Effects of Probiotic Mixture Supplementation and Evaluation of Intestinal Mucosal Tolerance and Gut Microbiome in Newborns with Perinatal Asphyxia Receiving Hypothermic Treatment: A Randomized, Multicentric, Blinded, Controlled TRIAL (VISNAT)

Abstract

\n IntroductionNeonatal encephalopathy is still a major cause of mortality and morbidity for newborns, although hypothermia treatment has improved the prognosis of term newborns with hypoxic-ischemic injury.Recent evidence suggests that one of the crucial but understudied mechanisms of secondary neuronal injury after global hypoxic-ischemic injury is inflammation.Hence, blocking the inflammatory reaction promotes neuroprotection and has a potential for use in the clinical treatment of ischemic brain injury.Many preclinical studies have shown bidirectional interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract, suggesting a prominent role for the gut microbiota in these gut-brain interactions. Early human studies suggest that altering the microbiota with beneficial bacteria, or probiotics, can lead to changes in brain function, as well as subjective reports of mood.Methods and analysisThe VISNAT trial is a PILOT STUDY developed according to SPIRIT checklist. It is a randomized, placebo-controlled, blinded, multicentre superiority trial with two parallel groups and a primary outcome of mortality and/or disability at 18 months of age.The experimental intervention will consist in administrating a high-dose multi-strain probiotic (SIVOMIXXTM) for 30 days in addition to hypothermic therapy.Primary outcome will be to compare mortality and/or disability at 18 month of age between the two groups. Disability will be assessed by means of the Bayley Mental Development Index. Secondary outcomes will be to compare inflammatory cytokines level and brain injury biomarkers (i.e. Tau and neurofilament light protein) between groups.A subgroup analysis will be performed stratifying patients according to both probiotic/placebo treatment and breast/artificial milk.DiscussionProbiotics supplementation represents a simple and reproducible intervention. If proven effective, probiotics supplementation in asphyxiated babies would improve clinical outcomes and reduce health cost. Hence, this study may cast a new light on the management of hypoxic-ischemic encephalopathy. Trial registration numberStudy has been registered on clinicaltrials.org on 23rd October 2019 with number NCT04145713. Trial StatusThe present trial (VISNAT Study Version 1.0 - 23 October 2019) has been approved by the Ethics Committees of the coordinator centre “Azienda Ospedaliera Universitaria Consorziale Policlinico di Bari”. Approval from the Ethics Committees of each participating hospital has also been requested. Enrollment of patients is planned to start in July 2021 and should last approximately 2 years.