# A new perfusion system to reduce the burden of central-venous-line-associated bloodstream infections in neonates

J. C. Picaud, S. Faton, P. Pradat, B. Pastor-Diez, A. Martelin, Xavier

Armoiry, S. Hays

► To cite this version:

J. C. Picaud, S. Faton, P. Pradat, B. Pastor-Diez, A. Martelin, et al.. A new perfusion system to reduce the burden of central-venous-line-associated bloodstream infections in neonates. Journal of Hospital Infection, 2024, 143, pp.203-212. 10.1016/j.jhin.2023.10.004. hal-04672922

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# A new perfusion system to reduce the burden of central-venous-line-associated bloodstream infections in neonates

J.C. Picaud<sup>a, b, *</sup>, S. Faton<sup>a</sup>, P. Pradat<sup>c</sup>, B. Pastor-Diez<sup>a</sup>, A. Martelin<sup>d</sup>, X. Armoiry<sup>e, f</sup>, S. Hays<sup>a</sup>

## ARTICLE INFO

**Article history:**
Received 25 July 2023
Accepted 8 October 2023
Available online 17 October 2023

**Keywords:**
Late-onset sepsis
Catheter-related infections
CLABSI
Nosocomial infection

<figure><img src="image_4.png" /></figure>

## SUMMARY

**Background:** Central-venous-line-associated bloodstream infection (CLABSI) is a significant cause of morbidity and mortality in preterm infants. As there is large variation in the reported effect of multi-modal preventive strategies, it could be relevant to propose new additional strategies.

**Aim:** To assess the impact of a new perfusion system on CLABSI rate.

**Methods:** A before-and-after study was performed in infants born at <32 weeks of gestation or with birth weight <1500 g who required a multi-perfusion system connected to a central venous line. In the first 12-month period ('before'), the pre-existing perfusion system (multiple stopcocks) was used. An intervention period then occurred with implementation of a new perfusion closed system, without change in 'bundles' related to various aspects of central line care. During the second 12-month period ('after'), the CLABSI rate was assessed and compared with the pre-intervention period.

**Findings:** In total, 313 infants were included in this study (before: N=163; after: N=150), and 46% had birth weight <1000 g. The change in perfusion system resulted in a significant decrease in CLABSI rate from 11.3 to 2.2 per 1000 catheter-days (*P*<0.001). The period was independently associated with an 88% reduction in the risk of CLABSI after implementation of the new perfusion system [odds ratio (OR) 0.12, 95% confidence interval (CI) 0.03–0.39; *P*<0.001]. The duration of central line use was also associated with CLABSIs (for each additional day: OR 1.05, 95% CI 1.02–1.07; *P*<0.001).

**Conclusions:** Implementation of the new perfusion system was feasible in a large neonatal unit, and reduced the CLABSI rate soon after implementation.

© 2023 The Authors. Published by Elsevier Ltd on behalf of The Healthcare Infection Society. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)).

<footnote><sup>a</sup>Service de néonatologie, Hôpital universitaire de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France</footnote>

<footnote><sup>b</sup>Laboratoire CarMen, INSERM, INRA, Claude Bernard University Lyon 1, Pierre-Bénite, France</footnote>

<footnote><sup>c</sup>Centre de recherche clinique, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France</footnote>

<footnote><sup>d</sup>Pharmacie, Hôpital de la Croix-Rousse, Lyon, France</footnote>

<footnote><sup>e</sup>University of Lyon, School of Pharmacy/UMR CNRS 5510 MATEIS/Edouard Herriot Hospital, Pharmacy Department, Lyon, France</footnote>

<footnote><sup>f</sup>University of Warwick, Warwick Medical School, Coventry, UK</footnote>

<footnote>* Corresponding author. Address: Neonatal Intensive Care Unit, Hôpital de la Croix-Rousse, 103 Grande rue de la Croix-Rousse, 69004 Lyon, France. Tel.: +33472001550.</footnote>

<footnote>E-mail address: jean-charles.picaud@chu-lyon.fr (J.C. Picaud).</footnote>
# Introduction

Preterm newborns are highly susceptible to late-onset sepsis (LOS; i.e. occurring after the third day of life) due to an immature immune system, poor skin integrity and the need for invasive procedures [1,2]. In very preterm infants, born at <32 weeks of gestation, LOS is associated with increased mortality, short- and long-term morbidity, and healthcare costs [3,4]. In this population, most cases of LOS are related to central-venous-line-associated bloodstream infections (CLABSIs) [5,6]. For instance, Zipursky et al. reported that 72% of 3306 very-low-birthweight infants with hospital-acquired infections, hospitalized in 30 Canadian tertiary care units, had CLABSIs [5]; and Sinha et al. reported that, in 218 very-low-birthweight infants with LOS, 206 of 311 LOS episodes (66%) were related to CLABSIs [6]. A reduction in the CLABSI rate in preterm infants could therefore help to reduce antibiotic exposure in this population. Data from 25 studies included in two systematic reviews performed to assess the effectiveness of strategies to prevent CLABSIs in neonatal units show that the baseline CLABSI rate in neonates is extremely variable, ranging from 1.33 to 31.6/1000 catheter-days worldwide, with significant geographical differences [7,8]. Indeed, it ranged from 1.33 to 15.6/1000 catheter-days in the 13 studies performed in North America, and from 3.1 to 31.6/1000 catheter-days for the 12 studies performed in other countries (Europe, Australia, Asia, South America) [7,8]; in France, the last national survey reported 12.4/1000 catheter-days [95% confidence interval (CI) 10.8–14.0] [9]. The incidence and severity of CLABSIs underscore the need for innovative and effective prevention strategies.

