Department of Internal Medicine, Division of Nephrology, Erasmus Medical Center, Dijkzigt Rotterdam, The Netherlands
Correspondence and offprint requests to: Michiel G. H. Betjes, MD, PhD, Erasmus Medical Center, Dijkzigt Rotterdam, Department of Internal Medicine, Division of Nephrology, Dr Molewater plein 40, 3015 GD Rotterdam, The Netherlands. Email: m.g.h.betjes{at}erasmusmc.nl
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Abstract |
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Methods. In a randomized prospective trial, patients receiving a dialysis catheter were included and catheters were locked with either heparin or a citratetaurolidine-containing solution. Blood cultures drawn from the catheter lumen were routinely taken every 2 weeks and at time of removal of the catheter to detect bacterial colonization. Catheter-related sepsis and exit-site infections were registered for both groups.
Results. A total of 76 catheters were inserted in 58 patients. The incidence of catheter colonization progressed slowly over time with no differences between dialysis catheters filled with heparin or citratetaurolidine-containing solution. The number of exit-site infections was also similar between both groups. In the heparin group, four cases of catheter-related sepsis occurred as opposed to no sepsis episodes in the patients with catheters locked with the citratetaurolidine-containing solution (P<0.5). No side effects with the use of citratetaurolidine catheter lock solution were noted.
Conclusions. This study shows that catheter filling with a solution containing the antimicrobial taurolidine may significantly reduce the incidence of catheter-related sepsis. Taurolidine appears to be effective and safe and does not carry the risk for side effects that have been reported for other antimicrobial lock solutions containing gentamicin or high concentrations of citrate.
Keywords: catheter; haemodialysis; lock; sepsis; taurolidine
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Introduction |
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Bacterial colonization of the intraluminal surface of the catheter with biofilm formation occurs in a high percentage of catheters and precedes peripheral bacteraemia and septic symptoms [4]. Several catheter fillings, such as highly concentrated citrate solutions and gentamicin, have been tested for their efficacy in reducing bacterial colonization and thereby lowering the incidence of CRS. Although effective, their use is restricted by undesirable side effects, such as the risk for hypocalcaemia and high trough levels of gentamicin [5,6].
Taurolidine, a derivative of the amino acid taurine, is an antimicrobial agent that inhibits and kills a broad range of micro-organisms [7,8]. The high concentrations that are needed to exert its antibacterial effect limits the use of taurolidine for parenteral use, but can be easily achieved intraluminal in a dialysis catheter. A catheter lock solution containing citrate and taurolidine has been developed and a low CRS incidence was observed when this lock solution was used in combination with subcutaneous catheter devices and tunnelled catheters [911]. In a single centre open label randomized trial, we tested the efficacy of citratetaurolidine lock solution compared with heparin in the prevention of CRS.
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Subjects and methods |
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Experienced nephrologists inserted all catheters and catheter placement was controlled for by a radiograph of the thorax. The choice of catheter was guided by the expected duration for the catheter to be in use. A non-tunnelled pre-curved single lumen catheter (Medcomp, Harleysville, PA, USA) was placed in the right jugular vein if the expected duration of use was <4 weeks and a double or single lumen tunnelled catheter was inserted for prolonged use (Tesio Cath and Ash Split Cath; Medcomp, Harleysville, PA, USA). The femoral vein was only used for catheters expected to be in place for <1 week.
Catheters were placed under strict aseptic conditions and the exit site was covered with a transparent, oxygen-permeable dressing. Patients were administered nasal mupirocin on a weekly basis, because this may reduce the number of catheter-related infections [5]. Exit-site care involved inspection of the catheter exit site at each dialysis, cleaning with chlorhexidine or iodine and covering with a new transparent dressing. Connecting and disconnecting of the dialysis catheter to the bloodlines was done under strict aseptic conditions, with nurses wearing facial masks, sterile gloves and a sterile gown. Before the catheter was opened, the catheter hub was wrapped for 5 min in gauzes soaked in iodine or chlorhexidine.
Patients were allocated to receive either heparin (5000 U/ml) or citratetaurolidine (1.35% taurolidine and 4% sodium citrate; NeutrolinTM, Biolink, Norwell, MA, USA) as a catheter lock solution using a computer-generated table of random numbers. The randomization procedure was done independent of type of catheter or place of insertion. The lock solution was withdrawn before each dialysis and the catheter was locked after dialysis with a volume equivalent to the lumen volume plus 0.1 ml. Patients clinical characteristics are shown in Table 1.
