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Intravascular catheter infections
Journal of Hospital Infection (2009) 73, 323e330
Available online at www.sciencedirect.com
www.elsevierhealth.com/journals/jhin
REVIEW
Intravascular catheter infections J. Edgeworth* Directorate of Infection, Guy’s and St Thomas’ Hospital, London SE1 7EH, UK Available online 22 August 2009
KEYWORDS Catheter-related bloodstream infection; Costebenefit analysis; Infection control
Summary Formerly an under-appreciated iatrogenic infection, catheterrelated bloodstream infections (CRBSIs) are now the focus of considerable preventive strategies. Although robust clinical definitions remain elusive due to the difficulty in identifying the focus of infection in hospitalised patients, surveillance definitions are proving useful to monitor and compare institutional rates of CRBSI and to target infection control resources. New catheter-sparing diagnostic techniques have been developed, that are probably most applicable to assessment of infection in stable ambulatory patients with single long-term tunnelled catheters rather than acutely unwell hospitalised patients. There is an impressive body of evidence that can be used to support implementation, surveillance and audit of basic infection control practices that should help institutions reduce CRBSI rates. The introduction of preventive antimicrobial strategies at the catheter site has been recommended by international guidelines, yet there remains justifiable concern about long-term selection of resistant organisms. This has not been adequately addressed in current studies. Economic analyses require data on the clinical effect of CRBSIs to adequately assess the benefit; such data are scarce, owing to the difficulty in assessing the contribution from comorbidities, with consequential conflicting results. Overall, institutions can justifiably first assess the benefit of a sustained programme of re-enforcing basic infection control practice on CRBSI before assessing whether the introduction of additional preventive antimicrobial strategies are likely to have any benefit. ª 2009 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction
* Tel.: þ44 207188 3107; fax: þ44 7261 9816. E-mail address: [email protected]
Intravascular catheters are indispensable for modern healthcare.1 They include short-term peripheral venous and arterial catheters, short-term central venous catheters (CVCs), long-term tunnelled
0195-6701/$ - see front matter ª 2009 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jhin.2009.05.008
324 and cuffed CVCs and long-term peripherally inserted CVCs. Venous catheters are predominantly used for administration of fluids, drugs, total parenteral nutrition and blood products and for renal replacement therapy. Arterial catheters are predominantly used for haemodynamic monitoring and collection of blood samples in the critical care setting. The main complication of catheter use is the development of an infection which can be either localised, within the bloodstream or distal.2,3 Such infections can have life-threatening consequences, particularly distal infections at sites such as heart valves and bones, which are most frequently due to Staphylococcus aureus.4e6 There are a number of new approaches to diagnosis and prevention that have been considered in recent comprehensive meta-analyses and reviews.1,7e10 This article provides an overview of the potential benefit of these new strategies in the context of current infection prevention and control practice.
Epidemiology It is estimated that about 250 000 CVCs are used in the UK each year, and in the USA nearly 300 million catheters are used yearly of which about 3 million are CVCs.7,8,11 Numbers of other catheters used, particularly peripheral venous catheters on general wards, are not known. Most epidemiological studies on vascular catheters report on the use of CVCs in intensive care units (ICUs), where there are comparatively high rates of both catheter use and infection within a limited, easily assessable, geographical setting. It is important to remember, however, that insertion of any vascular catheter in any clinical setting can result in a catheter infection. Most studies and surveillance schemes focus on catheter-related bloodstream infections (CRBSIs) as a measure of catheter infection and use different denominators to compare rates including number of patients, patient days, catheters and catheter days. A recent systematic review of 200 prospective studies estimated that incidence rates, expressed as CRBSIs/1000 catheterdays, range from 0.5 for peripheral venous catheters, to 1.6 for long-term CVCs, 1.7 for arterial catheters, 2.1 for peripherally inserted CVCs, and 2.7 for short-term CVCs.12
Clinical descriptions, microbiology and pathogenesis Local catheter infections occur at the exit site, along the subcutaneous tract of tunnelled long-
J. Edgeworth term catheters, and along the body and tip of the catheter within the intravascular compartment.3,13 Significant exit-site and tunnel infections are commonly due to pyogenic organisms, particularly S. aureus, resulting in a combination of a hot, red catheter exit site, cellulitis along the tract and pus formation. The visual signs usually prompt early removal of the catheter, although laboratory confirmation of infection is only made in a small proportion of cases, with mechanical and chemical irritation being alternative causes of local inflammation. Catheters lacking any overt signs of local infection are also frequently removed from patients suspected of having a healthcare-associated infection, and between 10% and 25% are found to grow significant numbers of organisms without an attendant bloodstream infection.3,10 This has been referred to as either catheter colonisation or infection. All organisms commonly cultured from hospitalised patients can also be isolated from catheter tips including skin staphylococci, Candida spp., enterococci and Gram-negative bacteria. The extent to which these organisms cultured from catheter tips contribute to a systemic inflammatory response in the absence of a documented CRBSI remains unclear. It is an area warranting further investigation. There are two main pathways leading to CRBSI.3,14,15 The first is contact between skin surface organisms either at the time of insertion or thereafter, leading to migration of organisms down, and colonisation of, the external catheter surface. It is thought to be the dominant mechanism associated with short-term catheters.15 The second involves transfer of organisms to the catheter hubs from patient skin or healthcare workers’ hands, usually leading to colonisation of the internal catheter surface, and is more common in long-term catheters.14,16 In both cases organisms should be present on the catheter tip and in the blood, although for the hub infections organisms may be confined to the internal catheter surface. Organisms colonise catheters through two main mechanisms: adherence to the catheter surface, facilitated by host proteins such as fibronectin and fibrinogen adsorbed on to the catheter surface, and formation of biofilm on the catheter surface, which protects organisms in a vegetative state where they resist both the innate immune system and antibiotics.3,13,17,18 S. aureus and coagulasenegative staphylococci (CoNS) both express surface adhesins that permit binding to host extracellular matrix proteins deposited on catheters and CoNS, in particular, can produce factors involved in formation of a biofilm.19e22 However, no single factor or group of related molecules has
Intravascular catheter infections been shown to be essential for catheter colonisation. Although staphylococci are the predominant organisms isolated from catheters, other hospital bacteria can be isolated from catheters suggesting other mechanisms of colonisation. Indeed, the dominance of staphylococci may be at least in part explained by the opportunity they have for contact with catheters due to their residence on skin.
