Central venous catheter (CVC) removal for adult patients with candidaemia

  • Protocol
  • Intervention

Authors

  • Susanne Janum,

    Corresponding author
    1. Herlev Hospital, Copenhagen University Hospital, Department of Anesthesiology and Intensive Care, Herlev, Denmark
    • Susanne Janum, Department of Anesthesiology and Intensive Care, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, Herlev, 2730, Denmark. susannejanum@gmail.com.

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  • Arash Afshari

    1. Hôpitaux Universitaires de Genève, Pediatric and Neonatal Intensive Care Service, Geneva, Switzerland
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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

The main purpose of this review is to examine the impact of CVC removal versus retaining the CVC on mortality in patients with candidaemia and with a CVC in place after controlling for confounders such as severity of illness and others.

Background

Invasive Candida infections have markedly increased in frequency during the 1990s to become the fourth more common aetiology of nosocomial bloodstream infections (Colombo 2006; Edmond 1999). The estimated additional cost of an episode of candidaemia in adult patients is approximately USD 40,000 (Fridkin 2005; Morgan 2005). Most patients with candidaemia have a central venous catheter (CVC) in place and the best CVC management in these patients has been highly debated (Nucci 2010; Pasqualotto 2008; Raad 2004).

Previous studies have shown that retention of vascular catheters colonized with Candida species is associated with prolonged fungaemia (Girmenia 1996; Rex 1995), an increased risk of metastatic complications (Girmenia 1996; Lecciones 1992; Rex 1995), and death in adult patients with candidaemia (Asmundsdottir 2005; Lecciones 1992; Raad 2004). Other investigations failed to confirm the benefit of early CVC removal (Nucci 2010; Rodriguez 2007). Removal of vascular catheters has been advocated as an adjunctive strategy for treating patients with candidaemia, particularly for non-neutropenic adults (Mermel 2009; Pappas 2003; Papas 2009).

However, other variables may also impact the outcome, particularly severity of illness and persistence of neutropenia (Nucci 2002). A policy of systematic CVC removal in patients with candidaemia may result in mechanical complications associated with the insertion of a new catheter, including bleeding, pneumothorax and eventually death. Although most international societies and experts recommend catheter removal in this scenario (Papas 2009), no clinical trial has ever documented a survival benefit from this intervention.

Description of the condition

Candidaemia describes the presence of any fungus of the species Candida in the bloodstream. It is a potentially devastating infection which predominantly affects severely ill, hospitalized patients. Most studies report a relatively low prevalence (Blumberg 2001; Marchetti 2004; Petri 1997; Tortorano 2006), but an incidence as high as 9.8/1000 ICU (intensive care unit) admissions has been reported (Rangel-Frausto 1999). Severity is inarguable, with reported crude mortality rates ranging from 30% to 60% and reported attributable mortality rates ranging from 25% to 40% (Blot 2002; Gudlaugsson 2003; Voss 1997; Wey 1988; Wisplinghoff 2004; Zaoutis 2005). Major risk factors include recent abdominal surgery, gastrointestinal perforation, compromised immune functions, treatment with broad spectrum antibacterial agents, CVCs, major organ dysfunction, malignancies and extremes of age (Glockner 2013).

Candidaemia requires systemic antifungal treatment aimed at eradication of free-floating Candida species as well as any primary focus or secondary manifestation. As mentioned, most patients presenting with candidaemia have a CVC in place (Nucci 2010; Raad 2004) which evokes the controversial and much debated issue of whether to remove this or not.

Description of the intervention

Removal of an indwelling CVC is a common and widely advocated strategy when candidaemia is suspected or diagnosed (Mermel 2009; Papas 2009). A new CVC may be inserted immediately as a replacement if required for treatment. CVC removal may be performed as a sole intervention or may be part of a strategy in which all indwelling catheters are removed and possibly replaced.

Despite conflicting evidence, one might argue that the a priori possibility of this intervention being effective in CVC-related infection is considerable. However, it is not possible to formally categorize candidaemia as being CVC-related or not without removing the CVC in question, as this requires detection of a significant quantum of Candida species on the catheter tip.

Removal may be either early or late following the diagnosis of candidaemia. For the purpose of this review we will consider removal on day zero or day one following the diagnosis of candidaemia as early and removal from day two to day seven as late.

As a comparison, a CVC may be retained in candidaemia while relevant treatment is initiated.

How the intervention might work

Like many other micro-organisms the Candida species may produce and embed themselves in a protective biofilm. Biofilm acts both as a mechanical barrier and as an environment for genetic exchange and thereby contributes to protection from elimination by the innate host immune defence and to emerging antibiotic resistance (Raad 1993).