Major risk factors for LOS are low birth weight, pre-term birth, and presence of a central venous catheter [1,2,10,11]. Catheter hub colonization, exit site colonization and connections/disconnections are major risk factors independently associated with catheter-related bloodstream infections [12,13]. In addition, the type of catheter used affects catheter-related bloodstream infections; in a review of 15 studies comparing single- and (mainly) triple-lumen catheters in adults with perfusion systems available in the 1980s, multi-lumen central venous catheters were associated with a slightly higher risk of infection compared with single-lumen catheters, but there was no significant difference when low-quality studies were excluded [14].

It is of note that CLABSI prevention strategies usually focus on catheter insertion and maintenance, and access to central venous lines [7,8]. However, intravenous administration of drugs and nutrition solutions requires a perfusion system between the catheter and the administration circuit (bags or syringes, and tubes). This perfusion system can be a ramp of stopcocks or perfusion sets with various tubing configurations; more recently, a new closed perfusion system was designed to reduce physical incompatibility during simultaneous administration of drugs in neonates [15–17]. As this is a closed system requiring fewer manipulations (fewer connections/disconnections, purging system, lifetime of 21 days), and is manipulated remotely from the patient, this perfusion system may have a beneficial effect on CLABSIs. As such, the objective of this study was to evaluate the effect of using the new

perfusion system on the incidence of CLABSIs in preterm infants.

# Methods

## Study design

This was a single-centre, before-and-after study.

## Population

This study was conducted in the 50-bed tertiary neonatal intensive care unit (NICU) of Croix-Rousse University Hospital (Lyon, France). Each year, approximately 650 infants are admitted to this unit, including 240–260 infants born at <32 weeks of gestation, and 90–100 infants with birth weight <1000 g. Infants born at <32 weeks of gestation or with birth weight <1500 g who survived for >3 days and required a multi-perfusion system connected to a central venous line (see below) were included in the present study. Infants were admitted either before (1st December 2018 to 30th November 2019) or after (1st January 2020 to 31st December 2020) implementation of the new perfusion system. In December 2019, the new system was implemented in infants who were already hospitalized, and then in newly hospitalized infants, so that, from 1st January 2020, all infants requiring a multi-perfusion system were equipped with the new system. Data collection was performed in infants admitted from 1st January 2020.

## Indications for central line

The need for central line placement or continuation was assessed daily during multi-disciplinary rounds. All infants born at <32 weeks of gestation or with birth weight <1200 g, as well as those with severe respiratory distress or haemodynamic failure, received an umbilical central line during the first 3–5 days of life. Next, a peripherally inserted central line was inserted when the duration of intravenous therapy was likely to exceed 6 days. The central catheter was removed as soon as it was no longer needed. Removal was considered when enteral feeding was ≥100 mL/kg/day. No blood products were administered through the peripherally inserted central lines.

## Perfusion systems used

Simultaneous infusion of several drugs and parenteral nutrition solution requires a central venous catheter and a perfusion system that connects the catheter to the infusion fluid or drug. Before implementation of the new perfusion system, a standard perfusion system based on three-way stopcocks (Cair, Lissieu, France) was used. Stopcocks were changed every 7 days, or earlier if broken. The stopcocks and hubs were disinfected for 30 s using gauze impregnated with 4% chlorhexidine immediately before and after each manipulation, and wrapped in sterile small drape dressing. The intervention was the implementation of the new perfusion system. The Edelwaiss Multiline NEO including an Escape-Line (Doran International, Toussieu, France) was used during the
<figure><img src="image_5.png" /><figcaption>**Figure 1.** Perfusion systems. (a) Schematic representation of the set-up of the new infusion device Edelwaiss Multiline NEO including an Escape-Line (Doran International, Toussieu, France). (b) Set-up of the new infusion device at bedside. (c) Schematic representation of the standard perfusion system (multiple three-way taps). (d) Schematic representation of the new perfusion system (eight separate lumens enclosed in a single 90-cm-long tube). The solution or drug with the highest flow is connected to the high-flow (HF) lumen to prevent incompatibility between drugs or solutions administered in the four other lumens connected to ports 1–4. It is a closed system, accessed from outside the incubator, except for the short emergency line. The Escape-Line avoids the delay between the application of the product and its administration to the newborn by purging the previous product into a bin bag.</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>**Figure 1.** (continued).</figcaption></figure>

second period (Figure 1). This is a closed system allowing the administration of eight medications or nutrition solution simultaneously without mixing to prevent physical incompatibility and precipitate formation [17]. Eight ports are connected to eight separate lumens enclosed in a single 90-cm-long tube. Seven ports are accessible outside the incubator, which reduces the need for intervention on the central line close to the insertion site inside the incubator and therefore in a warm and humid atmosphere [18]. One port – the high-flow port – is central, connected to the central lumen, and is used to administer the solution with the highest flow, which is often parenteral nutrition solution. Four other ports, numbered 1–4, are connected to four lumens. There are also two annex ports that are connected to two tubes close to the multi-lumen tube upstream of the three-way stopcock. The last port is the emergency port, allowing administration as close as possible to the patient. The Edelwaiss Multiline NEO is connected directly to the single lumen of the venous catheter through a Luer-lock connection. The Escape-Line is connected to a bin bag to purge products, and therefore avoids opening the system and also avoids delay between the application of a product and its administration to the patient. According to the manufacturer, the perfusion system is validated for a 21-day period (European Community marking), which may reduce the number of perfusion system changes, and therefore the number of manipulations of the central venous line [12,13]. A first version of this multi-lumen perfusion system was planned to be evaluated in a