Definitions of bloodstream infections Robust definitions of bloodstream infections are required for clinical diagnosis and management, surveillance and investigational studies. Definitions used depend upon these varied indications and also any mandated requirements and local resources. Healthcare-associated BSI have been divided into primary (unknown), secondary to a specified focus (such as skin and soft tissue, or the respiratory, urinary and gastrointestinal tracts) and catheterrelated events. Clinical definitions of CRBSI generally require culture of an organism from blood supported by one of a number of diagnostic tests (to be discussed later) implicating the catheter, and no apparent alternative focus for the infection.23 The difficulty with such clinical definitions is the extent to which alternative foci are sought and then deemed to be a ‘plausible’ alternative focus. Identification of foci for infection causing sepsis in ICU is notoriously difficult, and even when strict criteria are used the identification retains a degree of subjectivity in patients who are acutely unwell for other reasons. A review of five representative large ICU clinical studies shows a wide variation in the proportion of hospital-acquired bloodstream infection assigned to these three categories: primary (22e61%), secondary (16e60%), CRBSI (19e62%).24e28 Although this may represent heterogeneity in clinical practice and patient populations it probably also reflects differences in local interpretation, which complicates communication of studies in this field. Given the location of colonised catheters in the bloodstream, available evidence would equally support definitions where alternative foci for a bloodstream infection were considered only after catheters had been excluded. Surveillance definitions remove much of the subjectivity surrounding clinical definitions. The CDC definition of a catheter-associated infection is a positive blood culture in a patient in whom a central line has been in use <48 h previously.23 Surveillance definitions are expressed as per 1000 bed-days, per 1000 catheters or per 1000 catheter-days. Although per 1000 catheter-days is recognised to be the most informative measure
325 of risk, it requires the most resources, particularly if applied across a whole hospital.12
Improving diagnosis of CRBSI for clinical and economic benefit A common approach to diagnosis of CRBSI in a patient with suspected healthcare-associated infection with a single short-term peripheral catheter or CVC is to take a blood culture and remove the catheter for semiquantitative analysis.29 The catheter tip is ‘rolled’ across an agar plate and CRBSI is diagnosed if the same organism is isolated from blood culture and the tip culture, and the quantity of organisms isolated from the tip is >15 colonies. This approach is simple and cheap, and pooled data from 19 studies including short- and long-term catheters demonstrate a sensitivity and specificity of 85% and 82%, respectively.9 Alternatively a fixed length of catheter can be immersed in broth, sonicated and vortexed to release organisms into suspension that can then be plated out and counted to give a quantitative measure of catheter load. A cut-off of >103 organisms has been used. This technique has the advantage of removing organisms from the internal catheter surface. Pooled data from 14 studies indicate a sensitivity and specificity of 83% and 87%, respectively.9 Diagnoses requiring catheter removal are problematic in settings such as the ICU where patients have multiple short-term central venous and arterial catheters, any or none of which may be the cause of an infection. Replacement of all catheters is time-consuming, expensive and not without clinical risk including pneumothorax and haemorrhage, particularly in patients with a bleeding tendency. Similarly, in ambulatory patients who usually have a single long-term tunnelled catheter, immediate catheter removal often necessitates hospital admission with surgical and or radiological intervention and unnecessary replacement may compromise precious vascular access. In both settings, excluding a catheter as the infected source while still in situ can preserve the catheter life with potential clinical and economic benefit. A number of catheter-sparing diagnostic approaches have been developed, of which simultaneous, quantitative culture and differential time to positivity have shown the most promise.
Simultaneous quantitative blood cultures Equal volumes of blood, usually 10 mL, are drawn simultaneously through catheter(s) and a peripheral vein. Blood is lysed and centrifuged and the blood is plated out on agar. Although studies have reported
326 different cut-offs for a positive diagnosis, the Infectious Diseases Society of America has recommended a five-fold greater colony count from a catheter culture to indicate it as the source of CRBSI. A meta-analysis of diagnostic techniques has shown this to be the most accurate test with a sensitivity and specificity for short-term catheters of 75% and 97%, respectively, and for long-term catheters of 93% and 100%, respectively.9 This increases the number of blood cultures processed by a laboratory, however, and requires considerable additional work.
Differential time to positivity Blood cultures are usually monitored using a realtime continuous detection system which can record the time when organism growth is first detected. Studies have shown that, when blood cultures drawn through a catheter flag positive more than 2 h before a peripheral blood culture, the catheter can be implicated as the focus with a sensitivity and specificity of 89% and 87%, respectively, for short-term catheters and 90% and 72%, respectively, for long-term catheters.9 There are concerns that this method particularly may be compromised by antibiotics received through the catheter at or around the same time. Institutions considering catheter-sparing techniques should assess the impact on the laboratory before implementation. Where a single blood culture may have been taken from a patient with a suspected hospital-acquired infection, this may increase 3e5-fold in patients that have many catheters in situ such as those on ICU. Laboratory blood culture machines have a limited capacity. Furthermore, the simultaneous collection of blood through catheters can result in isolation of organisms such as meticillin-resistant S. aureus (MRSA), without confirmation of being a true CRBSI from a peripherally obtained culture; in the UK this is nonetheless recorded as an institutional MRSA bacteraemia for surveillance purposes and could potentially divert infection control resources and lead to unnecessary clinical interventions. Therefore, if catheter-sparing diagnostic techniques are being considered it seems most appropriate to introduce them in a setting such as renal dialysis or oncology where single long-term catheters are used and where catheter salvage probably has the greatest clinical benefit.