Most vascular devices develop biofilm within 24 hours after insertion (Raad 1993), and the occurrence of catheter-related blood stream infection is proportional to the occurrence of micro-organisms on the catheter tip. In case of catheter-related candidaemia, the removal of a catheter will eliminate the primary focus of infection and prevent micro-organisms embedded in the biofilm from further detachment of planktonic pathogens, embolization, establishment of metastatic infection and maintenance of systemic infection (Leonidou 2010; Schachter 2003). In case of candidaemia not primarily related to an indwelling device the removal of such device may prevent Candida species from embedding themselves in pre-existing or new biofilm on this device.

Also, with an indwelling device there is a risk of complicating superinfections through extraluminal or intraluminal contamination (Miller 2012), which may negatively affect outcome in patients already struggling with candidaemia.

On the other hand, candidaemia always requires systemic, antifungal treatment, which requires continuous intravenous access. Potentially, patients may require inotropes, haemodynamic monitoring, infusions of fluids or parenteral nutrition during illness, prompting the insertion of a new CVC if one is removed. This procedure involves risk of mechanical (bleeding, arterial puncture, pneumothorax, haemothorax) and infectious complications, which may also negatively affect outcome in patients with candidaemia.

Why it is important to do this review

The issue of whether catheters should be removed in patients with candidaemia remains controversial. The results generated by this review may potentially benefit patients by providing better evidence for medical care.

Objectives

The main purpose of this review is to examine the impact of CVC removal versus retaining the CVC on mortality in patients with candidaemia and with a CVC in place after controlling for confounders such as severity of illness and others.

Methods

Criteria for considering studies for this review

Types of studies

We will search for randomized controlled trials (RCTs) irrespective of publication status, date of publication, blinding status or language. We will contact the investigators and the authors to retrieve relevant data. We aim to include unpublished trials only if trial data and methodological descriptions are provided in written form or can be retrieved from the study authors. We will also include quasi-randomized trials because of the expected low number of trials that can be included, but we will exclude cross-over trials and observational studies.

However, two major factors make the conduct of RCTs in this population a difficult task: the large sample size required to document the impact of catheter removal in terms of overall mortality; and the lack of economic interest from the industry in conducting such a trial.

The authors have no knowledge of any existing RCTs concerning this subject and anticipate to find none. We do not plan to include non-randomized studies. Instead, we will provide a description of these studies and their results in an appendix.

Types of participants

This study will focus on patients of all ages with candidaemia who have a CVC in place. We will exclude data from patients with no candidaemia (for example other forms of invasive Candida infections such as Candida peritonitis) and from individuals with no CVC in place. We will only consider patients for whom the information about CVC management is available. We will include patients irrespective of their underlying diseases.

We will search for the following data for each patient entering the study.

  1. Demographic information.

  2. Main underlying diseases.

  3. Neutropenia.

  4. Severity of illness.

  5. CVC data and management.

  6. Data on candidaemia.

  7. Antifungal treatment.

  8. Outcome.

Demographic information will include age and sex. The main underlying diseases will include solid organ transplantation, haematopoietic stem cell transplantation, AIDS, diabetes mellitus, solid cancer, and haematological neoplasm. We will record abdominal surgeries performed in the two weeks preceding candidaemia as well as receipt of steroids.

We will define the presence and duration of neutropenia by an absolute neutrophil count ≤ 500 cells/µl in the last 30 days. We will consider neutropenia to have persisted if the neutrophil count did not recover (that is, with increases above 500 cells/µl) in the week following diagnosis of candidaemia.

We will obtain the following variables in order to determine the severity of candidaemia: acute physiology and chronic health evaluation (APACHE II score), stay in the ICU, shock requiring inotropic support, respiratory failure requiring invasive mechanical ventilation, renal failure (serum creatinine ≥ 2 mg/dl), renal failure requiring dialysis, and liver insufficiency (aminotransferases or bilirubins above five or 10 times the upper limit of detection, respectively). These variables will have been collected at the time the index blood culture was obtained.

CVC data will include: short versus long permanence CVC, and time for CVC removal. Both will be considered in relation to the date the blood culture was obtained and to the date antifungal therapy was initiated. The diagnosis of candidaemia will be established when Candida species are recovered from a blood culture taken from a patient with sepsis. Duration of candidaemia and time for CVC removal will be calculated from the day the first positive blood culture for Candida was obtained. We will stratify patients as having candidaemia lasting for: (i) three or less days; (ii) four to seven days; and (iii) more than seven days. We will record the Candida species causing candidaemia.

We will consider candidaemia to be CVC-related if significant growth of Candida species is documented from the catheter tip. This could be determined either by semi-quantitative (> 15 colony forming units (CFUs)/catheter segment) or quantitative (> 103 CFUs/catheter segment catheter) cultures. We will not consider differential time to positivity between blood taken from central lines and peripheral veins for the diagnosis of CVC-related candidaemia since this strategy has just been validated for bacterial infections (Mermel 2001; Mermel 2009).

