Journal of Antimicrobial Chemotherapy Advance Access published June 2, 2014
J Antimicrob Chemother doi:10.1093/jac/dku182
Adverse effects associated with ethanol catheter lock solutions: a systematic review Leonard A. Mermel1,2* and Neha Alang3 1
Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA; 2Division of Infectious Diseases, Rhode Island Hospital, Providence, RI, USA; 3Department of Medicine, Newport Hospital, Newport, RI, USA
Received 26 February 2014; returned 14 April 2014; revised 28 April 2014; accepted 1 May 2014 Background: Antimicrobial lock therapy has been widely utilized internationally for the prevention and management of intravascular catheter-related bloodstream infections. One of the agents commonly utilized for lock therapy is ethanol. However, a systematic review of adverse events associated with ethanol locks has not been published. Methods: PubMed was searched to collect articles published from May 2003 through March 2014. The bibliographies of relevant articles were also reviewed. Results: In vitro studies of the mechanical properties of catheters after ethanol immersion have revealed changes predominantly in polyurethane catheters and to a lesser extent silicone and Carbothane, catheters. An elution of polymers from polyurethane and Carbothane catheters has been observed at the ethanol concentrations used in ethanol lock therapy. Ethanol above a concentration of 28% leads to plasma protein precipitation. Ethanol locks were associated with catheter occlusion in 11 studies and independently increased the risk of thrombosis compared with heparin lock in a randomized trial. Six studies noted abnormalities in catheter integrity, including one case leading to catheter embolization. Of note, five of these studies involved silicone catheters. Ethanol lock use was associated with systemic side effects in 10 studies and possible side effects in one additional study. Four studies noted liver function test abnormalities, predominantly transaminase elevation, related to ethanol lock use. However, a prospective study did not find any difference in the risk of doubling the transaminase level above the normal range during use of ethanol locks compared with not using an ethanol lock. Conclusions: The use of ethanol locks has been associated with structural changes in catheters, as well as the elution of molecules from the catheter polymers. Clinical studies have revealed systemic toxicity, increased catheter occlusion and breaches in catheter integrity. Keywords: antimicrobial lock therapy, intravascular device infections, alcohol toxicity
Introduction Intravascular catheters have been flushed or locked with ethanol for various purposes over the last 25 years. Ethanol has been utilized to dissolve intraluminal obstruction caused by waxy lipid deposits associated with the administration of total parenteral nutrition.1 – 4 More recently, ethanol lock solutions have been used predominantly for the prevention and occasionally for the management of catheter-related infection, as noted in recent reviews5 – 8 and case series.9 Despite the enthusiasm for the use of ethanol lock solutions in various patient populations, as evidenced by the numerous publications cited in these reviews, few prospective, randomized trials exist that have thoroughly assessed their efficacy and safety. As such, most clinicians are unaware of the safety profile of ethanol lock solutions and the
effect of ethanol on proteins in plasma or erythrocytes in whole blood, on biofilms formed by various microbial pathogens, on catheter integrity and on the elution of catheter material after exposure to ethanol. Ethanol modifies the deformability and fluidity of erythrocytes in a dose-dependent fashion, which can increase risk of haemolysis.10,11 Ethanol is also known to precipitate plasma proteins in a dose-dependent fashion.12,13 Some in vitro studies suggest that ethanol can eradiate various bacteria within biofilms, with variable efficacy, depending on the ethanol concentration and the exposure time.14,15 However, other investigators have found that increasing concentrations of ethanol from 20% to 100%, particularly ethanol concentrations of 40% or more, correlate with increasing biofilm formation of Staphylococcus aureus.16 Additionally, exposure of S. aureus to ethanol increases the expression of antibiotic
# The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]
1 of 9
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
*Corresponding author. Division of Infectious Diseases, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA. Tel: +1-401-444-2608; Fax: +1-401-444-8154; E-mail: [email protected]
Systematic review
Methods PubMed was searched to collect articles available online published May 2003 through March 2014, as well as relevant articles from bibliographies to determine whether patients receiving ethanol catheter lock solutions had untoward effects potentially caused by ethanol lock solutions, and the available peer-reviewed literature regarding the effect of ethanol on intravascular catheter integrity. Search terms included ethanol lock technique, ethanol lock therapy, adverse effects of ethanol lock therapy, intravascular catheter occlusion/thrombosis, catheter-related infection and ethanol, catheter disruption and ethanol, leakage repair and ethanol, interaction of ethanol with other substances, systemic effects of alcohol lock, catheter-related infection and ethanol, and bloodstream infection, prevention and treatment and ethanol. Only peer-reviewed articles were assessed. Clinical studies were included in this analysis if it could be determined that the side effects of ethanol lock use had been assessed, and if so whether any patients had had an adverse reaction. In vitro studies were included if the methodology for assessing the interactions between the ethanol and the catheters had been noted.
Results Using PubMed, the above-noted search terms identified 402 articles. Eight in vitro studies and 20 clinical studies met our inclusion criteria. The in vitro studies on the impact of ethanol lock solutions on catheter integrity are summarized in Table S1 (available as Supplementary data at JAC Online). Studies utilizing scanning electron microscopy to assess the catheter surface after ethanol immersion have noted micro-cracks or degeneration of the internal wall of polyurethane catheters,23,24 but the concentration of ethanol used in some of these studies was greater than the concentration used in ethanol lock solutions. Time-dependent abnormalities of the inner surface of the catheter have been noted for Carbothane catheters, made of polycarbonate-based
2 of 9
aliphatic and aromatic polyurethanes,25 but no such changes have been noted with silicone catheters.26 Some studies have assessed the mechanical properties of catheters after ethanol immersion. One such study found that polyurethane, but not silicone, catheters showed an increased wall thickness after ethanol exposure, with a reduced modulus of elasticity for polyurethane and silicone catheters, but no significant change in the force at break, maximum stress at break or maximum segment elongation and strain immediately prior to break with either catheter type.27 The immersion of Carbothane catheters in ethanol led to a significantly reduced force at break, a shorter elongation at break and an increased catheter weight but no significant change in the modulus of elasticity.28 A number of studies have assessed the elution of various molecules from the catheters during immersion in ethanol. An elution of condensed polymers of 1,4-butanediol from polyurethane catheters has been noted.24 An elution of polydimethylsiloxanes from silicone catheters was noted after immersion in 95%, but not 60%, ethanol.26 A time-dependent elution of predominantly the polycarbonate diol component has been observed with Carbothane catheters.25 In sum, scanning electron microscopy studies have noted changes in Carbothane catheters at the ethanol concentrations used in ethanol lock solutions, but not in silicone catheters after exposure to ethanol. Changes in the mechanical properties of polyurethane and Carbothane catheters have been observed after ethanol exposure, but less so with silicone catheters. An elution of polymers has been observed from polyurethane and Carbothane catheters but not from silicone catheters at the ethanol concentrations commonly used in ethanol locks. Ethanol solutions above a concentration of 28% as a lock solution caused protein precipitation in plasma samples during the in vitro simulation of various catheter insertion positions.20 Of note, the precipitate cannot be redissolved by dilution with urokinase or alteplase. Studies revealing a systemic effect of ethanol lock use or an adverse impact on lumen patency or catheter integrity are summarized in Table 1. In 10 studies,29,31 – 35,42 – 44,47 patients demonstrated systemic symptoms likely to be related to ethanol lock use, with possibly the same noted in an additional study.36 The ethanol lock was flushed in five of these studies29,31,35,43,47 and aspirated in five studies,32,33,36,42,44 and no procedure was specified in one study.34 In the one prospective, randomized trial, the incidence of such symptoms was significantly greater in the ethanol lock group.35 In three studies29,36,38 and possibly an additional one,39 transaminase levels above baseline and/or greater than those seen in individuals not receiving ethanol locks was observed. Three of these four studies29,38,39 involved flushing of the ethanol lock. One prospective study assessed for a doubling in transaminase levels above the normal range and found no difference in patients receiving an ethanol lock compared with those receiving a lock solution not containing ethanol.47 Eleven studies19,30,34,36 – 38,40 – 42,45,46 noted problems with catheter occlusion. In seven of these studies the lock was aspirated,19,30,36,37,41,42,46 in three it was flushed38,40,45 and in one study no procedure was specified.34 In one prospective study this was significantly more common when an ethanol lock was used as opposed to a lock solution not containing ethanol.41 In one study, an ethanol lock independently increased the risk of thrombosis compared with a heparin lock (OR 10.5, 95% CI 1.2–91.3).46 Six studies34 – 37,42,46 noted a breach in catheter integrity with ethanol lock use. The ethanol lock was aspirated, flushed or not specified in four studies,36,37,42,46 one study35 and one study,34 respectively. Of note, five of these
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
resistance factors, as seen with the up-regulation of antibiotic efflux pumps.16 Low concentrations of ethanol have also been shown to enhance the biofilm formation of Staphylococcus epidermidis.17 Ethanol lock solutions have the potential for causing disulfiram reactions in patients receiving metronidazole.18 Ethanol may also interact with other medications instilled through the catheter after the use of ethanol lock solutions.7 Finally, ethanol has no anticoagulant properties and may induce coagulation by protein denaturation.19 The contents of catheter lock solutions leak into the bloodstream due to the parabolic flow distribution inside the catheter during injection and to a greater extent because of gravityinduced discharge from the distal end of the catheter because of differences in fluid density between the catheter lock solution and the blood.20 Leakage of lock solutions into the systemic circulation due to gravity varies depending on body position.21,22 As the lock solution is discharged from the distal end of the catheter, blood enters the catheter lumen, allowing plasma proteins to interact with the ethanol lock solution.20 Thus, the ethanol concentration within the lumen may vary, with a gradient of higher to lower concentration from the proximal to the distal end of the catheter, as has been demonstrated with antibiotic lock solutions.21 We set out to assess in vitro studies and clinical studies of ethanol lock solutions with the specific intent of assessing and shedding light on the risk of systemic side effects and the impact on the catheter material and intraluminal contents.