Basic and enhanced strategies for preventing CRBSI Comprehensive national and international guidelines include a large number of recommendations
J. Edgeworth on how to prevent CRBSI, supported by an impressive body of evidence.23,30 Some guidelines consider all catheters whereas most focus on long-term CVCs which are associated with the greatest infection burden.12 The challenge for healthcare institutions is to integrate these comprehensive guidelines into different clinical settings within available resources, supported by a surveillance system to monitor adherence and improvements. Core components of a strategy for preventing CRBSI include: hand hygiene; maximum sterile barrier precautions for CVC insertions; 2% chlorhexidine for skin antisepsis; use of sterile semipermeable dressings to facilitate daily inspection; documentation of exit site appearance; avoidance of the femoral site for insertion for CVCs; removal of the catheter as soon as it is no longer required; routine removal of peripheral venous catheters after 3 days; routine replacement of tubings and administration sets; and use of a tunnelled dual lumen catheter if placement is anticipated to be more than 21 days.23,30 There is a considerable body of data to support the majority of these interventions. One recent comprehensive review stated that, ‘This is a well researched area and few realistic research needs were identified in developing these guidelines.’30 Nonetheless, some aspects of care still require further investigation. For example, it has not been determined whether 2% chlorhexidine in 70% alcohol, the current preferred solution for skin antisepsis, is superior to 5% povidone iodine in 70% alcohol, which has itself been demonstrated as superior to 10% povidone iodine solution. It is also not clear exactly how frequently dressings and tubings should be changed. An important focus recently has been to integrate these recommendations into a care package that can be implemented across an institution. There have been a number of reports in the literature, mostly in ICUs, documenting considerable success using a combination of these interventions.31,32 One notable study combined improved hand hygiene, full barrier precautions for CVC insertion, chlorhexidine for skin antisepsis, avoidance of the femoral site and removal of unnecessary lines.32 It reported a reduction in CRBSIs from 7.7 per 1000 CVC-days to 2.3 per 1000 CVCdays, which remained at low rates for 18 months after the intervention period. Concerns have been raised about the before-and-after study design, compliance, potential for reversion to mean, lack of data on relative importance of individual components, definitions used and the Hawthorne effect of being involved in the study.
Intravascular catheter infections Nonetheless, it is consistent with previous studies and has contributed to a body of data supporting the UK national intervention programme, ‘Saving Lives’, which includes care bundles consisting of the core components described above to target peripheral catheters, long- and short-term CVCs.33 It is recognised that the success of individual institutional programmes will be dependent upon introducing a comprehensive education and training programme supported by pragmatic easyto-introduce audit, surveillance and feedback, clear lines of accountability from ‘board to floor’ and clinical engagement and leadership.
Antimicrobial strategies and antimicrobial lock A number of enhanced strategies have also been assessed that have as a common mechanism the provision of sustained antimicrobials or antiseptics at the catheter site.1,7,10 They include chlorhexidine-impregnated sponges and dressings, catheters impregnated with antimicrobial agents, and antimicrobial locks using antibiotics (including vancomycin, gentamicin, cephalosporins, minocycline and ciprofloxacin) or taurolidine.
Chlorhexidine-impregnated sponges These are placed over the CVC insertion site and covered with a transparent dressing. In theory they should prevent growth and migration of organisms along the external catheter surface but would have no effect on hub colonisation and migration on the internal surface. A number of randomised studies in adult and paediatric groups have shown variable reductions in CRBSI with use of these sponges.1 A meta-analysis of five randomised studies showed a significant reduction in catheter tip colonisation and a non-significant trend towards a reduction in CRBSI.34
Antimicrobial CVCs Impregnation of CVCs with antimicrobial agents is potentially an effective way of ensuring an appropriate concentration of antimicrobial along the whole length of the catheter to prevent colonisation.7 First-generation antimicrobial catheters have either chlorhexidine and silver sulphadiazine (CSS), or silver alone impregnated on the external catheter surface. Second-generation catheters are treated on both the external surface and internal lumen with either CSS, silver or benzalkonium
327 chloride, so as to prevent internal colonisation, thought to be a more common mechanism after the first couple of weeks of insertion. Catheters impregnated with either minocycline and rifampicin or miconazole and rifampicin have also been developed. There have been six systematic reviews of the clinical effectiveness of antimicrobial CVCs on reducing CRBSI, and a recent comprehensive Health Technology Assessment, in which earlier reviews were assessed and compared.8 The odds ratios (ORs) of reducing CRBSIs for first-generation, secondgeneration and antibiotic-coated CVCs all indicated an effect compared with standard catheters, although for first-generation catheters there was a wider, non-significant confidence interval (CI) (OR: 0.67, 95% CI: 0.43e1.06; 0.43, 0.26e0.70; 0.26, 0.15e0.46 respectively).8 It has been noted that when studies including first-generation catheters with short median insertion times (6 days; range: 5.2e7.5) are assessed, a significant reduction in CRBSI is observed (0.48, 0.25e0.91).35 Indeed, when all antimicrobial catheters are included, a significant reduction is only seen for studies in which average catheter insertion was 5e12 days and not 13e20 days (0.4, 0.27e0.58 and 0.69, 0.42e1.14 respectively) although the trend is in the same direction.8 Only one study with a catheter insertion of >20 days has been reported, demonstrating a significant benefit of the antimicrobial catheter.36 Overall, the number of antimicrobial catheters required to prevent one CRBSI ranges from 13 to 221 depending upon the rate in the control group.
Antimicrobial locks This strategy involves infusion of 2e3 mL of an antibiotic-containing solution, usually with an anticoagulant into a CVC at the end of a period of use. Since patients in critical care usually have frequently accessed multiple short-term catheters, this strategy has predominantly been assessed with long-term catheters in haemodialysis and oncology patients. A recent review identified three studies assessing vancomycin lock with heparin compared with heparin alone in a neonatal ICU, paediatric and adult cancer patients.10 Although each setting is quite different, all three studies demonstrated a significant reduction in CRBSI (0.37 vs 1.72 per 1000 catheter-days; 2.3 vs 17.8 per 1000 catheterdays; 0 per 60 vs 4/57 CVCs; vancomycin vs controls in each case).37e39 A few studies in haemodialysis patients have assessed use of gentamicin and one study using either a cephalosporin or neomycin have all shown a similar reduction.10 Three small
328 studies have assessed the use of a 1.38% taurolidine plus 3.8% citrate lock compared with heparin in haemodialysis patients. Two reported a significant reduction in either CRBSI (90 day bacteraemia free survival rate 94 vs 47%; P ¼ 0.001) or an increase in sepsis free catheter survival (0 vs 4 episodes; P ¼ 0.047), but one larger study reported no significant effect on CRBSI (0.85 vs 0.81 per 1000 catheter days).40e42 Further studies are warranted.
