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NDT Advance Access originally published online on March 10, 2008
Nephrology Dialysis Transplantation 2008 23(8):2604-2610; doi:10.1093/ndt/gfn023
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Comparison of tissue plasminogen activator–antibiotic locks with heparin–antibiotic locks in children with catheter-related bacteraemia

Ali Mirza Onder1, Jayanthi Chandar2, Nancy Simon3, Rosa Diaz2, Obioma Nwobi2, Carolyn L. Abitbol2 and Gaston Zilleruelo2

1 Division of Paediatric Nephrology, Department of Paediatrics, West Virginia University 2 Division of Paediatric Nephrology, Department of Paediatrics, University of Miami Miller School of Medicine 3 Division of Paediatric Pharmacy, Department of Pharmacy, Holtz Children's Hospital, Miami, FL, USA

Correspondence and offprint requests to: Jayanthi Chandar, Division of Paediatric Nephrology, University of Miami Miller School of Medicine, PO Box 016960 (M-714), Miami, FL 33101, USA. Tel: +1-305-585-6726; Fax: +1-305-585-7025; E-mail: jchanda2{at}med.miami.edu



   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Statistical methods
 Results
 Discussion
 References
 
Background. An accepted pathogenesis of catheter-related bacteraemia (CRB) is the seeding of microorganisms from the intraluminal biofilm of central venous catheters. Antibiotic locks (ABL) are solutions containing high concentrations of antimicrobials with or without anticoagulants that aim to destroy the biofilm.

Methods. In this study, two different ABL solutions, tissue plasminogen activator (TPA)-based and heparin-based ABL, used in conjunction with systemic antibiotics, were prospectively compared in the treatment of CRB.

Results. A total of 42 children on chronic haemodialysis with 11 016 catheter-days were observed for signs and symptoms of CRB over a period of 10 months. Twenty-four CRBs were diagnosed in 18 children (2.2 CRB/1000 catheter-days) and were treated with the protocol. Symptoms of CRB resolved in 83% within 48 h of treatment. None of the infected catheters required early emergent exchange or removal for poorly controlled CRB. Six children had recurrence of CRB within 6 weeks, of which four required catheter exchange. There was no specific microorganism or type of CRB that predisposed to higher recurrence rates. The mean infection-free survival of the catheters following TPA–ABL treatment was shorter than that following heparin–ABL treatment, but was not statistically significant by the log-rank test (126.8 ± 81.6 days versus 154.5 ± 70.4 days).

Conclusion. Both TPA–ABL and heparin–ABL used in conjunction with systemic antibiotics can effectively clear CRB without significant late recurrence at 6 weeks. Early use of ABL for management of CRB can potentially decrease the need for catheter removal, thus salvaging vascular access sites.

Keywords: antibiotic lock solutions; biofilm; catheter-related bacteraemia; haemodialysis; tissue plasminogen activator



   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Statistical methods
 Results
 Discussion
 References
 
Arteriovenous (AV) fistulae or graft is recommended for long-term vascular access in haemodialysis patients [1]. However, tunnelled cuffed central venous catheters are used as long-term vascular access in 60% of newly diagnosed and 30% of prevalent haemodialysis patients [2–5]. Such catheters are frequently used in children on haemodialysis. Successful placement and maintenance of AV fistulae and grafts in children are difficult and require the expertise of a dedicated vascular surgeon [6–9]. While concerted efforts have to be made to decrease the use of long-term catheters, the complications of catheters have to be addressed for improved outcomes.

Catheter-related bacteraemia (CRB), thrombosis and malfunction are the most common complications of long-term catheter use [10–12]. The reported incidence of CRB is 1.2–6.9 CRB/1000 catheter-days, with a predominance of gram-positive pathogens [10,13,14]. In addition to sepsis and shock, the most serious consequence of CRB is metastatic infections such as epidural abscess, osteomyelitis and infective endocarditis [15,16]. Systemic antibiotics can effectively clear only 35–65% of CRB [7,10,17]. Currently, K/DOQI Clinical Practice Guidelines (2006) recommend catheter exchange within 72 h of initiating systemic antibiotic therapy [1].