Systematic review
Table 1. Clinical studies of ethanol lock solutions with adverse events noted
Cited study Publication year Retrospective or prospective study
Ethanol lock % Ethanol volume aspirated or flushed at end of dwell time Flushed with saline after ethanol lock
Study population (patients receiving ethanol lock)
Dannenberg et al.29 2003 Retrospective
74% ethanola 2.3 mL flushed not specified
Laird et al.30 2005 Retrospective
100% ethanola 3 adults 3 mL aspirated yes 25%–70% ethanol (v/v) 9 adults 3 mL flushed yes
Opilla et al.31 2007 Retrospective
Sanders et al.32 70% ethanol (v/v) 2008 3 mL Prospective, randomized aspirated yes 70% ethanola Broom et al.33 2008 2 mL Prospective aspirated not specified 70% ethanola Mouw et al.34 2008 0.5– 2 mL Retrospective not specified not specified
18 (aged 2 –14 years)
Ethanol lock dwell time Duration of ethanol lock use Catheter type 20– 24 h 3 days Broviac silicone CVC
24 h duration unspecified catheter type and polymer unspecified 2 –4 h, 2 –7 days per week 6 –22 months Silicone Hickman CVC or PICC
34 adults
2 h daily up to 30 days silicone CVC
17 patients (aged 14 –73 years)
4 h daily 5 days Hickman CVC in 16 patients; Portacath in 1 patient 4 –14 h daily up to 36 months silicone CVC
10 children (average age¼7.6 months; range ¼3– 27 months)
Adverse effects tiredness, headaches, dizziness, nausea, lightheadedness; increase in aspartate aminotransferase or alanine aminotransferase or gamma-glutamyl transferase in 12 of 18 patients in ethanol lock group compared with 6 of 28 patients not receiving ethanol lock (P¼0.005) catheter occlusion and precipitated material noted in catheter lumens of all 3 patients
70% ethanol lock was changed to 25% ethanol lock in 2 patients due to nausea and dizziness but this did not reduce symptoms 6 patients felt lightheaded and ‘high’ for several seconds when saline flush used after ethanol lock dwell was complete 2 patients complained they tasted a ‘shot of vodka’ 1 episode of dyspnoea after first ethanol lock instillation
ethanol taste reported by 1 patient
1 patient had catheter-related thrombus after 630 days of ethanol lock 2 episodes of culture-negative disseminated intravascular coagulation 1 catheter removed due to ‘loss of line integrity thought to be caused by other factors’
3 of 9
JAC
Continued
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
Systematic review
Cited study Publication year Retrospective or prospective study
Ethanol lock % Ethanol volume aspirated or flushed at end of dwell time Flushed with saline after ethanol lock
Slobbe et al.35 70% ethanola 2010 3 mL Prospective, randomized flushed yes
Study population (patients receiving ethanol lock) 226 adults
Ethanol lock dwell time Duration of ethanol lock use Catheter type 15 min daily mean¼63 days (range¼2 – 486 days) silicone Hickman CVC
Kayton et al.36 2010 Prospective
70% ethanol (v/v) 12 children catheter lumen volume aspirated yes
Overnight ≤6 months silicone Portacath
Cober et al.37 2010 Retrospective
15 children 70% ethanol (v/v) catheter lumen volume plus 0.1– 0.2 mL aspirated yes
at least 2 h daily mean¼263 days (23 –652 days) silicone CVC
Adverse effects 1 catheter removed because of rupture of a catheter lumen 1 patient had syncope after initial but not subsequent flush of the ethanol lock in this blinded, placebo-controlled trial more ethanol lock patients discontinued lock therapy (P¼0.006) or continued with a frequency-adjusted regimen (P¼0.002) than the placebo group in the ethanol lock group there was more facial flushing (P, 0.001), altered taste (P¼0.04) and feeling of dizziness or drowsiness (P,0.001) morning blood alcohol level averaged 11 mg/dL (range¼0 – 80 mg/dL) 3 of 12 catheters had occluded lumens requiring device removal; all had dense thrombus in reservoir or catheter lumen 1 of 3 above-noted catheters also fractured, with central catheter embolization one patient’s urticaria worsened, ascribed to another medication transient rise in hepatic transaminases or alkaline phosphatase in 10 of 12 patients (hepatotoxicity: grade 1 in 7 children, grade 2 in 1 child, grade 3 in 2 children) abdominal pain (n¼4), vomiting (n¼4), sneezing (n¼4), slurred speech (n¼3), sleepiness (n¼3), change in personality (n ¼2) and pain on inspiration (n ¼1) all ascribed to another medication this study was discontinued early 20 occurrences in 7 patients of catheter leakage or disruption of one or both layers of silastic tubing requiring catheter repair deep vein thrombosis in 1 patient involving extremity of CVC insertion difficulty withdrawing ethanol lock in 3 patients from the CVC thrombolytic administration to ‘clear the line’ in some cases catheter repair for leak or disruption 6.4+10 events/1000 catheter days when ethanol lock used vs 3.1+5.2 events/ 1000 catheter days when not used (P¼0.2)
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
4 of 9
Table 1. Continued
70% ethanol (v/v) mean 0.5 mL (0.3 – 1.0 mL) flushed yes
59 patients (aged 2 months to 19 years)
Valentine39 2011 Retrospective
70% ethanola not specified flushed yes
20 patients (average age¼6 months, range ¼77 days-20 years)
Wales et al.40 2011 Not specified
70% ethanola 10 children (median 1 –3 mL age¼10 months, flushed range ¼31–129 months) no 60% ethanol (v/v) 30 adults catheter lumen volume aspirated yes
Heng et al.41 2011 Prospective (sequential use of ethanol or ‘standard’ lock)
Wong et al.19 2011 Not specified
70% ethanol (v/v) 4 children catheter lumen volume aspirated yes
4 to 25 h 1 –4 doses over ≤3 days Broviac silicone CVC (n ¼29), Portacath (n¼19), PICC (n ¼15), tunnelled/ powerline PICC (n¼12), Hickman CVC (n¼3), pheresis CVC (n¼1), haemodialysis CVC (n¼1), catheter type unspecified (n ¼1) PICC and Portacath predominantly polyurethane mean dwell time¼17 h (range¼4 – 48 h) daily 1 –5 days Broviac silicone catheters, mediports, PICCs, non-tunnelled CVCs ≥4 h daily mean¼227+64 days silicone tunnelled CVC and PICC (polymer unspecified) average¼44 h (between dialysis sessions) 6 weeks silicone dialysis CVC
catheter malfunction in 5 of 13 CVCs 2 of the 80 (3%) episodes post-ethanol lock therapy had transient difficulty with saline flush, both eventually resolved with one requiring tissue plasminogen activator infusion 12 of 48 reversible episodes of transaminase elevation after ethanol lock use
Systematic review
McGrath et al.38 2011 Retrospective
2 of 16 patients had mild transaminitis but ‘not different from their baseline levels’
catheter thrombosis in 2 patients CVC felt ‘sluggish’ at end of ethanol lock dwell period in 2 patients
5 of 9
Continued
JAC
transient increase in rate of catheter dysfunction [complete catheter occlusion or need to ‘reverse lines’ or difficulty withdrawing or instilling fluid into the catheter increased from 2.2% before ethanol lock use to 13.3% when it was used (P,0.001); complete catheter occlusion requiring fibrinolytic agent use or catheter exchange in 4 of 180 dialysis sessions during ethanol lock period vs 1 of 357 dialysis sessions when it was not used (P¼0.05)] Child 1 and 2: dwell time 12 h visible thrombosis in Child 1 visible thrombosis in Child 2 between nights on CVC occlusion in Child 3 (patent without thrombolytic after hyperalimentation discontinued ethanol lock use) Child 3 and 4: 2 – 12 h per day 3 visible thrombosis in Child 4 times a week Child 1: 413 days Child 2: 168 days, co-administered warfarin Child 3: 3 days; co-administered warfarin Child 4: 9 days; co-administered warfarin Broviac silicone CVC
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
Systematic review
6 of 9 Table 1. Continued
Cited study Publication year Retrospective or prospective study
Ethanol lock % Ethanol volume aspirated or flushed at end of dwell time Flushed with saline after ethanol lock
Study population (patients receiving ethanol lock)
Ethanol lock dwell time Duration of ethanol lock use Catheter type
Adverse effects
Broom et al.42 70% ethanol (v/v) 2012 3 mL Prospective, randomized aspirated not specified
25 adults
48 h, once weekly duration unknown tunnelled dialysis CVC (polymer not specified)
John et al.43 2012 Retrospective
31 adults
12 h, 4 –7 days per week duration unspecified tunnelled silicone CVC
14 patients (mean age¼4.3 years; IQR¼0.4– 19.1 years)
2 h per week 1 patient had facial flushing and irritability while receiving average¼690 days 1 mL of ethanol lock; side effects resolved when lock silicone catheters (Broviac, 12; volume reduced to 0.8 mL Hickman, 1; Portacath, 1) 24 h once weekly 2 patients with Mediport catheters had complete catheter duration unspecified occlusion after 15 months and 2 months, respectively 11 Mediport catheters, 2 Broviac catheters Daily for at least 4 h 0 and 23 line repair events when catheters were locked with 691 catheter days heparin or ethanol, respectively (0 and 6.3 events/1000 (range¼198– 782 days) catheter days, respectively). Median line age at tunnelled silicone CVC repair¼42 days (IQR¼111 days). Line size increase from 2.7 Fr to 9.6 Fr independently reduced risk of line repair (OR 0.13, 95% CI 0.03 – 0.58) 1 and 12 patients receiving heparin versus ethanol locks had thrombotic events requiring tissue plasminogen activator use, respectively (0.46 and 3.27/1000 catheter days, respectively). Median line age at time of thrombosis was 80 days (IQR ¼141 days). Ethanol lock increased risk of thrombosis by logistic regression analysis (OR 10.5, 95% CI 1.2–91.3)
Rajpurkar et al.45 2014 Retrospective Abu-El-Haija et al.46 2014 Retrospective
6 children
7 children (aged 1 day to 24 months)
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
Pieroni et al.44 2013 Retrospective
70% ethanol (v/v) 3 mL flushed no 70% ethanol (v/v) 1 –2 mL aspirated yes 70% ethanola catheter lumen volume flushed yes 70% ethanola catheter lumen volume aspirated yes
5 of 25 required catheter removal due to flow problems (compared with 3 of 24 in heparin group) 1 patient’s catheter ‘split’ 1 patient complained of stinging at the exit site after ethanol lock administered 1 patient complained of dry lips and thirst alcohol taste in 21 of 31 patients (68%) after ethanol lock flushed
JAC
Systematic review
CVC, central venous catheter; PICC, peripherally inserted central venous catheter. a Ethanol in % g or % v/v not specified.
