Ethanol Lock Technique: Review of the Literature

Transcription

1 infection control and hospital epidemiology november 2009, vol. 30, no. 11 review article Ethanol Lock Technique: Review of the Literature Melissa Maiefski; Mark E. Rupp, MD; Elizabeth D. Hermsen, PharmD, MBA, BCPS-ID Central venous catheters (CVCs) are commonly used among adult and pediatric patients for administration of fluids, medications, and nutrition. Central line associated (CLA) bloodstream infection (BSI) is a serious complication following CVC insertion. The aim of this review is to summarize available data regarding the ethanol lock technique, which is a proposed method for sterilizing the lumen of the catheter by instilling an ethanol solution and allowing it to dwell in the catheter for a certain amount of time. Studies on ethanol lock technique differ in ethanol concentrations, luminal dwell times, catheter types, inclusion of anticoagulants, use of systemic antibiotics, and use of the technique for prevention or for treatment of CLA BSI. In vitro studies demonstrate the efficacy of ethanol in the eradication of various pathogens. Definitive catheter integrity data are limited. Clinical trials report tolerable adverse events with ethanol locks, as well as encouraging results for prevention and treatment of CLA BSI. Infect Control Hosp Epidemiol 2009; 30: Every year in the United States, more than 1 billion intravascular devices are purchased to administer intravenous products. 1 Among the various devices, 5 million central venous catheters (CVCs) are inserted per year, 2 and despite advancements in pre- and postinsertion care, intensive care units report 80,000 central line associated (CLA) bloodstream infections (BSIs) yearly. 3 Increased hospital costs and length of stay have been independently associated with CLA BSI. 4-7 Each case of CLA BSI is associated with an estimated cost of up to $56,000 8 and an average of 6.5 additional hospital days in critically ill patients. 9 Although CLA BSI has not been shown independently to increase mortality, CLA BSI has been associated with up to 25% mortality according to some reports. 3,9 Patients with CLA BSI often require catheter replacement 10,11 and thus may experience an interruption in necessary intravenous therapies. Therefore, treating and potentially preventing CLA BSI would substantially reduce morbidity and healthcare costs. 9 The ethanol lock technique is 1 proposed method to prevent and treat CLA BSI. This technique involves instilling an ethanol solution to completely fill the catheter and allowing the solution to dwell for a certain amount of time. Maintenance of catheter patency, reduction of morbidity, prevention of antimicrobial resistance associated with antibiotic use, and a decrease in the healthcare costs associated with CLA BSI are a few potential benefits of ethanol lock therapy. The decisions regarding whether, when, and how to use ethanol lock therapy in clinical practice is made more difficult by the limited data available. Studies that have evaluated ethanol lock therapy vary in the type of catheters studied (including manufacturer and catheter polymer), the protocol for the ethanol lock (dwell time, ethanol concentration, volume, duration), and whether the technique was used for prevention or for treatment. Moreover, available studies are limited by small sample sizes, and most are retrospective. Information regarding ethanol lock therapy was obtained via a literature search of the PubMed database from January 1985 through January 2008 and a review of the references from relevant studies and is summarized in this review. Single case reports were excluded. Search terms included ethanol lock technique, ethanol lock therapy, catheter-related infection, and bloodstream infection, prevention, and treatment. catheter-related infection The organisms that cause CLA BSI most commonly include Staphylococcus spp, Candida spp, and Enterococcus spp. 1,12-14 CLA BSIs that develop in short-term vascular devices used for less than 10 days are commonly caused by normal skin flora such as coagulase-negative staphylococci and Staphylococcus aureus. 15 Infections in catheters that have been in place for longer than 1 month are usually due to hub contamination and subsequent intraluminal colonization of bacteria. 16 These infections are caused by a broader range of infectious agents, such as Candida spp, Enterococcus spp, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter spp, Corynebacterium spp, and Bacillus spp Within 24 hours of catheter insertion, host proteins such From the Department of Pharmaceutical and Nutrition Care, Nebraska Medical Center (M.M., E.D.H.), the Department of Pharmacy Practice, College of Pharmacy (E.D.H.), and the Section of Infectious Diseases, Department of Internal Medicine (M.E.R., E.D.H.), University of Nebraska Medical Center, Omaha, Nebraska. Received March 9, 2009; accepted June 10, 2009; electronically published October 5, by The Society for Healthcare Epidemiology of America. All rights reserved X/2009/ $ DOI: /606162

2 ethanol lock technique: review of literature 1097 as fibronectin and fibrinogen coat the catheter lumen to form a conditioning film. With microbial colonization of the catheter, extracellular matrices are formed that contain a congregation of organisms in a 3-dimensional structure called a biofilm. Bacteria contained within biofilms are more resistant to treatment as a result of a variety of factors, such as decreased antimicrobial penetration, 12 heterogeneous populations of cells including metabolically quiescent persister cells, and biofilm interactions with host defense mechanisms. A CLA BSI occurs as microcolonies continue to grow and organisms detach, become free floating, and seed the bloodstream. Antimicrobial concentrations high enough to eradicate bacteria growing in biofilms are not attainable with systemic therapy alone. 23 This has led to the use of highly concentrated antimicrobial solutions, termed antibiotic locks, to be administered into the lumen of the CVC. While guidelines from the Infectious Diseases Society of America and the Centers for Disease Control and Prevention include the antibiotic lock technique as a therapeutic option for intraluminal infections, 1,17 inherent concerns are associated with the use of antibiotic lock therapy. Of considerable concern is the risk of resistance. Organisms in biofilm have been shown to exhibit decreased susceptibility compared to planktonic cells on the order of 10- to 1,000-fold for most antibiotic classes. 