Catheters can be removed and replaced or exchanged over a guide wire. Risks due to anesthesia and line insertion are common to both procedures and include an increased burden of cost. Moreover, each catheter manipulation increases the risk of sclerosis of the vessel wall. Therefore, in addition to appropriate management of CRB, strategies for salvage of vascular access sites need to be developed. There are numerous reports regarding the use of antibiotic-lock solutions (ABL) for the treatment of CRB without catheter removal. ABLs are solutions containing high concentrations of antibiotics with or without anticoagulants that are left to dwell (locked) in the catheter lumen, exposing the internal lumen of the catheter to persistent antibacterial action. Different antibiotics and anticoagulants have been used in ABL solutions in conjunction with systemic antibiotics [18–21]. The success rate of these studies has led to the recommendation of using ABLs for the management of uncomplicated CRB by an advisory panel for infection control [22].

The aim of this study was to compare the effectiveness of TPA-based ABL versus heparin-based ABL as adjunct treatment with systemic antibiotics for CRB in children with central venous catheters on chronic haemodialysis. The study was randomized, prospective and non-blinded, without a placebo arm.



   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Statistical methods
 Results
 Discussion
 References
 
The study protocol was approved by our institutional review board. A written informed consent was obtained from parents or legal guardians and assent in children >7 years. All children were treated in the paediatric haemodialysis unit at the University of Miami, Holtz Children's Hospital. A total of 42 children were on chronic haemodialysis during the study period from 1 April 2005 to 31 January 2006. Study participants continued to be observed for 6 months after the study period. Thirty-seven children (88%) were using long-term catheters as access for at least part of the study period. Tunnelled cuffed Split Cath® or Hemo-Cath® double lumen haemodialysis catheters (Medcomp®) were used for vascular access and were placed percutaneously by the interventional radiologist or by the paediatric surgical team in children <15 kg. The size and length of the catheters were based on the patient's size. The right internal jugular vein was used whenever possible.

Catheter care
Haemodialysis catheters were handled only during dialysis sessions with no intervention between treatments. The catheter hubs were soaked with a Betadine solution for 5 min prior to connecting to the patient for the first 4 months of the study. After that period, catheter hubs were cleaned with Chloraprep® sticks (chlorhexidine gluconate 2% and isopropyl alcohol 70%). The exit site was cleaned with Chloraprep® sticks once a week and then covered with a chlorhexidine-impregnated dressing (Biopatch®) as well as a transparent dressing. At the end of each dialysis session, each port of the catheter was instilled with 5000 units/ml of heparin solution according to the volume of the ports.

Definitions
Catheter-related bacteraemia (CRB) was defined as the occurrence of a positive blood culture from the catheter with or without a positive peripheral blood culture in a child with systemic symptoms (fever, chills and/or hypotension) and no other identified source of infection. Eradication of CRB was defined as having at least two negative blood cultures from the catheter 1 week apart after a CRB with resolution of systemic symptoms. Recurrence of CRB was defined as the occurrence of CRB within 6 weeks from the treatment of the index CRB, either with the same or different microorganism.

A patient was considered to be at high risk for CRB if there were >10 CRBs/1000 catheter-days prior to starting the protocol.

Polymicrobial CRB
was defined as the documented growth of at least two or more microorganisms in the first or sequential blood cultures during a CRB.

Infection-free survival
of a catheter following a CRB was defined as the time period between the final dose of antibiotics and the first subsequent positive blood culture obtained from that catheter. Censored events were transfer to another facility, catheter exchange for malfunction, elective removal of the catheter (AV fistula or graft, kidney transplantation) or end of study.

Diagnosis and management of CRB
Blood cultures were obtained from both ports of the catheter when children presented with fever, chills and/or hypotension during treatment. Peripheral blood cultures were obtained when possible. All symptomatic children were examined for a clear source of infection, and if none found, they were presumed to have CRB until the initial results of blood cultures were available. The initial empiric treatment consisted of broad-spectrum intravenous (IV) antibiotics for both gram-positive and gram-negative microorganisms. A loading dose of 15 mg/kg/dose of Vancomycin, and 10 mg/kg/dose of Levofloxacin were given. The choice of antibiotics was based on etiology and sensitivity patterns of CRB in our population and was ultimately tailored to the treatment of the specific microorganism [10]. Maintenance doses of antibiotics were given for 2 weeks, and two blood cultures 1 week apart with no growth were documented in this period. Persistence of positive blood cultures resulted in exchange of the catheters even if the patient was symptom free. In cases of polymicrobial CRB, treatment was continued with both vancomycin and levofloxacin. The protocol was discontinued if blood cultures revealed no growth after 5 days. Following the eradication of CRB, no surveillance blood cultures were obtained in asymptomatic children.