Pe´rez-Granda et al.47 70% ethanola 2014 1 mL Prospective, randomized flushed yes
Discussion Although ethanol lock solutions demonstrate efficacy when used in a prophylactic fashion and for the management of catheterrelated bloodstream infection,5 – 9 untoward effects have been noted by several investigators. The incidence of systemic side effects, breaches in the integrity of the catheter or catheter obstruction due to ethanol lock use may be underappreciated since most articles in the published literature are retrospective and these details may have been missed by clinicians at the time or during retrospective chart review, or may have been observed and otherwise explained or not documented. In the four prospective, randomized trials32,35,42,47 severe adverse events occurred only in the ethanol lock group,35,47 rupture or splitting of the catheter was seen only in the ethanol group35,42 and a significant difference in early discontinuation of the randomized lock use occurred only in the ethanol group.35,47 In the one prospective trial alternating ethanol and standard lock use,41 there was a significantly greater incidence of both catheter dysfunction and complete catheter occlusion when an ethanol lock was used. What is clear from the published literature is that systemic symptoms may be observed with ethanol locks of various concentrations whether or not they have been aspirated after the dwell time or flushed, the former due to inexorable seepage from the distal aspect of the catheter. In some studies, such seepage has also been associated with elevation of transaminase levels. An increased incidence of catheter occlusion has been noted in several studies correlating with in vitro studies of plasma precipitation in catheter lumens from blood that has filled the intraluminal void after seepage of the lock solution. This may also reflect the fact that ethanol is not an anticoagulant. Finally, breaches in catheter integrity have been noted in several clinical studies, in some cases with embolization of the catheter36 despite the minimal changes in the mechanical properties of silicone catheters noted in in vitro studies. Based on the available literature, we have the following recommendations regarding ethanol lock solution: (1) All manufacturers should rigorously assess the effect of various concentrations of ethanol lock solutions on catheter integrity and polymer elution to guide the use of such solutions in the clinical setting. Ethanol locks should only be used in catheters approved for such use by manufacturers. (2) Consensus recommendations should be made regarding the optimal ethanol concentration, the minimal dwell time for efficacy and catheter compatibility, and the recommendations should note whether additional ingredients are necessary to minimize intraluminal obstruction and inhibition rather than the stimulation of biofilm formation. At the present time an ethanol lock should be used with great caution and only in catheters that are manufacturer-approved for use with ethanol locks, and the lock solution should be aspirated rather than flushed after the dwell time is complete, as well as with close observation for symptoms and monitoring for laboratory evidence of alcohol toxicity. Adding an additional
7 of 9
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
113 adults (mean age¼67.3 years, 2 h every 3 days standard deviation¼13.1 years) median ¼6 days (IQR¼4 – 8 days) CVC or Swan– Ganz catheter
early discontinuation of lock solution occurred in 7 of 113 patients and 0 of 87 patients with ethanol and non-ethanol lock solution, respectively (P¼0.02). Severe immediate events occurred in 2 of 113 and 0 of 87 such patients (P¼0.2), catheter lumen rupture in 1 of 113 and 0 of 87 such patients (P¼0.4) and doubling of aspartate aminotransferase or alanine aminotransferase occurred in 42 and 33 such patients (0.9).
studies34 – 37,46 specified the catheter material and in each case a silicone catheter was used. In one study increasing the catheter size from 2.7 Fr to 9.6 Fr independently reduced the risk of line repair (OR 0.13, 95% CI 0.03–0.58).46
Systematic review
Acknowledgements
7 Wolf J, Shenep JL, Clifford V et al. Ethanol lock therapy in pediatric hematology and oncology. Pediatr Blood Cancer 2013; 60: 18 –25. 8 Tan M, Lau J, Guglielmo BJ. Ethanol locks in the prevention and treatment of catheter-related bloodstream infections. Ann Pharmacother 2014; 48: 607–15. 9 Kubiak DW, Gilmore ET, Buckley MW et al. Adjunctive management of central line-associated bloodstream infections with 70% ethanol-lock therapy. J Antimicrob Chemother 2014; 69: 1665– 8. 10 Chi LM, Wu WG. Mechanism of hemolysis of red blood cell mediated by ethanol. Biochim Biophys Acta 1991; 1062: 46–50. 11 Sonmez M, Ince HY, Yalcin O et al. The effect of alcohols on red blood cell mechanical properties and membrane fluidity depends on their molecular size. PLoS One 2013; 8: e76579. 12 Cohn EJ, Hughes WL, Weare JH. Preparation and properties of serum and plasma proteins; crystallization of serum albumins from ethanol water mixtures. J Am Chem Soc 1947; 69: 1753 –61. 13 Blackwood RA, Klein KC, Micel LN et al. Ethanol locks therapy for resolution of fungal catheter infections. Pediatr Infect Dis J 2011; 30: 1105– 7. 14 Balestrino D, Souweine B, Charbonnel N et al. Eradication of microorganisms embedded in biofilm by an ethanol-based catheter lock solution. Nephrol Dial Transplant 2009; 24: 3204– 9.
We thank Tomimo Komura with Japanese translation of two articles.
15 Peters BM, Ward RM, Rane HS et al. Efficacy of ethanol against Candida albicans and Staphylococcus aureus polymicrobial biofilms. Antimicrob Agents Chemother 2013; 57: 74– 82.
Funding
16 Redelman CV, Maduakolam C, Anderson GG. Alcohol treatment enhances Staphylococcus aureus biofilm development. Immunol Med Microbiol 2012; 66: 411–8.
This study was supported by internal funding.
Transparency declarations L. A. M.’s potential conflicts of interest since 2011 include serving as a consultant for or receiving research funding from 3M, Cormedix, ICU Medical, Catheter Connections, Marvao, Fresenius, Bard, Teleflex, CareFusion and Semprus. N. A. has no conflicts of interest to report.
Supplementary data
17 Milisavljevic V, Tran LP, Batmalle C et al. Benzyl alcohol and ethanol can enhance the pathogenic potential of clinical Staphylococcus epidermidis strains. Am J Infect Control 2008; 36: 552– 8. 18 Jones BA, Hull MA, Richardson DS et al. Efficacy of ethanol locks in reducing central venous catheter infections in pediatric patients with intestinal failure. J Pediatr Surg 2010; 45: 1287 –93. 19 Wong T, Clifford V, McCallum Z et al. Central venous catheter thrombosis associated with 70% ethanol locks in pediatric intestinal failure patients on home parenteral nutrition: a case series. JPEN J Parenter Enteral Nutr 2012; 36: 358–60.
