Katie Harron1, Quen Mok2, Kerry Dwan3, Colin H Ridyard4, Tracy Moitt3, Michael Millar5, Padmanabhan Ramnarayan2, Shane M Tibby6, Berit Muller-Pebody7, Dyfrig A Hughes4, Carrol Gamble3, Ruth E Gilbert1. 1. Institute of Child Health, University College London, London, UK. 2. Great Ormond Street Hospital, London, UK. 3. Medicines for Children Clinical Trials Unit, University of Liverpool, Liverpool, UK. 4. Centre for Health Economics and Medicines Evaluation, Bangor University, Bangor, UK. 5. Barts Health NHS Trust, London, UK. 6. Evelina London Children's Hospital, London, UK. 7. Healthcare Associated Infection and Antimicrobial Resistance (HCAI & AMR) Department, National Infection Service, Public Health England, London, UK.
Abstract
BACKGROUND:Impregnated central venous catheters (CVCs) are recommended for adults to reduce bloodstream infection (BSI) but not for children. OBJECTIVE: To determine the effectiveness of impregnated compared with standard CVCs for reducing BSI in children admitted for intensive care. DESIGN: Multicentre randomised controlled trial, cost-effectiveness analysis from a NHS perspective and a generalisability analysis and cost impact analysis. SETTING: 14 English paediatric intensive care units (PICUs) in England. PARTICIPANTS: Children aged < 16 years admitted to a PICU and expected to require a CVC for ≥ 3 days. INTERVENTIONS:Heparin-bonded, antibiotic-impregnated (rifampicin and minocycline) or standard polyurethane CVCs, allocated randomly (1 : 1 : 1). The intervention was blinded to all but inserting clinicians. MAIN OUTCOME MEASURE: Time to first BSI sampled between 48 hours after randomisation and 48 hours after CVC removal. The following data were used in the trial: trial case report forms; hospital administrative data for 6 months pre and post randomisation; and national-linked PICU audit and laboratory data. RESULTS: In total, 1859 children were randomised, of whom 501 were randomised prospectively and 1358 were randomised as an emergency; of these, 984 subsequently provided deferred consent for follow-up. Clinical effectiveness - BSIs occurred in 3.59% (18/502) of children randomised to standard CVCs, 1.44% (7/486) of children randomised to antibiotic CVCs and 3.42% (17/497) of children randomised to heparin CVCs. Primary analyses comparing impregnated (antibiotic and heparin CVCs) with standard CVCs showed no effect of impregnated CVCs [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.37 to 1.34]. Secondary analyses showed that antibiotic CVCs were superior to standard CVCs (HR 0.43, 95% CI 0.20 to 0.96) but heparin CVCs were not (HR 1.04, 95% CI 0.53 to 2.03). Time to thrombosis, mortality by 30 days and minocycline/rifampicin resistance did not differ by CVC. Cost-effectiveness - heparin CVCs were not clinically effective and therefore were not cost-effective. The incremental cost of antibiotic CVCs compared with standard CVCs over a 6-month time horizon was £1160 (95% CI -£4743 to £6962), with an incremental cost-effectiveness ratio of £54,057 per BSI avoided. There was considerable uncertainty in costs: antibiotic CVCs had a probability of 0.35 of being dominant. Based on index hospital stay costs only, antibiotic CVCs were associated with a saving of £97,543 per BSI averted. The estimated value of health-care resources associated with each BSI was £10,975 (95% CI -£2801 to £24,751). Generalisability and cost-impact - the baseline risk of BSI in 2012 for PICUs in England was 4.58 (95% CI 4.42 to 4.74) per 1000 bed-days. An estimated 232 BSIs could have been averted in 2012 using antibiotic CVCs. The additional cost of purchasing antibiotic CVCs for all children who require them (£36 per CVC) would be less than the value of resources associated with managing BSIs in PICUs with standard BSI rates of > 1.2 per 1000 CVC-days. CONCLUSIONS: The primary outcome did not differ between impregnated and standard CVCs. However, antibiotic-impregnated CVCs significantly reduced the risk of BSI compared with standard and heparin CVCs. Adoption of antibiotic-impregnated CVCs could be beneficial even for PICUs with low BSI rates, although uncertainty remains whether or not they represent value for money to the NHS. Limitations - inserting clinicians were not blinded to allocation and a lower than expected event rate meant that there was limited power for head-to-head comparisons of each type of impregnation. Future work - adoption of impregnated CVCs in PICUs should be considered and could be monitored through linkage of electronic health-care data and clinical data on CVC use with laboratory surveillance data on BSI. TRIAL REGISTRATION: ClinicalTrials.gov NCT01029717. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 18. See the NIHR Journals Library website for further project information.