Catheters were removed if there was malfunction, catheter breakage, cuff extrusion, persistence of symptoms beyond 48 h of treatment, recurrent CRB, growth of methicillin-resistant Staphylococcus aureus or fungus that persisted with positive blood cultures. All catheter exchanges were done by wire-guided exchange (WGE). No catheters were removed and replaced during the study period.

Antibiotic lock solutions (ABL)
Tobramycin and vancomycin were the antibiotics used in the ABL. TPA (2 mg/2 ml) and heparin (5000 units/ml) were the two different anticoagulants used in this study. Each patient was randomized to either the TPA or the heparin arm of the protocol at the time when initial blood cultures were drawn. Patients with positive blood cultures kept their initial anticoagulant in their ABLs throughout the 2 weeks of treatment. The lock solution was prepared to achieve an antibiotic concentration of 5 mg/ml in the ABL with each of the anticoagulants. Tobramycin locks were prepared by mixing 0.25 ml (10 mg) of tobramycin (from a vial containing 80 mg/2 ml) with 1.75 ml of TPA or heparin. The achieved final concentration of 5 mg/ml tobramycin–TPA or tobramycin–heparin ABL was instilled into the catheter according to the volume of the lumen. Vancomycin locks were prepared by diluting a vial of 500 mg with 5 ml of normal saline. One milliliter (100 mg) of this mixture was drawn and mixed with 9 ml of normal saline to reach a concentration of 10 mg/ml. One milliliter of this solution was mixed with 1 ml of TPA or heparin to give a final concentration of 5 mg/ml vanomycin–TPA or vanomycin–heparin ABL. Vanomycin-based ABL was used for gram-positive CRB and tobramycin-based ABL for gram-negative CRB. Tobramycin-based ABL was used as initial empiric treatment of all CRBs. Vancomycin- and tobramycin-based ABL were alternated for polymicrobial CRB. The ABL did not contain more than one antibiotic. One dose of empiric ABL and six doses of CRB-specific ABLs were used for a total of 2 weeks along with systemic antibiotics. Each ABL was installed in the catheter at the end of each haemodialysis treatment. The catheters were locked with heparin at the termination of the protocol when CRB was cleared.

In vitro compatibility of the ABL solution was confirmed by our pharmacy. The ABL was prepared in a syringe and left at room temperature for 8–12 h to observe for signs of crystallization. The four different types of ABL—vancomycin–TPA, vancomycin–heparin, tobramycin–TPA and tobramycin–heparin—were approved after documentation of no crystallization. Our protocol was adapted from published data [23–25].

The ABL was left to dwell in each catheter lumen for 48–72 h between each haemodialysis session. It was drawn and discarded prior to haemodialysis. Tobramycin levels were not done as part of the study protocol. Prior to the study, we had determined that significant systemic levels were not reached with a concentration of 5 mg/ml of tobramycin–anticoagulant lock solution.

Outcome parameters
The primary endpoints were successful clearance of CRB at the end of 2 weeks of treatment (short-term success) and for catheters to be infection free at 6 weeks following the completion of treatment (long-term success). Secondary endpoints were infection-free catheter survival, overall catheter survival and susceptibility of types of CRB to ABL.

Data were obtained on serum albumin, haemoglobin, ferritin, phosphorous and calcium from the samples collected as routine monthly laboratory studies. Patients’ age, gender, etiology of end-stage renal disease, cumulative catheter days when entering the protocol and oral methylprednisolone treatments were also documented.



   Statistical methods
Top
 Abstract
 Introduction
 Materials and methods
 Statistical methods
Results
 Discussion
 References
 
Mean, standard deviation (mean ± SD) and percentage values were used to summarize baseline characteristics and outcome data. P-values <0.05 were considered significant. Chi-square tests were used to compare proportions. Biochemical parameters between the two groups were compared by the unpaired t-test for normative data and the Mann–Whitney U-test for non-normative data. Differences in biochemical parameters between groups with recurrent CRB, versus 1 CRB, versus no CRB were analyzed by ANOVA or the Kruskal–Wallis test. Graphpad® statistical software was used for statistical analysis. The study was initially designed to have a power of 0.80 (alpha level 0.05) resulting in a sample size of 35.