Table S1 is available as Supplementary data at JAC Online (http://jac. oxfordjournals.org/).
20 Schilcher G, Schlagenhauf A, Schneditz D et al. Ethanol causes protein precipitation—new safety issues for catheter locking techniques. PLoS One 2013; 8: e84869.
References
21 Soriano A, Bregada E, Marques JM et al. Decreasing gradient of antibiotic concentration in the lumen of catheters locked with vancomycin. Eur J Clin Microbiol Infect Dis 2007; 26: 659– 61.
1 Pennington CR, Pithie AD. Ethanol lock in the management of catheter occlusion. JPEN J Parenter Enteral Nutr 1987; 11: 507– 8. 2 Klem W, Pharm B, Bentdal EH et al. Effects of different rinsing regimen on totally implantable vascular access after 70 days infusion of total parental nutrition in vitro. JPEN J Parenter Enteral Nutr 1987; 11: 566– 8. 3 Johnston DA, Walker K, Richards J et al. Ethanol flush for the prevention of catheter occlusion. Clin Nutr 1992; 11: 97 –100. 4 Werlin SA, Lausten T, Jessen S et al. Treatment of central venous catheter occlusions with ethanol and hydrochloric acid. JPEN J Parenter Enteral Nutr 1995; 19: 416– 8. 5 Maiefski M, Rupp ME, Hermsen ED. Ethanol lock technique: review of the literature. Infect Control Hosp Epidemiol 2009; 30: 1096– 108. 6 Oliveira C, Nasr A, Brindle M et al. Ethanol locks to prevent catheter-related bloodstream infections in parenteral nutrition: a meta-analysis. Pediatrics 2012; 129: 318– 29.
8 of 9
22 Schilcher G, Schneditz D, Ribitsch W et al. Loss of antimicrobial effect of trisodium citrate due to ‘lock’ spillage from haemodialysis catheters. Nephrol Dial Transplant 2014; 29: 914– 9. 23 Yokoyama H, Aoyama T, Matsuyama T et al. The cause of polyurethane catheter cracking during constant infusion of etoposide (VP-16) injections. Yakugaku Zasshi 1998; 118: 581–8. 24 Yokoyama H, Aoyama T, Nakajima K et al. Investigation of the cause of polyurethane catheter cracking during constant infusion of etoposide (VP-16) injection (2)-analysis of ethanol eluting materials from catheter. Yakugaku Zasshi 2003; 123: 799–803. 25 Msakni N, Galmier MJ, Couret MJ et al. Complementary mass spectrometric approaches and scanning electron microscopy to study the structural stability of polyurethane tunneled dialysis catheters after exposure to ethanol solutions. Rapid Commun Mass Spectrom 2013; 27: 2343– 54.
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
agent such as citrate to ethanol lock solutions may reduce intraluminal thrombus formation but the impact on plasma precipitation is less clear. (3) Large, prospective, randomized trials are needed to assess the safety (i.e. signs and symptoms of ethanol toxicity and hepatotoxicity) and efficacy of ethanol lock solutions in various patient populations, with catheters approved by manufacturers in terms of the safety of ethanol lock use, which are inserted in different anatomical sites that are associated with variable degrees of seepage of lock solution into the bloodstream. (4) The release of material from the catheter increases with increasing ethanol concentration and duration of exposure25,26 and plasma protein precipitation after exposure to ethanol is also concentration dependent. As such, if an ethanol lock is used, the shortest dwell time and lowest concentration needed to eradicate microbes in biofilm may reduce the risk of seepage and systemic toxicity, plasma precipitation and altered catheter integrity.
Systematic review
26 Guenu S, Heng AE, Charbonne´ F et al. Mass spectrometry and scanning electron microscopy study of silicone tunneled dialysis catheter integrity after an exposure of 15 days to 60% ethanol solution. Rapid Commun Mass Spectrom 2007; 21: 229–36. 27 Crinch CJ, Halfmann JA, Crone WC et al. The effects of prolonged ethanol exposure on the mechanical properties of polyurethane and silicone catheters used for intravascular access. Infect Control Hosp Epidemiol 2005; 26: 708–14. 28 Bell AL, Jayaraman R, Vercaigne LM. Effect of ethanol/trisodium citrate lock on the mechanical properties of carbothane hemodialysis catheters. Clin Nephrol 2006; 65: 342–8. 29 Dannenberg C, Bierbach U, Rothe A et al. Ethanol-lock technique in the treatment of bloodstream infections in pediatric oncology patients with broviac catheter. J Pediatr Hematol Oncol 2003; 25: 616– 21.
31 Opilla MT, Kirby DF, Edmond MB. Use of ethanol lock therapy to reduce the incidence of catheter-related bloodstream infections in home parenteral nutrition patients. JPEN J Parenter Enteral Nutr 2007; 31: 302– 5. 32 Sanders J, Pithie A, Ganly P et al. A prospective double-blind randomized trial comparing intraluminal ethanol with heparinized saline for the prevention of catheter-associated bloodstream infection in immunosuppressed haematology patients. J Antimicrob Chemother 2008; 62: 809–15. 33 Broom J, Woods M, Allworth A et al. Ethanol lock therapy to treat tunnelled central venous catheter-associated blood stream infections: results from a prospective trial. Scand J Infect Dis 2008; 40: 399– 406. 34 Mouw E, Chessman K, Lesher A et al. Use of ethanol lock to prevent catheter-related infections in children with short bowel syndrome. J Pediatr Surg 2008; 43: 1025– 9. 35 Slobbe L, Doorduijn JK, Lugtenburg PJ et al. Prevention of catheter-related bacteremia with a daily ethanol lock in patients with tunnelled catheters: a randomized, placebo-controlled trial. PLoS One 2010; 5: e10840. 36 Kayton ML, Garmey EG, Ishill NM et al. Preliminary results of a phase I trial of prophylactic ethanol-lock administration to prevent mediport catheter-related bloodstream infections. J Pediatr Surg 2010; 45: 1961– 6. 37 Cober MP, Kovacevich DS, Teitelbaum DH. Ethanol-lock therapy for the prevention of central venous access device infections in pediatric
patients with intestinal failure. JPEN J Parenter Enteral Nutr 2011; 35: 67 –73. 38 McGrath EJ, Salloum R, Chen X et al. Short-dwell ethanol lock therapy in children is associated with increased clearance of central line-associated bloodstream infections. Clin Pediatr (Phila) 2011; 50: 943–51. 39 Valentine KM. Ethanol lock therapy for catheter-associated blood stream infections in a pediatric intensive care unit. Pediatr Crit Care Med 2011; 12: e292– 6. 40 Wales PW, Kosar C, Carricato M et al. Ethanol lock therapy to reduce the incidence of catheter-related bloodstream infections in home parenteral nutrition patients with intestinal failure: preliminary experience. J Pediatr Surg 2011; 46: 951– 6. 41 Heng AE, Abdelkader MH, Diaconita M et al. Impact of short term use of interdialytic 60% ethanol lock solution on tunneled silicone catheter dysfunction. Clin Nephrol 2011; 75: 534– 41. 42 Broom JK, Krishnasamy R, Hawley CM et al. A randomised controlled trial of Heparin versus EthAnol Lock THerapY for the prevention of Catheter Associated infecTion in Haemodialysis patients—the HEALTHY-CATH trial. BMC Nephrol 2012; 13: 146. 43 John BK, Khan MA, Speerhas R et al. Ethanol lock therapy in reducing catheter-related bloodstream infections in adult home parenteral nutrition patients: results of a retrospective study. JPEN J Parenter Enteral Nutr 2012; 36: 603– 10. 44 Pieroni KP, Nespor C, Ng M et al. Evaluation of ethanol lock therapy in pediatric patients on long-term parenteral nutrition. Nutr Clin Pract 2013; 28: 226– 31. 45 Rajpurkar M, McGrath E, Joyce J et al. Therapeutic and prophylactic ethanol lock therapy in patients with bleeding disorders. Haemophilia 2014; 20: 52– 7. 46 Abu-El-Haija M, Schultz J, Rahhal RM. Effects of 70% ethanol locks on rates of central line infection, thrombosis, breakage and replacement in pediatric intestinal failure. J Pediatr Gastroenterol Nutr 2014; doi:10.1097/MPG.0000000000000354. 47 Pe´rez-Granda MJ, Barrio JM, Mun˜oz P et al. Ethanol lock therapy (E-lock) in the prevention of catheter-related bloodstream infections (CR-BSI) after major heart surgery (MHS): a randomized clinical trial. PLoS One 2014; 9: e91838. 48 McHugh GJ, Wild DJ, Havill JH. Polyurethane central venous catheters, hydrochloric acid and 70% ethanol: a safety evaluation. Anaesth Intensive Care 1997; 25: 350–3.
9 of 9
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
30 Laird J, Soutar R, Butcher I. Complications of the ethanol-lock technique in the treatment of central venous catheter sepsis. J Infect 2005; 51: 338.
