Articles
Treatment and secondary prophylaxis with ethanol lock therapy for central line-associated bloodstream infection in paediatric cancer: a randomised, double-blind, controlled trial

https://doi.org/10.1016/S1473-3099(18)30224-XGet rights and content

Summary

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.

Introduction

Children undergoing cancer treatment or haemopoietic stem-cell transplantation often require long-term central venous catheters (CVCs) for blood collection and administration of chemotherapy, fluids, or other drugs. Although CVCs are indispensable to cancer care, central line-associated bloodstream infection (CLABSI) can be life threatening. About 25% of paediatric patients with cancer in high-income countries experience at least one episode of CLABSI. Such episodes require prolonged antibiotic therapy, a median hospital stay of 12 days, and, in the USA, they incur median attributable costs of US$69 332.1, 2 CLABSI also increases the risk of other CVC-related complications, including occlusion and venous thrombosis, and patients with CLABSI often require their catheter to be removed (37–46% of cases) or intensive care for sepsis (10–19% of cases), with a mortality rate of about 2%.2

Conservative treatment of CLABSI with antibiotics alone (ie, without CVC removal) is common.3, 4 CVC replacement reduces the risk of persistent infection or relapse, but replacement procedures are invasive and increase the risk of a new CLABSI.3, 4 The overall risk of treatment failure, consisting of persistent infection, relapse of infection, and development of a new CLABSI, is at least 33%.4, 5 Relapse of infection is more common in patients with totally implantable ports, whereas new infections are more common in those with external CVCs.5 Treatment failure might be attributable to biofilms on the luminal surface of the CVC, which are resistant to systemic antibiotic therapy and to clearance by the immune system.2, 6

Research in context

Evidence before this study

We searched PubMed for studies published between inception and Sept 21, 2017 with the terms central venous catheter* AND infection* AND ethanol OR alcohol. We reviewed all reports that described the use of single-agent ethanol as lock therapy to treat or prevent central line-associated bloodstream infection (CLABSI) in any human population. We identified additional relevant articles from reference lists. 28 articles described the use of ethanol lock therapy as primary prophylaxis, of which nine were controlled trials. In controlled studies, the reported efficacy of prophylaxis with ethanol lock therapy ranged from a non-significant 300% increase in treatment failure to a 91% reduction. In the only controlled trial performed in children with cancer, there was a significant 45% reduction in the risk of CLABSI. 19 articles described the use of ethanol lock therapy for treatment of CLABSI, of which one was a controlled trial performed in patients receiving haemodialysis. This controlled trial showed a significant 79% reduction in the risk of treatment failure. There was one observational study in children with cancer, which showed a non-significant 38% reduction in treatment failure. Reported adverse effects of ethanol lock therapy included infusion reactions and catheter occlusion. We found no controlled studies of the use of ethanol lock therapy as treatment and secondary prophylaxis for CLABSI.

Added value of this study

Our findings showed that treatment and secondary prophylaxis with ethanol lock therapy for CLABSI in children with cancer or haematological disorders was not effective and that such therapy increased the risk of catheter occlusion requiring thrombolytic therapy.

Implications of all the available evidence

There is no high-quality evidence to support the use of ethanol lock therapy as treatment or secondary prophylaxis for CLABSI in children with cancer or haematological disorders, and the regimen tested in this study was both ineffective and associated with adverse effects. Other populations and some subgroups might benefit from ethanol lock therapy as treatment or secondary prophylaxis for CLABSI, but it should not be used routinely in children with cancer or haematological disorders.

Adjunctive antimicrobial catheter lock therapy is thought to reduce the risk of therapeutic failure and is sometimes used for this purpose in clinical practice.2, 3, 4, 7 This technique allows an antimicrobial drug to dwell inside the CVC and improve the killing of microorganisms in biofilms.2 Ethanol lock therapy is a logical option because ethanol has excellent activity against microorganisms in biofilm,8 regardless of their antibiotic susceptibility, and primary prophylaxis with ethanol lock therapy reduces the incidence of CLABSI.2, 9 Although adjunctive ethanol lock therapy is used in clinical practice with the intent to treat CLABSI, no prospective, controlled, efficacy trials have been reported for ethanol lock therapy as treatment and secondary prophylaxis for CLABSI.2, 3, 4, 7 We did this randomised trial to determine the efficacy and tolerability of ethanol lock therapy as treatment and secondary prophylaxis for CLABSI in children and adolescents who were being treated for cancer or haematological disorders or were undergoing haemopoietic stem-cell transplantation.

Section snippets

Study design and participants

For this parallel-design, randomised, double-blind, placebo-controlled, group-sequential, superiority trial, participants were recruited between Dec 14, 2011, and Sept 12, 2016. Recruitment was done at St Jude Children's Research Hospital, which is a 69-bed paediatric oncology centre in Memphis, TN, USA, and at The Royal Children's Hospital Melbourne, a 334-bed paediatric quaternary referral centre in Melbourne, VIC, Australia. The Melbourne site was added in October, 2013, as a protocol

Results

Of the 749 participants assessed, 95 were enrolled between Dec 14, 2011, and Sept 12, 2016 (figure 1). At the second interim analysis, the stopping boundary for futility was met, so enrolment was stopped. 49 patients were assigned to the ethanol lock therapy group and 46 to the placebo group. One participant withdrew consent after randomisation but before receiving lock therapy and was not included in any of the analyses. One participant was still receiving study intervention at the time the

Discussion

This randomised, double-blind, superiority trial is the first prospective controlled trial of ethanol lock therapy as treatment and secondary prophylaxis for CLABSI. Routine addition of ethanol lock therapy to standard care did not reduce the risk of treatment failure but did increase the risk of CVC occlusion requiring thrombolytic therapy.

Our study has several strengths related to the trial design and implementation. Stratified randomisation reduced important baseline differences between

References (31)

  • J Wolf et al.

    Central line-associated bloodstream infection in children: an update on treatment

    Pediatr Infect Dis J

    (2013)
  • PM Flynn et al.

    Catheter design influences recurrence of catheter-related bloodstream infection in children with cancer

    J Clin Oncol

    (2003)
  • RM Donlan et al.

    Biofilms: survival mechanisms of clinically relevant microorganisms

    Clin Microbiol Rev

    (2002)
  • LA Mermel et al.

    Adverse effects associated with ethanol catheter lock solutions: a systematic review

    J Antimicrob Chemother

    (2014)
  • Bloodstream infection event (central line-associated bloodstream infection and non-central line-associated bloodstream infection)

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