Discover Portal

preterm baby in neonatal care

NIHR Signal Antimicrobial central venous catheters do not reduce infections in pre-term babies

Published on 20 June 2019

doi: 10.3310/signal-000782

Central venous catheters (CVCs) impregnated with antimicrobial agents are no better than standard CVCs for avoiding bloodstream infection in pre-term babies.

This NIHR-funded trial compared peripherally inserted CVCs that had been impregnated with a combination of the antifungal miconazole and the broad-spectrum antibiotic rifampicin, against standard non-antimicrobial-impregnated CVCs for preterm babies in intensive care. Rates of bloodstream infections were similar in both groups, and no differences in other clinical outcomes were found.

Researchers reported no evidence of clinical benefit or harm from the antimicrobial-impregnated CVCs. They noted these antimicrobial-impregnated CVCs are rarely used in the UK and are more expensive than standard alternatives.

Share your views on the research.

Why was this study needed?

Around 70% of pre-term babies born before 32 weeks of gestation need CVCs for nutrition, fluids, and medications. Bloodstream infection is the most common serious complication arising from their use and can be fatal. Infection is more common in very pre-term babies, with rates of up to 30%.

Previous small trials have suggested that adults and children may benefit from antimicrobial-impregnated CVCs, and national guidelines reflect this. However, a 2015 Cochrane review noted insufficient evidence to recommend use in newborn babies and called for a large randomised controlled trial. This study examined whether antimicrobial impregnated CVCs provided enough benefit to neonatal intensive care patients to recommend their use.

What did this study do?

PREVAIL, a randomised controlled trial, took place in 18 neonatal intensive care units around the UK. Newborn babies who required a CVC for any purpose were eligible for the trial. Researchers randomly assigned 861 babies (88% born before 32 weeks) to receive either miconazole and rifampicin-impregnated CVCs or standard CVCs.

Researchers assessed bloodstream or cerebrospinal fluid infection by microbiological testing where clinically indicated. Results were analysed on an intention-to-treat basis.

The study was designed to detect a 50% reduction in bloodstream infections, based on previous trials in adults and children. Clinicians were not blinded as rifampicin causes brown staining of CVCs.

What did it find?

  • The time from allocation to first bloodstream infection was similar in each group (hazard ratio 1.11, 95% confidence interval (CI) 0.73 to 1.67); approximately 10-11% of babies in each group developed a bloodstream infection.
  • The rates of bloodstream infection per 1,000 days with a CVC were similar in each group at 13.15 per 1,000 days with an antimicrobial-impregnated CVC and 10.87 with a standard CVC (hazard ratio 1.21, 95% CI 0.78 to 1.88).
  • There were no differences in clinical outcomes between the groups when measured at discharge, or in deaths within six months of treatment allocation.
  • There was no evidence of a difference in treatment effect for babies born before 28 week’s gestation compared with those of 28 weeks or more.
  • The median time to removal of the CVC was similar in each group, at about 8 days.

What does current guidance say on this issue?

The 2014 epic3 guidelines for preventing healthcare-associated infections in NHS hospitals in England include detailed advice on insertion, care and maintenance of CVCs. They provide general principles but do not consider care of babies less than one year old. The guidelines recommend the use of antimicrobial-impregnated CVCs in adults under specific circumstances.

The 2018 revision of the British Association of Perinatal Medicine guidelines on the use of CVCs in neonates does not mention antimicrobial-impregnated CVCs.

What are the implications?

The trial does not support the use of antimicrobial-impregnated CVCs to prevent bloodstream infection for babies in neonatal intensive care.

The authors note that sick pre-term babies are at risk of infection from multiple sources due to invasive procedures and devices, high gut permeability, and immature immune systems. Many of the infections seen in this study may not have been directly related to the CVC, and research is required into alternative approaches for preventing infection.

A linked editorial asks whether CVCs impregnated with other antimicrobials should now be tested. However, they note that a single intervention, such as antimicrobial impregnation of CVCs, may not demonstrate significant benefit now that infection control strategies in intensive care units have already greatly reduced infection rates.

Citation and Funding

Gilbert R, Brown M, Rainford N et al. Antimicrobial-impregnated central venous catheters for prevention of neonatal bloodstream infection (PREVAIL): an open-label, parallel-group, pragmatic, randomised controlled trial. Lancet Child Adolesc Health. 2019;3(6):381-90.

 The study was funded by the NIHR Health Technology Assessment programme (project number 12/167/02).

