JAC Advance Access published online on July 11, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn284
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Original research |
A prospective double-blind randomized trial comparing intraluminal ethanol with heparinized saline for the prevention of catheter-associated bloodstream infection in immunosuppressed haematology patients
1 Department of Pathology, Christchurch School of Medicine and Health Sciences, Otago University, Christchurch, New Zealand 2 Department of Clinical Haematology, Christchurch Hospital, Christchurch, New Zealand 3 Department of Infectious Diseases, Christchurch Hospital, Christchurch, New Zealand 4 Department of Psychological Medicine, Christchurch School of Medicine and Health Sciences, Otago University, Christchurch, New Zealand 5 Pharmacy Department, Christchurch Hospital, Christchurch, New Zealand
* Corresponding author. Tel: +64-33640640; Fax: +64-33640064; E-mail: alan.pithie{at}cdhb.govt.nz
Received 8 April 2008; returned 8 May 2008; revised 6 June 2008; accepted 11 June 2008
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Abstract |
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Objectives: The aim of this study was to prospectively evaluate the use of intraluminal ethanol for the prevention of catheter-associated bloodstream infection (CABSI) in immunosuppressed haematology patients.
Patients and methods: Patients receiving chemotherapy for haematological malignancy or haematopoietic cell transplantation were randomized in a double-blinded manner to receive either intraluminal 70% ethanol/water or heparinized saline locks on a daily basis throughout a prophylactic treatment period. The primary endpoint was an episode of CABSI (defined as ‘bacteraemia in a febrile patient with a central venous catheter that was in use within the preceding 48 h and with no other identified focus of infection’). The trial was registered with the Australian Clinical Trials Register: number ACTRN012605000383662.
Results: There were 34 and 30 prophylactic treatment periods in the ethanol and control groups, respectively. CABSI occurred in 3 (9%, 0.60/100 catheter-days) and 11 (37%, 3.11/100 catheter-days) prophylactic treatment periods in the ethanol and control groups, respectively (OR = 0.18, 95% CI 0.05–0.65, P = 0.008). Eleven (32%) and 5 (17%) patients in the ethanol and control groups, respectively, remained afebrile throughout the prophylactic treatment (P = 0.18).
Conclusions: The daily administration of ethanol locks into lumens of central venous catheters effectively reduces the incidence of CABSI.
Key Words: catheter-related infections , ethanol , RCTs , CABSI
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Introduction |
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Central venous catheters play a pivotal role in the delivery of care to immunocompromised patients requiring treatment such as blood products, chemotherapy, parenteral nutrition, broad-spectrum antibiotics and antiviral agents. Despite advances in catheter insertion and post-insertion care, catheter infection remains a major complication, causing significant morbidity and mortality. In the intensive care setting, catheter infection is associated with a mortality rate of 12% to 25%.1,2 In children, most nosocomial bloodstream infections (BSIs) are associated with the use of intravascular devices, and in patients receiving chemotherapy for haematological malignancy, 10% to 20% of tunnelled catheters become infected.3,4 While catheter infection is common, the diagnosis can be difficult and catheters may be unnecessarily removed for suspected but unconfirmed sepsis. Catheter infection generally arises from bacterial colonization of the internal surface of the intravascular catheter.5,6 Several strategies have been developed to reduce this, including skin antisepsis at catheter insertion, barrier precautions during insertion, exit site care with antibacterial dressings, thrombosis prevention, antimicrobial and antiseptic impregnated catheters.7–20 Once catheter infection occurs, salvage of the infected catheter has been attempted with intraluminal antibiotic locks.21–23 This approach is moderately successful, but concerns remain over the promotion of hypersensitivity and antibiotic resistance.
When catheters become colonized, a biofilm gradually develops on the internal lumen. Biofilm formation is a process in which microorganisms attach to a solid surface and grow into complex communities encased within a polysaccharide matrix. Within biofilm, microorganisms behave in a different manner to freely suspended (planktonic) organisms and, in particular, exhibit increased antibiotic resistance.24 Increased resistance in the order of 10- to 1000-fold has been described for most antibiotic classes. Therefore, biofilm-associated infections are often difficult to treat and require high-dose, long-term antimicrobial therapy.25 This explains the imperfect success of antibiotic lock techniques for the treatment of catheter infection. The mechanism for this increased antimicrobial resistance is unclear but is probably multifactorial, including the inhibition of antimicrobial diffusion through the polysaccharide matrix.