24 Because of decreased susceptibility, infections associated with biofilms may require high-dose, longterm antimicrobial therapy, which may subject the patient to greater complications. Despite statements that antibiotic locks may decrease the systemic toxic effects of antibiotics, 14 a study by Dogra et al, which used gentamicin-containing locks, demonstrated blood levels associated with a substantial risk of ototoxic effects in subjects with chronic renal failure. 25 These limitations may be remedied by ethanol lock therapy. ethanol lock technique Ethanol is an antiseptic that demonstrates bactericidal and fungicidal activity against a broad range of gram-positive and gram-negative bacteria and fungi. Interest in the ethanol lock technique was initially sparked by reports of the successful use of an ethanol lock in oncology patients and in patients receiving total parenteral nutrition. 26,27 This technique involves instilling an ethanol-containing solution into the catheter lumen and allowing the solution to dwell for a certain amount of time, with the goal of prevention of colonization or of sterilization of the catheter lumen(s). Ethanol acts by nonspecific protein denaturation and thus is less likely to promote antimicrobial resistance, which is a concern with systemic antibiotics or antibiotic lock use. 28 While most studies that used the ethanol lock technique report very mild or no adverse events experienced by study subjects, these studies are limited by retrospective design and/ or small sample size. 26,28-31 Potential toxic effects related to ethanol include central nervous system depression, arrhythmias, local venous irritation, and flushing. Although limited, the available data regarding the stability of ethanol in silicone and polyurethane catheters, 32,33 along with the ability to retain catheter patency, 34 make ethanol lock therapy an attractive option for the prevention and treatment of CLA BSI. Further benefits of ethanol lock therapy include the readily accessible and inexpensive nature of ethanol and its long history of use as an antiseptic or disinfectant. Thrombosis commonly prompts catheter removal. Hence, many studies of antibiotic lock therapy have included a combination of an antibiotic and heparin. However, a precipitate instantly forms when heparin is mixed with ethanol. 33 Furthermore, ethanol appears to possess intrinsic anticoagulant activity, as evidenced by the use of ethanol to restore catheter patency Accordingly, clinical studies of ethanol lock therapy have not combined ethanol with heparin, although 2 of the in vitro studies 33,38 evaluated the combination of ethanol and trisodium citrate (an anticoagulant). in vitro studies Several in vitro studies have been conducted to evaluate ethanol lock therapy for the prevention of growth or for treatment of infections due to bacterial pathogens that commonly cause CLA BSI. In addition, studies examining the effect of prolonged ethanol exposure on the mechanical properties of catheters have been conducted (Table 1). Efficacy Studies Sherertz et al compared lock efficacies of vancomycin, ciprofloxacin, minocycline, minocycline with rifampin, ciprofloxacin with rifampin, vancomycin with rifampin, ethanol, ethylenediaminetetraacetic acid (EDTA), minocycline with EDTA, and taurolidine with polyvinylpyrolidine against S. aureus, Staphylococcus epidermidis, P. aeruginosa, and Candida albicans growing in biofilms. 13 Silicone Hickman catheter segments were incubated overnight to allow growth of each organism. Segments were rinsed and incubated in various lock solutions for 0, 2, 4, or 24 hours at 37 C. Each experiment was duplicated. Pharmacologic concentrations of ethanol were 10%, 20%, 30%, 50%, 70%, and 100% (with or without 30 mg/ml EDTA). Ethanol concentrations of at least 30% produced log units of killing of S. aureus at 2, 4, and 24 hours, which was superior to all other single and combination lock solutions. The results for ethanol versus other studied organisms were not reported. The authors concluded that ethanol was a promising potential lock solution. The limitations of this study include the fact that only 1 catheter polymer and type were studied and that the ethanol results, including the use of ethanol and EDTA in combination, were not fully reported. Takla et al tested the effectiveness of an ethanol and anticoagulant solution for prevention of in vitro biofilm formation by the pathogens that most commonly cause CLA BSI in hemodialysis patients. 38 Two clinical isolates each of S. aureus, methicillin-resistant S. aureus (MRSA), S. epider-

3 table 1. In Vitro Studies of the Effect of Ethanol Lock Therapy on the Mechanical Properties of Catheters Study Ethanol concentration Study conditions Dwell time Outcomes Results Efficacy studies Sherertzetal 13 10%, 20%, 30%, 50%, 70%, 100% ethanol (with or without 30 mg/ml EDTA) vs various antibiotic and anticoagulant locks Takla et al 38 30% ethanol with 4% trisodium citrate Raad et al 39 25% ethanol alone or in combination with 30 mg/ml EDTA and/or 3 mg/ml minocycline Mukherjee et al 40 30%, 50%, 75%, 85%, 95%, 100% ethanol in polyurethane catheters and 50% ethanol vs heparin in silicone catheters Silicone Hickman catheters with Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Candida albicans growing in biofilms incubated in various lock solutions at 37 C Calgary biofilm device plate filled with lock solution or control solution, inoculated with S. aureus, S. epidermidis, P. aeruginosa, MRSA, and Escherichia coli, and incubated at 37 C Modified Robbins device with silicone catheter segments and a silicone disk biofilm colonization model with MRSA and Candida parapsilosis incubated at 37 C Silicone catheters in rabbits and polyurethane catheters in rats inoculated with C. albicans, S. epidermidis, or S. aureus and incubated 0, 2, 4, and 24 h Reduction in bacterial burden as determined by counts of CFU and transformation to log 10 units 72 h Bacterial growth as determined by counts of CFU per milliliter 15 min (modified Robbins device) or 60 min (silicone disk) 30 min (rabbits) or 10 min (rats) Eradication of bacteria and fungus within biofilms determined by counts of CFU per milliliter Bacterial and fungal growth within biofilms measured by fluorescence microscopy analysis; disruption of biofilm growth in the presence of a mutated alcohol dehydrogenase gene measured by