We will stratify patients according to the antifungal drug they received since some drug classes (for example, echinocandins and polyenes) are known to have antibiofilm activity. We will also collect data on the appropriateness of antibacterial therapy for candidaemic patients with a concomitant bacterial bloodstream infection. Therapy will be considered as appropriate if the prescribed antibacterial drug was shown to be active against the bacteria isolated in the blood culture.

We will record time to death and time for hospital discharge in the case of survivors. For the purpose of survival analysis, patients will be censored at week six after the diagnosis of candidaemia.

Types of interventions

For the purpose of this review we will consider CVC removal as removal or replacement of all central venous lines within seven days of the diagnosis of candidaemia (date at which the positive blood culture for Candida was drawn). This criterion will not apply to CVCs exchanged over a guidewire; we will analyse these cases separately.

We will consider a CVC not removed within seven days after the diagnosis of candidaemia to be a comparison.

Types of outcome measures

Primary outcomes
  1. Overall mortality. We will use the longest follow-up data from each trial regardless of the period of follow-up*.

Secondary outcomes
  1. Time required for clearance of blood culture for Candida species*.

  2. Frequency of persistent candidaemia (defined as any blood culture that remained positive for Candida species after three days of effective antifungal therapy)*.

  3. Complications probably related to candidaemia (metastatic foci of infection (including endocarditis, endophthalmitis and hepatosplenic candidosis)*.

  4. Complications probably related to the intervention: local suppurative and mechanical complications (e.g. pneumothorax, arterial puncture or bleeding requiring blood transfusion).*

  5. Complications during inpatient stay not specific to the trial intervention (e.g. pneumonia, congestive cardiac failure, respiratory failure, renal failure).

  6. Duration of mechanical ventilation*.

  7. Length of stay in the ICU.*

  8. Length of stay in the hospital*.

  9. Species-related mortality.

* Indicates key outcomes to be included in the 'Summary of findings' table in the review.

Search methods for identification of studies

We will conduct searches to identify all published and unpublished studies evaluating CVC removal in patients with candidaemia. We will not apply any language restrictions; when necessary, we will translate papers in languages other than English. We may contact study authors and drug companies in order to obtain additional data from the selected trials.

Electronic searches

We will search the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Appendix 1); MEDLINE (interface PubMed) (1966 to date) (Appendix 2); EMBASE (1966 to date) (Appendix 3); LILACS (1982 to date) (Appendix 4); BIOSIS (1999 to date) (Appendix 5); ISI Web of Knowledge (1945 to date) (Appendix 6); and SCOPUS (1960 to date) (Appendix 7). We will combine the strategies described in Section 6.4 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to search for RCTs in MEDLINE and EMBASE. We will check the reference lists of all retrieved primary studies for additional relevant studies. Additionally, we will check all references of relevant reviews, meta-analyses, society guidelines, and commentaries identified both in PubMed and EMBASE.

Searching other resources

We will handsearch the reference lists of reviews, randomized and non-randomized studies and editorials to locate additional studies. We will contact the main authors of studies and experts in this field to ask for any missed, unreported or ongoing studies. We will try to contact pharmaceutical companies to ask about any unpublished trials, and we will search for ongoing clinical trials and unpublished studies on the following Internet sites.

  1. Current Controlled Trials (http://www.controlled-trials.com)

  2. ClinicalTrials.gov (http://clinicaltrials.gov)

  3. CenterWatch (http://www.centerwatch.com)

Data collection and analysis

We will use the standard methods of the Cochrane Anaesthesia Review Group (CARG) to identify studies and to assess the methodological quality of eligible trials. We will use the Review Manager statistical package (RevMan 2012) provided by The Cochrane Collaboration to analyse the data. We will consider the frequency of autopsy rate as well as frequency of daily blood culture in the five days following candidaemia and the percentage of patients excluded after screening for the purpose of quality evaluation.

Selection of studies

We will search for RCTs and quasi-RCTs involving adult patients with candidaemia and in which patients were randomized for CVC removal (the intervention under study). As already mentioned, we will select trials irrespective of their original language.

Two review authors will independently read all the abstracts in the records retrieved by electronic search to identify eligible publications. They will select studies to be reviewed according to prespecified inclusion criteria. This process will be performed without blinding of authors, institution, journal of publication or results. We will resolve disagreements by discussion, and if no agreement can be found, we may consult a third independent person.

We will provide a detailed description of this search and assessment in the form of a PRISMA flow chart in the review.

Data extraction and management

We will assess the quality of eligible trials using the criteria described by the Cochrane Effective Practice and Organisation of Care Group (EPOC) (Reeves 2008). Data extraction will be completed independently by two authors using a data extraction sheet developed for the purposes of this review (Appendix 8). We will conduct an individual patient data (IPD) meta-analysis in a subgroup of trials evaluating specific outcomes in the more homogeneous populations described below.

For each of the trials we will record the following data.