prospective study registered in 2015 (ClinicalTrials.gov, NCT02633124) [19], but the study was stopped in 2020 for technical reasons related to product availability. Since then, a modified version has been manufactured, including the addition of an Escape-line and two supplementary ports, allowing the administration of eight medications simultaneously, to better correspond to the needs of drug administration in the most severely ill neonates (Figure 1).

The same central line insertion and maintenance procedures were used before and after implementation of the new perfusion system (Table S1, see online supplementary material). These concerned hand hygiene, barrier precautions, skin antisepsis, dressing assessment and change, replacement of administration sets, and catheter hub disinfection.

Training sessions are mandatory before using the new perfusion system, according to the manufacturer's recommendations. These sessions were organized for all members of the team likely to use the new perfusion system (nurses and neonatologists).

## Data collected

Characteristics of infants at birth and at discharge, neonatal morbidities and treatment (insulin, vancomycin and systemic postnatal steroids) during hospitalization were collected from electronic medical files (ICCA; Philips, Suresnes, France). Infants were considered to be inborn when they were born at a
tertiary care centre. Data were collected about moderate or
severe bronchopulmonary dysplasia (BPD; ventilatory support
or oxygen therapy at 36 weeks), patent ductus arteriosus (PDA),
grade ≥3 intraventricular haemorrhage (IVH), periventricular
leukomalacia (PVL), stage ≥2 retinopathy of prematurity (ROP)
and grade ≥2 necrotizing enterocolitis (NEC). Severe morbidity
was defined as the presence of at least one of the following:
surgical PDA, stage ≥2 ROP, grade ≥2 NEC, moderate or severe
BPD, grade ≥3 IVH or PVL. Anthropometric data were collected
at birth and at 36 weeks or discharge, whichever came first. Z-
scores were calculated, with infants considered to be small for
gestational age when the z-score for body weight was ≤-1.28
(10th percentile equivalent) [20].

The number of LOS cases was noted, with LOS defined as infection occurring after the third day of life. The main outcome measure was the CLABSI rate, expressed as the number of infections/1000 catheter-days. CLABSI was defined as a laboratory-confirmed bloodstream infection (see below), not related to an infection from another site, which developed 48 h after placement of a central line or within 48 h of its removal [21]. When a skin commensal was identified, infection was confirmed when the micro-organism grew in two blood cultures; and when only one blood culture was positive, infection was confirmed only when at least one of the following criteria were present: C-reactive protein >10 mg/L, bacterial growth <15 h, another sterile site with identical antimicrobial susceptibility pattern of each isolate, and clinical signs suggestive of infection together with positive laboratory results not related to an infection at another site [22,23]. CLABSI was diagnosed by two senior neonatologists based on these criteria. There was no change in antibiotic treatment guidelines between the two periods.

For each central venous catheter insertion, the type of
catheter (umbilical or peripherally inserted) used and duration
of use were noted to calculate the number of catheter-days (i.e.
number of days with a central line). The catheter utilization
ratio was calculated by dividing the number of catheter-days
by the number of patient-days for the total study population.

Diagnosis of bloodstream infection

In infants with suspected infection, two blood cultures were obtained. The minimum volume for a blood culture inoculated in each (aerobic and anaerobic) bottle was 1 mL (Bac/Alert; bioMérieux, Marcy l'Etoile, France). Blood cultures were incubated in a continuous detection automaton (Bactalert Virtuo; bioMérieux) for 5 days. When it revealed bacterial or fungal growth, subculture was performed on adapted plates followed by identification by matrix-assisted laser-desorption and ionization time-of-flight mass spectrometry (Vitek MS; bioMérieux), and antibiotic susceptibility testing was performed using a Vitek 2 instrument or disc diffusion method, according to the recommendations of the Committee on Anti-biogram of the French Society of Microbiology/European Committee on Antimicrobial Susceptibility Testing.

Safety

Since 2012, care-related adverse events have been col-
lected prospectively through an online system (ENNOV Soft-
ware, Ennov, Paris, France) at the study centre. Each file
completed by any health professional is reviewed and analysed

by the risk management team (senior attending and senior
nurses) who propose corrective action if needed, and provide
half-yearly reports to the team. Adverse events specifically
related to the perfusion system during the study period were
extracted from these reports from the following two catego-
ries: mild events (i.e. procedure not followed, broken device
without any effect for the patient, etc.); and severe events
(i.e. events requiring immediate medical intervention, such as
involuntary drug bolus with clinical effect). The number of
central line losses due to obstruction was also noted.