Western and Northern blotting analyses Ethanol concentrations of at least 30% yielded a reduction in log 10 CFU of against S. aureus and maintained this effect for 24 h, which was superior to all other single and combination lock solutions. Ethanol results were not reported for the other studied organisms. Compared to control solution, which grew biofilm from 6 # 10 6 to 7.4 # 10 7 CFU/mL, ethanol-exposed organisms did not form a detectable biofilm after 72 h. Modified Robbins device: complete eradication of MRSA found with minocycline/ethanol combination; compete eradication of C. parapsilosis found with EDTA/ethanol combination or triple combination minocycline/ethanol/ EDTA. Silicone disk biofilm colonization: complete eradication of MRSA and C. parapsilosis found only with triple combination minocycline ethanol EDTA. Silicone catheters incubated with 50% ethanol inhibited biofilm growth by C. albicans but not S. epidermidis or S. aureus; blotting analyses of polyurethane catheters showed that disruption of the alcohol dehydrogenase gene significantly enhanced the ability of C. albicans to form biofilm; 10% ethanol significantly inhibited bioflim in polyurethane catheters. 1098

4 Chambers et al 41 70% ethanol vs heparinized saline (100 U/mL) Single-lumen silicone Broviac catheters in 11 3-year old Coopworth sheep inoculated with S. epidermidis and locked with 1 ml ethanol; ethanol was withdrawn from the catheter after dwell time followed by 0.9% saline flush Integrity studies Crnich et al 32 70% ethanol 16 silicone and 15 polyurethane catheters locked with ethanol; control catheters (17 silicone, 17 polyurethane) had no lock solution; all catheters submerged in Hank s balanced salt solution at 37 C Guenu et al 42 60%, 95% ethanol vs 0.9% sodium chloride Bell et al 33 30% ethanol with 4% trisodium citrate vs heparin 5,000 U/mL or 4% trisodium citrate Uncuffed, tunneled, silicone catheters immersed in 0.9% sodium chloride (n p 5), 60% ethanol (n p 5), and 95% ethanol (n p 5) solutions within a flask and incubated at 37 C Cuffed, tunneled, Carbothane polyurethane hemodialysis catheters; 6 catheters each filled with 1 of 3 lock solutions and immersed in phosphate-buffered saline at 37 C and a ph of h Sterilization of catheters as determined by endoluminal brushes, blood cultures, roll plates of catheter tips, catheter-flushed broth cultures, and hub swabs 1 10 weeks of continuous exposure 4h,15days,or15 days after renewal of solution following a first storage of 4 h 9 weeks; lock solutions changed 3 times weekly Force at break, failure stress, elongation at failure, maximum strain, modulus of elasticity, modulus of toughness, and wall thickness Scanning electron microscopy of inner surface of catheters exposed to 0.9% sodium chloride and 95% ethanol; solutions evaluated by GC/MS and MALDI-TOFMS for presence of degradation products Force at break, elongation at break, elastic modulus, and catheter weight 9 of 11 ethanol-treated catheters were sterile vs 0 of 12 heparinized saline-treated catheters ( P!.01 ). Blood culture results were positive in 2 of 11 ethanol-treated catheters vs 12 of 12 heparin-treated catheters ( P!.01 ). Marginal reduction in the modulus of elasticity for silicone and polyurethane catheters and minor increases in the wall area for only polyurethane catheters. A 70% ethanol lock solution does not substantially alter the integrity of polyurethane and silicone catheters with a duration of exposure to ethanol many times greater than in clinical practice Scanning electron microscopy showed no difference in morphologic abnormalities after 15 days of exposure to 0.9% sodium chloride vs 95% ethanol. GC/MS and MALDI- TOFMS showed no difference in the release of silicone particles for 0.9% sodium chloride vs 60% ethanol, but this difference was significant for 0.9% sodium chloride vs 95% ethanol ( P!.01 ) and 60% ethanol vs 95% ethanol ( P!.01 ). Most silicone release occurred during the first 4 h of solution exposure. Force at break and elongation at break was significantly lower for ethanol-exposed catheters ( P!.01 for each). No significant difference was seen for the mean elastic modulus. Catheter weight increased after exposure to lock solutions and remained stable for 9 weeks; the greatest increase in weight was seen in ethanol-exposed catheters. note. CFU, colony-forming units; EDTA, ethylenediaminetetraacetic acid; GC-MS, gas chromatography mass spectrometry; MALDI-TOFMS, matrix-assisted laser desorption/ionization time-offlight mass spectrometry; MRSA, methicillin-resistant Staphylococcus aureus. 1099

5 1100 infection control and hospital epidemiology november 2009, vol. 30, no. 11 midis, P. aeruginosa, and Escherichia coli were obtained. A polystyrene Calgary biofilm device (MBEC Bioproducts) was used to compare the ability of a lock solution of 30% ethanol with 4% trisodium citrate to prevent biofilm formation with that of a control solution of 0.9% sodium chloride and Mueller-Hinton broth. All organisms exposed to the control solution developed 6 7 biofilms that yielded 6 # 10 to 7.4 # 10 colony-forming units (CFU) per milliliter, whereas organisms exposed to ethanol did not develop detectable biofilm after 72 hours of incubation. This study revealed that 30% ethanol with 4% trisodium citrate prevented biofilm growth formation of all tested isolates in vitro. This study is limited by the lack of a true CLA BSI model, the use of a low concentration of ethanol compared to that used most often in the clinical setting, outcome assessment at 72 hours only, and the combination of ethanol with trisodium citrate, which has not been used in published clinical trials. Raad et al studied the use of 25% ethanol alone or in combination with minocycline and/or EDTA to treat MRSA and Candida parapsilosis in biofilm-colonized catheter segments. 