  • (A) Year of publication, country of origin and source of study funding.

  • (B) Details of participants including demographic characteristics and criteria for inclusion.

  • (C) Details of the type of intervention.

  • (D) Details of the outcomes reported, including method of assessment and time intervals.

Individual patient data (IPD)

We will attempt to contact the investigators of the selected trials by email or telephone to invite them to contribute IPD. In the review we will include data from studies in which IPD are not available. In such cases, we will obtain aggregate data and we will combine these with IPD.

Assessment of risk of bias in included studies

Two review authors will independently assess the risk of bias without blinding using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve disagreements by discussion, and if no agreement is found, we may consult a third person. Each domain will be assessed systematically as described by the following.

1) Random sequence generation

  • Assessment of randomisation: the sufficiency of the method in producing two comparable groups before intervention.

  • Grading:

    • 'Low risk’ (a truly random process, e.g. random computer number generator, coin tossing or throwing dice);

    • 'High risk’ (any non-random process, e.g. date of birth, date of admission by hospital, clinic record number, or by availability of the intervention); or

    • 'Unclear risk'.

2) Allocation concealment

  • Allocation method prevented investigators or participants from foreseeing assignment.

  • Grading:

    • 'Low risk’ (central allocation or sealed envelopes);

    • 'High risk’ (using open allocation schedule or other unconcealed procedure); or

    • 'Unclear risk’.

3) Blinding of participants and personnel

  • Assessment of appropriate blinding of investigation team and participants: person responsible for participant’s care, participants and eventual others.

  • Grading:

    • 'Low risk': we consider blinding as adequate if participants and personnel are kept unaware of intervention allocations after inclusion of participants in the study and if the method of blinding involves placebo or an intervention disguised in the same manner as a placebo, because mortality is an objective outcome;

    • 'High risk’: not double blinded; categorized as an open-label study or without use of placebo or an intervention disguised in the same manner as a placebo; or

    • 'Unclear': blinding not described.

4) Blinding of outcome assessor

  • Assessment of appropriate blinding of outcome assessor.

  • Grading:

    • 'Low risk’: we consider blinding as adequate if outcome assessors are kept unaware of intervention allocations after inclusion of participants in the study and if the method of blinding involves placebo or an intervention disguised in the same manner as a placebo, because mortality is an objective outcome;

    • 'High risk’: not double blinded, categorized as an open-label study or without use of placebo or an intervention disguised in the same manner as a placebo; or

    • 'Unclear risk’: blinding not described.

5) Incomplete outcome data

  • Completeness of outcome data including attrition and exclusions.

  • Grading:

    • 'Low risk’ (if the numbers and the reasons for dropouts and withdrawals in the intervention groups are described, or if it is specified that no dropouts or withdrawals occurred)

    • 'High risk' (if no description of dropouts and withdrawals is provided); or

    • 'Unclear risk’ (if the report gives the impression that no dropouts or withdrawals occurred, but this is not specifically stated).

  • 6) Selective reporting

  • The possibility of selective outcome reporting.

  • Grading:

    • 'Low risk’ (if the reported outcomes are those prespecified in an available study protocol or official trial registration, if this is not available, the published report includes all expected outcomes);

    • 'High risk' (if not all prespecified outcomes have been reported, or if they have been reported using non-prespecified subscales or have been reported incompletely or if report fails to include a key outcome that would have been expected to have been reported for such a study); or

    • 'Unclear risk'.

7) Other bias

  • Assessment of any possible sources of bias not addressed in domains 1 to 5.

  • Grading:

    • 'Low risk’ (if the report appears to be free of such bias);

    • 'High risk’ (if at least one important bias related to study design is present, or early stopping due to some data dependent process, extreme baseline imbalance, claimed fraudulence or other problems); or

    • 'Unclear risk’ (insufficient information or evidence that an identified problem will introduce bias).

With reference to domains 1 to 6 above, we will assess the likely magnitude and direction of the bias and whether we may consider it likely that it will impact on our findings. We will assess the impact of bias in the sensitivity analyses.

Measures of treatment effect

We will calculate the risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous data (binary outcome).

We will calculate the mean difference (MD) with 95% CIs for continuous data if they are measured the same way. To combine trials which measure the same outcome but in different ways we will measure the standardized mean difference (SMD).

Unit of analysis issues

Cluster-randomization: We will exclude any cluster-randomized trials as factors related to clustering may contribute to outcome.

Multiple intervention groups: In studies with multiple intervention groups we will combine groups to create a single pair-wise comparison (Higgins 2011).

Unit of analysis issues related to cross-over trials, reoccurring events, repeated observations, multiple treatment attempts and interventions on multiple body parts are considered not relevant with this intervention and outcome.