Statistical analysis

Categorical variables have been described in terms of number and percentage, and continuous variables in terms of median and interquartile range (IQR). For categorical variables, comparisons between groups were performed using Chi-squared test or Fisher's exact test, as appropriate. For continuous variables, comparisons between groups were performed using Student's t-test for normally distributed data and a sample size >30 in each group, or the non-parametric Mann-Whitney U-test otherwise. Normality was tested using the Shapiro-Wilk test.

Univariate and multi-variable logistic regression analyses were carried out in order to identify factors potentially associated with CLABSIs. Variables with *P*<0.05 on univariate analysis or known or suspected to be associated with the endpoint were included in the multi-variable analysis. Results of this analysis are expressed as odds ratios (OR) and 95% CI. Multi-collinearity was assessed by calculating the variance inflation factor (VIF). *P*<0.05 was considered to indicate significance. All analyses were performed using R Version 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria).

Ethical approval

The study was approved by the Hospices Civils de Lyon Ethics
Committee (n°21_658) and registered on [ClinicalTrials.gov](https://ClinicalTrials.gov). (NCT05058534).

Results

Among 1294 infants admitted between 1st December 2018 and 31st December 2020, 313 were eligible and all were included; 163 received the standard perfusion system (before) and 150 received the new perfusion system (after; Figure 2).

Characteristics of infants were not significantly different
before and after implementation of the new perfusion system,
except a significantly higher number of infants were treated by
vancomycin before implementation compared with after
implementation (Table I). Nearly half (45.4%) of the infants had
birth weight <1000 g, and this did not differ significantly
between the two periods (48.5% vs 42.1%; *P*=0.33); the vast
majority of infants were exposed to antenatal steroids [92.6%
(before: 91.4%; after: 94.0%); *P*=0.53] and were inborn [81.5%
(before: 79.8%; after: 83.3%); *P*=0.42]. No infants were trans-
ferred from another hospital with a central line already *in situ*.

There was no significant difference in central venous line
use between the two periods (Table II). Twenty-six adverse
events were observed: 10 before and 16 after implementation
of the new perfusion system. All 16 cases after implementation
of the new perfusion system were mild events, while two of 10
<figure><img src="image_7.png" /><figcaption>**Figure 2.** Flow diagram of 322 neonates included in the study and the number of infants with different insertion sites for central venous lines. P1, before implementation of new perfusion system; P2, after implementation of new perfusion system.</figcaption></figure>

cases were severe (hypoglycaemia, hypertension) before implementation of the new perfusion system. Obstruction of the central venous line occurred in 2.5% (4/163) infants before implementation of the new perfusion system and 1.3% (2/150) infants after implementation of the new perfusion system (P=0.69).

The number of infants with CLABSIs decreased between the two periods (before: N=23; after: N=5). There was a significant reduction in the CLABSI rate between the two periods (before: 11.3/1000 catheter-days, 95% CI 7.3–16.5; after: 2.2/1000 catheter-days, 95% CI 0.8–4.7; P<0.001; Figure 3). Most CLABSIs were related to coagulase-negative staphylococci, and there was no significant difference between the two periods (Table III). The number of infants treated by vancomycin was significantly higher before than after implementation of the new perfusion system (Table I). The factors independently associated with CLABSIs were the period, associated with an 88% reduction in the risk of CLABSIs after implementation of the new perfusion system (OR 0.12, 95% CI 0.03–0.39; P<0.001), and the duration of central line use (for each additional day: OR 1.05, 95% CI 1.02–1.07; P<0.001; Table IV). Since the duration of parenteral nutrition and duration of central line use are highly correlated (r>0.9 in study dataset), both variables cannot be entered into the multi-variate model simultaneously, so the authors decided to enter duration of central line use alone. All VIF scores were close to 1 (1.21 for period, 1.14 for gestational age, 1.02 for small for gestational age, 1.36 for duration of central line use), suggesting the absence of multi-collinearity.

## Discussion

In a population of very preterm infants, the implementation of a new multi-perfusion system was found to be associated with a significant reduction in CLABSI rate.

The baseline CLABSI rate was in line with the previously reported rate in France (12.4/1000 catheter-days; 95% CI 10.8–14.0) [9], and also rates in other European countries, such as Belgium (8.4/1000 catheter-days) [24], Greece (12.0/1000 catheter-days) [25], the Netherlands (12.9/1000 catheter-days, 95% CI 5.1–27.0) [26], Portugal (14.1/1000 catheter-days) [27] and Austria (13.9/1000 catheter-days) [28], as well as certain centres in North America where the incidence is generally lower than elsewhere (15.6/1000 catheter-days [29]; 11.6/1000 catheter-days [30]). The pooled rate of CLABSI rates in neonatal intensive care units reported by the International Nosocomial Infection Control Consortium is 16.4 (95% CI 15.2–17.6) in a population of 14171 neonates, including 32% with a birth weight <1000 g (45.4% in the study population) [31]. The beneficial effect on CLABSI rates observed herein is therefore likely reproducible in other neonatal units. This may be of great importance as, after multi-line implementation, the CLABSI rate was low [2.2 (95% CI 0.8–4.7) per 1000 catheter-days], and it is of note that only 10 of 25 studies included in the two large systematic reviews reported a post-intervention CLABSI rate <2.2 per 1000 catheter-days [7,8]. In addition, the reduction in CLABSI rate after implementation of the new perfusion system represented an 88% decrease, and it is of note that only three of 25 studies included in the
<caption>**Table I**</caption>