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The primary end-point was CRS. This was defined as a symptomatic patient with a positive bacterial blood culture drawn from the dialysis catheter with no other apparent source of infection.
Clinical exit-site infection was defined according to the Centers for Disease Control criteria [12]: erythema, tenderness and/or induration within 2 cm of the exit site with or without a purulent exudate or microbiological exit-site infection where the exudate yields a micro-organism on culture.
As a secondary end-point, bacterial colonization of the catheter was chosen. Bacterial colonization was defined as a positive bacterial culture in blood drawn routinely every 2 weeks and at the time of removal from the catheter lumen before starting dialysis.
CRS or bacterial colonization-free survival was defined as the number of days from catheter insertion to diagnosis of CRS or positive bacterial blood culture during routine control. Exit from the study for any event other than CRS was treated as a censored observation for the purposes of survival analysis. Catheter use was defined as the number of days from catheter insertion to CRS or censored observation.
Statistical analysis
Based on the observed CRS incidence of 3.5 CRS episodes per 1000 catheter days in our dialysis unit, the power analysis revealed that at least 35 catheters per group were required to demonstrate an effect size of >80% with an -value of 0.05 and 80% power.
The effect size of 80% was chosen on the basis of results with taurolidine as a catheter filling in previous reports [10,11]. All statistical analyses were performed using SPSS (version 10.0; SPSS Inc., Chicago, IL, USA). Independent t-tests were used to compare continuous variables between groups and skewed variables were analysed with the MannWhitney U-test. Cumulative infection-free catheter survival was analysed by the KaplanMeier method and log-rank test.
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Results |
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Three catheters were removed because of catheter malfunction, probably caused by thrombus formation (two in the heparin group and one in the citratetaurolidine group). Median catheter use was 158 days (range: 14169 days) for tunnelled catheters, 28 days (range: 7119 days) for non-tunnelled catheters in the jugular or subclavian vein and 7 days (range: 121 days) for catheters inserted in the femoral vein. Groups did not differ in the type of catheter inserted or median catheter use (Table 1).
Figure 1 shows the result of the primary end-point CRS. A total of four CRS episodes were registered in four different patients. Three CRS episodes were caused by Staphylococcus aureus (two pre-curved catheters in the jugular vein and one catheter in the femoral vein) and one by S.epidermidis (in a tunnelled catheter). All these cases were registered in the heparin-filling group (Table 2). The CRS incidence in this group was 2.1 per 1000 catheter days and the sepsis-free survival was significantly lower in patients allocated to the heparin catheter lock compared with the citratetaurolidine-filling group (P = 0.047; Figure 1). The CRS incidence was 1.7 per 1000 catheter days for tunnelled catheters and 2.6 per 1000 catheter days for non-tunnelled catheters. When non-tunnelled catheters in the femoral vein were excluded, the CRS incidence for non-tunnelled catheters was 1.8 per 1000 catheter days. Analysed separately, the sepsis-free survival for non-tunnelled catheters was lower in patients allocated to the heparin catheter lock compared with the citratetaurolidine-filling group, but this difference did not reach statistical significance (P = 0.066). When CRS with S.aureus was diagnosed, the catheter was removed and vancomycin given intravenously for 3 weeks. CRS with S.epidermidis was treated with vancomycin intravenously for 2 weeks.
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There were no adverse events reported with the use of citratetaurolidine solution as a catheter filling.
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Discussion |
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The other recently published study by Allon [9] includes 20 patients with tunnelled dialysis catheters that were studied for 90 days using citratetaurolidine lock solution. The CRS incidence in this period was compared with the historical CRS incidence on heparin in this group as well as a non-randomized control group using heparin filling. A 90% reduction in the CRS incidence of 5.6 cases per 1000 catheter days was observed in the citratetaurolidine group, in which only one case of CRS (Enterococcus) was observed in 1679 catheter days. The total number of catheter days was similar to our study and the majority of micro-organisms isolated in the heparin-filling group were also Staphylococcus species.