39 Two methods were used to test the effectiveness of the lock solution on biofilms, a modified Robbins device and a silicone disk biofilm colonization model. The modified Robbins device method consists of 25 specimen plugs, each connected to a silicone catheter segment (Allegiance Healthcare). Biofilms formed with the modified Robbins device method 5 2 developed 2 # 10 CFU/mL MRSA or 2 # 10 CFU/mL C. parapsilosis. Catheter segments were then exposed for 15 minutes to a control solution of Mueller-Hinton broth or to solutions of 30 mg/ml EDTA, 3 mg/ml minocycline, and 25% ethanol used alone and in combination. The silicone disk biofilm model consists of inserting sterile silicone disks into human plasma, followed by a series of incubation periods. For this method, isolated organisms were diluted to # 10 CFU/mL in Mueller-Hinton broth. MRSA and C. parapsilosis were exposed to the same combination of solutions in the silicone disk biofilm model and allowed to dwell for 60 minutes. The modified Robbins device method revealed complete eradication of MRSA after 15 minutes exposure to minocycline in combination with 25% ethanol with or without EDTA. However, a triple combination of minocycline, 25% ethanol, and EDTA or a combination of EDTA and 25% ethanol was needed to eradicate C. parapsilosis. Similarly, the triple combination of minocycline, 25% ethanol, and EDTA was the only solution found to completely eradicate MRSA and C. parapsilosis that had formed by using the silicone disk biofilm colonization method. Complete eradication was defined as no organism regrowth after 24 hours of reincubation at 37 C in broth solution. Ethanol 25% alone was not sufficient to eradicate the organisms grown with either of the 2 biofilm methods. This study is limited by the use of a low concentration of ethanol compared to that used most often in the clinical setting, of short exposure periods, and of only 1 catheter polymer. Mukherjee et al used proteomics and Western and Northern blotting analyses to examine the effect of alcohol dehydrogenase, by means of the ADH1 gene, on C. albicans contained in biofilms. 40 The goals of the study were to draw a clinical correlation between the ability of isogenic C. albicans to form biofilms in vitro, in an engineered human oral mucosa, and in a rat model of Candida-associated catheter biofilm. After in vitro tests were performed, rats were used to compare the ability of various strains to form biofilm, and rabbits were used to evaluate the ability of ethanol to inhibit C. albicans biofilm formation in vivo. Polyethylene catheters were placed into the external jugular 6 vein of the rats and were inoculated with 1 # 10 cells per square centimeter of C. albicans for 4 hours. The catheters were then removed and dehydrated in 30%, 50%, 75%, 85%, 95%, or 100% ethanol for 10 minutes. Conversely, in 3 groups of 10 rabbits each, silicone catheters were surgically inserted and infected with C. albicans, S. epidermidis, ors. aureus. Half of the rabbits in each group received 300 ml of 50% ethanol for 30 minutes per day for 7 days, and the other half received 100 U of daily heparin flushes. Catheters removed from animals in both the ethanol group and the heparin group were imaged by means of scanning electron microscopy. To test the abilities of the isogenic Candida strains to form biofilm on engineered human oral mucosa tissue, oral 6 mucosa was infected with 1 # 10 cells per square centimeter of wild-type C. albicans, the ADH1 mutant, or a revertant strain. Tissues treated with no Candida cells served as uninfected controls for 24 hours. Proteomics and Western and Northern blotting analyses revealed that disruption of the ADH1 gene substantially enhanced the ability of C. albicans to form biofilms. Engineered human oral mucosa models revealed that the effect of the ADH1 mutant strain on biofilm production is mediated by enzymatic activity. Rat models revealed that 10% ethanol substantially inhibited biofilm in vitro. The rabbit biofilm model with 50% ethanol revealed inhibition of biofilm growth for C. albicans but not for S. epidermidis or for S. aureus. The limitations of this study include the use of a low concentration of ethanol in comparison to that used most often in the clinical setting, of short exposure periods, and of only 1 catheter polymer. Although not an in vitro study, a crossover trial in sheep evaluated the ability of a single treatment of 70% ethanol locked into a CVC to sterilize catheters infected with S. epidermidis. 41 Single-lumen silicone CVCs (Broviac, Bard Access Systems) were placed in the internal jugular veins of 12 sheep, flushed with normal saline, and locked with heparinized saline. Two catheters were placed in each sheep, the first one on day 0 and the second one on the contralateral side after 8 catheter-free days. One catheter was treated with 70% ethanol, and the other catheter was treated with heparinized normal saline (100 U/mL). After a S. epidermidis inoculum

6 ethanol lock technique: review of literature 1101 had been locked in the catheter for 72 hours, the inoculum was withdrawn and replaced with 1 ml of the ethanol or heparin lock solution for 3 hours. After the dwell time, the catheters were locked with the heparin solution. Two days later, the catheters were removed, and culture samples were obtained. All sheep completed the saline treatment regimen, and 11 of 12 sheep completed the ethanol treatment regimen. Overall, 0 of 12 catheters were sterile after 1 administration of saline lock, whereas 9 of 11 catheters were sterile after 1 administration of ethanol lock ( P!.01). Blood cultures revealed positive results in all the saline-treated catheters and 2 of 11 ethanol-treated catheters ( P!.01). Sheep 7 was excluded from the study because the second catheter became blocked, and all results were discarded from statistical analysis. The blockage was not attributed to ethanol treatment, as it occurred after inoculation of the lumen and before administration of the lock. The authors conclude that a single, 3-hour exposure to ethanol lock therapy was more effective than the use of heparinized saline-treated catheters. This study is limited in a few ways. First, this was an animal model, and the applicability to humans is unknown. In addition, only 1 organism was studied, and only 1 catheter polymer and type were evaluated. Catheter Integrity Studies Catheter integrity after ethanol lock exposure is another topic of interest for researchers. Crnich et al tested 2 types of peripherally inserted central catheters: polyurethane (single lumen, Arrow International) and silicone (single lumen, Cook Critical Care). 