Characteristics at birth and during hospitalization of infants admitted before or after implementation of the Edelwaiss Multiline NEO perfusion system

<table><thead><tr><th></th><th>Before N=163</th><th>After N=150</th><th>P-value</th></tr></thead><tbody><tr><td>At birth</td><td></td><td></td><td></td></tr><tr><td>Male sex, N (%)</td><td>76 (46.6)</td><td>73 (48.7)</td><td>0.72</td></tr><tr><td>Gestational age, weeks</td><td>28 [26–29]</td><td>28 [27–29]</td><td>0.65</td></tr><tr><td>Birth weight, g</td><td>1000 [805–1220]</td><td>1050 [810–1260]</td><td>0.51</td></tr><tr><td>Birth weight &lt;-1 SD, N (%)</td><td>28 (17.2)</td><td>26 (17.3)</td><td>0.97</td></tr><tr><td>Birth weight &lt;1000 g, N (%)</td><td>79 (48.5)</td><td>63 (42.1)</td><td>0.33</td></tr><tr><td>Length, cm</td><td>35 [33–38]</td><td>36 [34–38]</td><td>0.44</td></tr><tr><td>Head circumference, cm</td><td>25 [24–27]</td><td>25 [24–27]</td><td>0.99</td></tr><tr><td>During hospitalization</td><td></td><td></td><td></td></tr><tr><td>PDA</td><td>61 (38.3)</td><td>54 (36.2)</td><td>0.11</td></tr><tr><td>Parenteral nutrition, days</td><td>11 [6–16.5]</td><td>11 [8–18]</td><td>0.45</td></tr><tr><td>Assisted ventilation, h</td><td>86 [14–481]</td><td>110 [15–438]</td><td>0.57</td></tr><tr><td>Insulin treatment, days</td><td>7 [4–10]</td><td>8 [6–10.8]</td><td>0.11</td></tr><tr><td>Non-invasive ventilation, days</td><td>36.4 [19.7–50.1]</td><td>38.4 [21.8–59.0]</td><td>0.25</td></tr><tr><td>Brain lesions (IVH ≥grade 3, PVL), N (%)</td><td>12 (7.5)</td><td>13 (8.7)</td><td>0.71</td></tr><tr><td>Late-onset sepsis, N (%)</td><td>48 (29.9)</td><td>26 (17.5)</td><td>0.03</td></tr><tr><td>Vancomycin treatment, N (%)</td><td>43 (26.4)</td><td>17 (11.3)</td><td>&lt;0.001</td></tr><tr><td>NEC ≥grade 2, N (%)</td><td>5 (3.2)</td><td>4 (2.7)</td><td>0.99</td></tr><tr><td>Moderate or severe BPD, N (%)</td><td>52 (44.4)</td><td>60 (53.1)</td><td>0.19</td></tr><tr><td>Systemic postnatal steroids, N (%)</td><td>23 (14.1)</td><td>32 (21.3)</td><td>0.09</td></tr><tr><td>ROP grade ≥2, N (%)</td><td>11 (6.9)</td><td>7 (4.7)</td><td>0.40</td></tr><tr><td>Severe morbidity, N (%)</td><td>69 (42.9)</td><td>68 (45.3)</td><td>0.66</td></tr><tr><td>Hospital stay, days</td><td>52 [36–74]</td><td>62.5 [6.5–80]</td><td>0.15</td></tr></tbody></table>

PDA, persistent ductus arteriosus; NEC, necrotizing enterocolitis; BPD, bronchopulmonary dysplasia; ROP, retinopathy of prematurity; IVH, intraventricular haemorrhage; PVL, periventricular leukomalacia; SD, standard deviation.

Continuous variables presented as median [interquartile range]. Categorical variables were compared using Chi-squared test or Fisher's exact test, and continuous variables were compared using Student's t-test or Mann-Whitney test, as appropriate.

Severe morbidity was defined as at least one of the following complications: surgical PDA, stage ≥2 ROP, grade ≥2 NEC, moderate or severe BPD, grade ≥3 IVH or PVL.

<caption>**Table II**</caption>

Central venous line and type of catheter in preterm infants born before or after implementation of the new perfusion system

<table><thead><tr><th></th><th>Before N=163</th><th>After N=150</th><th>P-value</th></tr></thead><tbody><tr><td>Duration of central venous line use</td><td></td><td></td><td></td></tr><tr><td>Total, days</td><td>10 [5–14]</td><td>10 [6–17]</td><td>0.36</td></tr><tr><td>Peripherally inserted catheter, days</td><td>9 [6–15]</td><td>9 [7–17]</td><td>0.48</td></tr><tr><td>Umbilical venous catheter, days</td><td>4 [3–5]</td><td>3 [2–5]</td><td>0.60</td></tr><tr><td>Catheter utilization ratio<sup>a</sup></td><td>0.19 [0.12–0.33]</td><td>0.19 [0.12–0.38]</td><td>0.90</td></tr><tr><td>Insertion site</td><td></td><td></td><td>0.50</td></tr><tr><td>UVC then PIC, N (%)</td><td>115 (70.5)</td><td>111 (74.0)</td><td></td></tr><tr><td>UVC alone, N (%)</td><td>48 (29.5)</td><td>39 (26.0)</td><td></td></tr></tbody></table>

UVC, umbilical venous catheter; PIC, peripherally inserted catheter.