RCT Entities:
BACKGROUND: Impregnated central venous catheters (CVCs) are recommended for adults to reduce bloodstream infection (BSI) but not for children. OBJECTIVE: To determine the effectiveness of impregnated compared with standard CVCs for reducing BSI in children admitted for intensive care. DESIGN: Multicentre randomised controlled trial, cost-effectiveness analysis from a NHS perspective and a generalisability analysis and cost impact analysis. SETTING: 14 English paediatric intensive care units (PICUs) in England. PARTICIPANTS: Children aged < 16 years admitted to a PICU and expected to require a CVC for ≥ 3 days. INTERVENTIONS:Heparin-bonded, antibiotic-impregnated (rifampicin and minocycline) or standard polyurethane CVCs, allocated randomly (1 : 1 : 1). The intervention was blinded to all but inserting clinicians. MAIN OUTCOME MEASURE: Time to first BSI sampled between 48 hours after randomisation and 48 hours after CVC removal. The following data were used in the trial: trial case report forms; hospital administrative data for 6 months pre and post randomisation; and national-linked PICU audit and laboratory data. RESULTS: In total, 1859 children were randomised, of whom 501 were randomised prospectively and 1358 were randomised as an emergency; of these, 984 subsequently provided deferred consent for follow-up. Clinical effectiveness - BSIs occurred in 3.59% (18/502) of children randomised to standard CVCs, 1.44% (7/486) of children randomised to antibiotic CVCs and 3.42% (17/497) of children randomised to heparin CVCs. Primary analyses comparing impregnated (antibiotic and heparin CVCs) with standard CVCs showed no effect of impregnated CVCs [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.37 to 1.34]. Secondary analyses showed that antibiotic CVCs were superior to standard CVCs (HR 0.43, 95% CI 0.20 to 0.96) but heparin CVCs were not (HR 1.04, 95% CI 0.53 to 2.03). Time to thrombosis, mortality by 30 days and minocycline/rifampicin resistance did not differ by CVC. Cost-effectiveness - heparin CVCs were not clinically effective and therefore were not cost-effective. The incremental cost of antibiotic CVCs compared with standard CVCs over a 6-month time horizon was £1160 (95% CI -£4743 to £6962), with an incremental cost-effectiveness ratio of £54,057 per BSI avoided. There was considerable uncertainty in costs: antibiotic CVCs had a probability of 0.35 of being dominant. Based on index hospital stay costs only, antibiotic CVCs were associated with a saving of £97,543 per BSI averted. The estimated value of health-care resources associated with each BSI was £10,975 (95% CI -£2801 to £24,751). Generalisability and cost-impact - the baseline risk of BSI in 2012 for PICUs in England was 4.58 (95% CI 4.42 to 4.74) per 1000 bed-days. An estimated 232 BSIs could have been averted in 2012 using antibiotic CVCs. The additional cost of purchasing antibiotic CVCs for all children who require them (£36 per CVC) would be less than the value of resources associated with managing BSIs in PICUs with standard BSI rates of > 1.2 per 1000 CVC-days. CONCLUSIONS: The primary outcome did not differ between impregnated and standard CVCs. However, antibiotic-impregnated CVCs significantly reduced the risk of BSI compared with standard and heparin CVCs. Adoption of antibiotic-impregnated CVCs could be beneficial even for PICUs with low BSI rates, although uncertainty remains whether or not they represent value for money to the NHS. Limitations - inserting clinicians were not blinded to allocation and a lower than expected event rate meant that there was limited power for head-to-head comparisons of each type of impregnation. Future work - adoption of impregnated CVCs in PICUs should be considered and could be monitored through linkage of electronic health-care data and clinical data on CVC use with laboratory surveillance data on BSI. TRIAL REGISTRATION: ClinicalTrials.gov NCT01029717. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 18. See the NIHR Journals Library website for further project information.
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