Bibliography

British Association of Perinatal Medicine. Use of central venous catheters in neonates: a framework for practice. London: British Association of Perinatal Medicine; revised 2018.

Khatami A and Isaacs D. Antibiotic-impregnated central venous catheters in the neonatal intensive care unit—PREVAILing questions. Lancet Child Adolesc Health. 2019;3(6):366-7.

Loveday HP, Wilson J, Pratt RJ et al. epic3: national evidence-based guidelines for preventing healthcare-associated infections in NHS hospitals in England. J Hosp Infect. 2014;86(suppl 1):S1-70.

Why was this study needed?

Around 70% of pre-term babies born before 32 weeks of gestation need CVCs for nutrition, fluids, and medications. Bloodstream infection is the most common serious complication arising from their use and can be fatal. Infection is more common in very pre-term babies, with rates of up to 30%.

Previous small trials have suggested that adults and children may benefit from antimicrobial-impregnated CVCs, and national guidelines reflect this. However, a 2015 Cochrane review noted insufficient evidence to recommend use in newborn babies and called for a large randomised controlled trial. This study examined whether antimicrobial impregnated CVCs provided enough benefit to neonatal intensive care patients to recommend their use.

What did this study do?

PREVAIL, a randomised controlled trial, took place in 18 neonatal intensive care units around the UK. Newborn babies who required a CVC for any purpose were eligible for the trial. Researchers randomly assigned 861 babies (88% born before 32 weeks) to receive either miconazole and rifampicin-impregnated CVCs or standard CVCs.

Researchers assessed bloodstream or cerebrospinal fluid infection by microbiological testing where clinically indicated. Results were analysed on an intention-to-treat basis.

The study was designed to detect a 50% reduction in bloodstream infections, based on previous trials in adults and children. Clinicians were not blinded as rifampicin causes brown staining of CVCs.

What did it find?

  • The time from allocation to first bloodstream infection was similar in each group (hazard ratio 1.11, 95% confidence interval (CI) 0.73 to 1.67); approximately 10-11% of babies in each group developed a bloodstream infection.
  • The rates of bloodstream infection per 1,000 days with a CVC were similar in each group at 13.15 per 1,000 days with an antimicrobial-impregnated CVC and 10.87 with a standard CVC (hazard ratio 1.21, 95% CI 0.78 to 1.88).
  • There were no differences in clinical outcomes between the groups when measured at discharge, or in deaths within six months of treatment allocation.
  • There was no evidence of a difference in treatment effect for babies born before 28 week’s gestation compared with those of 28 weeks or more.
  • The median time to removal of the CVC was similar in each group, at about 8 days.

What does current guidance say on this issue?

The 2014 epic3 guidelines for preventing healthcare-associated infections in NHS hospitals in England include detailed advice on insertion, care and maintenance of CVCs. They provide general principles but do not consider care of babies less than one year old. The guidelines recommend the use of antimicrobial-impregnated CVCs in adults under specific circumstances.

The 2018 revision of the British Association of Perinatal Medicine guidelines on the use of CVCs in neonates does not mention antimicrobial-impregnated CVCs.

What are the implications?

The trial does not support the use of antimicrobial-impregnated CVCs to prevent bloodstream infection for babies in neonatal intensive care.

The authors note that sick pre-term babies are at risk of infection from multiple sources due to invasive procedures and devices, high gut permeability, and immature immune systems. Many of the infections seen in this study may not have been directly related to the CVC, and research is required into alternative approaches for preventing infection.

A linked editorial asks whether CVCs impregnated with other antimicrobials should now be tested. However, they note that a single intervention, such as antimicrobial impregnation of CVCs, may not demonstrate significant benefit now that infection control strategies in intensive care units have already greatly reduced infection rates.

Citation and Funding

Gilbert R, Brown M, Rainford N et al. Antimicrobial-impregnated central venous catheters for prevention of neonatal bloodstream infection (PREVAIL): an open-label, parallel-group, pragmatic, randomised controlled trial. Lancet Child Adolesc Health. 2019;3(6):381-90.

 The study was funded by the NIHR Health Technology Assessment programme (project number 12/167/02).

Bibliography

British Association of Perinatal Medicine. Use of central venous catheters in neonates: a framework for practice. London: British Association of Perinatal Medicine; revised 2018.

Khatami A and Isaacs D. Antibiotic-impregnated central venous catheters in the neonatal intensive care unit—PREVAILing questions. Lancet Child Adolesc Health. 2019;3(6):366-7.