Continuous variables presented as median [interquartile range].

a Number of catheter-days divided by the number of patient-days.

systematic reviews reported a reduction in CLABSI rate >88% [29,32–34]. However, further multi-centre trials are needed to confirm that these beneficial effects can be achieved in other settings with different baseline practices. Another point of note is that the decrease in CLABSI rate occurred quickly after implementation of the new perfusion system, but it is not comparable to care bundle interventions with multiple interacting components that include behaviour changes and last for a few months to a few years [6,28–30]. In addition, there was also a significant reduction in exposure to vancomycin related

to the significant reduction in the number of CLABSI cases, as there was no change in antibiotic treatment guidelines between the two periods. This reduction is potentially beneficial for the health of preterm infants as it is well known that antibiotic exposure favours dysbiosis, and this has been associated with increased risk of NEC, BPD and ROP [35,36]. However, this study was not designed to evaluate these potential benefits.

During the study period, no severe adverse events related to the perfusion system were observed. There were more mild
<figure><img src="image_8.png" /><figcaption>**Figure 3.** Incidence of central-line-associated bloodstream infections (CLABSIs). Hatched area represents national CLABSI rates (12.4 per 1000 days, 95% confidence interval 10.8–14.0) before and after implementation of the new perfusion system in 313 very preterm infants.</figcaption></figure>

**Table III**

Pathogens identified in 28 infants with central-venous-line-associated bloodstream infections (CLABSIs) observed in 313 pre-term infants born before (P1) or after (P2) implementation of the new perfusion system

<table><thead><tr><th></th><th>P1</th><th>P2</th></tr></thead><tbody><tr><td>N</td><td>23</td><td>5</td></tr><tr><td>Coagulase-negative staphylococci, N (%)</td><td>19 (83)</td><td>4 (80)</td></tr><tr><td>Staphylococcus aureus, N (%)</td><td>2 (9)</td><td>0</td></tr><tr><td>Gram-negative bacilli, N (%)</td><td>1 (4)</td><td>1 (20)</td></tr><tr><td>Bacillus, N (%)</td><td>1 (4)</td><td>0</td></tr></tbody></table>

adverse events after implementation of the new perfusion system than before, which is related to the learning curve [37].

The main limitation of this study is the before-and-after design. Firstly, this implied that the staff were not blinded; however, although a double-blind randomized controlled trial is not feasible to evaluate such a new perfusion system, a stepped wedge design could be used in future studies seeking to further investigate the efficacy of a new perfusion system.

Secondly, practice changes could explain the CLABSI rate reduction. This is, however, unlikely because the only change that occurred between the two periods was the use of the new perfusion system. Specific training sessions on the new perfusion system started at the end of 2018, but it did not influence practices as the standard perfusion system was the only system used until December 2019. Routine monthly hygiene education sessions were performed similarly during the two periods. Therefore, practices did not differ between the two periods, notably hygiene practices during aseptic procedures, but also the use of central lines and catheter use rates. As the study was conducted over the course of the coronavirus disease 2019 pandemic, infection control measures were heightened after March 2020, and this could have enhanced adherence to these measures. The authors cannot, however, confirm this as the design of the study did not allow the assessment of adherence to infection control measures and no audit was performed, but infection control measures could have contributed to the decrease in CLABSI rates which started from January 2020. Another limitation could have been related to the number of subjects, because this study only analysed a 2-year period.

**Table IV**

Univariate and multi-variate analysis for the risk of central-venous-line-associated bloodstream infection in 322 preterm infants

<table><thead><tr><th rowspan="2"></th><th colspan="2">Univariate analysis</th><th colspan="2">Multi-variable analysis</th></tr><tr><th>OR (95% CI)</th><th>P-value</th><th>OR (95% CI)</th><th>P-value</th></tr></thead><tbody><tr><td>Period (after implementation vs before)</td><td>0.21 (0.08–0.57)</td><td>0.002</td><td>0.12 (0.04–0.41)</td><td>&lt;0.001</td></tr><tr><td>Sex (female vs male)</td><td>0.90 (0.41–1.96)</td><td>0.790</td><td>-</td><td>-</td></tr><tr><td>Gestational age (for each additional week)</td><td>0.69 (0.56–0.84)</td><td>&lt;0.001</td><td>0.84 (0.66–1.07)</td><td>0.163</td></tr><tr><td>Antenatal steroids</td><td>0.98 (0.52–1.83)</td><td>0.944</td><td>-</td><td>-</td></tr><tr><td>Small for gestational age at birth</td><td>2.52 (1.07–5.94)</td><td>0.033</td><td>1.55 (0.58–4.14)</td><td>0.378</td></tr><tr><td>Duration of central line use (for each additional day)</td><td>1.04 (1.02–1.07)</td><td>&lt;0.001</td><td>1.05 (1.01–1.07)</td><td>0.004</td></tr><tr><td>Severe morbidity</td><td>1.09 (0.51–2.36)</td><td>0.820</td><td>-</td><td>-</td></tr></tbody></table>

CI, confidence interval.
However, this did not prevent the observation of a significant
difference between the two periods. Further analyses of 2021
and 2022 are planned to obtain a longer follow-up period.

In conclusion, the present study showed that implementa-
tion of a new perfusion system in a large tertiary care unit was
associated with a significant reduction in CLABSI rate. This can
help to design future randomized trials in populations large
enough to confirm the effect on CLABSI rates in other settings,
and to assess the impact on short- and long-term health of very
premature infants.