When meta-analysis is used in combining results from several studies with binary outcomes (i.e. event or no event), adverse effects may be rare, but serious, and hence important (Sutton 2002). Most meta-analytical software does not include trials with 'zero event' in both arms (intervention versus control) when calculating RR. Exempting these trials from the calculation of RR and 95% CI may lead to overestimation of the treatment effect. The Cochrane Collaboration recommends application of the Peto odds ratio (OR), which is the best method of estimating OR when many trials with no event in one or both arms are included (Higgins 2011). However, the Peto method is generally less useful when the trials are small, or when treatment effects are large. We plan to conduct a sensitivity analysis by applying the Peto OR if this sensitivity analysis is seen as a valid option.

In a single trial, interim analysis increases the risk of type I errors. To avoid type I errors, group sequential monitoring boundaries (Lan 1983) are applied to reveal whether a trial could be terminated early because of a sufficiently small P value, that is, the cumulative z-curve crosses the monitoring boundaries. Sequential monitoring boundaries, called trial sequential monitoring boundaries, can be applied to meta-analysis as well.

In trial sequential analysis (TSA), the addition of each trial into a cumulative meta-analysis is regarded as an interim meta-analysis and helps the investigator to decide whether additional trials are needed. The idea behind TSA is that if the cumulative z-curve crosses the boundary, a sufficient level of evidence is reached, and no further trials are needed. If the z-curve does not cross the boundary, then evidence is insufficient to allow investigators to reach a conclusion. To construct the trial sequential monitoring boundaries, the information size is required and is calculated as the least number of participants needed in a well powered single trial (Brok 2008; Pogue 1997; Pogue 1998; Wetterslev 2008; Wetterslev 2009).

We will apply TSA (TSA 2010) because this prevents an increase in the risk of type I error (< 5%) due to potential multiple updating and sparse data in a cumulative meta-analysis and provides us with important information to allow us to estimate the level of evidence for the experimental intervention. Additionally, TSA provides us with important information regarding the need for additional trials and the required information size. We want to perform TSA in anticipation of an intervention effect as indicated by the trials included in the traditional meta-analysis, or even the intervention effect suggested by the upper confidence limit from the intervention effect estimate found in the traditional meta-analysis, to cover any uncertainty displayed by the present data.

We aim to calculate the diversity-adjusted required information size using the pooled variance from the traditional meta-analysis (Turner 2013; Wetterslev 2009), as well as the control event proportion from the meta-analysis of the included trials.

Dealing with missing data

We will contact the corresponding author of all studies with missing data in an attempt to retrieve the relevant data. For all included studies, we will note number of exclusions and whether they are accounted for and assess risk of attrition bias. In case of missing data, we will choose a 'complete case analysis' for our primary outcome, which simply excludes all participants with the outcome missing from the analysis.

Assessment of heterogeneity

We will assess clinical heterogeneity by examining the types of participants, interventions and outcomes in each study. As a preliminary assessment of heterogeneity, we will examine statistical heterogeneity between the summary statistics of different studies by checking the usual statistical test where P values will be obtained by comparing the distribution of the Chi2 statistic. We will take care in the interpretation of the Chi2 statistical test since this has limited power in the (common) situation in which trials have a small sample size or are few in number. We will also assess statistical heterogeneity with the I2 statistic thereby estimating the percentage of total variance across studies that is due to heterogeneity rather than chance (Higgins 2002). We will consider a value of greater than 40% as definitely considerable if it is also significant. In combined analysis of IPD and abstracted data, as well as sensitivity analysis with IPD data only, covariates and random study effect will be used to attempt to explain between-study heterogeneity.

Assessment of reporting biases

Selective outcome reporting occurs when non-significant results are selectively withheld from publication (Chan 2004). It is defined as the selection, on the basis of results, of a subset of the original variables recorded for inclusion in publication of trials (Hutton 2000). We will check publications against their protocols or official registrations of trials when available, in an attempt to detect possible selective outcome reporting.

Publication bias arises when the dissemination of research findings is influenced by the nature and direction of results (Higgins 2011).

We will evaluate the level of publication bias related to the included trials by providing a funnel plot. For studies with binary outcomes, we will apply the test proposed in Rucker 2008. This test has the advantage of including trials with no events.

If the number of included trials does not exceed 10, we will not carry out these tests, as suggested by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Funding bias is related to the possible delay or discouragement to publish undesired results in trials sponsored by the industry (Higgins 2011). To explore the role of funding, we will conduct a sensitivity analysis based on our primary endpoint.

Data synthesis

We will perform the analysis using Review Manager software (RevMan 2012) and other software if needed. As a general rule, we will use a random-effects model since we do not expect an identical treatment effect across studies, and we intend to draw conclusions for the general population rather than only the included studies. We will compare outcomes across trials and treatment regimens to assess clinical heterogeneity and compare patient populations. Comparisons between health outcomes will be restricted by the different measurement tools used and the method of reporting in the included trials.