Ethanol is a potential agent for the prevention and treatment of catheter infection. It is widely used as an antiseptic and is effective against a wide range of microorganisms, including those commonly causing catheter infections. Importantly, in vitro biofilms are susceptible to 30% to 90% ethanol, but require up to 2 h of contact time to achieve eradication of all microorganisms.26 About 70% ethanol can achieve an effective concentration even allowing for any dilution after instillation as a lock. Two retrospective studies in children and one prospective study in adults have shown that 70% ethanol locks can treat catheter infections.27–29 In a case report of a patient with multiple episodes of polymicrobial catheter infection complicating parenteral nutrition for short bowel syndrome, ethanol effectively eradicated catheter infection, and daily use over the next 3 years prevented recurrence.30 Reassuringly, there was no evidence of catheter damage from the ethanol over this prolonged time, and systematic study of the effect of ethanol on the integrity of catheters commonly used in clinical practice has shown that a 70% ethanol lock solution has a negligible impact on their mechanical properties, despite continuous exposure for as long as 10 weeks.31 Finally, a recent study in a sheep model suggests that a single 3 h lock of 70% ethanol is adequate to eradicate Staphylococcus epidermidis from central venous catheters.32 Here, we present the results of a double-blind randomized study in which ethanol was compared with heparinized saline for the prevention of catheter infection in patients with haematological malignancy undergoing chemotherapy or haematopoietic stem cell transplantation.
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Patients and methods |
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Study design and treatment protocol
Between March 2003 and August 2006, patients with tunnelled cuffed intravascular catheters inserted into subclavian veins were randomized to prophylactic treatment using 70% ethanol (ethanol arm) or heparinized saline (control arm) for the prevention of catheter-associated bloodstream infection (CABSI). The allocation to each study arm was by a computer-generated randomization code held centrally in the hospital pharmacy and concealed from all staff except the pharmacist who prepared the locks in the sterile unit. The patient and all other staff remained blinded to the treatment allocation until study analysis. The primary endpoint was the occurrence of CABSI. Inclusion criteria were an age 
18 years or older and admission as an inpatient to receive intensive chemotherapy likely to produce neutropenia (<0.5 x 109 L–1) for the treatment of haematological disease, including haematopoietic stem cell transplantation. Exclusion criteria were abnormal liver function tests or a history of alcohol abuse. Patients who had previously entered this study were excluded, unless a new intravascular catheter had been sited and a minimum of 3 months had elapsed since previous entry. Patients receiving prophylactic antibiotics, as occurred routinely in the early part of the study, had this treatment recorded but were not excluded. The study period commenced at first administration of chemotherapy and ended with either diagnosis of CABSI, removal or failure of catheter, discharge from hospital, death or end of study period after an arbitrary 30 days.
Three millilitres of trial treatment (70% ethanol/water or heparinized saline) was prepared by the non-blinded pharmacist in the pharmacy intravenous sterile unit and supplied to blinded nursing staff. The allocated treatment was injected into each lumen of the catheter daily and left for 2 h before being entirely removed and replaced with heparinized saline. Besides the trial treatment, all other care was delivered as per the standard procedures in operation within the haematology unit of Christchurch Hospital at the time of study. Thus, patients with neutropenic fever had at least one set of blood cultures taken from both peripheral blood and intravascular catheter in addition to culture of any clinically apparent focus. Patients were then treated with a single dose of gentamicin and a broad-spectrum antibiotic (tazocin or cefepime). Antimicrobial therapy was modified according to microbiological findings, and vancomycin was added if a sensitive organism was isolated. The Upper South B Regional Ethics Committee approved this study (application number: CTY/02/09/148). Written informed consent was obtained from all patients. The trial was registered with the Australian Clinical Trials Register: number ACTRN012605000383662.
These followed standard guidelines.33 Thus, laboratory-confirmed blood stream infection (BSI) was defined as the culture of a recognized pathogen from one or more blood cultures, unrelated to infection at another site. In the case of a common skin contaminant rather than a recognized pathogen, the definition was met when it was isolated from either two or more sets of blood cultures drawn on separate occasions from a febrile patient or from one set of cultures taken from a patient with an intravascular line for whom appropriate antibiotic therapy was instituted. CABSI was defined as the occurrence of a BSI in a patient with a central venous catheter whose catheter was in use within the preceding 48 h.