JAC
J Antimicrob Chemother doi:10.1093/jac/dku182
Adverse effects associated with ethanol catheter lock solutions: a systematic review Leonard A. Mermel1,2* and Neha Alang3 1
Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA; 2Division of Infectious Diseases, Rhode Island Hospital, Providence, RI, USA; 3Department of Medicine, Newport Hospital, Newport, RI, USA
Received 26 February 2014; returned 14 April 2014; revised 28 April 2014; accepted 1 May 2014 Background: Antimicrobial lock therapy has been widely utilized internationally for the prevention and management of intravascular catheter-related bloodstream infections. One of the agents commonly utilized for lock therapy is ethanol. However, a systematic review of adverse events associated with ethanol locks has not been published. Methods: PubMed was searched to collect articles published from May 2003 through March 2014. The bibliographies of relevant articles were also reviewed. Results: In vitro studies of the mechanical properties of catheters after ethanol immersion have revealed changes predominantly in polyurethane catheters and to a lesser extent silicone and Carbothane, catheters. An elution of polymers from polyurethane and Carbothane catheters has been observed at the ethanol concentrations used in ethanol lock therapy. Ethanol above a concentration of 28% leads to plasma protein precipitation. Ethanol locks were associated with catheter occlusion in 11 studies and independently increased the risk of thrombosis compared with heparin lock in a randomized trial. Six studies noted abnormalities in catheter integrity, including one case leading to catheter embolization. Of note, five of these studies involved silicone catheters. Ethanol lock use was associated with systemic side effects in 10 studies and possible side effects in one additional study. Four studies noted liver function test abnormalities, predominantly transaminase elevation, related to ethanol lock use. However, a prospective study did not find any difference in the risk of doubling the transaminase level above the normal range during use of ethanol locks compared with not using an ethanol lock. Conclusions: The use of ethanol locks has been associated with structural changes in catheters, as well as the elution of molecules from the catheter polymers. Clinical studies have revealed systemic toxicity, increased catheter occlusion and breaches in catheter integrity. Keywords: antimicrobial lock therapy, intravascular device infections, alcohol toxicity
Introduction Intravascular catheters have been flushed or locked with ethanol for various purposes over the last 25 years. Ethanol has been utilized to dissolve intraluminal obstruction caused by waxy lipid deposits associated with the administration of total parenteral nutrition.1 – 4 More recently, ethanol lock solutions have been used predominantly for the prevention and occasionally for the management of catheter-related infection, as noted in recent reviews5 – 8 and case series.9 Despite the enthusiasm for the use of ethanol lock solutions in various patient populations, as evidenced by the numerous publications cited in these reviews, few prospective, randomized trials exist that have thoroughly assessed their efficacy and safety. As such, most clinicians are unaware of the safety profile of ethanol lock solutions and the
effect of ethanol on proteins in plasma or erythrocytes in whole blood, on biofilms formed by various microbial pathogens, on catheter integrity and on the elution of catheter material after exposure to ethanol. Ethanol modifies the deformability and fluidity of erythrocytes in a dose-dependent fashion, which can increase risk of haemolysis.10,11 Ethanol is also known to precipitate plasma proteins in a dose-dependent fashion.12,13 Some in vitro studies suggest that ethanol can eradiate various bacteria within biofilms, with variable efficacy, depending on the ethanol concentration and the exposure time.14,15 However, other investigators have found that increasing concentrations of ethanol from 20% to 100%, particularly ethanol concentrations of 40% or more, correlate with increasing biofilm formation of Staphylococcus aureus.16 Additionally, exposure of S. aureus to ethanol increases the expression of antibiotic
# The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]
1 of 9
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
*Corresponding author. Division of Infectious Diseases, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA. Tel: +1-401-444-2608; Fax: +1-401-444-8154; E-mail: [email protected]
Systematic review
Methods PubMed was searched to collect articles available online published May 2003 through March 2014, as well as relevant articles from bibliographies to determine whether patients receiving ethanol catheter lock solutions had untoward effects potentially caused by ethanol lock solutions, and the available peer-reviewed literature regarding the effect of ethanol on intravascular catheter integrity. Search terms included ethanol lock technique, ethanol lock therapy, adverse effects of ethanol lock therapy, intravascular catheter occlusion/thrombosis, catheter-related infection and ethanol, catheter disruption and ethanol, leakage repair and ethanol, interaction of ethanol with other substances, systemic effects of alcohol lock, catheter-related infection and ethanol, and bloodstream infection, prevention and treatment and ethanol. Only peer-reviewed articles were assessed. Clinical studies were included in this analysis if it could be determined that the side effects of ethanol lock use had been assessed, and if so whether any patients had had an adverse reaction. In vitro studies were included if the methodology for assessing the interactions between the ethanol and the catheters had been noted.
Results Using PubMed, the above-noted search terms identified 402 articles. Eight in vitro studies and 20 clinical studies met our inclusion criteria. The in vitro studies on the impact of ethanol lock solutions on catheter integrity are summarized in Table S1 (available as Supplementary data at JAC Online). Studies utilizing scanning electron microscopy to assess the catheter surface after ethanol immersion have noted micro-cracks or degeneration of the internal wall of polyurethane catheters,23,24 but the concentration of ethanol used in some of these studies was greater than the concentration used in ethanol lock solutions. Time-dependent abnormalities of the inner surface of the catheter have been noted for Carbothane catheters, made of polycarbonate-based
2 of 9
aliphatic and aromatic polyurethanes,25 but no such changes have been noted with silicone catheters.26 Some studies have assessed the mechanical properties of catheters after ethanol immersion. One such study found that polyurethane, but not silicone, catheters showed an increased wall thickness after ethanol exposure, with a reduced modulus of elasticity for polyurethane and silicone catheters, but no significant change in the force at break, maximum stress at break or maximum segment elongation and strain immediately prior to break with either catheter type.27 The immersion of Carbothane catheters in ethanol led to a significantly reduced force at break, a shorter elongation at break and an increased catheter weight but no significant change in the modulus of elasticity.28 A number of studies have assessed the elution of various molecules from the catheters during immersion in ethanol. An elution of condensed polymers of 1,4-butanediol from polyurethane catheters has been noted.24 An elution of polydimethylsiloxanes from silicone catheters was noted after immersion in 95%, but not 60%, ethanol.26 A time-dependent elution of predominantly the polycarbonate diol component has been observed with Carbothane catheters.25 In sum, scanning electron microscopy studies have noted changes in Carbothane catheters at the ethanol concentrations used in ethanol lock solutions, but not in silicone catheters after exposure to ethanol. Changes in the mechanical properties of polyurethane and Carbothane catheters have been observed after ethanol exposure, but less so with silicone catheters. An elution of polymers has been observed from polyurethane and Carbothane catheters but not from silicone catheters at the ethanol concentrations commonly used in ethanol locks. Ethanol solutions above a concentration of 28% as a lock solution caused protein precipitation in plasma samples during the in vitro simulation of various catheter insertion positions.20 Of note, the precipitate cannot be redissolved by dilution with urokinase or alteplase. Studies revealing a systemic effect of ethanol lock use or an adverse impact on lumen patency or catheter integrity are summarized in Table 1. In 10 studies,29,31 – 35,42 – 44,47 patients demonstrated systemic symptoms likely to be related to ethanol lock use, with possibly the same noted in an additional study.36 The ethanol lock was flushed in five of these studies29,31,35,43,47 and aspirated in five studies,32,33,36,42,44 and no procedure was specified in one study.34 In the one prospective, randomized trial, the incidence of such symptoms was significantly greater in the ethanol lock group.35 In three studies29,36,38 and possibly an additional one,39 transaminase levels above baseline and/or greater than those seen in individuals not receiving ethanol locks was observed. Three of these four studies29,38,39 involved flushing of the ethanol lock. One prospective study assessed for a doubling in transaminase levels above the normal range and found no difference in patients receiving an ethanol lock compared with those receiving a lock solution not containing ethanol.47 Eleven studies19,30,34,36 – 38,40 – 42,45,46 noted problems with catheter occlusion. In seven of these studies the lock was aspirated,19,30,36,37,41,42,46 in three it was flushed38,40,45 and in one study no procedure was specified.34 In one prospective study this was significantly more common when an ethanol lock was used as opposed to a lock solution not containing ethanol.41 In one study, an ethanol lock independently increased the risk of thrombosis compared with a heparin lock (OR 10.5, 95% CI 1.2–91.3).46 Six studies34 – 37,42,46 noted a breach in catheter integrity with ethanol lock use. The ethanol lock was aspirated, flushed or not specified in four studies,36,37,42,46 one study35 and one study,34 respectively. Of note, five of these
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
resistance factors, as seen with the up-regulation of antibiotic efflux pumps.16 Low concentrations of ethanol have also been shown to enhance the biofilm formation of Staphylococcus epidermidis.17 Ethanol lock solutions have the potential for causing disulfiram reactions in patients receiving metronidazole.18 Ethanol may also interact with other medications instilled through the catheter after the use of ethanol lock solutions.7 Finally, ethanol has no anticoagulant properties and may induce coagulation by protein denaturation.19 The contents of catheter lock solutions leak into the bloodstream due to the parabolic flow distribution inside the catheter during injection and to a greater extent because of gravityinduced discharge from the distal end of the catheter because of differences in fluid density between the catheter lock solution and the blood.20 Leakage of lock solutions into the systemic circulation due to gravity varies depending on body position.21,22 As the lock solution is discharged from the distal end of the catheter, blood enters the catheter lumen, allowing plasma proteins to interact with the ethanol lock solution.20 Thus, the ethanol concentration within the lumen may vary, with a gradient of higher to lower concentration from the proximal to the distal end of the catheter, as has been demonstrated with antibiotic lock solutions.21 We set out to assess in vitro studies and clinical studies of ethanol lock solutions with the specific intent of assessing and shedding light on the risk of systemic side effects and the impact on the catheter material and intraluminal contents.