Subgroup analysis and investigation of heterogeneity

We will perform subgroup analyses for subgroups of participants and for subgroups of the intervention with the variables as listed before (see Types of participants).

Sensitivity analysis

We will perform sensitivity analyses of trials with low risk of bias versus high risk of bias. If evidence of small-study effects is observed, we will also perform sensitivity analyses. We also plan to test the robustness of the results by repeating the analysis using different measures of effect size (for example, RD and OR) and different statistical models (fixed-effect and random-effects models).

Summary of findings

We will use the principles of the GRADE system (Guyatt 2008) to assess the quality of the body of evidence associated with specific outcomes (overall mortality, duration of candidaemia, frequency of persistent candidaemia, incidence of metastatic infection, local suppurative/mechanical complications, length of hospital/ICU stay and species-related mortality) in our review and construct a 'Summary of findings' (SoF) table using the GRADE software. 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 quality of a body of evidence takes into consideration 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.

Acknowledgements

We are in debt to Alessandro C Pasqualotto, David Andes, Dimitrios P Kontoyiannis, Felipe Tuon, Elias Anaissie, Marcio Nucci, Issam Raad, Junfeng Sun and Andre C Kalil for their great work with the initial preparation for this protocol.

We are grateful to Abjørn Hrobjartsson and Anne Juul Wikkelsø for sharing their advice and experience during the preparation of this protocol.

We would also like to thank the editors and peer reviewers of the initial protocol (Nicola Petrucci (content editor); Cathal Walsh (statistical editor); Hilmar Wisplinghoff, Mazen Bader, Peter Pappas (peer reviewers); and Karl Gallegos (Cochrane Consumer Network)).

Appendices

Appendix 1. Cochrane Central Register of Controlled trial (CENTRAL) search strategy

#1 candaemia [Mesh]

#2 candidiasis [Mesh]

#3 candid*emia [Mesh]

#4 Fung*emia [Mesh]

#5 “catherization central venous”[MESH]

#6 “central venous line” [Mesh]

#7 catheter* or CVC [Mesh]

#8 (#1 OR #2 OR #3 OR #4)

#9 (#5 OR #6 OR #7)

#10 (#8 AND #9)

Appendix 2. MEDLINE (interface PubMed) search strategy

#1. randomized controlled trial[pt]

#2. controlled clinical trial[pt]

#3. randomized controlled trials[mh]

#4. random allocation[mh]

#5. clinical trial[pt]

#6. clinical trials[mh]

#7. "clinical trial"[tw]

#8. random*[tw]

#9. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8

#10.research design

#11. comparative study[tw]

#12. evaluation studies [tw]

#13. follow up studies [tw]

#14. prospective studies [tw]

#15. Cohort

#16. #10 OR #11 OR #12 OR #13 OR #14 OR #15

#17. #9 OR #16

#18. animal[mh] NOT human[mh]

#19. #17 NOT #18

#20. candidemia[tw]

#21. candidaemia[tw]

#22. "Candidiasis"[Mesh] NOT ("Candidiasis, Vulvovaginal"[Mesh] OR "Candidiasis, Oral"[Mesh] OR "Candidiasis, Cutaneous"[Mesh] OR "Urinary Tract Infections"[Mesh])

#23. "Fungemia"[Mesh] NOT ("Cryptococcosis"[Mesh] OR "Aspergillosis"[Mesh] OR "Zygomycosis"[Mesh] OR "Fusarium"[Mesh] OR "Scedosporium"[Mesh] OR "Histoplasmosis"[Mesh] OR "Penicillium"[Mesh] OR "Phialemonium"[tw] OR "Geotrichum"[Mesh] OR "Rhodotorula"[Mesh] OR "Paecilomyces"[Mesh] OR "Trichosporon"[Mesh])

#24. #20 OR #21 OR #22 OR #23

#25. "Central venous catheter" [tw]

#26. CVC [tw]

#27. "Severity of Illness Index"[mh]

#28. (central venous line [tw] or catheter [tw] or CVC [tw]) AND ((remov[tw] or replace*[tw] or switch* [tw] or chang*[tw] or swap [tw]) or (management [mh] or retention [mh]))

#29. (catheter[tw] or CVC [tw]) AND (remov[tw] or replace[tw]) and (impact or effects or influence or systematic or adjunctive strategy)

#30. #25 OR #26 OR #27 OR #28 OR #29

#31. #24 AND #30

#32. #19 AND #31

Appendix 3. EMBASE search strategy

#1. “randomized controlled  trial”

#2. “controlled clinical trial”

#3. “randomized controlled  trials”

#4. “random allocation”

#5. “clinical trial”

#6. (clinical ADJ trials). ti.ab.hw.sh.tw.

#7. (Random). ti.ab.hw.sh.tw.

#8.Exp comparative  study

#9. Exp prospective  studies

#10 Exp cohort

#11 . (prognosis). ti.ab.hw.sh.tw.