Clinical and economic evaluation of the benefit of enhanced antimicrobial strategies The EPIC (Evidence-based Practice in Infection Control) guidelines have recommended antimicrobial CVC for adult patients at risk of CRBSI who require central venous access for 1e3 weeks.30 The Healthcare Infection Control Practices Advisory Committee (HICPAC) of the Centers for Disease Control and Prevention has recommended the use of antimicrobial CVCs in adults whose catheter is expected to remain in situ for >5 days and where the CRBSI rate is above the goal set by the institution despite implementation of a comprehensive strategy to reduce rates.23 There are frequent methodological concerns in reported studies, including the diagnostic criteria used, inadequate blinding and in many cases poor randomisation, so it is understandable that different views have emerged on implementation of these recommendations.7,10 It is useful to review the clinical and economic evaluation of the benefit of preventing CRBSIs that have underpinned these recommendations. There have been three formal cost-effectiveness studies of antimicrobial catheters performed in high risk or ICU settings.43e45 All included economic models informed by a combination of patient-level data from randomised studies and outcome data from other sources. Models were tested using multivariate sensitivity analysis across a range of clinical and economic assumptions. All concluded that antimicrobial catheters were cost-effective. None was performed in the UK. An estimate has been made of the cost-effectiveness of using antimicrobial catheters to prevent CRBSIs in the UK using a simple economic model.8 The model used parameter estimates derived from published studies with an incidence of CRBSI at 3% (range: 2e5%), relative risk reduction with antimicrobial catheters of 54% (range: 38e66%), cost of CRBSI of £9,148 (range: £2,500e£71,000) and a price differential between normal and
J. Edgeworth antimicrobial catheters of £10 (range: £2.50e £25). All but one of the 81 potential scenarios tested in their model using multivariate sensitivity analysis demonstrated an economic benefit of antimicrobial catheters. Antimicrobial catheters were shown not to be cost-effective only at the lowest rate of CRBSI in control population, lowest relative risk reduction, highest cost different for the antimicrobial catheters, and lowest cost of a CRBSI e a scenario the authors consider to be very unlikely in the real world. Many ICU studies have attempted to estimate the excess length of stay (LOS) due to CRBSI as a proxy for additional costs; these have reported between 10 and 20 days.8 None has been performed in the UK. Most of these studies have used a caseecontrol design which is fraught with difficulties in both selecting controls and adjusting for potential confounding variables. Traditional statistical approaches cannot overcome the problem that whereas a CRBSI can increase LOS, the reverse may be equally true. Alternative statistical approaches are being used that overcome these inherent confounders, such as longitudinal modelling, where effects of variables on LOS can be assessed daily and so a temporal relationship between healthcare-acquired infection and increased length of stay can be made. One study using such an approach reported a non-significant increase in LOS for CRBSI of 2.6 days.46 An important clinical consideration for use of enhanced interventions to prevent CRBSI is the potential to save lives. The attributable mortality of CRBSI in caseecontrol studies, mostly recruiting patients from ICUs, has been reported to vary from 0 to 35%.26,28,47e51 Studies have used a wide range of matching criteria to select controls based on admission parameters [specialty, diagnosis, Acute Physiological Assessment and Chronic Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS), Logistic Organ Dysfunction (LOD) score] and on-unit parameters (3 day recalibrated outcome score). Adjustments have also been made for confounders occurring on the unit prior to the CRBSI that impact on mortality using a day 3 or day 4 LOD score. Studies that employed these sophisticated approaches have generally not been able to show significant effects of CRBSI on mortality when all organisms are included.26,47,49,51 One large study performed a subgroup analysis and reported no attributable mortality even when CoNS were excluded, either for S. aureus or for Gram-negative CRBSI alone.47 At an institutional level a number of additional questions may well be raised before introducing antimicrobial catheters. For example, it is
Intravascular catheter infections probable that meta-analyses of randomised studies have been able to show a significant benefit only because more than half of CRBSIs are CoNS; although a significant clinical burden in a neonatal unit and perhaps ambulatory patients with longterm catheters, CoNS are less significant in adult critical care. There is also concern about resistance to both antiseptics and antibiotics; qacA/B and other efflux pumps conferring in vitro resistance to cationic biocides including chlorhexidine are carried by both CoNS and increasingly in some strains of MRSA.52 Resistance to rifampicin has been noted in CoNS at the catheter site in one ICU study.53 Two studies have also noted an increased risk of catheter colonisation with candida [10/187 (5.2%) vs 2/180 (1.1%); relative risk: 4.9; 95% CI: 1.07e22.2].54,55 It may be tempting to wait for a larger, more comprehensive study to be performed, but in an era of reduced incidence of CRBSI in institutions that have re-enforced basic infection control measures e arguably the setting where such studies should be conducted e it is estimated that 10 000 patients would be required in each study arm to address the methodological concerns of previous investigations, and so such a study is unlikely to take place.8 Conflict of interest statement None declared. Funding sources None.