Identical dual lumen Hickman central venous catheters (Broviac® Fr. Radiopaque Silicone Catheter with SureCuff Tissue Ingrowth Cuff and Clamp, 10 mm Lumen, Bard Access Systems, Salt Lake City, UT, USA) were used in all patients. Catheters were inserted by a consultant radiologist using full aseptic technique. A chlorhexidine gluconate adhesive dressing (Biopatch® Johnson and Johnson Medical, TX, USA) was placed over the exit site at the time of insertion and changed weekly.
We anticipated that there would be 
40% CABSI per prophylactic treatment period in the control group; therefore, to detect a 75% reduction in the ethanol group, 40 patient-prophylactic treatment periods would be required to show this effect as statistically significant (two-tailed 
= 0.05) with a power of 80%. For each prophylactic treatment arm, the proportion of CABSI and the rate of CABSI/100 catheter-days were compared using 
2 tests, and the survival of the catheter without CABSI was compared using the Kaplan–Meier method. The mean number of days the catheter was inserted prior to randomization and the mean number of days on study were compared between randomized arms using Mann–Whitney U-tests. A Cox proportional hazards regression compared treatment arms. All statistical analysis was conducted using the SPSS software (version 13).
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Patient and intravascular catheter characteristics
Of 65 eligible patients, 5 refused to participate. Four patients were randomized twice, each with a second central venous catheter that had been inserted between 3 and 29 months after the first study entry. Thus, 64 prophylactic treatment periods were studied (Figure 1). One patient in each group withdrew from the study. The two study groups were well matched for age, gender and primary disease. The time the catheter had been inserted prior to study entry, the time the catheter was on study treatment and the proportion of patients on prophylactic antibacterial medication were not significantly different between the groups. Despite the apparent longer duration of neutropenia for catheters in the ethanol arm, due to more reaching the endpoint of CABSI in the control arm and ending the study before resolution of neutropenia, this difference was not significant (Table 1).
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Catheter-associated bloodstream infection
During 501 and 353 study days, the primary endpoint of CABSI occurred in 3 of 34 (9%, 0.60/100 catheter-days) and 11 of 30 (37%, 3.11/100 catheter-days) prophylactic treatment periods in the ethanol and control groups, respectively (OR = 0.18, 95% CI 0.05–0.65, P = 0.008) (Table 2). CABSI occurred early and thereafter regularly throughout the study period in the control group. In comparison, catheters survived without CABSI significantly longer in the ethanol group (P = 0.003) (Figure 2). One of 3 and 2 of 11 CABSI occurred in patients on prophylactic antibiotics in the ethanol and control groups, respectively.
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Non-CABSI febrile episodes
In addition to febrile episodes classified as CABSI, there were a further 20 and 14 first febrile episodes in the ethanol and control groups, respectively. Localized infections, mainly gastrointestinal, were the most frequent causes of fever in both patient groups (Table 2). Eleven (32%) and five (17%) of the patients in the ethanol and control groups, respectively, remained afebrile throughout their study course (RR = 1.94, 95% CI 0.8–5.0, P = 0.18). Although the difference was not significant, a trend is suggested.
More central than peripheral cultures were taken in both groups since not all blood culture sets were paired. Two of 3 and 4 of 11 CABSIs in the ethanol and control arms, respectively, had positive isolates in central but not peripheral cultures. These met the definition of CABSI, in that either recognized pathogens were isolated or patients were febrile and appropriate antibiotic therapy was instituted. The frequency of positive cultures was significantly lower in the ethanol arm than the control arm for both central (5% versus 28%/central blood culture, P < 0.001) and peripheral blood cultures (2% versus 20%/peripheral blood culture, P < 0.001). All blood culture isolates from either central venous catheters or peripheral blood are shown in Table 3. No fungi were isolated. The difference in the number of Gram-negative isolates was most striking with one in the ethanol group and seven in the control group.
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Adverse events
One patient in the ethanol group experienced an episode of dyspnoea immediately after the first treatment and withdrew from the study. One patient in the control group withdrew after 7 days with an unusual taste sensation and anxiety. These withdrawals did not lead to un-blinding and both patients were included in the final analysis. There were no deaths and no other adverse events. There were no problems with strength and durability of the catheters in either of the arms. Five catheters were removed before the end of prophylactic treatment in each group. None of the catheters in the ethanol group was removed for CABSI and three in the control group were removed for this reason. Only one of these three catheters had its tip cultured and it yielded no growth. There was one exit site infection in each group and both required catheter removal. One catheter in the ethanol group was removed because of thrombosis. All other catheters were removed because of the end of the treatment.