Systematic review
Table 1. Clinical studies of ethanol lock solutions with adverse events noted
Cited study Publication year Retrospective or prospective study
Ethanol lock % Ethanol volume aspirated or flushed at end of dwell time Flushed with saline after ethanol lock
Study population (patients receiving ethanol lock)
Dannenberg et al.29 2003 Retrospective
74% ethanola 2.3 mL flushed not specified
Laird et al.30 2005 Retrospective
100% ethanola 3 adults 3 mL aspirated yes 25%–70% ethanol (v/v) 9 adults 3 mL flushed yes
Opilla et al.31 2007 Retrospective
Sanders et al.32 70% ethanol (v/v) 2008 3 mL Prospective, randomized aspirated yes 70% ethanola Broom et al.33 2008 2 mL Prospective aspirated not specified 70% ethanola Mouw et al.34 2008 0.5– 2 mL Retrospective not specified not specified
18 (aged 2 –14 years)
Ethanol lock dwell time Duration of ethanol lock use Catheter type 20– 24 h 3 days Broviac silicone CVC
24 h duration unspecified catheter type and polymer unspecified 2 –4 h, 2 –7 days per week 6 –22 months Silicone Hickman CVC or PICC
34 adults
2 h daily up to 30 days silicone CVC
17 patients (aged 14 –73 years)
4 h daily 5 days Hickman CVC in 16 patients; Portacath in 1 patient 4 –14 h daily up to 36 months silicone CVC
10 children (average age¼7.6 months; range ¼3– 27 months)
Adverse effects tiredness, headaches, dizziness, nausea, lightheadedness; increase in aspartate aminotransferase or alanine aminotransferase or gamma-glutamyl transferase in 12 of 18 patients in ethanol lock group compared with 6 of 28 patients not receiving ethanol lock (P¼0.005) catheter occlusion and precipitated material noted in catheter lumens of all 3 patients
70% ethanol lock was changed to 25% ethanol lock in 2 patients due to nausea and dizziness but this did not reduce symptoms 6 patients felt lightheaded and ‘high’ for several seconds when saline flush used after ethanol lock dwell was complete 2 patients complained they tasted a ‘shot of vodka’ 1 episode of dyspnoea after first ethanol lock instillation
ethanol taste reported by 1 patient
1 patient had catheter-related thrombus after 630 days of ethanol lock 2 episodes of culture-negative disseminated intravascular coagulation 1 catheter removed due to ‘loss of line integrity thought to be caused by other factors’
3 of 9
JAC
Continued
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
Systematic review
Cited study Publication year Retrospective or prospective study
Ethanol lock % Ethanol volume aspirated or flushed at end of dwell time Flushed with saline after ethanol lock
Slobbe et al.35 70% ethanola 2010 3 mL Prospective, randomized flushed yes
Study population (patients receiving ethanol lock) 226 adults
Ethanol lock dwell time Duration of ethanol lock use Catheter type 15 min daily mean¼63 days (range¼2 – 486 days) silicone Hickman CVC
Kayton et al.36 2010 Prospective
70% ethanol (v/v) 12 children catheter lumen volume aspirated yes
Overnight ≤6 months silicone Portacath
Cober et al.37 2010 Retrospective
15 children 70% ethanol (v/v) catheter lumen volume plus 0.1– 0.2 mL aspirated yes
at least 2 h daily mean¼263 days (23 –652 days) silicone CVC
Adverse effects 1 catheter removed because of rupture of a catheter lumen 1 patient had syncope after initial but not subsequent flush of the ethanol lock in this blinded, placebo-controlled trial more ethanol lock patients discontinued lock therapy (P¼0.006) or continued with a frequency-adjusted regimen (P¼0.002) than the placebo group in the ethanol lock group there was more facial flushing (P, 0.001), altered taste (P¼0.04) and feeling of dizziness or drowsiness (P,0.001) morning blood alcohol level averaged 11 mg/dL (range¼0 – 80 mg/dL) 3 of 12 catheters had occluded lumens requiring device removal; all had dense thrombus in reservoir or catheter lumen 1 of 3 above-noted catheters also fractured, with central catheter embolization one patient’s urticaria worsened, ascribed to another medication transient rise in hepatic transaminases or alkaline phosphatase in 10 of 12 patients (hepatotoxicity: grade 1 in 7 children, grade 2 in 1 child, grade 3 in 2 children) abdominal pain (n¼4), vomiting (n¼4), sneezing (n¼4), slurred speech (n¼3), sleepiness (n¼3), change in personality (n ¼2) and pain on inspiration (n ¼1) all ascribed to another medication this study was discontinued early 20 occurrences in 7 patients of catheter leakage or disruption of one or both layers of silastic tubing requiring catheter repair deep vein thrombosis in 1 patient involving extremity of CVC insertion difficulty withdrawing ethanol lock in 3 patients from the CVC thrombolytic administration to ‘clear the line’ in some cases catheter repair for leak or disruption 6.4+10 events/1000 catheter days when ethanol lock used vs 3.1+5.2 events/ 1000 catheter days when not used (P¼0.2)
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
4 of 9
Table 1. Continued
70% ethanol (v/v) mean 0.5 mL (0.3 – 1.0 mL) flushed yes
59 patients (aged 2 months to 19 years)
Valentine39 2011 Retrospective
70% ethanola not specified flushed yes
20 patients (average age¼6 months, range ¼77 days-20 years)
Wales et al.40 2011 Not specified
70% ethanola 10 children (median 1 –3 mL age¼10 months, flushed range ¼31–129 months) no 60% ethanol (v/v) 30 adults catheter lumen volume aspirated yes
Heng et al.41 2011 Prospective (sequential use of ethanol or ‘standard’ lock)
Wong et al.19 2011 Not specified
70% ethanol (v/v) 4 children catheter lumen volume aspirated yes
4 to 25 h 1 –4 doses over ≤3 days Broviac silicone CVC (n ¼29), Portacath (n¼19), PICC (n ¼15), tunnelled/ powerline PICC (n¼12), Hickman CVC (n¼3), pheresis CVC (n¼1), haemodialysis CVC (n¼1), catheter type unspecified (n ¼1) PICC and Portacath predominantly polyurethane mean dwell time¼17 h (range¼4 – 48 h) daily 1 –5 days Broviac silicone catheters, mediports, PICCs, non-tunnelled CVCs ≥4 h daily mean¼227+64 days silicone tunnelled CVC and PICC (polymer unspecified) average¼44 h (between dialysis sessions) 6 weeks silicone dialysis CVC
catheter malfunction in 5 of 13 CVCs 2 of the 80 (3%) episodes post-ethanol lock therapy had transient difficulty with saline flush, both eventually resolved with one requiring tissue plasminogen activator infusion 12 of 48 reversible episodes of transaminase elevation after ethanol lock use
Systematic review
McGrath et al.38 2011 Retrospective
2 of 16 patients had mild transaminitis but ‘not different from their baseline levels’
catheter thrombosis in 2 patients CVC felt ‘sluggish’ at end of ethanol lock dwell period in 2 patients
5 of 9
Continued
JAC
transient increase in rate of catheter dysfunction [complete catheter occlusion or need to ‘reverse lines’ or difficulty withdrawing or instilling fluid into the catheter increased from 2.2% before ethanol lock use to 13.3% when it was used (P,0.001); complete catheter occlusion requiring fibrinolytic agent use or catheter exchange in 4 of 180 dialysis sessions during ethanol lock period vs 1 of 357 dialysis sessions when it was not used (P¼0.05)] Child 1 and 2: dwell time 12 h visible thrombosis in Child 1 visible thrombosis in Child 2 between nights on CVC occlusion in Child 3 (patent without thrombolytic after hyperalimentation discontinued ethanol lock use) Child 3 and 4: 2 – 12 h per day 3 visible thrombosis in Child 4 times a week Child 1: 413 days Child 2: 168 days, co-administered warfarin Child 3: 3 days; co-administered warfarin Child 4: 9 days; co-administered warfarin Broviac silicone CVC
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
Systematic review
6 of 9 Table 1. Continued
Cited study Publication year Retrospective or prospective study
Ethanol lock % Ethanol volume aspirated or flushed at end of dwell time Flushed with saline after ethanol lock
Study population (patients receiving ethanol lock)
Ethanol lock dwell time Duration of ethanol lock use Catheter type
Adverse effects
Broom et al.42 70% ethanol (v/v) 2012 3 mL Prospective, randomized aspirated not specified
25 adults
48 h, once weekly duration unknown tunnelled dialysis CVC (polymer not specified)
John et al.43 2012 Retrospective
31 adults
12 h, 4 –7 days per week duration unspecified tunnelled silicone CVC
14 patients (mean age¼4.3 years; IQR¼0.4– 19.1 years)
2 h per week 1 patient had facial flushing and irritability while receiving average¼690 days 1 mL of ethanol lock; side effects resolved when lock silicone catheters (Broviac, 12; volume reduced to 0.8 mL Hickman, 1; Portacath, 1) 24 h once weekly 2 patients with Mediport catheters had complete catheter duration unspecified occlusion after 15 months and 2 months, respectively 11 Mediport catheters, 2 Broviac catheters Daily for at least 4 h 0 and 23 line repair events when catheters were locked with 691 catheter days heparin or ethanol, respectively (0 and 6.3 events/1000 (range¼198– 782 days) catheter days, respectively). Median line age at tunnelled silicone CVC repair¼42 days (IQR¼111 days). Line size increase from 2.7 Fr to 9.6 Fr independently reduced risk of line repair (OR 0.13, 95% CI 0.03 – 0.58) 1 and 12 patients receiving heparin versus ethanol locks had thrombotic events requiring tissue plasminogen activator use, respectively (0.46 and 3.27/1000 catheter days, respectively). Median line age at time of thrombosis was 80 days (IQR ¼141 days). Ethanol lock increased risk of thrombosis by logistic regression analysis (OR 10.5, 95% CI 1.2–91.3)
Rajpurkar et al.45 2014 Retrospective Abu-El-Haija et al.46 2014 Retrospective
6 children
7 children (aged 1 day to 24 months)
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
Pieroni et al.44 2013 Retrospective
70% ethanol (v/v) 3 mL flushed no 70% ethanol (v/v) 1 –2 mL aspirated yes 70% ethanola catheter lumen volume flushed yes 70% ethanola catheter lumen volume aspirated yes
5 of 25 required catheter removal due to flow problems (compared with 3 of 24 in heparin group) 1 patient’s catheter ‘split’ 1 patient complained of stinging at the exit site after ethanol lock administered 1 patient complained of dry lips and thirst alcohol taste in 21 of 31 patients (68%) after ethanol lock flushed
JAC
Systematic review
CVC, central venous catheter; PICC, peripherally inserted central venous catheter. a Ethanol in % g or % v/v not specified.