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J. Edgeworth 41. Betjes MG, van Agteren M. Prevention of dialysis catheterrelated sepsis with a citrateetaurolidine-containing lock solution. Nephrol Dial Transplant 2004;19:1546e1551. 42. Quarello F, Forneris G. Prevention of hemodialysis catheterrelated bloodstream infection using an antimicrobial lock. Blood Purif 2002;20:87e92. 43. Marciante KD, Veenstra DL, Lipsky BA, Saint S. Which antimicrobial impregnated central venous catheter should we use? Modeling the costs and outcomes of antimicrobial catheter use. Am J Infect Control 2003;31:1e8. 44. Shorr AF, Humphreys CW, Helman DL. New choices for central venous catheters: potential financial implications. Chest 2003;124:275e284. 45. Veenstra DL, Saint S, Saha S, Lumley T, Sullivan SD. Efficacy of antiseptic-impregnated central venous catheters in preventing catheter-related bloodstream infection: a meta-analysis. J Am Med Assoc 1999;281:261e267. 46. Beyersmann J, Gastmeier P, Grundmann H, et al. Use of multistate models to assess prolongation of intensive care unit stay due to nosocomial infection. Infect Control Hosp Epidemiol 2006;27:493e499. 47. Blot SI, Depuydt P, Annemans L, et al. Clinical and economic outcomes in critically ill patients with nosocomial catheterrelated bloodstream infections. Clin Infect Dis 2005;41: 1591e1598. 48. Digiovine B, Chenoweth C, Watts C, Higgins M. The attributable mortality and costs of primary nosocomial bloodstream infections in the intensive care unit. Am J Respir Crit Care Med 1999;160:976e981. 49. Garrouste-Orgeas M, Timsit JF, Tafflet M, et al. Excess risk of death from intensive care unit-acquired nosocomial bloodstream infections: a reappraisal. Clin Infect Dis 2006;42:1118e1126. 50. Rello J. Impact of nosocomial infections on outcome: myths and evidence. Infect Control Hosp Epidemiol 1999;20: 392e394. 51. Soufir L, Timsit JF, Mahe C, Carlet J, Regnier B, Chevret S. Attributable morbidity and mortality of catheter-related septicemia in critically ill patients: a matched, riskadjusted, cohort study. Infect Control Hosp Epidemiol 1999;20:396e401. 52. Smith K, Gemmell CG, Hunter IS. The association between biocide tolerance and the presence or absence of qac genes among hospital-acquired and community-acquired MRSA isolates. J Antimicrob Chemother 2008;61:78e84. 53. Chatzinikolaou I, Hanna H, Graviss L, et al. Clinical experience with minocycline and rifampin-impregnated central venous catheters in bone marrow transplantation recipients: efficacy and low risk of developing staphylococcal resistance. Infect Control Hosp Epidemiol 2003;24:961e963. 54. Leon C, Ruiz-Santana S, Rello J, et al. Benefits of minocycline and rifampin-impregnated central venous catheters. A prospective, randomized, double-blind, controlled, multicenter trial. Intensive Care Med 2004;30:1891e1899. 55. Sampath LA, Tambe SM, Modak SM. In vitro and in vivo efficacy of catheters impregnated with antiseptics or antibiotics: evaluation of the risk of bacterial resistance to the antimicrobials in the catheters. Infect Control Hosp Epidemiol 2001;22:640e646.
Available online at www.sciencedirect.com
www.elsevierhealth.com/journals/jhin
REVIEW
Intravascular catheter infections J. Edgeworth* Directorate of Infection, Guy’s and St Thomas’ Hospital, London SE1 7EH, UK Available online 22 August 2009
KEYWORDS Catheter-related bloodstream infection; Costebenefit analysis; Infection control
Summary Formerly an under-appreciated iatrogenic infection, catheterrelated bloodstream infections (CRBSIs) are now the focus of considerable preventive strategies. Although robust clinical definitions remain elusive due to the difficulty in identifying the focus of infection in hospitalised patients, surveillance definitions are proving useful to monitor and compare institutional rates of CRBSI and to target infection control resources. New catheter-sparing diagnostic techniques have been developed, that are probably most applicable to assessment of infection in stable ambulatory patients with single long-term tunnelled catheters rather than acutely unwell hospitalised patients. There is an impressive body of evidence that can be used to support implementation, surveillance and audit of basic infection control practices that should help institutions reduce CRBSI rates. The introduction of preventive antimicrobial strategies at the catheter site has been recommended by international guidelines, yet there remains justifiable concern about long-term selection of resistant organisms. This has not been adequately addressed in current studies. Economic analyses require data on the clinical effect of CRBSIs to adequately assess the benefit; such data are scarce, owing to the difficulty in assessing the contribution from comorbidities, with consequential conflicting results. Overall, institutions can justifiably first assess the benefit of a sustained programme of re-enforcing basic infection control practice on CRBSI before assessing whether the introduction of additional preventive antimicrobial strategies are likely to have any benefit. ª 2009 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved.
Introduction
* Tel.: þ44 207188 3107; fax: þ44 7261 9816. E-mail address: [email protected]
Intravascular catheters are indispensable for modern healthcare.1 They include short-term peripheral venous and arterial catheters, short-term central venous catheters (CVCs), long-term tunnelled
0195-6701/$ - see front matter ª 2009 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jhin.2009.05.008
324 and cuffed CVCs and long-term peripherally inserted CVCs. Venous catheters are predominantly used for administration of fluids, drugs, total parenteral nutrition and blood products and for renal replacement therapy. Arterial catheters are predominantly used for haemodynamic monitoring and collection of blood samples in the critical care setting. The main complication of catheter use is the development of an infection which can be either localised, within the bloodstream or distal.2,3 Such infections can have life-threatening consequences, particularly distal infections at sites such as heart valves and bones, which are most frequently due to Staphylococcus aureus.4e6 There are a number of new approaches to diagnosis and prevention that have been considered in recent comprehensive meta-analyses and reviews.1,7e10 This article provides an overview of the potential benefit of these new strategies in the context of current infection prevention and control practice.
Epidemiology It is estimated that about 250 000 CVCs are used in the UK each year, and in the USA nearly 300 million catheters are used yearly of which about 3 million are CVCs.7,8,11 Numbers of other catheters used, particularly peripheral venous catheters on general wards, are not known. Most epidemiological studies on vascular catheters report on the use of CVCs in intensive care units (ICUs), where there are comparatively high rates of both catheter use and infection within a limited, easily assessable, geographical setting. It is important to remember, however, that insertion of any vascular catheter in any clinical setting can result in a catheter infection. Most studies and surveillance schemes focus on catheter-related bloodstream infections (CRBSIs) as a measure of catheter infection and use different denominators to compare rates including number of patients, patient days, catheters and catheter days. A recent systematic review of 200 prospective studies estimated that incidence rates, expressed as CRBSIs/1000 catheterdays, range from 0.5 for peripheral venous catheters, to 1.6 for long-term CVCs, 1.7 for arterial catheters, 2.1 for peripherally inserted CVCs, and 2.7 for short-term CVCs.12
Clinical descriptions, microbiology and pathogenesis Local catheter infections occur at the exit site, along the subcutaneous tract of tunnelled long-
J. Edgeworth term catheters, and along the body and tip of the catheter within the intravascular compartment.3,13 Significant exit-site and tunnel infections are commonly due to pyogenic organisms, particularly S. aureus, resulting in a combination of a hot, red catheter exit site, cellulitis along the tract and pus formation. The visual signs usually prompt early removal of the catheter, although laboratory confirmation of infection is only made in a small proportion of cases, with mechanical and chemical irritation being alternative causes of local inflammation. Catheters lacking any overt signs of local infection are also frequently removed from patients suspected of having a healthcare-associated infection, and between 10% and 25% are found to grow significant numbers of organisms without an attendant bloodstream infection.3,10 This has been referred to as either catheter colonisation or infection. All organisms commonly cultured from hospitalised patients can also be isolated from catheter tips including skin staphylococci, Candida spp., enterococci and Gram-negative bacteria. The extent to which these organisms cultured from catheter tips contribute to a systemic inflammatory response in the absence of a documented CRBSI remains unclear. It is an area warranting further investigation. There are two main pathways leading to CRBSI.3,14,15 The first is contact between skin surface organisms either at the time of insertion or thereafter, leading to migration of organisms down, and colonisation of, the external catheter surface. It is thought to be the dominant mechanism associated with short-term catheters.15 The second involves transfer of organisms to the catheter hubs from patient skin or healthcare workers’ hands, usually leading to colonisation of the internal catheter surface, and is more common in long-term catheters.14,16 In both cases organisms should be present on the catheter tip and in the blood, although for the hub infections organisms may be confined to the internal catheter surface. Organisms colonise catheters through two main mechanisms: adherence to the catheter surface, facilitated by host proteins such as fibronectin and fibrinogen adsorbed on to the catheter surface, and formation of biofilm on the catheter surface, which protects organisms in a vegetative state where they resist both the innate immune system and antibiotics.3,13,17,18 S. aureus and coagulasenegative staphylococci (CoNS) both express surface adhesins that permit binding to host extracellular matrix proteins deposited on catheters and CoNS, in particular, can produce factors involved in formation of a biofilm.19e22 However, no single factor or group of related molecules has
Intravascular catheter infections been shown to be essential for catheter colonisation. Although staphylococci are the predominant organisms isolated from catheters, other hospital bacteria can be isolated from catheters suggesting other mechanisms of colonisation. Indeed, the dominance of staphylococci may be at least in part explained by the opportunity they have for contact with catheters due to their residence on skin.