   Results
Top
 Abstract
 Introduction
 Materials and methods
 Statistical methods
 Results
Discussion
 References
 
There were a total of 42 paediatric haemodialysis patients in our unit during the course of the study. The mean age of the patients was 15.1 ± 6.8 years (range 2–21 years), and 20 were males. There were 26 African Americans, 14 Hispanics and 2 Caucasians. Five patients had AV fistulae or grafts throughout the study, and three more had AV grafts placed during the study. The primary etiology for end-stage renal disease was obstructive uropathy/renal dysplasia in nine patients, lupus nephritis/vasculitis in four, chronic glomerulonephritis in seven, HIV nephropathy in five and unknown or other etiology in seven. Ten of 42 patients (24%) had failed allografts. Thirteen of 42 (31%) patients were using low-dose oral steroids during the study for their failed allograft or the underlying autoimmune disease. Ten of 42 patients (24%) had first-time catheters. The average cumulative catheter-days of children with prior catheter usage were 493.2 ± 279.7 days. Four in this sub-population had never experienced CRB prior to the study, and 10 were at high risk for CRB (>10 CRBs/1000 catheter-days).

There were a total of 59 catheters in this study. Twenty-eight were pre-existing catheters, 10 were first-time catheters, 4 were wire-guided exchanges for recurrent CRB and 17 were wire-guided exchanges for malfunction or extrusion of the catheter. Forty-two catheters were in the right internal jugular vein (IJ), 15 in the left IJ and 2 in the subclavian vein. Right IJ catheters constituted 17/24 CRBs and left IJ catheters 7/24 CRBs. There was no malfunction or occlusion of catheters while children were on ABL for the treatment of CRB.

The study period involved a total of 11 016 catheter-days. Empiric treatment with ABL was initiated for 35 episodes of suspected CRB. Blood cultures were positive for 24 CRBs in 18 children resulting in 2.2 CRBs/1000 catheter-days. Six children had two episodes of CRB each during the study period. Polymicrobial CRB was observed in 4/24 (17%), gram-positive CRB in 12/24 (50%) and gram-negative CRB in 8/24 (33%) children. All of the gram-positive isolates were sensitive to vancomycin with the predominant organism being coagulase-negative Staphylococcus species. The most prevalent gram-negative microorganism was Enterobacter cloacae followed by Klebsiella pneumoniae. Levofloxacin sensitivity among the gram-negative isolates was 83%, with 17% reported to have intermediate sensitivity. No organisms were resistant to levofloxacin. Cumulative sensitivity to tobramycin was 63% for both gram-positive (53%) and gram-negative microorganisms (75%). There was one fungal growth (Candida parapsilosis), sensitive to fluconazole.

The most frequent symptom leading to CRB was fever which occurred in 22/24 cases. Hypotension occurred in 8/24 CRBs. All of the children who had a combination of fever and two or more symptoms had a positive blood culture. Hypotension during haemodialysis treatment (in a previously normotensive or hypertensive child) was always associated with a positive blood culture. Eight patients with CRB were admitted with septic shock and were hospitalized for an average of 5.3 ± 2.2 days.

Of the 35 (69%) cases, 24 initially randomized to the study protocol had positive blood cultures and therefore were able to complete the protocol. The distribution of CRB types in the two arms of the study is shown in Table 1. Of 24 (83%) CRBs treated with the protocol, 20 were symptom free at 48 h of treatment. All patients were symptom free after 72 h of treatment. None of the patients had hypotension or septic shock after the first day of treatment. Of 24 (21%) CRBs, 5 had a second positive blood culture when repeated at 48–72 h. However, subsequent blood cultures were negative. Twenty-three CRBs completed 2 weeks of ABL and systemic antibiotic therapy with 2 negative blood cultures 1 week apart. One patient had polymicrobial/fungal CRB and was treated with 4 weeks of systemic antifungal therapy. Therefore, there was no short-term failure of treatment. None of the CRB required early emergent catheter exchange.