Acknowledgements

The authors wish to thank Julie Mennetrey and Violaine Suchail Drutel (Neonatology, Hôpital de la Croix-Rousse, Lyon) for supporting the implementation of the new perfusion system, Marion Masclef Imbert (Neonatology, Hôpital de la Croix-Rousse, Lyon) for help in data collection, Philip Robinson (Hospices Civils de Lyon) for help in manuscript preparation, and Philippe Buisson (Doran International Toussieu, France), inventor of the Edelvaiss Multiline NEO, for providing technological expertise. No compensation was received for their roles.

**Conflict of interest statement**

None declared.

**Funding sources**

None.

**Author contributions**

Jean-Charles Picaud conceptualized and designed the study, designed the data collection instruments, drafted the initial manuscript, and critically revised the manuscript. Sarah Faton collected data, contributed to the analysis of data, and critically revised the manuscript. Pierre Pradat designed the data collection instruments, supervised data collection, carried out analyses, and critically reviewed and revised the manuscript. Blandine Pastor-Diez designed the data collection instruments, contributed to data collection, and critically revised the manuscript. Anthony Martelin contributed to the design of the study, collected data, and critically reviewed and revised the manuscript. Xavier Armoiry contributed to the design of the study and critically revised the manuscript. Dr Stephane Hays designed the study, carried out the initial analyses, and critically revised the manuscript. All authors approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

**Appendix A. Supplementary data**

Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jhin.2023.10.004.

**References**

[1] Tissières P, Ochoda A, Dunn-Siegrist I, Drifte G, Morales M, Pfister R, et al. Innate immune deficiency of extremely premature neonates can be reversed by interferon-γ. PLoS One 2012;7:e32863.

[2] Qazi KR, Bach Jensen G, van der Heiden M, Björkander S, Holmlund U, Haileselassie Y, et al. Extremely preterm infants have significant alterations in their conventional T cell compartment during the first weeks of life. J Immunol 2020;204:68–77.

[3] Flannery DD, Edwards EM, Coggins SA, Horbar JD, Puopolo KM. Late-onset sepsis among very preterm infants. Pediatrics 2022;150:e2022058813.

[4] Mukhopadhyay S, Puopolo KM, Hansen NI, Lorch SA, DeMauro SB, Greenberg RG, et al.; NICHD Neonatal Research Network. Neuro-developmental outcomes following neonatal late-onset sepsis and blood culture-negative conditions. Arch Dis Child Fetal Neonatal Ed 2021;106:467–73.

[5] Zipursky AR, Yoon EW, Emberley J, Bertelle V, Kanungo J, Lee SK, et al.; Canadian Neonatal Network Investigators. Central line-associated blood stream infections and non-central line-associated blood stream infections surveillance in Canadian tertiary care neonatal intensive care units. J Pediatr 2019;208:176–182.e6.

[6] Sinha AK, Murthy V, Nath P, Morris JK, Millar M. Prevention of late onset sepsis and central-line associated blood stream infection in preterm infants. Pediatr Infect Dis J 2016;35:401–6.

[7] Ista E, van der Hoven B, Kornelisse RF, van der Starre C, Vos MC, Boersma E, et al. Effectiveness of insertion and maintenance bundles to prevent central-line-associated bloodstream infections in critically ill patients of all ages: a systematic review and meta-analysis. Lancet Infect Dis 2016;16:724–34.

[8] Payne V, Hall M, Prieto J, Johnson M. Care bundles to reduce central line-associated bloodstream infections in the neonatal unit: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal 2018;103:F422–9.

[9] Centre d'Appui pour la Prévention des Infections Associées aux Soins. Surveillance des cathéters veineux centraux en néonatologie. Réseau Néocat: Résultats 2019 CPIAS; 2019. Available at: https://www.cpias-ile-de-france.fr/surveillance/neocat/2019/Neocat2019_Rapport.pdf.

[10] Mahieu LM, De Muynck AO, leven MM, De Dooy JJ, Goossens HJ, Van Reempts PJ. Risk factors for central vascular catheter-associated bloodstream infections among patients in a neonatal intensive care unit. J Hosp Infect 2001;48:108–16.

[11] Perlman SE, Saiman L, Larson EL. Risk factors for late-onset health care-associated bloodstream infections in patients in neonatal intensive care units. Am J Infect Control 2007;35:177–82.

[12] Mahieu LM, De Dooy JJ, Lenaerts AE, leven MM, De Muynck AO. Catheter manipulations and the risk of catheter-associated bloodstream infection in neonatal intensive care unit patients. J Hosp Infect 2001;48:20–6.

[13] Mahieu LM, De Dooy JJ, De Muynck AO, Van Melckebeke G, leven MM, Van Reempts PJ. Microbiology and risk factors for catheter exit-site and -hub colonization in neonatal intensive care unit patients. Infect Control Hosp Epidemiol 2001;22:357–62.

[14] Dezfulian C, Lavelle J, Nallamothu BK, Kaufman SR, Saint S. Rates of infection for single-lumen versus multilumen central venous catheters: a meta-analysis. Crit Care Med 2003;31:2385–90.