Definitions of bloodstream infections Robust definitions of bloodstream infections are required for clinical diagnosis and management, surveillance and investigational studies. Definitions used depend upon these varied indications and also any mandated requirements and local resources. Healthcare-associated BSI have been divided into primary (unknown), secondary to a specified focus (such as skin and soft tissue, or the respiratory, urinary and gastrointestinal tracts) and catheterrelated events. Clinical definitions of CRBSI generally require culture of an organism from blood supported by one of a number of diagnostic tests (to be discussed later) implicating the catheter, and no apparent alternative focus for the infection.23 The difficulty with such clinical definitions is the extent to which alternative foci are sought and then deemed to be a ‘plausible’ alternative focus. Identification of foci for infection causing sepsis in ICU is notoriously difficult, and even when strict criteria are used the identification retains a degree of subjectivity in patients who are acutely unwell for other reasons. A review of five representative large ICU clinical studies shows a wide variation in the proportion of hospital-acquired bloodstream infection assigned to these three categories: primary (22e61%), secondary (16e60%), CRBSI (19e62%).24e28 Although this may represent heterogeneity in clinical practice and patient populations it probably also reflects differences in local interpretation, which complicates communication of studies in this field. Given the location of colonised catheters in the bloodstream, available evidence would equally support definitions where alternative foci for a bloodstream infection were considered only after catheters had been excluded. Surveillance definitions remove much of the subjectivity surrounding clinical definitions. The CDC definition of a catheter-associated infection is a positive blood culture in a patient in whom a central line has been in use <48 h previously.23 Surveillance definitions are expressed as per 1000 bed-days, per 1000 catheters or per 1000 catheter-days. Although per 1000 catheter-days is recognised to be the most informative measure
325 of risk, it requires the most resources, particularly if applied across a whole hospital.12
Improving diagnosis of CRBSI for clinical and economic benefit A common approach to diagnosis of CRBSI in a patient with suspected healthcare-associated infection with a single short-term peripheral catheter or CVC is to take a blood culture and remove the catheter for semiquantitative analysis.29 The catheter tip is ‘rolled’ across an agar plate and CRBSI is diagnosed if the same organism is isolated from blood culture and the tip culture, and the quantity of organisms isolated from the tip is >15 colonies. This approach is simple and cheap, and pooled data from 19 studies including short- and long-term catheters demonstrate a sensitivity and specificity of 85% and 82%, respectively.9 Alternatively a fixed length of catheter can be immersed in broth, sonicated and vortexed to release organisms into suspension that can then be plated out and counted to give a quantitative measure of catheter load. A cut-off of >103 organisms has been used. This technique has the advantage of removing organisms from the internal catheter surface. Pooled data from 14 studies indicate a sensitivity and specificity of 83% and 87%, respectively.9 Diagnoses requiring catheter removal are problematic in settings such as the ICU where patients have multiple short-term central venous and arterial catheters, any or none of which may be the cause of an infection. Replacement of all catheters is time-consuming, expensive and not without clinical risk including pneumothorax and haemorrhage, particularly in patients with a bleeding tendency. Similarly, in ambulatory patients who usually have a single long-term tunnelled catheter, immediate catheter removal often necessitates hospital admission with surgical and or radiological intervention and unnecessary replacement may compromise precious vascular access. In both settings, excluding a catheter as the infected source while still in situ can preserve the catheter life with potential clinical and economic benefit. A number of catheter-sparing diagnostic approaches have been developed, of which simultaneous, quantitative culture and differential time to positivity have shown the most promise.
Simultaneous quantitative blood cultures Equal volumes of blood, usually 10 mL, are drawn simultaneously through catheter(s) and a peripheral vein. Blood is lysed and centrifuged and the blood is plated out on agar. Although studies have reported
326 different cut-offs for a positive diagnosis, the Infectious Diseases Society of America has recommended a five-fold greater colony count from a catheter culture to indicate it as the source of CRBSI. A meta-analysis of diagnostic techniques has shown this to be the most accurate test with a sensitivity and specificity for short-term catheters of 75% and 97%, respectively, and for long-term catheters of 93% and 100%, respectively.9 This increases the number of blood cultures processed by a laboratory, however, and requires considerable additional work.