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  		Table 1 Distribution of types of CRB and specific etiologies for the two arms of the study

 
The mean infection-free survival of the catheters following TPA–ABL treatment was shorter than that following heparin–ABL treatment, but was not statistically significant by the log-rank test (126.8 ± 81.6 days versus 154.5 ± 70.4 days). There was an equal distribution of gram-positive, gram-negative and polymicrobial CRB between the two arms, as demonstrated in Table 1. The infection-free survival of Coagulase negative Staphylococcus CRB and polymicrobial CRB was not different between the two treatment arms, as shown in Table 1.

After completion of 2 weeks of treatment, there was recurrence of symptoms of CRB in six patients within 6 weeks. This group had predominantly gram-negative CRB. They were randomized to either arm during their first CRB and were placed on the other arm for the second CRB without randomization. Wire-guided catheter exchange was performed in four of six patients in this group and two were again successfully treated with ABL and systemic antibiotics. Five of the six children in this sub-population had recurrent CRB prior to the study. There was no recurrence of polymicrobial CRB, which was successfully treated with the study protocol.

After we stopped randomizing new patients into the protocol, we observed all the involved catheters for another 6 months. In the recurrent CRB group, one of four exchanged catheters and one of two catheters treated with the ABL protocol experienced another CRB in the 6-month observation period. In the rest, 9 of 18 catheters were exchanged due to malfunction and 5 had CRB. Three catheters were removed (one for successful functioning of the AV fistula and two for transplantation). One patient was transferred to another facility.

Biochemical parameters were compared between the TPA and heparin arm of the study. The heparin–ABL group had lower serum albumin and calcium–phosphorous product as shown in Table 2. When biochemical parameters were compared between patients with no CRB versus those with one CRB versus those with recurrent CRB, patients with recurrent CRB had higher serum albumin and ferritin, as demonstrated in Table 3.


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  		Table 2 Comparison of children in the two arms of the study according to demographic and biochemical features. The calcium–phosphorous product and haemoglobin were higher in the TPA arm

 

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  		Table 3 Comparison of biochemical parameters in children with no CRB versus those with one CRB, versus those with recurrent CRB. Serum albumin was higher in children with recurrent CRB compared to those with no CRB. Therefore hypoalbuminaemia was not a risk factor for CRB in this study

 
There was no mortality or metastatic infection during the study period.



   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Statistical methods
 Results
 Discussion
References
 
This is the first prospective trial in children comparing the outcomes of two different ABL solutions in the treatment of CRB. Our study revealed that both TPA–ABL and heparin–ABL can successfully eradicate CRB when used concomitantly with systemic antibiotics. The ABL protocol caused resolution of symptoms within 48 h of treatment in the majority of cases. All catheters were cleared of CRB and were retained at the end of 2 weeks of treatment. Moreover, 83% remained infection free at 6 weeks after treatment. There was no difference in infection-free survival between TPA and heparin–ABL groups.

Systemic antibiotics alone can clear only 35–65% of CRB, even if infused through the infected catheter [7,10,17]. Scanning electron microscopy studies demonstrate the formation of biofilms on external and internal surfaces of indwelling catheters within 24 h following placement [26–28]. The fibrinous and proteinaceous structure of the biofilm creates antimicrobial resistance. Intraluminal concentrations of systemic antibiotics never reach concentrations above the minimal inhibitory concentration (MIC). Therefore, use of a high concentration of antibiotics with anticoagulants can potentially clear the biofilm, resulting in salvage of the catheter. TPA is used to salvage catheters that are occluded because of its fibrinolytic ability [25]. Despite the advantage offered by its fibrinolytic activity, there was an increased failure rate on the TPA arm, although it was not statistically significant. Unique aspects of this study were that most patients had exchanged or replaced catheters, thus enabling us to test the effect of ABL on different types of microorganisms and CRB. Although this was a small study, no patients were excluded on the basis of etiology of CRB, allowing us to successfully use ABL in gram-positive, gram-negative and polymicrobial CRB. This observation has to be further corroborated in larger studies as some studies have reported high failure rates with certain types of CRB [29,30].