32 The polyurethane ( n p 15) and silicone ( n p 16) catheters were exposed to 70% ethanol and com- pared with control catheters (17 of each type) with no lock solution. Mechanical tests on the catheters included force-atbreak, failure stress, elongation at failure, maximum strain, modulus of elasticity, modulus of toughness, and wall thickness. Mechanical tests were performed at 1, 2, 3, 5, 6, and 9 weeks for polyurethane catheters and 1, 2, 3, 4, 7, 9, and 10 weeks for silicone catheters. There was a slight reduction in the modulus of elasticity for both types of catheters and a minor increase in the wall area for polyurethane catheters after ethanol exposure. No substantial difference was seen between the ethanol-exposed and the control catheters for any of the other mechanical properties. The authors concluded that minor changes in modulus of elasticity and wall area would not likely have an effect on clinical performance given that all other mechanical properties were unaffected by ethanol exposure. They elaborate that the force-at-break, stress-at-break, maximum strain, and modulus of toughness are more reliable predictors of catheter integrity during clinical use. This belief is supported by the International Organization for Standardization, which recommends that force-at-break be the sole test of catheter integrity. 43 Study results indicate that 70% ethanol has a negligible effect on the integrity of selected polyurethane and silicone catheters with exposure of up to 10 weeks. Limitations of this study include the evaluation of catheters made by only 1 manufacturer for each type, the use of different time points for testing the polyurethane versus silicone catheters, and a lack of assessment of the catheter hub or the place where the hub meets the catheter lumen. Guenu et al examined concerns about ethanol-induced catheter structural degradation by using scanning electron microscopy, gas chromatography mass spectrometry, and matrixassisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOFMS). 42 Silicone hemodialysis catheters (DualCath, Medcomp; Hemotech) were immersed at 37 C in 3 different solutions, 0.9% sodium chloride, 60% ethanol, and 95% ethanol, for 4 hours, for 15 days, or for 15 days after renewal of the solution following an initial storage of 4 hours. Five catheters were used with each solution. Scanning electron microscopy (original magnification, #2,000 20,000) of the inner surface of the catheter revealed no damage to the lumen surfaces of catheters immersed in 95% ethanol for 15 days compared with the reference catheter. Gas chromatography mass spectrometry and MALDI-TOFMS analysis of the storage solutions revealed a significantly greater release of polydimethylsiloxanes with 95% ethanol than with 0.9% sodium chloride ( P!.01), with most of the release occurring during the first 4 hours of exposure, but no significant difference in release between 60% ethanol and 0.9% sodium chloride. The potential toxic effects associated with the release of polydimethylsiloxanes into the human bloodstream are unknown. The authors conclude that prolonged exposure to 60% ethanol had no major effect on catheter structure. This study included only 1 catheter polymer and evaluated concentrations of ethanol that are not commonly used in clinical practice. Bell et al investigated the effect of lock solutions on the mechanical properties of Carbothane polyurethane hemodialysis catheters (dual lumen, Ash Split Cath II; Medcomp). 33 The catheters were exposed in vitro to 1 of 3 lock solutions: heparin, 5,000 U/mL; 4% trisodium citrate; or 30% ethanol with 4% trisodium citrate. Each solution was locked into 6 catheters and bathed at 37 C for 9 weeks; solutions were changed 3 times weekly. Tensile testing included force-atbreak, elongation-at-break, and elastic modulus of the catheters. The ethanol with trisodium citrate lock significantly lowered the force-at-break and elongation-at-break compared with the heparin and trisodium citrate groups ( P!.01 for each). No significant difference was detected in elastic modulus. Catheters were weighed 3 times weekly to determine whether the lock solutions were being absorbed into the catheter polymer. Ethanol-exposed catheters demonstrated the largest change in weight. The authors report that the effect of the ethanol and trisodium citrate lock on the catheters is unlikely to hamper clinical use, given that after 9 weeks the catheters could still be stretched to 22 times their length and withstand 11.5 kg (113 N) of force. Forces produced clinically during hemodialysis are many times smaller than those re-

7 1102 infection control and hospital epidemiology november 2009, vol. 30, no. 11 quired to break the catheters in the study. The authors concluded that ethanol with trisodium citrate shows promise as a new solution for the treatment of CLA BSI. The use of only 1 catheter polymer and manufacturer, of a relatively low concentration of ethanol, and of the combination of ethanol and trisodium citrate and a lack of evaluation of the hub and the place where the hub meets the catheter lumen limit this study. These in vitro studies provide valuable information about efficacy and catheter integrity following ethanol exposure. However, the studies vary in the concentrations of ethanol used, in the use of ethanol in combination with an anticoagulant, and in the types of catheters evaluated. Furthermore, the in vitro environment does not account for certain in vivo factors (eg, host immunity) that may be important in biofilmassociated infections, the effect of which can be addressed only in clinical studies. clinical studies Clinical studies of ethanol lock therapy can be divided into those evaluating the utility of ethanol lock therapy for prevention of CLA BSI and those that consider treatment of CLA BSI (Tables 2 and 3). Prevention Trials Opilla et al evaluated CLA BSIs in 9 patients who received parenteral nutrition at home. 31 Patients were offered ethanol lock therapy only after standard strategies failed to decrease infection frequency. The ethanol lock contained 3 ml of 25% or 70% ethanol that was instilled in each lumen of a silicone Hickman catheter or peripherally inserted central catheter for 2 7 days per week for a dwell time of 2 4 hours. Following the dwell period, the ethanol was flushed through the line. Dwell times, frequencies, and volumes instilled varied throughout the study period. Before ethanol lock therapy was used there were 81 cases of CLA BSI (8.3 per 1,000 catheterdays), whereas with ethanol lock therapy there were 9 cases of CLA BSI (2.7 per 1,000 catheter-days) (relative risk [RR], [95% confidence interval (CI), ]; P p.001). Catheters were changed 69 times (7 times per 1,000 catheterdays) before ethanol lock therapy was used and only once (0.3 times per 1,000 catheter-days) with ethanol lock therapy (RR, [95% CI, ]; P!.0001). Eight of 9 subjects experienced