Loveday HP, Wilson J, Pratt RJ et al. epic3: national evidence-based guidelines for preventing healthcare-associated infections in NHS hospitals in England. J Hosp Infect. 2014;86(suppl 1):S1-70.

Antimicrobial-impregnated central venous catheters for prevention of neonatal bloodstream infection (PREVAIL):an open-label, parallel-group, pragmatic, randomisedcontrolled trial

Published on 27 April 2019

Ruth Gilbert, Michaela Brown, Naomi Rainford, Chloe Donohue, Caroline Fraser, Ajay Sinha, Jon Dorling, Jim Gray, William McGuire, Carrol Gamble, Sam J Oddie,

The Lancet Child & Adolescent Health , 2019

Background Bloodstream infection is associated with high mortality and serious morbidity in preterm babies. Evidence from clinical trials shows that antimicrobial-impregnated central venous catheters (CVCs) reduce catheter-related bloodstream infection in adults and children receiving intensive care, but there is a paucity of similar evidence for babies receiving neonatal intensive care. Methods This open-label, parallel-group, pragmatic, randomised controlled trial was done in 18 neonatal intensive care units in England. Newborn babies who needed a peripherally inserted CVC (PICC) were allocated randomly (1:1) to receive either a PICC impregnated with miconazole and rifampicin or a standard (non-antimicrobial-impregnated) PICC. Random allocation was done with a web-based program, which was centrally controlled to ensure allocation concealment. Randomisation sequences were computer-generated in random blocks of two and four, and stratified by site. Masking of clinicians to PICC allocation was impractical because rifampicin caused brown staining of the antimicrobial-impregnated PICC. However, participant inclusion in analyses and occurrence of outcome events were determined following an analysis plan that was specified before individuals saw the unblinded data. The primary outcome was the time from random allocation to first microbiologically confirmed bloodstream or cerebrospinal fluid (CSF) infection between 24 h after randomisation and 48 h after PICC removal or death. We analysed outcome data according to the intention-to-treat principle. We excluded babies for whom a PICC was not inserted from safety analyses, as these analyses were done with groups defined by the PICC used. This trial is registered with ISRCTN, number 81931394. Findings Between Aug 12, 2015, and Jan 11, 2017, we randomly assigned 861 babies (754 [88%] born before 32 weeks of gestation) to receive an antimicrobial-impregnated PICC (430 babies) or standard PICC (431 babies). The median time to PICC removal was 8·20 days (IQR 4·77–12·13) in the antimicrobial-impregnated PICC group versus 7·86 days (5·00–12·53) days in the standard PICC group (hazard ratio [HR] 1·03, 95% CI 0·89–1·18, p=0·73), with 46 (11%) of 430 babies versus 44 (10%) of 431 babies having a microbiologically confirmed bloodstream or CSF infection. The time from random allocation to first bloodstream or CSF infection was similar between the two groups (HR 1·11, 95% CI 0·73–1·67, p=0·63). Secondary outcomes relating to infection, rifampicin resistance in positive blood or CSF cultures, mortality, clinical outcomes at neonatal unit discharge, and time to PICC removal were similar between the two groups, although rifampicin resistance in positive cultures of PICC tips was higher in the antimicrobial-impregnated PICC group (relative risk 3·51, 95% CI 1·16–10·57, p=0·018). 60 adverse events were reported from 49 (13%) patients in the antimicrobial-impregnated PICC group and 50 events from 45 (10%) babies in the standard PICC group. Interpretation We found no evidence of benefit or harm associated with miconazole and rifampicin-impregnated PICCs compared with standard PICCs for newborn babies. Future research should focus on other types of antimicrobial impregnation of PICCs and alternative approaches for preventing infection. Funding UK National Institute for Health Research Health Technology Assessment programme.

Expert commentary

Blood-borne infection is a common complication in preterm babies, on occasions causing death or long-term harm. Central venous catheter insertion for delivery of intravenous nutrition is a known risk factor for blood-borne infection. In addition, some babies who require intravenous nutrition are not receiving breast milk so are at additional risk of infection.

This large study found neither benefit nor harm arising from the use of a catheter impregnated with two specific microbial agents. Cost analysis was not performed.

This indicates that there is no recommendation to use this particular product. However, it is important that there is continued study of alternatives which may be better matched to the organisms most commonly causing neonatal infection.

Dr Jane Hawdon, Consultant Neonatologist, Royal Free London NHS Foundation Trust

The commentator declares previously working in the same department as one of the study authors