Joshua Wolf1, Tom G Connell2, Kim J Allison3, Li Tang4, Julie Richardson5, Kristen Branum3, Eloise Borello6, Jeffrey E Rubnitz7, Aditya H Gaur8, Hana Hakim3, Yin Su4, Sara M Federico9, Francoise Mechinaud10, Randall T Hayden11, Paul Monagle12, Leon J Worth13, Nigel Curtis2, Patricia M Flynn8. 1. Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia. Electronic address: joshua.wolf@stjude.org. 2. Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia; Infectious Diseases Unit, Department of General Medicine, Royal Children's Hospital Melbourne, Parkville, VIC, Australia; Murdoch Children's Research Institute, Royal Children's Hospital Melbourne, Parkville, VIC, Australia. 3. Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA. 4. Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA. 5. Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA. 6. Children's Cancer Center, Royal Children's Hospital Melbourne, Parkville, VIC, Australia. 7. Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA. 8. Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA. 9. Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA. 10. Murdoch Children's Research Institute, Royal Children's Hospital Melbourne, Parkville, VIC, Australia; Children's Cancer Center, Royal Children's Hospital Melbourne, Parkville, VIC, Australia. 11. Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA. 12. Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia; Murdoch Children's Research Institute, Royal Children's Hospital Melbourne, Parkville, VIC, Australia; Department of Clinical Haematology, Royal Children's Hospital Melbourne, Parkville, VIC, Australia. 13. Department of Infectious Diseases and Infection Prevention, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; National Centre for Infections in Cancer, National Health and Medical Research Council Centre for Research Excellence, The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Victorian Healthcare Associated Infection Surveillance System Coordinating Centre, Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
Abstract
BACKGROUND: Central line-associated bloodstream infections (CLABSIs) affect about 25% of children with cancer, and treatment failure is common. Adjunctive ethanol lock therapy might prevent treatment failure but high-quality evidence is scarce. We evaluated ethanol lock therapy as treatment and secondary prophylaxis for CLABSI in children with cancer or haematological disorders. METHODS: This randomised, double-blind, placebo-controlled superiority trial, with two interim futility and efficacy analyses (done when the first 46 and 92 evaluable participants completed study requirements), was done at two paediatric hospitals in the USA and Australia. Patients aged 6 months to 24 years, inclusive, with cancer or a haematological disorder and new CLABSI were eligible. Participants were randomly assigned (1:1) to receive either ethanol lock therapy (70% ethanol) or placebo (heparinised saline) for 2-4 h per lumen daily for 5 days (treatment phase), then for up to 3 non-consecutive days per week for 24 weeks (prophylaxis phase). The primary composite outcome was treatment failure, consisting of attributable catheter removal or death, new or persistent (>72 h) infection, or additional lock therapy during the treatment phase, and recurrent CLABSI during the prophylaxis phase. This trial is registered with ClinicalTrials.gov, number NCT01472965. FINDINGS:94 evaluable participants were enrolled between Dec 14, 2011, and Sept 12, 2016, of whom 48 receivedethanol lock therapy and 46 received placebo. The study met futility criteria at the second interim analysis. Treatment failure was similar with ethanol lock therapy (21 [44%] of 48) and placebo (20 [43%] of 46; relative risk [RR] 1·0, 95% CI 0·6-1·6; p=0·98). Some adverse events, including infusion reactions and catheter occlusion, were more frequent in the ethanol lock therapy group than in the placebo group. Catheter occlusion requiring thrombolytic therapy was more common with ethanol lock therapy (28 [58%] of 48) than with placebo (15 [33%] of 46; RR 1·8, 95% CI 1·1-2·9; p=0·012). Discontinuation of lock therapy because of adverse effects or patient request occurred in a similar proportion of participants in the ethanol lock therapy (nine [19%] of 48) and placebo groups (ten [22%] of 46; p=0·72). INTERPRETATION:Ethanol lock therapy did not prevent CLABSI treatment failure and it increased catheter occlusion. Routine ethanol lock therapy for treatment or secondary prophylaxis is not recommended in this population. FUNDING: American Lebanese Syrian Associated Charities to St Jude Children's Research Hospital and an Australian Government Research Training Scholarship.
RCT Entities:
BACKGROUND: Central line-associated bloodstream infections (CLABSIs) affect about 25% of children with cancer, and treatment failure is common. Adjunctive ethanol lock therapy might prevent treatment failure but high-quality evidence is scarce. We evaluated ethanol lock therapy as treatment and secondary prophylaxis for CLABSI in children with cancer or haematological disorders. METHODS: This randomised, double-blind, placebo-controlled superiority trial, with two interim futility and efficacy analyses (done when the first 46 and 92 evaluable participants completed study requirements), was done at two paediatric hospitals in the USA and Australia. Patients aged 6 months to 24 years, inclusive, with cancer or a haematological disorder and new CLABSI were eligible. Participants were randomly assigned (1:1) to receive either ethanol lock therapy (70% ethanol) or placebo (heparinised saline) for 2-4 h per lumen daily for 5 days (treatment phase), then for up to 3 non-consecutive days per week for 24 weeks (prophylaxis phase). The primary composite outcome was treatment failure, consisting of attributable catheter removal or death, new or persistent (>72 h) infection, or additional lock therapy during the treatment phase, and recurrent CLABSI during the prophylaxis phase. This trial is registered with ClinicalTrials.gov, number NCT01472965. FINDINGS: 94 evaluable participants were enrolled between Dec 14, 2011, and Sept 12, 2016, of whom 48 received ethanol lock therapy and 46 received placebo. The study met futility criteria at the second interim analysis. Treatment failure was similar with ethanol lock therapy (21 [44%] of 48) and placebo (20 [43%] of 46; relative risk [RR] 1·0, 95% CI 0·6-1·6; p=0·98). Some adverse events, including infusion reactions and catheter occlusion, were more frequent in the ethanol lock therapy group than in the placebo group. Catheter occlusion requiring thrombolytic therapy was more common with ethanol lock therapy (28 [58%] of 48) than with placebo (15 [33%] of 46; RR 1·8, 95% CI 1·1-2·9; p=0·012). Discontinuation of lock therapy because of adverse effects or patient request occurred in a similar proportion of participants in the ethanol lock therapy (nine [19%] of 48) and placebo groups (ten [22%] of 46; p=0·72). INTERPRETATION:Ethanol lock therapy did not prevent CLABSI treatment failure and it increased catheter occlusion. Routine ethanol lock therapy for treatment or secondary prophylaxis is not recommended in this population. FUNDING: American Lebanese Syrian Associated Charities to St Jude Children's Research Hospital and an Australian Government Research Training Scholarship.
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