adverse events with the ethanol lock therapy. Six patients felt light-headed and high for several seconds, and 2 of the 6 felt nauseated as well. In patients who experienced nausea, the frequency of ethanol lock use was decreased and the ethanol concentration was decreased from 70% to 25%; in 1 patient the volume was also decreased to 1 ml. None of the modifications reduced symptoms. Two patients reported tasting a shot of vodka, but sucking hard candy relieved this. Three patients related nonadherence due to the difficulty of adding another task to a busy routine. After receiving ethanol lock therapy, the 70% ethanol group experienced 8 CLA BSIs, while the 25% ethanol group experienced only 1 CLA BSI. The higher number of infections experienced by the 70% ethanol group may have been related to the length of time that the catheter was in place before ethanol lock therapy began; more of the patients in the 70% ethanol group had a catheter in place for longer than 2 months. The authors conclude that ethanol lock therapy holds potential for prevention of CLA BSI, but catheter age may be related to success. This study is limited by a number of confounders, including a small sample size, varying ethanol lock protocols (concentration, volume, frequency, dwell time), and lack of a concurrent control group. Only patients receiving home parenteral nutrition were included in the study, and no descriptive information about the patients is provided. The investigators studied only 1 catheter polymer and provided no information regarding the manufacturer(s). No information about catheter insertion technique or postinsertion care is provided. In a retrospective review of medical records, prevention of CLA BSI was evaluated in 10 children (mean age, 7.55 months; range, 3 27 months) with short bowel syndrome who received home parenteral nutrition and received daily 70% ethanol lock therapy. 29 Children with tunneled, silicone CVCs, excluding peripherally inserted central catheters or implantable ports, were given ml of 70% ethanol for ethanol lock therapy daily during their cycled off period of home parenteral nutrition, which lasted 4 14 hours. Before the next cycle of home parenteral nutrition began, the ethanol was flushed through the central line. No statistical analysis of the data was performed. Half the patients had CLA BSI data available from before ethanol lock therapy began, which revealed cases of CLA BSI per 1,000 catheter-days (6 cases in 538 catheterdays) before treatment and 2.07 cases of CLA BSI per 1,000 catheter-days (4 cases in 1,936 catheter-days) after ethanol treatment. All but 2 cases of CLA BSI were successfully treated with systemic antimicrobial medications and ethanol lock therapy. Two CVCs were removed secondary to CLA BSI. The remaining 5 patients started ethanol lock therapy at the time of first catheter placement. These patients experienced 2 CLA BSIs during 1,081 catheter-days, for a rate of 1.85 CLA BSIs per 1,000 catheter-days. One CVC was removed because of CLA BSI with Klebsiella pneumoniae. Parents and healthcare providers reported no adverse reactions, although 1 patient developed CVC-related thrombus, and 1 patient had 2 episodes of disseminated intravascular coagulation. Patient adherence seemed to be a nonissue save for 1 patient whose ethanol syringes were returned unused and who was not consistently administered home parenteral nutrition. Of note, this patient had 3 of the 6 CLA BSIs documented after ethanol lock therapy was initiated. The authors concluded that 70% ethanol lock therapy for the prevention of CLA BSI in pediatric patients with short bowel syndrome was safe and effective.

8 table 2. Trials of Ethanol Lock Therapy for Prevention of Central Line Associated (CLA) Bloodstream Infection (BSI) Study Population Treatment Catheter type Definition of CLA BSI Dwell time and administration parameters Results Opilla et al 31 9 home parenteral nutrition patients (ages unreported) Mouw et al pediatric short bowel syndrome patients receiving home parenteral nutrition (mean age, 7.55 months [range, 3 27 months]) Sanders et al immunosuppressed hematology patients (mean age, 52.4 years) (64 treatment periods) 25% or 70% ethanol Silicone Hickman CVC or peripherally inserted central catheter Symptoms of fever with correlating positive peripheral and CVC blood cultures 3mLfor2 4hperdayor 1 2 times per week; ethanol flushed through line followed by standard flush regimen 70% ethanol Tunneled, silicone CVC None provided ml for 4 14 h daily during cycled off period of home parenteral nutrition; ethanol flushed through the line after dwell time 70% ethanol Silicone, dual-lumen Hickman CVC Culture of a recognized pathogen from 1 or more blood cultures unrelated to infection at another site and a CVC in use the preceding48h 3 ml for 2 h daily; ethanol removed and replaced with heparinized saline CLA BSI rate before ethanol lock therapy, 8.3 per 1,000 catheterdays; rate with ethanol lock therapy, 2.7 per 1,000 catheter-days (RR, [95% CI, ]; P p.001). Catheter change rate before ethanol lock therapy, 7 per 1,000 catheter-days; rate with ethanol lock therapy, 0.3 per 1,000 catheter-days (RR, [95% CI, ]; P!.0001). The 25% ethanol group experienced fewer infections than the 70% ethanol group. More patients in the 70% ethanol group had catheters in place for more than 2 months. No serious adverse events; light-headedness (n p 6), nausea (n p 2), and taste of alcohol (n p 2). Pre-/post-data available for only 5 patients; 5 patients received ethanol lock therapy following the first catheter insertion. CLA BSI rate before ethanol lock therapy (n p 5), per 1,000 catheter-days; rate with ethanol lock therapy, 2.07 per 1,000 catheter-days. CLA BSI rate with ethanol use with first catheter insertion, 1.85 per 1,000 catheter-days. Three CVCs removed as a result of infection. No adverse events reported during ethanol lock instillation. CLA BSI rate with ethanol lock therapy, 0.6 per 100 catheter-days; CLA BSI rate with heparinized saline, 3.11 per 100 catheterdays (P p.008). Catheters survived significantly longer without a CLA BSI with ethanol lock therapy (P p.003). One patient withdrew from the study because of an episode of dyspnea after the first treatment. A second patient experienced an unusual taste sensation with anxiety and withdrew after 7 days. No deaths and no other adverse events were reported. CI, confidence interval; CVC, central venous catheter; RR, relative risk.