#12. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11

#13. Animal NOT human

#14. #12 NOT #13

#15.exp candidemia/

#16 exp candidaemia/

#17 (candidemia). ti.ab.hw.sh.tw.

#18. (candidaemia). ti.ab.hw.sh.tw.

#19.  #15 OR #16 OR #17 OR #18

#20 (“Catheterization Central Venous”). ti.ab.hw.sh.tw

#21 “central venous line”/

#22  (catheter venous central) ti.ab.hw.sh.tw.

#23 ( CVC). ti.ab.hw.sh.tw.

#24 (CVC adj critically adj3non?neutropenic pati CVC).ti.ab.hw.sh.tw.

#25 (remov$ adj CVC).

#26 #20 OR  #21 OR #22 OR #23 OR #24 OR #25 

#27 #19 AND #26

#28 #14 AND #23

Appendix 4. LILACS search strategy

#1 Candida

# 2 CVC

#3 Cateter venoso central

#4 Infecção

Appendix 5. BIOSIS search strategy

#1 candid*

#2 Central venous catheter

# 3 (CVC)  

#4 #2 OR #3

#5 #1 AND #4

Appendix 6. ISI of Knowledge search strategy

#1 Candid*

# 2 CVC

#3 remov*

Appendix 7. SCOPUS search strategy

#1. randomized controlled trial

#2. controlled clinical trial

#3. randomized controlled trials

#4. random allocation

#5. clinical trial

#6. "clinical trials"

#7. random*

#8. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7

#9.research design

#10. comparative study

#11. evaluation studies

#12. follow up studies

#13. prospective studies

#14. Cohort

#16 #10 OR #11 OR #12 OR #13 OR #14

#17 #8 OR #16

#18. animal NOT human

#19. #17 NOT #18

#20. Candidemia

#21. candidaemia

#22. "Candidiasis”

#23. "Fungemia

#24. #20 OR #21 OR #22 OR #23

#25.” Central venous catheter”

#26 (CVC)

#27  "Severity of Illness Index"

#28.  “central venous line”

#29  catheter

#30 (CVC) AND (remov[tw] or replace*[tw] or switch*or chang*[tw] or swap [tw] management or retention))

30. #25 OR #26 OR #27 OR #28 OR #29

31. #24 AND #30

32. #19 AND #31

Appendix 8. Cochrane Anesthesia Review group - Data Extraction Form

Study Selection, Quality Assessment & Data Extraction Form

First authorJournal/Conference Proceedings etcYear
   

Study eligibility

RCT/Quasi/CCT (delete as appropriate)Relevant participantsRelevant interventionsRelevant outcomes
Yes / No / UnclearYes / No / UnclearYes / No / UnclearYes / No* / Unclear

* issue relates to selective reporting – when authors may have taken measurements for particular outcomes, but not reported these within the paper(s). Reviewers should contact trialists for information on possible non-reported outcomes & reasons for exclusion from publication. Study should be listed in ‘Studies awaiting assessment’ until clarified. If no clarification is received after three attempts, study should then be excluded.

Do not proceed if any of the above answers are ‘No’. If study to be included in ‘Excluded studies’ section of the review, record below the information to be inserted into ‘Table of excluded studies’
 

Participants and trial characteristics

Participant characteristics
 Further details
Age (mean, median, range, etc) 
Sex of participants (numbers / %, etc) 
Disease status / type, etc (if applicable) 
Other 

Methodological quality

Adequate sequence generation
State here method used to generate allocation and reasons for gradingGrade (circle)
 Adequate (Random) (YES)
Inadequate (e.g. alternate) (NO)
Unclear

Allocation concealment

Process used to prevent foreknowledge of group assignment in a RCT, which should be seen as distinct from blinding

State here method used to conceal allocation and reasons for gradingGrade (circle)
 Adequate (YES)
Inadequate (NO)
Unclear
Blinding
Person responsible for participants careYes / No
ParticipantYes / No
Outcome assessorYes / No
Other (please specify)Yes / No

Intention-to-treat

An intention-to-treat analysis is one in which all the participants in a trial are analysed according to the intervention to which they were allocated, whether they received it or not

All participants entering trial 
15% or fewer excluded 
More than 15% excluded 
Not analysed as ‘intention-to-treat’ 
Unclear 

Were withdrawals described? Yes / No / Not clear /

Discuss if appropriate…………………………………………………………………………………………

…………………………………………………………………………………………………………

Incomplete outcome data addressed?
The completeness of outcome data including attrition’s and exclusionsGrade (circle)
 Adequate (YES)
Inadequate (NO)
Unclear
Free of selective reporting?
The possibility of selective outcome reportingGrade (circle)
 Adequate (YES)
Inadequate (NO)
Unclear

Free of other bias?