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Discussion |
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In this study, we hypothesized that ethanol, a widely available disinfectant with a well-characterized safety profile, could exert a local antibacterial effect in tunnelled intravascular catheters and reduce the incidence of CABSI in immunocompromised patients. Our immunocompromised patients were evenly balanced between two groups that were randomly assigned to receive either ethanol or heparinized saline intraluminal locks. We concluded our study recruitment with over 40 catheters randomized to each arm of prophylactic treatment as planned. However, some patients had been randomized more than once and could not be considered as completely independent. These were not included in our final analysis, which contains 80% of our intended catheter prophylactic treatment periods.
The principal finding was a highly significant difference in laboratory-confirmed BSI rates between the two treatment groups, with 4-fold fewer episodes of CABSI in the group receiving ethanol compared with the control group (Table 2). The definition of CABSI lacks specificity and does not exclude BSI from an unrecognized focus. The catheter is more strongly incriminated as the source of BSI in the clinical entity called catheter-related BSI, which is defined as bacteraemia in a patient with an intravascular catheter with at least one positive blood culture obtained from a peripheral vein, clinical manifestations of infection and no apparent source for the BSI except the catheter. Crucially, to satisfy this definition, the same organism must be recovered from the catheter tip (if removed), as from peripheral blood, or simultaneous quantitative blood cultures should contain at least five times the number of organisms in intravascular catheter versus peripheral blood, or catheter blood cultures should become positive at least 2 h earlier than peripheral blood cultures. Since many infected catheters were salvaged and not removed, and since quantitative blood cultures were not available, we used the less stringent CABSI as the endpoint in our study, recognizing that we must have included some cases of BSI from an unrecognized focus apart from the catheter. Nevertheless, as the ethanol was withdrawn and replaced by saline before the blood cultures were drawn, it is highly unlikely that tiny amounts of alcohol that might have got into the systemic circulation or remained in the lumen of the catheter could have inhibited the growth of blood cultures drawn either peripherally or centrally, and ethanol would not be expected to prevent bacteraemia from any other source than the central catheter. Therefore, the most likely explanation for the substantial reduction in bacteraemia rates is that catheter-related infection accounts for many cases of bacteraemia in this patient group. During treatment with chemotherapy or haemopoietic stem cell transplantation, central catheters are accessed multiple times per day. Time-to-CABSI curves separated early in the treatment course (Figure 2). We found that preventable bacteraemia can occur within days of commencing chemotherapy and that the risk continues throughout the treatment. Ethanol exerted a protective effect throughout this period.
A surprising finding was the effect of ethanol on Gram-negative bacteraemia rates. Traditionally, it is thought that in neutropenic patients, such infections arise from chemotherapy-induced inflammation of intestinal mucosa. However, we found that ethanol was as likely to prevent Gram-negative as Gram-positive bacteraemia, suggesting that both can arise through the infection of the central catheter (Table 3). One patient in each study arm prematurely withdrew from the study, and neither appeared to be treatment related. Ethanol did not cause line damage or more frequent line occlusion.
This study suggests that in immunosuppressed haematology patients most bacteraemia is secondary to intravascular catheter infection and that ethanol can effectively prevent this. Ethanol locks did not reduce the overall incidence of fever requiring antibiotic therapy, but the study was not powered to show a difference that might exist. Organisms were not identified in 87% and 56% of febrile episodes encountered in the ethanol and control groups, respectively. Prophylactic antibiotic use may have influenced this finding, but they were not widely used in these patients and such fevers with no discernible cause may also be due to non-bacterial infection or have a non-infectious cause. Ethanol locks are promising for the prevention of catheter infection, may significantly reduce bacteraemia in immunosuppressed patients and should be studied in more patients with different indications for intravascular catheters.
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This study was funded by a Research Grant from the Canterbury District Health Board.
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None to declare.
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Acknowledgements |
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We wish to thank the patients who participated, the nurses from the South Island Bone Marrow Transplant Unit, Stephanie Smith and Bevan Harden.
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References |
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