9 table 3. Trials of Ethanol Lock Therapy for Treatment of Central Line Associated (CLA) Bloodstream Infection (BSI) Study Population Treatment Catheter type Definition of CLA BSI Dwell time Results Dannenberg et al pediatric oncology patients (39 cases of CLA BSI) (median age, 10.5 years [range, 2 18 years]) Onland et al pediatric patients (51 cases of CLA BSI) (median age, 3.9 years [range, years]) Broom et al patients with CLA BSI (median age, 47 years [range, years]) 74% ethanol plus systemic antibiotics (n p 18) or systemic antibiotics alone (n p 13) 70% ethanol plus systemic antibiotics 70% ethanol plus systemic antibiotics Tunneled, multilumen Broviac CVC Tunneled, silicone single- or multilumen CVC and implantable ports Positive blood culture and fever or rise in WBCs (38.5 C and WBC 11 # 10 9 /L or 38.0 C and WBCs!1 # 10 9 /L) Presence of positive CVC blood cultures 48 h after appropriate intravenous antimicrobial use Tunneled CVC Recognizable pathogen from 1 set of blood cultures with symptoms of sepsis 2.3 ml for h alternated between each lumen every 3 days; ethanol flushed through the line after dwell time ml for h for 5 days; ethanol was withdrawn from the catheter after dwell time followed by 0.9% saline flush 2 ml for 4 h daily for 5 days; ethanol was withdrawn from the catheter after dwell time and replaced by a heparinized saline lock Overall CLA BSI rate, 2.66 per 1,000 catheter-days; 67% of CLA BSIs cleared without recurrence within 4 weeks of the end of therapy for the ethanol group vs 47% with systemic antibiotics alone. One catheter in each group was removed because of infection. No severe adverse events reported; fatigue, headaches, dizziness, nausea, and light-headedness were mild clinical adverse events. CLA BSI rate, 10 per 1,000 catheter-days. Infections cleared without recurrence in 88% of cases. Six cases of recurrent CLA BSI within 30 days occurred among 3 patients. No catheters were removed as a result of persistent infection. No adverse events reported. 12/17 patients retained CVCs for more than 14 days; 15/17 patients did not have recurrent infection with the original organism. Reinfection occurred in 6 patients. Recurrent infection occurred in 2 patients. No serious adverse events reported; 1 patient tasted alcohol during lock instillation. note. CVC, central venous catheter; WBC, white blood cell.

10 ethanol lock technique: review of literature 1105 The main limitations of this study are the small sample size and retrospective nature. Although there was no statistical analysis of the data, some results of the study, coupled with the small sample size, do not reflect positively on ethanol lock therapy. For example, 3 of 10 CVCs were reportedly removed secondary to infection during ethanol lock therapy. Additional limitations include the lack of a definition of CLA BSI and varying ethanol lock protocols. Adherence to ethanol lock therapy was not monitored. Only 1 catheter polymer was evaluated, catheter manufacturer data are not provided, and no information regarding catheter insertion technique or postinsertion care is given. In a prospective double-blind, randomized trial, use of ethanol lock therapy for the prevention of CLA BSI in adult, immunosuppressed patients with hematologic malignancy was evaluated. 24 Patients with dual-lumen silicone Hickman CVCs were randomly assigned to receive heparinized saline (28 patients) or 70% ethanol (32 patients). Patients who had previously entered the study were excluded unless a new catheter was inserted and 3 months had elapsed since previous entry. A radiologist using full aseptic technique inserted the catheters; a chlorhexidine gluconate dressing was placed over the exit site at insertion and changed weekly thereafter. For each patient, 3 ml of the appropriate solution was locked into each catheter lumen for 2 hours daily before being removed and replaced with heparinized saline. Four patients participated twice and were randomly assigned to a study group each time, with a period of 3 29 months between placement of the first and placement of the second catheter. Thus, a total of 64 prophylactic treatment periods were studied with a similar match in patient age, sex, and primary disease. The CLA BSI rate was 0.6 per 100 catheter-days (3 cases in 501 catheter-days) in the ethanol group versus 3.12 per 100 catheter-days (11 in 353 catheter-days) in the control group (odds ratio, 0.18 [95% CI, ]; P p.008). Two of 3 and 4 of 11 CLA BSIs in the ethanol and control groups, respectively, did not produce positive peripheral culture results but met the study CLA BSI definition. Compared with the catheters used by the patients in the control group, the catheters used by patients who received ethanol lock treatment remained free of CLA BSI longer ( P p.003). The reported adverse events occurred in 2 patients in the group that received ethanol. One patient experienced an episode of dyspnea, and another experienced an unusual taste sensation and anxiety. No deaths were reported. While 5 catheters in each group were removed before the end of the study, removal in the ethanol group was not associated with CLA BSI, whereas 3 removals in the control group were attributed to CLA BSI. This study is limited by a number of factors. First, because the definition of CLA BSI was nonspecific, patients with colonization or contamination may have been classified as having CLA BSI. Second, patients were permitted to receive systemic prophylactic antibiotics, which could confound the results attributed to ethanol lock therapy. Last, only 1 catheter polymer and type was studied. Treatment Trials A retrospective review investigated ethanol lock therapy in treating CLA BSI in pediatric oncology patients with tunneled, multilumen, Broviac CVCs. 26 The presence of CLA BSI was defined as a positive CVC blood culture result with signs of infection. Before ethanol lock therapy became standard, the treatment protocol consisted of systemic antibiotic therapy alone; after implementation of ethanol lock therapy, lock therapy was used in conjunction with systemic antibiotics. The authors analyzed the study population in 2 retrospective groups: patients treated with antibiotics alone and patients treated with antibiotics plus ethanol lock therapy. Among 28 included patients there were 39 episodes of infection. Three subjects were treated in both groups for separate episodes of infection. Ethanol lock therapy was applied such that 2.3 ml of 74% ethanol solution was locked in the catheter lumen for hours. The solution was flushed through to prevent catheter clotting. Each port of the multilumen catheter was alternately locked at hour intervals for 3 days; the unlocked port could be used to administer medication and nutrition. Ethanol lock therapy was used 24 times in 18 patients, while antibiotics alone were used 15 times in 13 patients. The overall CLA BSI rate was 2.66 per 1,000 catheter-days (39 cases in 14,680 catheter-days). No severe adverse events were reported with ethanol lock therapy. Coagulase-negative staphylococci were the most common causative organism. Fatigue, headaches, dizziness, nausea, and light-headedness were the only clinical adverse events experienced by patients who received ethanol lock therapy. The authors reported no substantial difference in