Pe´rez-Granda et al.47 70% ethanola 2014 1 mL Prospective, randomized flushed yes
Discussion Although ethanol lock solutions demonstrate efficacy when used in a prophylactic fashion and for the management of catheterrelated bloodstream infection,5 – 9 untoward effects have been noted by several investigators. The incidence of systemic side effects, breaches in the integrity of the catheter or catheter obstruction due to ethanol lock use may be underappreciated since most articles in the published literature are retrospective and these details may have been missed by clinicians at the time or during retrospective chart review, or may have been observed and otherwise explained or not documented. In the four prospective, randomized trials32,35,42,47 severe adverse events occurred only in the ethanol lock group,35,47 rupture or splitting of the catheter was seen only in the ethanol group35,42 and a significant difference in early discontinuation of the randomized lock use occurred only in the ethanol group.35,47 In the one prospective trial alternating ethanol and standard lock use,41 there was a significantly greater incidence of both catheter dysfunction and complete catheter occlusion when an ethanol lock was used. What is clear from the published literature is that systemic symptoms may be observed with ethanol locks of various concentrations whether or not they have been aspirated after the dwell time or flushed, the former due to inexorable seepage from the distal aspect of the catheter. In some studies, such seepage has also been associated with elevation of transaminase levels. An increased incidence of catheter occlusion has been noted in several studies correlating with in vitro studies of plasma precipitation in catheter lumens from blood that has filled the intraluminal void after seepage of the lock solution. This may also reflect the fact that ethanol is not an anticoagulant. Finally, breaches in catheter integrity have been noted in several clinical studies, in some cases with embolization of the catheter36 despite the minimal changes in the mechanical properties of silicone catheters noted in in vitro studies. Based on the available literature, we have the following recommendations regarding ethanol lock solution: (1) All manufacturers should rigorously assess the effect of various concentrations of ethanol lock solutions on catheter integrity and polymer elution to guide the use of such solutions in the clinical setting. Ethanol locks should only be used in catheters approved for such use by manufacturers. (2) Consensus recommendations should be made regarding the optimal ethanol concentration, the minimal dwell time for efficacy and catheter compatibility, and the recommendations should note whether additional ingredients are necessary to minimize intraluminal obstruction and inhibition rather than the stimulation of biofilm formation. At the present time an ethanol lock should be used with great caution and only in catheters that are manufacturer-approved for use with ethanol locks, and the lock solution should be aspirated rather than flushed after the dwell time is complete, as well as with close observation for symptoms and monitoring for laboratory evidence of alcohol toxicity. Adding an additional
7 of 9
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
113 adults (mean age¼67.3 years, 2 h every 3 days standard deviation¼13.1 years) median ¼6 days (IQR¼4 – 8 days) CVC or Swan– Ganz catheter
early discontinuation of lock solution occurred in 7 of 113 patients and 0 of 87 patients with ethanol and non-ethanol lock solution, respectively (P¼0.02). Severe immediate events occurred in 2 of 113 and 0 of 87 such patients (P¼0.2), catheter lumen rupture in 1 of 113 and 0 of 87 such patients (P¼0.4) and doubling of aspartate aminotransferase or alanine aminotransferase occurred in 42 and 33 such patients (0.9).
studies34 – 37,46 specified the catheter material and in each case a silicone catheter was used. In one study increasing the catheter size from 2.7 Fr to 9.6 Fr independently reduced the risk of line repair (OR 0.13, 95% CI 0.03–0.58).46
Systematic review
Acknowledgements
7 Wolf J, Shenep JL, Clifford V et al. Ethanol lock therapy in pediatric hematology and oncology. Pediatr Blood Cancer 2013; 60: 18 –25. 8 Tan M, Lau J, Guglielmo BJ. Ethanol locks in the prevention and treatment of catheter-related bloodstream infections. Ann Pharmacother 2014; 48: 607–15. 9 Kubiak DW, Gilmore ET, Buckley MW et al. Adjunctive management of central line-associated bloodstream infections with 70% ethanol-lock therapy. J Antimicrob Chemother 2014; 69: 1665– 8. 10 Chi LM, Wu WG. Mechanism of hemolysis of red blood cell mediated by ethanol. Biochim Biophys Acta 1991; 1062: 46–50. 11 Sonmez M, Ince HY, Yalcin O et al. The effect of alcohols on red blood cell mechanical properties and membrane fluidity depends on their molecular size. PLoS One 2013; 8: e76579. 12 Cohn EJ, Hughes WL, Weare JH. Preparation and properties of serum and plasma proteins; crystallization of serum albumins from ethanol water mixtures. J Am Chem Soc 1947; 69: 1753 –61. 13 Blackwood RA, Klein KC, Micel LN et al. Ethanol locks therapy for resolution of fungal catheter infections. Pediatr Infect Dis J 2011; 30: 1105– 7. 14 Balestrino D, Souweine B, Charbonnel N et al. Eradication of microorganisms embedded in biofilm by an ethanol-based catheter lock solution. Nephrol Dial Transplant 2009; 24: 3204– 9.
We thank Tomimo Komura with Japanese translation of two articles.
15 Peters BM, Ward RM, Rane HS et al. Efficacy of ethanol against Candida albicans and Staphylococcus aureus polymicrobial biofilms. Antimicrob Agents Chemother 2013; 57: 74– 82.
Funding
16 Redelman CV, Maduakolam C, Anderson GG. Alcohol treatment enhances Staphylococcus aureus biofilm development. Immunol Med Microbiol 2012; 66: 411–8.
This study was supported by internal funding.
Transparency declarations L. A. M.’s potential conflicts of interest since 2011 include serving as a consultant for or receiving research funding from 3M, Cormedix, ICU Medical, Catheter Connections, Marvao, Fresenius, Bard, Teleflex, CareFusion and Semprus. N. A. has no conflicts of interest to report.
Supplementary data
17 Milisavljevic V, Tran LP, Batmalle C et al. Benzyl alcohol and ethanol can enhance the pathogenic potential of clinical Staphylococcus epidermidis strains. Am J Infect Control 2008; 36: 552– 8. 18 Jones BA, Hull MA, Richardson DS et al. Efficacy of ethanol locks in reducing central venous catheter infections in pediatric patients with intestinal failure. J Pediatr Surg 2010; 45: 1287 –93. 19 Wong T, Clifford V, McCallum Z et al. Central venous catheter thrombosis associated with 70% ethanol locks in pediatric intestinal failure patients on home parenteral nutrition: a case series. JPEN J Parenter Enteral Nutr 2012; 36: 358–60.