Differential time to positivity Blood cultures are usually monitored using a realtime continuous detection system which can record the time when organism growth is first detected. Studies have shown that, when blood cultures drawn through a catheter flag positive more than 2 h before a peripheral blood culture, the catheter can be implicated as the focus with a sensitivity and specificity of 89% and 87%, respectively, for short-term catheters and 90% and 72%, respectively, for long-term catheters.9 There are concerns that this method particularly may be compromised by antibiotics received through the catheter at or around the same time. Institutions considering catheter-sparing techniques should assess the impact on the laboratory before implementation. Where a single blood culture may have been taken from a patient with a suspected hospital-acquired infection, this may increase 3e5-fold in patients that have many catheters in situ such as those on ICU. Laboratory blood culture machines have a limited capacity. Furthermore, the simultaneous collection of blood through catheters can result in isolation of organisms such as meticillin-resistant S. aureus (MRSA), without confirmation of being a true CRBSI from a peripherally obtained culture; in the UK this is nonetheless recorded as an institutional MRSA bacteraemia for surveillance purposes and could potentially divert infection control resources and lead to unnecessary clinical interventions. Therefore, if catheter-sparing diagnostic techniques are being considered it seems most appropriate to introduce them in a setting such as renal dialysis or oncology where single long-term catheters are used and where catheter salvage probably has the greatest clinical benefit.
Basic and enhanced strategies for preventing CRBSI Comprehensive national and international guidelines include a large number of recommendations
J. Edgeworth on how to prevent CRBSI, supported by an impressive body of evidence.23,30 Some guidelines consider all catheters whereas most focus on long-term CVCs which are associated with the greatest infection burden.12 The challenge for healthcare institutions is to integrate these comprehensive guidelines into different clinical settings within available resources, supported by a surveillance system to monitor adherence and improvements. Core components of a strategy for preventing CRBSI include: hand hygiene; maximum sterile barrier precautions for CVC insertions; 2% chlorhexidine for skin antisepsis; use of sterile semipermeable dressings to facilitate daily inspection; documentation of exit site appearance; avoidance of the femoral site for insertion for CVCs; removal of the catheter as soon as it is no longer required; routine removal of peripheral venous catheters after 3 days; routine replacement of tubings and administration sets; and use of a tunnelled dual lumen catheter if placement is anticipated to be more than 21 days.23,30 There is a considerable body of data to support the majority of these interventions. One recent comprehensive review stated that, ‘This is a well researched area and few realistic research needs were identified in developing these guidelines.’30 Nonetheless, some aspects of care still require further investigation. For example, it has not been determined whether 2% chlorhexidine in 70% alcohol, the current preferred solution for skin antisepsis, is superior to 5% povidone iodine in 70% alcohol, which has itself been demonstrated as superior to 10% povidone iodine solution. It is also not clear exactly how frequently dressings and tubings should be changed. An important focus recently has been to integrate these recommendations into a care package that can be implemented across an institution. There have been a number of reports in the literature, mostly in ICUs, documenting considerable success using a combination of these interventions.31,32 One notable study combined improved hand hygiene, full barrier precautions for CVC insertion, chlorhexidine for skin antisepsis, avoidance of the femoral site and removal of unnecessary lines.32 It reported a reduction in CRBSIs from 7.7 per 1000 CVC-days to 2.3 per 1000 CVCdays, which remained at low rates for 18 months after the intervention period. Concerns have been raised about the before-and-after study design, compliance, potential for reversion to mean, lack of data on relative importance of individual components, definitions used and the Hawthorne effect of being involved in the study.
Intravascular catheter infections Nonetheless, it is consistent with previous studies and has contributed to a body of data supporting the UK national intervention programme, ‘Saving Lives’, which includes care bundles consisting of the core components described above to target peripheral catheters, long- and short-term CVCs.33 It is recognised that the success of individual institutional programmes will be dependent upon introducing a comprehensive education and training programme supported by pragmatic easyto-introduce audit, surveillance and feedback, clear lines of accountability from ‘board to floor’ and clinical engagement and leadership.
Antimicrobial strategies and antimicrobial lock A number of enhanced strategies have also been assessed that have as a common mechanism the provision of sustained antimicrobials or antiseptics at the catheter site.1,7,10 They include chlorhexidine-impregnated sponges and dressings, catheters impregnated with antimicrobial agents, and antimicrobial locks using antibiotics (including vancomycin, gentamicin, cephalosporins, minocycline and ciprofloxacin) or taurolidine.
Chlorhexidine-impregnated sponges These are placed over the CVC insertion site and covered with a transparent dressing. In theory they should prevent growth and migration of organisms along the external catheter surface but would have no effect on hub colonisation and migration on the internal surface. A number of randomised studies in adult and paediatric groups have shown variable reductions in CRBSI with use of these sponges.1 A meta-analysis of five randomised studies showed a significant reduction in catheter tip colonisation and a non-significant trend towards a reduction in CRBSI.34
Antimicrobial CVCs Impregnation of CVCs with antimicrobial agents is potentially an effective way of ensuring an appropriate concentration of antimicrobial along the whole length of the catheter to prevent colonisation.7 First-generation antimicrobial catheters have either chlorhexidine and silver sulphadiazine (CSS), or silver alone impregnated on the external catheter surface. Second-generation catheters are treated on both the external surface and internal lumen with either CSS, silver or benzalkonium
327 chloride, so as to prevent internal colonisation, thought to be a more common mechanism after the first couple of weeks of insertion. Catheters impregnated with either minocycline and rifampicin or miconazole and rifampicin have also been developed. There have been six systematic reviews of the clinical effectiveness of antimicrobial CVCs on reducing CRBSI, and a recent comprehensive Health Technology Assessment, in which earlier reviews were assessed and compared.8 The odds ratios (ORs) of reducing CRBSIs for first-generation, secondgeneration and antibiotic-coated CVCs all indicated an effect compared with standard catheters, although for first-generation catheters there was a wider, non-significant confidence interval (CI) (OR: 0.67, 95% CI: 0.43e1.06; 0.43, 0.26e0.70; 0.26, 0.15e0.46 respectively).8 It has been noted that when studies including first-generation catheters with short median insertion times (6 days; range: 5.2e7.5) are assessed, a significant reduction in CRBSI is observed (0.48, 0.25e0.91).35 Indeed, when all antimicrobial catheters are included, a significant reduction is only seen for studies in which average catheter insertion was 5e12 days and not 13e20 days (0.4, 0.27e0.58 and 0.69, 0.42e1.14 respectively) although the trend is in the same direction.8 Only one study with a catheter insertion of >20 days has been reported, demonstrating a significant benefit of the antimicrobial catheter.36 Overall, the number of antimicrobial catheters required to prevent one CRBSI ranges from 13 to 221 depending upon the rate in the control group.
