versus expectant management, it is surprising that this question has not yet been addressed in any randomised controlled trials. This may in part be due to historical differences and inconsistencies in defining CVC-associated bloodstream infections. Over the past decade, consensus definitions of nosocomial infections have become more widely accepted in practice, for example in neonatal network benchmarking and audit process where infection incidence is an established key quality indicator (Stoll 2002; Lee 2009). The availability of validated definitions should help in planning future trials and facilitate synthesis of data from individual trials that adhere to broadly consistent definitions (Modi 2009).
In the absence of trial data, decisions regarding the timing of removal of CVCs in infants with bloodstream infections continue to rely on the findings of observational studies. Some retrospective cohort studies have indicated that bloodstream infections progress to persistent bacteraemia or fungaemia with end-organ damage if the CVC is not removed promptly (Eppes 1989; Karlowicz 2000; Benjamin 2001; Nazemi 2003). However, these studies have inherent methodological weaknesses with potential for bias and should be interpreted with caution since their findings may be due to confounding factors such as clinicians electing to delay CVC removal in smaller, less mature, or sicker infants. The variation in policy and practice between neonatal centres and clinicians reflects the ongoing uncertainty with which the available observational data are viewed (Karlowicz 2002; Rubin 2002).
Similarly, there appears to be limited data to inform decisions about CVC removal in other populations of patients with bloodstream infections (Rijnders 2004; O'Grady 2011). Recent practice guidelines published by the European Society for Clinical Nutrition and Metabolism and the Infectious Diseases Society of America recommend that peripherally-inserted PCVCs should be removed in patients with a bloodstream infection. However, the level of evidence to support these statements is acknowledged to be low, being based largely on data from retrospective cohort studies (Mermel 2009; Pittiruti 2009).
There are no randomised controlled trials to inform practice. Retrospective cohort studies suggest that early CVC removal is associated with a lower risk of persistent infection but these findings were not systematically reviewed and should be interpreted with caution because of biases inherent in the study design.
Given the potential for benefit and harm to be associated with the timing of removal of the CVC in a neonate with a bloodstream infection, a pragmatic randomised controlled trial of early removal versus expectant management seems warranted. Such a trial might first address this issue in infants with confirmed bloodstream infections (defined using established and validated criteria) and should ideally be powered to allow pre-specified subgroup analyses based on the infecting organism.
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. HHSN267200603418C.
None noted.
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