(Bias not addressed in the other domains)

State here method used to conceal allocation and reasons for gradingGrade (circle)
 Adequate (YES)
Inadequate (NO)
Unclear

Data extraction

Outcomes relevant to your review

Copy and paste from ‘Types of outcome measures’

 Reported in paper (circle)
Overall mortalityYes / No
Overall 28 days mortality (30 days M. included)Yes / No
Time required for clearance of blood culture for Candida speciesYes / No

Frequency of persistent candidaemia

(Positive culture after three days of effective antifungal therapy)

Yes / No
Complications probably related to candidaemia, e.g. metastatic foci, endocarditis, endophthalmitis, hepatosplenic candidosisYes / No
Complications probably related to the intervention, e.g. pneumothorax, arterial puncture, bleeding requiring blood transfusion, local suppurative complicationsYes / No
Complications during inpatient stay not specific to trial intervention, e.g. pneumonia, congestive heart failure, respiratory failure, renal failureYes / No
Duration of mechanical ventilationYes / No
Ventilator free daysYes / No
Mean length of days in hospitalYes / No
Mean length of stay in intensive care unit (ICU)Yes / No
Species-related mortalityYes / No
For Continuous data
Code of paperOutcomes (rename)Unit of measurementIntervention groupControl groupDetails if outcome only described in text
nMean (SD)nMean (SD) 
A etcTime required for clearance of blood culture for Candida species      
 Duration of mechanical ventilation      
 Ventilator free days      
 Mean length of days in hospital      
For Dichotomous data
Code of paperOutcomes (rename)

Intervention group (n)

n = number of participants, not number of events

Control group (n)

n = number of participants, not number of events

AOverall mortality  
 Overall mortality (28 days)  
 

Persistent candidaemia

(Positive culture after three days of effective antifungal therapy)

  
 Complications probably related to candidaemia, e.g. metastatic foci, endocarditis, endophthalmitis, hepatosplenic candidosis  
 Complications probably related to the intervention, e.g. pneumothorax, arterial puncture, bleeding requiring blood transfusion, local suppurative complications  
 Complications during inpatient stay not specific to trial intervention, e.g. pneumonia, congestive heart failure, respiratory failure, renal failure  

Other information which you feel is relevant to the results

Indicate if: any data were obtained from the primary author; if results were estimated from graphs etc; or calculated by you using a formula (this should be stated and the formula given). In general if results not reported in paper(s) are obtained this should be made clear here to be cited in review

 
Freehand space for writing actions such as contact with study authors and changes

References to other trials

Did this report include any references to published reports of potentially eligible trials not already identified for this review?
First authorJournal / ConferenceYear of publication
   
Did this report include any references to unpublished data from potentially eligible trials not already identified for this review? If yes, give list contact name and details
 
Trial characteristics
 Further details
Single centre / multicentre 
Country / Countries 
How was participant eligibility defined? 
How many people were randomised? 
Number of participants in each intervention group 
Number of participants who received intended treatment 
Number of participants who were analysed 
Drug treatment(s) used 
Dose / frequency of administration 
Duration of treatment (State weeks / months, etc, if cross-over trial give length of time in each arm) 
Median (range) length of follow-up reported in this paper (state weeks, months or years or if not stated) 
Time-points when measurements were taken during the study 
Time-points reported in the study 
Time-points you are using in RevMan 
Trial design (e.g. parallel / cross-over*) 
Other 

Contributions of authors

Arash Afshari (AA), Susanne Janum (SJ)

Conceiving the review: Alessandro C Pasqualotto (ACP)

Co-ordinating the review: AA

Screening search results: SJ and AA

Organizing retrieval of papers: SJ and AA

Screening retrieved papers against inclusion criteria: SJ and AA

Appraising quality of papers: SJ and AA

Abstracting data from papers: SJ and AA

Writing to authors of papers for additional information: SJ

Providing additional data about papers: SJ and AA

Obtaining and screening data on unpublished studies: SJ and AA

Data management for the review: SJ and AA

Entering data into Review Manager (RevMan 2012): SJ

RevMan statistical analysis: SJ and AA

Other statistical analysis not using RevMan: SJ and AA

Double entry of data: (data entered by person one: SJ; data entered by person two: AA)

Interpretation of data: SJ and AA

Statistical inferences: SJ and AA

Writing the review: SJ and AA

Securing funding for the review: SJ

Performing previous work that was the foundation of the present study: AA

Guarantor for the review (one author): AA

Authors responsible for reading and checking the review before submission: SJ and AA

Declarations of interest

The authors (Arash Afshari and Susanne Janum) declare that they have no financial or non-financial conflicts of interest.

In accordance with the Cochrane Collaboration sponsorship policy, this review was not funded by any companies whose products are mentioned in the review.

Sources of support

Internal sources

  • No source of support supplied, Other.

External sources

  • No sources of support supplied

Ancillary