Most reported protocols start ABL treatments after documentation and identification of CRB. Early institution of ABL probably contributed to the success of our protocol despite using 2 weeks of systemic antibiotics rather than 3 weeks. A shorter treatment course was designed with the goal of decreasing the development of antimicrobial resistance. As shown previously, treatment failure correlates with the number of positive blood cultures obtained on successive days and results in decreased catheter survival [10]. Twenty-one percent of patients had two positive successive blood cultures that were subsequently negative on continuation of the protocol. Therefore, early institution of ABL (when CRB is suspected) and continuation of therapy has the potential to decrease the number of positive blood cultures. Tobramycin was the initial empiric antibiotic of choice in the ABL as it has both gram-positive and gram-negative coverage. Vancomycin and levofloxacin were the initial empiric systemic antibiotics of choice prior to definitive treatment based on the susceptibility patterns of microorganisms in our dialysis unit, and may have contributed to a better outcome despite a shorter treatment course of 2 weeks. No breakthrough or metastatic infections were noted. Children who had recurrence of CRB in this study were previously identified to be at high risk for CRB and had predominantly gram-negative isolates. Polymicrobial CRB is usually more difficult to treat requiring catheter replacement [10]. An interesting observation in this study was that polymicrobial CRB was eradicated with the use of ABL.

Among the biochemical markers, patients with recurrent CRB had higher serum albumin in contrast to other studies which report hypoalbuminaemia as a risk factor for bacteraemia [30]. Low haemoglobin is also considered a risk factor for bacteraemia in the haemodialysis patient population. Although there was a statistically significant difference in serum haemoglobin and calcium–phosphorous products between the two randomization arms, there was no significant difference in the final outcome.

A concentration of 5 mg/ml of gentamicin and vancomycin was considered to be effective against Staphylococcus species with systemically insignificant levels [19,24,31]. Hence the concentration of 5 mg/ml of aminoglycoside as a lock solution was made based on these observations in our study. There is a potential for ototoxicity with the use of aminoglycoside lock solutions that has been demonstrated with higher concentrations [32]. Loss of residual renal function and development of antimicrobial resistance are added concerns. Antimicrobial resistance was a rare phenomenon reported after prolonged use of vancomycin and heparin as the lock solution [33]. Bioactivity of TPA after 48–72 h of dwelling in the catheter was not evaluated in this study. Other investigators have found no difference in anticoagulant activity between short and long dwells of TPA in dysfunctional central venous catheters [34].

Thirty-three percent of patients with CRB were initially hospitalized with septic shock. However, there was no mortality or metastatic infections. Studies on adults with CRB report a mortality of up to 10% [32]. Multiple prospective trials have shown that the use of prophylactic ABLs can significantly decrease the incidence of CRBs and the associated mortality in haemodialysis patients [35–37]. However, recent K/DOQI guidelines for vascular access do not make recommendations for the preventive use of ABLs [1]. Large multicenter studies are needed to investigate the effectiveness of prophylactic ABLs.

In conclusion, both TPA–ABL and heparin–ABL used in conjunction with systemic antibiotics can effectively clear CRB without significant late recurrence at 6 weeks. Early use of ABL for the management of CRB can potentially increase the chance of successful treatment and decrease the need for catheter removal, thus salvaging vascular access sites. The weakness of this study is the small number of patients, a non-homogenous cohort with a history of prior catheter use and CRB, and not having a control group treated with only systemic antibiotics. A multi-center trial can overcome this weakness and help determine the safety of shorter treatment courses, the antibiotic and anticoagulant of choice in the ABL and effect of ABL use on the overall catheter survival.



   Acknowledgments
 
We would like to thank our dialysis nurses for their meticulous care and support in implementing the treatment protocol, and our patients and their parents who cooperated with us. We also thank Ali Sina Onder for assisting with data organization and statistical analysis.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Materials and methods
 Statistical methods
 Results
 Discussion
 References
 

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Received for publication: 29. 8.07
Accepted in revised form: 11. 1.08


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D. R. Ashby, A. Power, S. Singh, P. Choi, D. H. Taube, N. D. Duncan, and T. D. Cairns
Bacteremia Associated with Tunneled Hemodialysis Catheters: Outcome after Attempted Salvage
Clin. J. Am. Soc. Nephrol., October 1, 2009; 4(10): 1601 - 1605.
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