Table S1 is available as Supplementary data at JAC Online (http://jac. oxfordjournals.org/).
20 Schilcher G, Schlagenhauf A, Schneditz D et al. Ethanol causes protein precipitation—new safety issues for catheter locking techniques. PLoS One 2013; 8: e84869.
References
21 Soriano A, Bregada E, Marques JM et al. Decreasing gradient of antibiotic concentration in the lumen of catheters locked with vancomycin. Eur J Clin Microbiol Infect Dis 2007; 26: 659– 61.
1 Pennington CR, Pithie AD. Ethanol lock in the management of catheter occlusion. JPEN J Parenter Enteral Nutr 1987; 11: 507– 8. 2 Klem W, Pharm B, Bentdal EH et al. Effects of different rinsing regimen on totally implantable vascular access after 70 days infusion of total parental nutrition in vitro. JPEN J Parenter Enteral Nutr 1987; 11: 566– 8. 3 Johnston DA, Walker K, Richards J et al. Ethanol flush for the prevention of catheter occlusion. Clin Nutr 1992; 11: 97 –100. 4 Werlin SA, Lausten T, Jessen S et al. Treatment of central venous catheter occlusions with ethanol and hydrochloric acid. JPEN J Parenter Enteral Nutr 1995; 19: 416– 8. 5 Maiefski M, Rupp ME, Hermsen ED. Ethanol lock technique: review of the literature. Infect Control Hosp Epidemiol 2009; 30: 1096– 108. 6 Oliveira C, Nasr A, Brindle M et al. Ethanol locks to prevent catheter-related bloodstream infections in parenteral nutrition: a meta-analysis. Pediatrics 2012; 129: 318– 29.
8 of 9
22 Schilcher G, Schneditz D, Ribitsch W et al. Loss of antimicrobial effect of trisodium citrate due to ‘lock’ spillage from haemodialysis catheters. Nephrol Dial Transplant 2014; 29: 914– 9. 23 Yokoyama H, Aoyama T, Matsuyama T et al. The cause of polyurethane catheter cracking during constant infusion of etoposide (VP-16) injections. Yakugaku Zasshi 1998; 118: 581–8. 24 Yokoyama H, Aoyama T, Nakajima K et al. Investigation of the cause of polyurethane catheter cracking during constant infusion of etoposide (VP-16) injection (2)-analysis of ethanol eluting materials from catheter. Yakugaku Zasshi 2003; 123: 799–803. 25 Msakni N, Galmier MJ, Couret MJ et al. Complementary mass spectrometric approaches and scanning electron microscopy to study the structural stability of polyurethane tunneled dialysis catheters after exposure to ethanol solutions. Rapid Commun Mass Spectrom 2013; 27: 2343– 54.
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
agent such as citrate to ethanol lock solutions may reduce intraluminal thrombus formation but the impact on plasma precipitation is less clear. (3) Large, prospective, randomized trials are needed to assess the safety (i.e. signs and symptoms of ethanol toxicity and hepatotoxicity) and efficacy of ethanol lock solutions in various patient populations, with catheters approved by manufacturers in terms of the safety of ethanol lock use, which are inserted in different anatomical sites that are associated with variable degrees of seepage of lock solution into the bloodstream. (4) The release of material from the catheter increases with increasing ethanol concentration and duration of exposure25,26 and plasma protein precipitation after exposure to ethanol is also concentration dependent. As such, if an ethanol lock is used, the shortest dwell time and lowest concentration needed to eradicate microbes in biofilm may reduce the risk of seepage and systemic toxicity, plasma precipitation and altered catheter integrity.
Systematic review
26 Guenu S, Heng AE, Charbonne´ F et al. Mass spectrometry and scanning electron microscopy study of silicone tunneled dialysis catheter integrity after an exposure of 15 days to 60% ethanol solution. Rapid Commun Mass Spectrom 2007; 21: 229–36. 27 Crinch CJ, Halfmann JA, Crone WC et al. The effects of prolonged ethanol exposure on the mechanical properties of polyurethane and silicone catheters used for intravascular access. Infect Control Hosp Epidemiol 2005; 26: 708–14. 28 Bell AL, Jayaraman R, Vercaigne LM. Effect of ethanol/trisodium citrate lock on the mechanical properties of carbothane hemodialysis catheters. Clin Nephrol 2006; 65: 342–8. 29 Dannenberg C, Bierbach U, Rothe A et al. Ethanol-lock technique in the treatment of bloodstream infections in pediatric oncology patients with broviac catheter. J Pediatr Hematol Oncol 2003; 25: 616– 21.
31 Opilla MT, Kirby DF, Edmond MB. Use of ethanol lock therapy to reduce the incidence of catheter-related bloodstream infections in home parenteral nutrition patients. JPEN J Parenter Enteral Nutr 2007; 31: 302– 5. 32 Sanders J, Pithie A, Ganly P et al. A prospective double-blind randomized trial comparing intraluminal ethanol with heparinized saline for the prevention of catheter-associated bloodstream infection in immunosuppressed haematology patients. J Antimicrob Chemother 2008; 62: 809–15. 33 Broom J, Woods M, Allworth A et al. Ethanol lock therapy to treat tunnelled central venous catheter-associated blood stream infections: results from a prospective trial. Scand J Infect Dis 2008; 40: 399– 406. 34 Mouw E, Chessman K, Lesher A et al. Use of ethanol lock to prevent catheter-related infections in children with short bowel syndrome. J Pediatr Surg 2008; 43: 1025– 9. 35 Slobbe L, Doorduijn JK, Lugtenburg PJ et al. Prevention of catheter-related bacteremia with a daily ethanol lock in patients with tunnelled catheters: a randomized, placebo-controlled trial. PLoS One 2010; 5: e10840. 36 Kayton ML, Garmey EG, Ishill NM et al. Preliminary results of a phase I trial of prophylactic ethanol-lock administration to prevent mediport catheter-related bloodstream infections. J Pediatr Surg 2010; 45: 1961– 6. 37 Cober MP, Kovacevich DS, Teitelbaum DH. Ethanol-lock therapy for the prevention of central venous access device infections in pediatric
patients with intestinal failure. JPEN J Parenter Enteral Nutr 2011; 35: 67 –73. 38 McGrath EJ, Salloum R, Chen X et al. Short-dwell ethanol lock therapy in children is associated with increased clearance of central line-associated bloodstream infections. Clin Pediatr (Phila) 2011; 50: 943–51. 39 Valentine KM. Ethanol lock therapy for catheter-associated blood stream infections in a pediatric intensive care unit. Pediatr Crit Care Med 2011; 12: e292– 6. 40 Wales PW, Kosar C, Carricato M et al. Ethanol lock therapy to reduce the incidence of catheter-related bloodstream infections in home parenteral nutrition patients with intestinal failure: preliminary experience. J Pediatr Surg 2011; 46: 951– 6. 41 Heng AE, Abdelkader MH, Diaconita M et al. Impact of short term use of interdialytic 60% ethanol lock solution on tunneled silicone catheter dysfunction. Clin Nephrol 2011; 75: 534– 41. 42 Broom JK, Krishnasamy R, Hawley CM et al. A randomised controlled trial of Heparin versus EthAnol Lock THerapY for the prevention of Catheter Associated infecTion in Haemodialysis patients—the HEALTHY-CATH trial. BMC Nephrol 2012; 13: 146. 43 John BK, Khan MA, Speerhas R et al. Ethanol lock therapy in reducing catheter-related bloodstream infections in adult home parenteral nutrition patients: results of a retrospective study. JPEN J Parenter Enteral Nutr 2012; 36: 603– 10. 44 Pieroni KP, Nespor C, Ng M et al. Evaluation of ethanol lock therapy in pediatric patients on long-term parenteral nutrition. Nutr Clin Pract 2013; 28: 226– 31. 45 Rajpurkar M, McGrath E, Joyce J et al. Therapeutic and prophylactic ethanol lock therapy in patients with bleeding disorders. Haemophilia 2014; 20: 52– 7. 46 Abu-El-Haija M, Schultz J, Rahhal RM. Effects of 70% ethanol locks on rates of central line infection, thrombosis, breakage and replacement in pediatric intestinal failure. J Pediatr Gastroenterol Nutr 2014; doi:10.1097/MPG.0000000000000354. 47 Pe´rez-Granda MJ, Barrio JM, Mun˜oz P et al. Ethanol lock therapy (E-lock) in the prevention of catheter-related bloodstream infections (CR-BSI) after major heart surgery (MHS): a randomized clinical trial. PLoS One 2014; 9: e91838. 48 McHugh GJ, Wild DJ, Havill JH. Polyurethane central venous catheters, hydrochloric acid and 70% ethanol: a safety evaluation. Anaesth Intensive Care 1997; 25: 350–3.
9 of 9
Downloaded from http://jac.oxfordjournals.org/ at Georgetown University on September 8, 2014
30 Laird J, Soutar R, Butcher I. Complications of the ethanol-lock technique in the treatment of central venous catheter sepsis. J Infect 2005; 51: 338.
JAC