[15] Decaudin B, Dewulf S, Lannoy D, Simon N, Secq A, Barthélémy C, et al. Impact of multiaccess infusion devices on in vitro drug delivery during multi-infusion therapy. Anesth Analg 2009;109:1147–55.

[16] Foinard A, Décaudin B, Barthélémy C, Debaene B, Odou P. Prevention of drug delivery disturbances during continuous intravenous infusion: an in vitro study on a new multi-lumen infusion access device. Ann Fr Anesth Reanim 2013;32:e107–12.

[17] Perez M, Decaudin B, Foinard A, Barthélémy C, Debaene B, Lebuffe G, et al. Compatibility of medications during multi-infusion therapy: a controlled in vitro study on a multilumen infusion device. Anaesth Crit Care Pain Med 2015;34:83–8.

[18] de Goffau MC, Bergman KA, de Vries HJ, Meessen NE, Degener JE, van Dijl JM, et al. Cold spots in neonatal incubators are hot spots for microbial contamination. Appl Environ Microbiol 2011;77:8568–72.
[19] Maiguy-Foinard A, Decaudin B, Tourneux P, Guillois B, Blanc T, Galène-Gromez S, et al. Effect of multi-lumen perfusion line on catheter-related bacteremia in premature infants: study protocol for a cluster-randomized crossover trial. Trials 2019;20:115.

[20] Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr 2013;13:59.

[21] Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control 2008;36:309–32.

[22] Leistner R, Piening B, Gastmeier P, Geffers C, Schwab F. Nosocomial infections in very low birthweight infants in Germany: current data from the National Surveillance System NEO-KISS. Klin Padiatr 2013;225:75–80.

[23] American Academy of Pediatrics. Coagulase-negative staphylococcal infections. In: Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, editors. Red Book: 2021 Report of the Committee on Infectious Diseases. Itasca, IL: American Academy of Pediatrics; 2021. p. 692–4.

[24] Bierlaire S, Danhaive O, Carkeek K, Piersigilli F. How to minimize central line-associated bloodstream infections in a neonatal intensive care unit: a quality improvement intervention based on a retrospective analysis and the adoption of an evidence-based bundle. Eur J Pediatr 2021;180:449–60.

[25] Rallis D, Karagianni P, Papakotoula I, Nikolaidis N, Tsakalidis C. Significant reduction of central line-associated bloodstream infection rates in a tertiary neonatal unit. Am J Infect Control 2016;44:485–7.

[26] Arnts IJ, Schrijvers NM, van der Flier M, Groenewoud JM, Antonius T, Liem KD. Central line bloodstream infections can be reduced in newborn infants using the modified Seldinger technique and care bundles of preventative measures. Acta Paediatr 2015;104:e152–7.

[27] Almeida CC, Pissarra da Silva SMS, Flor de Lima Caldas de Oliveira FSD, Guimarães Pereira Areias MHF. Nosocomial sepsis: evaluation of the efficacy of preventive measures in a level-III neonatal intensive care unit. J Matern Fetal Neonatal Med 2017;30:2036–41.

[28] Steiner M, Langgartner M, Cardona F, Waldhör T, Schwindt J, Haiden N, et al. Significant reduction of catheter-associated blood stream infections in preterm neonates after implementation of a care bundle focusing on simulation training of central line insertion. Pediatr Infect Dis J 2015;34:1193–6.

[29] Kime T, Mohsini K, Nwankwo MU, Turner B. Central line "attention" is their best prevention. Adv Neonatal Care 2011;11: 242–8.

[30] Holzmann-Pazgal G, Kubanda A, Davis K, Khan AM, Brumley K, Denson SE. Utilizing a line maintenance team to reduce central-line-associated bloodstream infections in a neonatal intensive care unit. J Perinatol 2012;32:281–6.

[31] Rosenthal VD, Al-Abdely HM, El-Kholy AA, AlKhawaja SAA, Leblebicioglu H, Mehta Y, et al. International Nosocomial Infection Control Consortium report, data summary of 50 countries for 2010–2015: device-associated module. Am J Infect Control 2016;44:1495–504.

[32] Shepherd EG, Kelly TJ, Vinsel JA, Cunningham DJ, Keels E, Beauseau W, et al. Significant reduction of central-line associated bloodstream infections in a network of diverse neonatal nurseries. J Pediatr 2015;167:41–6.e1-3.

[33] Wang W, Zhao C, Ji Q, Liu Y, Shen G, Wei L. Prevention of peripherally inserted central line-associated blood stream infections in very low-birth-weight infants by using a central line bundle guideline with a standard checklist: a case control study. BMC Pediatr 2015;15:69.

[34] Wilder KA, Wall B, Haggard D, Epperson T. CLABSI reduction strategy: a systematic central line quality improvement initiative integrating line-rounding principles and a team approach. Adv Neonatal Care 2016;16:170–7.

[35] d'Haens EJ, Zwickink RD, Belzer C, Hemels MAC, van Lingen RA, Renes IB, et al. Short-term changes of intestinal microbiota composition in preterm infants after two prophylactic doses of vancomycin. Acta Paediatr 2019;108:1919–20.

[36] Zhang JY, Greenwald MJ, Rodriguez SH. Gut microbiome and retinopathy of prematurity. Am J Pathol 2023;193:1683–90.

[37] Le Morvan P, Stock B. Medical learning curves and the Kantian ideal. J Med Ethics 2005;31:513–8.