Effect of in-line filtration in newborns: study protocol of the Intravenous Neonatal Central Access Safety (INCAS) randomized controlled trial
Authors: Cresi Francesco , Maggiora Elena , Capetti Cecilia , Capitanio Martina , Ferroglio Mattia , Spada Elena , De Matteis Francesca , Cosimi Sara , Mosca Fabio , Coscia Alessandra ,   INCAS Trial Research Group, Aceti Arianna , Amato Orsola , Ancora Gina , Baldassarre Maria Elisabetta , Barone Giovanni , Bellan Cristina , Borgarello Gabriella , Bottino Roberto , Campagnoli Francesca , Capasso Antonella , Capretti Maria Grazia , Carpentieri Mauro , Cinelli Roberto , Corvaglia Luigi , Costa Simonetta , Dani Carlo , D’Amato Gabriele , D’Andrea Vito , Dotta Andrea , Farina Daniele , Ferrari Stefania , Foglianese Alessandra , Fracchiolla Annalisa , Gallo Elena , Ghirardello Stefano , Laforgia Nicola , Lista Gianluca , Luciano Mattia , Maddaloni Chiara , Maffei Gianfranco , Maggio Alessandra , Maggio Luca , Maino Marzia , Mangili Giovanna , Mantelli Simona Semeria , Manzari Raffaele , Mondello Isabella , Natale Maria Pia , Peila Chiara , Petrillo Flavia , Pivetti Valentina , Pontiggia Federica , Raimondi Francesco , Romitti Maria Grazia , Sannia Andrea , Levet Patrizia Savant , Savarese Immacolata , Spagnuolo Ferdinando , Varalda Alessia , Villani Paolo Ernesto , Terrin Gianluca , Ummarino Dario , Vento Giovanni 
Published: July 2024

Abstract
Background
Particulate contamination due to infusion therapy (administration of parenteral nutrition and medications) carries a potential health risk for infants in neonatal intensive care units (NICUs). This particulate consists of metals, drug crystals, glass fragments, or cotton fibers and can be generated by drug packaging, incomplete reconstitution, and chemical incompatibilities. In-line filters have been shown to remove micro-organisms, endotoxin, air, and particles in critically ill adults and older infants, but its benefits in newborn remain to be demonstrated. Moreover, 50% of inflammatory episodes in the setting of NICUs are blood culture-negative. These episodes could be partly related to the presence of particles in the infusion lines.

Methods
A multicenter randomized single-blind controlled trial was designed. All infants admitted to NICUs for which prolonged infusion therapy is expected will be enrolled in the study and randomized to the Filter or Control arm. All patients will be monitored until discharge, and data will be analyzed according to a “full analysis set.” The primary outcome is the frequency of patients with at least one sepsis-like event, defined by any association of suspected sepsis symptoms with a level of c-reactive protein (CRP) > 5 mg/L in a negative-culture contest. The frequency of sepsis, phlebitis, luminal obstruction, and the duration of mechanical ventilation and of catheter days will be evaluated as secondary outcomes. The sample size was calculated at 368 patients per arm.

Discussion
This is the first multicenter randomized control trial that compares in-line filtration of parenteral nutrition and other intravenous drugs to infusion without filters. Sepsis-like events are commonly diagnosed in clinical practice and are more frequent than sepsis in a positive culture contest. The risk of these episodes in the target population is estimated at 30–35%, but this data is not confirmed in the literature. If the use of in-line filters results in a significant decrease in sepsis-like events and/or in any other complications, the use of in-line filters in all intravenous administration systems may be recommended in NICUs.

Trial registration
ClinicalTrials.gov, NCT05537389, registered on 12 September 2022 (https://classic.clinicaltrials.gov/ct2/show/results/NCT05537389?view=results).