Antimicrobial locks This strategy involves infusion of 2e3 mL of an antibiotic-containing solution, usually with an anticoagulant into a CVC at the end of a period of use. Since patients in critical care usually have frequently accessed multiple short-term catheters, this strategy has predominantly been assessed with long-term catheters in haemodialysis and oncology patients. A recent review identified three studies assessing vancomycin lock with heparin compared with heparin alone in a neonatal ICU, paediatric and adult cancer patients.10 Although each setting is quite different, all three studies demonstrated a significant reduction in CRBSI (0.37 vs 1.72 per 1000 catheter-days; 2.3 vs 17.8 per 1000 catheterdays; 0 per 60 vs 4/57 CVCs; vancomycin vs controls in each case).37e39 A few studies in haemodialysis patients have assessed use of gentamicin and one study using either a cephalosporin or neomycin have all shown a similar reduction.10 Three small
328 studies have assessed the use of a 1.38% taurolidine plus 3.8% citrate lock compared with heparin in haemodialysis patients. Two reported a significant reduction in either CRBSI (90 day bacteraemia free survival rate 94 vs 47%; P ¼ 0.001) or an increase in sepsis free catheter survival (0 vs 4 episodes; P ¼ 0.047), but one larger study reported no significant effect on CRBSI (0.85 vs 0.81 per 1000 catheter days).40e42 Further studies are warranted.
Clinical and economic evaluation of the benefit of enhanced antimicrobial strategies The EPIC (Evidence-based Practice in Infection Control) guidelines have recommended antimicrobial CVC for adult patients at risk of CRBSI who require central venous access for 1e3 weeks.30 The Healthcare Infection Control Practices Advisory Committee (HICPAC) of the Centers for Disease Control and Prevention has recommended the use of antimicrobial CVCs in adults whose catheter is expected to remain in situ for >5 days and where the CRBSI rate is above the goal set by the institution despite implementation of a comprehensive strategy to reduce rates.23 There are frequent methodological concerns in reported studies, including the diagnostic criteria used, inadequate blinding and in many cases poor randomisation, so it is understandable that different views have emerged on implementation of these recommendations.7,10 It is useful to review the clinical and economic evaluation of the benefit of preventing CRBSIs that have underpinned these recommendations. There have been three formal cost-effectiveness studies of antimicrobial catheters performed in high risk or ICU settings.43e45 All included economic models informed by a combination of patient-level data from randomised studies and outcome data from other sources. Models were tested using multivariate sensitivity analysis across a range of clinical and economic assumptions. All concluded that antimicrobial catheters were cost-effective. None was performed in the UK. An estimate has been made of the cost-effectiveness of using antimicrobial catheters to prevent CRBSIs in the UK using a simple economic model.8 The model used parameter estimates derived from published studies with an incidence of CRBSI at 3% (range: 2e5%), relative risk reduction with antimicrobial catheters of 54% (range: 38e66%), cost of CRBSI of £9,148 (range: £2,500e£71,000) and a price differential between normal and
J. Edgeworth antimicrobial catheters of £10 (range: £2.50e £25). All but one of the 81 potential scenarios tested in their model using multivariate sensitivity analysis demonstrated an economic benefit of antimicrobial catheters. Antimicrobial catheters were shown not to be cost-effective only at the lowest rate of CRBSI in control population, lowest relative risk reduction, highest cost different for the antimicrobial catheters, and lowest cost of a CRBSI e a scenario the authors consider to be very unlikely in the real world. Many ICU studies have attempted to estimate the excess length of stay (LOS) due to CRBSI as a proxy for additional costs; these have reported between 10 and 20 days.8 None has been performed in the UK. Most of these studies have used a caseecontrol design which is fraught with difficulties in both selecting controls and adjusting for potential confounding variables. Traditional statistical approaches cannot overcome the problem that whereas a CRBSI can increase LOS, the reverse may be equally true. Alternative statistical approaches are being used that overcome these inherent confounders, such as longitudinal modelling, where effects of variables on LOS can be assessed daily and so a temporal relationship between healthcare-acquired infection and increased length of stay can be made. One study using such an approach reported a non-significant increase in LOS for CRBSI of 2.6 days.46 An important clinical consideration for use of enhanced interventions to prevent CRBSI is the potential to save lives. The attributable mortality of CRBSI in caseecontrol studies, mostly recruiting patients from ICUs, has been reported to vary from 0 to 35%.26,28,47e51 Studies have used a wide range of matching criteria to select controls based on admission parameters [specialty, diagnosis, Acute Physiological Assessment and Chronic Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS), Logistic Organ Dysfunction (LOD) score] and on-unit parameters (3 day recalibrated outcome score). Adjustments have also been made for confounders occurring on the unit prior to the CRBSI that impact on mortality using a day 3 or day 4 LOD score. Studies that employed these sophisticated approaches have generally not been able to show significant effects of CRBSI on mortality when all organisms are included.26,47,49,51 One large study performed a subgroup analysis and reported no attributable mortality even when CoNS were excluded, either for S. aureus or for Gram-negative CRBSI alone.47 At an institutional level a number of additional questions may well be raised before introducing antimicrobial catheters. For example, it is
Intravascular catheter infections probable that meta-analyses of randomised studies have been able to show a significant benefit only because more than half of CRBSIs are CoNS; although a significant clinical burden in a neonatal unit and perhaps ambulatory patients with longterm catheters, CoNS are less significant in adult critical care. There is also concern about resistance to both antiseptics and antibiotics; qacA/B and other efflux pumps conferring in vitro resistance to cationic biocides including chlorhexidine are carried by both CoNS and increasingly in some strains of MRSA.52 Resistance to rifampicin has been noted in CoNS at the catheter site in one ICU study.53 Two studies have also noted an increased risk of catheter colonisation with candida [10/187 (5.2%) vs 2/180 (1.1%); relative risk: 4.9; 95% CI: 1.07e22.2].54,55 It may be tempting to wait for a larger, more comprehensive study to be performed, but in an era of reduced incidence of CRBSI in institutions that have re-enforced basic infection control measures e arguably the setting where such studies should be conducted e it is estimated that 10 000 patients would be required in each study arm to address the methodological concerns of previous investigations, and so such a study is unlikely to take place.8 Conflict of interest statement None declared. Funding sources None.
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