toxic effects on the liver between ethanol lock therapy and systemic antibiotics alone. Four weeks after study completion, no subsequent CLA BSI had occurred in 16 of 24 patients (67%) in the group that received ethanol lock therapy versus 7 of 15 patients (47%) in the group that received systemic antibiotics alone. The CVC was removed once in each study group because of infection. The authors concluded that ethanol lock therapy can be used safely in pediatric oncology patients with CLA BSI. Limitations of this study include the retrospective design and small sample size. In addition, because the CLA BSI definition necessitated only 1 positive blood culture result from a sample obtained through the CVC and because the most commonly implicated organisms were coagulase-negative staphylococci, many of these cases could represent blood culture contamination or CVC colonization rather than infection. The authors also did not provide a definition of treatment success. Furthermore, the investigators evaluated only 1 catheter polymer and type and did not provide any manufacturer data. Onland et al conducted a retrospective review to evaluate

11 1106 infection control and hospital epidemiology november 2009, vol. 30, no. 11 possible salvage of CVCs by using ethanol lock therapy and systemic antibiotics in 40 pediatric patients with persistent or recurrent CLA BSI. 30 The volume of the 70% ethanol lock solution was based on the CVC intraluminal volume capacity. A single-lumen tunneled Broviac catheter necessitated 0.8 ml (1.2 ml for Medcomp catheter), a dual-lumen tunneled catheter necessitated 1.2 ml, and Port-A-Cath devices necessitated 1.4 ml in any port. The solution was instilled for hours in single-lumen catheters, withdrawn and discarded, and followed by a 0.9% sodium chloride flush; this was repeated for 5 days. For dual-lumen catheters, the dwell time was 24 hours, alternating between lumina for 10 days. Treatment success was defined as resolution of fever within 24 hours, no recurrence of positive blood culture results with the same organism, and retention of the CVC. Treatment failure was defined as CLA BSI recurrence within 30 days with the same pathogen or removal of the CVC because of a persistent infection. The CLA BSI rate was 10 per 1,000 catheter-days. All CVCs treated with ethanol lock therapy were retained and used throughout the study period. Bacteremia recurred after 30 days in 3 patients with 4 different pathogens. Episodes cleared in 45 of 51 (88%) of the treated infections without recurrence. Infections with polymicrobial and with monomicrobial isolates were successfully treated in 12 of 16 (75%) and 33 of 35 (94%) of cases, respectively. No adverse events were reported. This study is limited by the retrospective design and lack of a control group. The long dwell time necessitated that a peripheral catheter be placed for administration of fluids, medications, and nutrition in the case of a single-lumen CVC. The CLA BSI definition necessitated only 1 positive blood culture result from a sample obtained through the CVC, and the most commonly implicated organisms were coagulasenegative staphylococci; likewise, many of these cases could represent blood culture contamination or CVC colonization rather than infection. Finally, only 1 catheter polymer was evaluated. Broom et al prospectively analyzed the benefits of ethanol lock therapy in combination with antibiotic therapy in 19 patients with CLA BSI. 28 CLA BSI was defined as isolation of a recognized pathogen from at least 1 set of blood cultures or of a potential skin contaminant from at least 2 sets of blood cultures from patients who had clinical manifestations of sepsis with no other apparent source of sepsis. Intravenous antibiotic therapy that was appropriate for the specific isolated pathogen was started for each patient and was continued until symptom resolution. A 2-mL solution of 70% ethanol was locked into each lumen for a dwell time of 4 hours per day for 5 days. The ethanol solution was aspirated from the catheter following the dwell period. Successful treatment was defined by negative results on blood cultures for the original pathogen with samples taken from all CVC lumina 1 day after therapy completion (day 6), with catheter retention for 14 days and no subsequent CVC or peripheral isolation of the original pathogen. Nineteen patients were treated with ethanol lock therapy for CLA BSI. Two patients did not complete all 5 days of ethanol lock therapy, which yielded 17 total study participants. On day 6, no blood culture samples grew the original infecting organism. Three of the 17 patients had a positive blood culture result on day 6; the organisms found in 2 of these blood cultures were considered contaminants, as there were no clinical signs of infection and no further blood samples grew any organisms. Reinfection of the CVC with a different organism than during study entry occurred in 6 patients. Infection recurred in 2 patients, although 1 recurrence was not thought to be related to the original CLA BSI because of differences in the organism s susceptibility patterns. In summary, 12 of 17 study patients who completed ethanol lock therapy retained their CVC for more than 14 days with no subsequent isolation of the original organism. No important adverse events were noted apart from 1 patient who tasted alcohol during the lock instillation. Line patency did not appear to diminish. Limitations of the study include lack of a control group, small sample size, and lack of catheter manufacturer data. discussion Ethanol lock therapy is an attractive option for treatment or prevention of intraluminal CLA BSI because it is inexpensive and because concerns about development of resistance are limited. In vitro studies have shown the efficacy of ethanol, alone or in combination with other agents, as a lock solution for eradication of S. aureus (including MRSA) and C. parapsilosis and for prevention of biofilm formation due to S. aureus (including MRSA), S. epidermidis, P. aeruginosa, and C. albicans. In vitro studies testing the integrity of catheters exposed to ethanol demonstrate small effects on polyurethane and silicone catheter integrity; however, these changes are not thought to be clinically relevant, although the data are limited. These in vitro studies are limited by the use of widely varying ethanol concentrations, of various additive components, and of limited types of catheter polymers and manufacturers in each experiment and by lack of catheter hub assessment. In addition, the potential for and clinical importance of systemic toxic effects due to release of plastic components after ethanol lock use needs to be evaluated and compared with the leaching of chemicals associated with other lock solutions. A letter by Laird et al reported 3 cases of catheter occlusion due to precipitate formation after catheters were locked with 100% ethanol for 24 hours. 44 Whether this precipitation was related to a physical incompatibility between ethanol and a concomitantly administered medication, such as heparin, or due to breakdown of the catheter is unknown. The catheter type and catheter polymer were not reported in this letter. Clinical trials assessing the use of ethanol lock therapy for the prevention of CLA BSI have shown a decreased or low