Deep cerebral venous abnormalities in premature babies with GMH-IVH: a single-centre retrospective study

Purpose Germinal matrix haemorrhage/intraventricular haemorrhage (GMH-IVH) is a multifactorial injury with both anatomic and haemodynamic involvement. Normal variants in preterm deep cerebral venous anatomy associated with GMH-IVH have been previously described using MRI susceptibility weighted imaging (SWI). The aims of this study were to use SWI to compare the deep venous systems of a cohort of preterm neonates with various grades of GMH-IVH to a group of age-matched controls without GMH-IVH and to present novel retrospective SWI imaging findings.Methods A neuroradiologist retrospectively evaluated 3T MRI SWI and phase imaging of 56 preterm neonates with GMH-IVH (14 of each grade) and 27 controls without GMH-IVH, scoring the venous irregularities according to three variables: decreased venous patency, increased lumen susceptibility and the presence of collaterals. Eight different venous locations, including indicated bilateral components, were evaluated: straight sinus, vein of galen, internal cerebral, direct lateral, thalamostriate, atrial and the anterior septal veins. Variables were analysed for statistical significance. Inter-rater reliability was determined via subset evaluation by a second paediatric radiologist.Results Deep venous abnormalities were significantly more common in patients with GMH-IVH, with Wilcoxon Rank Sum Test demonstrating significant increase with GMH-IVH for total decreased venous patency (W=0, p<0.0001), increased lumen susceptibility and collateral formation. Venous abnormalities were also positively correlated with an increase in GMH-IVH grade from I to IV (patency, ρ=0.782, p<0.01) (increased lumen susceptibility, ρ=0.739, p<0.01) (collaterals, ρ=0.649, p<0.01), not just GMH-IVH alone.Conclusion Deep venous abnormalities are significantly correlated with GMH-IVH alone and an increase in GMH-IVH grade. Further study is needed to determine cause and effect

Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia

INTRODUCTION: Neonates with hypoxic-ischemic encephalopathy (HIE) undergoing hypothermia may benefit from adjunctive therapy with melatonin. However, melatonin safety, pharmacokinetics (PK), and dosage in this sensitive population is still unknown. METHODS AND RESULTS: This study assessed the PK and safety of melatonin enteral administration to neonates with HIE undergoing hypothermia. Melatonin was infused at 0.5 mg/kg in five neonates with HIE undergoing hypothermia. Infusion started 1 h after the neonates reached the target temperature of 33.5 °C. Blood samples were collected before and at selective times after melatonin infusion. Abdominal complications or clinically significant changes in patients' vital signs were not found during or after melatonin. The peak plasma concentration reached 0.25 μg/ml. The area under the curve in 24 h was 4.35 μg/mL*h. DISCUSSION: Melatonin half-life and clearance were prolonged, and the distribution volume decreased compared to adults. In silico simulation estimated that the steady state can be reached after four infusions. Hypothermia does not affect melatonin PK. In humans high blood concentrations with lower doses can be achieved compared to animal experimentation, although intravenous administration is advised in the neonate population. Our study is a preparatory step for future clinical studies aimed at assessing melatonin efficacy in HIE. This article is protected by copyright. All rights reserved

Human-rat integrated microRNAs profiling identified a new neonatal cerebral hypoxic-ischemic pathway melatonin-sensitive

Neonatal encephalopathy (NE) is a pathological condition affecting long-term neurodevelopmental outcomes. Hypothermia is the only therapeutic option, but does not always improve outcomes; hence, researchers continue to hunt for pharmaceutical compounds. Melatonin treatment has benefitted neonates with hypoxic-ischemic (HI) brain injury. However, unlike animal models that enable the study of the brain and the pathophysiologic cascade, only blood is available from human subjects. Therefore, due to the unavailability of neonatal brain tissue, assumptions about the pathophysiology in pathways and cascades are made in human subjects with NE. We analyzed animal and human specimens to improve our understanding of the pathophysiology in human neonates. A neonate with NE who underwent hypothermia and enrolled in a melatonin pharmacokinetic study was compared to HI rats treated/untreated with melatonin. MicroRNA (miRNA) analyses provided profiles of the neonate's plasma, rat plasma, and rat brain cortexes. We compared these profiles through a bioinformatics tool, identifying Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways common to HI brain injury and melatonin treatment. After evaluating the resulting pathways and the literature, to validate the method, the key proteins expressed in HI brain injury were investigated using cerebral cortexes. The upregulated miRNAs in human neonate and rat plasma helped identify two KEGG pathways, glioma and long-term potentiation, common to HI injury and melatonin treatment. A unified neonatal cerebral melatonin-sensitive HI pathway was designed and validated by assessing the expression of protein kinase Cα (PKCα), phospho (p)-Akt, and p-ERK proteins in rat brain cortexes. PKCα increased in HI-injured rats and further increased with melatonin. p-Akt and p-ERK returned phosphorylated to their basal level with melatonin treatment after HI injury. The bioinformatics analyses validated by key protein expression identified pathways common to HI brain injury and melatonin treatment. This approach helped complete pathways in neonates with NE by integrating information from animal models of HI brain injury