Of interest to note is that in the current study a clinically relevant case-mix of catheters was prospectively included and the majority of catheters were non-tunnelled as opposed to the selected cases of tunnelled catheters and subcutaneous devices in the studies by Soderman et al. and Allon [9,10]. In our centre, the choice between insertion of a tunnelled or non-tunnelled catheter is primarily based on the expected duration of catheter use (see Subjects and methods), because, in our own experience and that of others [14], the non-cuffed pre-curved catheters have an almost identical CRS incidence as the tunnelled catheters. Using non-tunnelled catheters filled with heparin lock, the CRS incidence was acceptable in our dialysis centre but could be substantially reduced with the use of citratetaurolidine catheter lock solution, confirming the data obtained in previous studies. The antimicrobial effect of the citratetaurolidine catheter lock is most likely related to the presence of taurolidine, because a 4% citrate concentration in vitro has little to no antibacterial effect [6].
Allon [9] found an increased requirement for thrombolytic interventions to maintain catheter patency among patients receiving citratetaurolidine solution, indicating a less effective anticoagulant activity of 4% sodium citrate compared with heparin. In our study, we did not observe such a difference and only three catheters (two with heparin lock) were replaced because of persistent flow problems. Others also reported an equally effective anticoagulant activity for heparin and citrate-containing catheter locks at concentrations similar to those used in the current study [15].
Most central vein catheters develop a bacterial biofilm on their surface that can already occur within 24 h after placement [4,16]. Bacteria gain access to the circulation via this biofilm and by embolization during dialysis, thereby causing CRS. In in vitro studies, taurolidine has a broad antibacterial activity and can prevent biofilm formation on dialysis catheters. Surveillance of biofilm formation by weekly blood cultures from the catheter has been advocated for early detection and treatment of bacterial colonization [4]. In a prospective study it was shown that 68% of dialysis catheters became colonized (defined as a positive bacterial blood culture from the catheter lumen) after a mean time of 27 days after placement [4]. Staphylococcus epidermidis was the colonizing micro-organism in the majority of cases. In our study, the rate of bacterial colonization of the dialysis catheters was much lower. This difference might be caused by differences in culture technique or, more likely, is related to our meticulous nursing techniques. Optimal catheter care by an experienced nursing team may reduce the rate of CRS up to eight times [3]. We were unable to show a difference in bacterial colonization incidence for catheters filled with citratetaurolidine or heparin. It is conceivable that more sensitive methods to detect catheter bacterial colonization (e.g. catheter flushing with broth) could have shown such a difference. However, these techniques are, in general, not applicable with catheters in situ and also not clinically relevant since the risk for bacteraemia is closely related to the presence of a high count of colony forming units per ml [4,17]. We could not identify a relationship between intraluminal bacterial colonization and a CRS episode. A possible explanation might be that S.aureus, which was isolated in the majority of CRS episodes, is rapidly causing CRS after colonization of the catheter lumen, thereby preventing its detection by routine blood culture once every 2 weeks.
Exit-site infections may also contribute to the pathogenesis of CRS [3]. In our group of patients, a low incidence of exit-site infections was observed with, as expected, no difference between the heparin- and citratetaurolidine-filling groups. The micro-organisms cultured from the exit site were predominantly Gram-negative organisms and the culture results did not correlate with the bacterial blood culture results. Therefore, in our population, exit-site infections are, in general, not predisposing for intraluminal bacterial colonization and CRS. A similar observation was made in a recent study evaluating the relation between exit-site inflammation, catheter bacterial colonization and CRS in 1263 non-cuffed central venous catheters [18].
CRS is a potential serious complication of the use dialysis catheters and may lead to septic emboli and even death [3]. The frequent administration of antibiotics for the treatment of CRS can give rise to multiple antibiotic-resistant bacteria [19]. Catheter filling with taurolidine seems an effective and safe way to achieve a substantial reduction in CRS incidence. Taurolidine has a simple and general antimicrobial action and in vitro assays using sub-inhibitory concentrations of taurolidine did not show the emergence of resistance [7,20]. Therefore, it seems unlikely that prolonged intraluminal instillation of taurolidine in the dialysis catheter will give rise to drug-resistant bacterial infection. No adverse effects of taurolidine have been observed so far. It is rapidly metabolized to the final harmless products taurine and carbon dioxide and large daily quantities of taurolidine can be given daily without apparent toxicity [21]. Antibacterial lock solutions containing taurolidine, therefore, seem safe to administer over a prolonged period of time.
In conclusion, this study shows that citratetaurolidine catheter filling is effective and safe for the prevention of CRS. It may lead to a sizeable reduction in CRS incidence, even in a dialysis centre where CRS incidence is already low using heparin filling.
Conflict of interest statement. None declared.
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References |
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