Vitamin K insufficiency and the prophylaxis strategy in term healthy infants: A multicentre study.

BACKGROUND/AIM: Late vitamin K deficiency bleeding (VKDB) during early infancy is a serious problem worldwide. Vitamin K (VK) deficiency commonly occurs in newborns who are exclusively breastfed. Protein Induced by VK Absence (PIVKA-II) has been identified as an early indicator of subclinical VK deficiency in neonates, surpassing prothrombin time. To assess PIVKA-II levels at 48 h, 1 and 3 months of age in full-term newborns who were exclusively breastfed and received varying VKDB prophylaxis regimens. METHODS: A prospective observational study was conducted in four hospitals, enrolling 105 newborns. PIVKA-II levels were measured using a sandwich-type enzyme-linked immunosorbent assay. RESULTS: At 48 h of age, there was no significant difference in PIVKA-II concentrations between newborns who received intramuscular administration of 1 mg of phylloquinone (VK1) and those who received oral administration of 2 mg of VK1 at birth. At 1 and 3 months of life, infants who received any supplementation regimen between 2 and 14 weeks exhibited significantly lower PIVKA-II concentrations compared to infants who received only 1 mg of intramuscular VK1 at birth. The prophylaxis involving a dose of 1 mg of intramuscular VK1 at birth followed by oral administration of 150 µg/day of VK1 from the 2nd to the 14th week of life showed the lowest PIVKA-II blood concentrations. CONCLUSIONS: Oral supplementation of VK1 after discharge significantly reduced PIVKA-II concentrations in exclusively breastfed term infants. These findings suggest the importance of oral VK1 supplementation in exclusively breastfed infants during their first 3 months of life to avoid the risk of VK insufficiency.

Variation in delivery room management of preterm infants across Europe: a survey of the Union of European Neonatal and Perinatal Societies.

The aim of the present study, endorsed by the Union of European Neonatal and Perinatal Societies (UENPS) and the Italian Society of Neonatology (SIN), was to analyze the current delivery room (DR) stabilization practices in a large sample of European birth centers that care for preterm infants with gestational age (GA) < 33 weeks. Cross-sectional electronic survey was used in this study. A questionnaire focusing on the current DR practices for infants < 33 weeks' GA, divided in 6 neonatal resuscitation domains, was individually sent to the directors of European neonatal facilities, made available as a web-based link. A comparison was made between hospitals grouped into 5 geographical areas (Eastern Europe (EE), Italy (ITA), Mediterranean countries (MC), Turkey (TUR), and Western Europe (WE)) and between high- and low-volume units across Europe. Two hundred and sixty-two centers from 33 European countries responded to the survey. At the time of the survey, approximately 20,000 very low birth weight (VLBW, < 1500 g) infants were admitted to the participating hospitals, with a median (IQR) of 48 (27-89) infants per center per year. Significant differences between the 5 geographical areas concerned: the volume of neonatal care, ranging from 86 (53-206) admitted VLBW infants per center per year in TUR to 35 (IQR 25-53) in MC; the umbilical cord (UC) management, being the delayed cord clamping performed in < 50% of centers in EE, ITA, and MC, and the cord milking the preferred strategy in TUR; the spotty use of some body temperature control strategies, including thermal mattress mainly employed in WE, and heated humidified gases for ventilation seldom available in MC; and some of the ventilation practices, mainly in regard to the initial FiO2 for < 28 weeks' GA infants, pressures selected for ventilation, and the preferred interface to start ventilation. Specifically, 62.5% of TUR centers indicated the short binasal prongs as the preferred interface, as opposed to the face mask which is widely adopted as first choice in > 80% of the rest of the responding units; the DR surfactant administration, which ranges from 44.4% of the birth centers in MC to 87.5% in WE; and, finally, the ethical issues around the minimal GA limit to provide full resuscitation, ranging from 22 to 25 weeks across Europe. A comparison between high- and low-volume units showed significant differences in the domains of UC management and ventilation practices.    Conclusion: Current DR practice and ethical choices show similarities and divergences across Europe. Some areas of assistance, like UC management and DR ventilation strategies, would benefit of standardization. Clinicians and stakeholders should consider this information when allocating resources and planning European perinatal programs. What is Known: • Delivery room (DR) support of preterm infants has a direct influence on both immediate survival and long-term morbidity. • Resuscitation practices for preterm infants often deviate from the internationally defined algorithms. What is New: • Current DR practice and ethical choices show similarities and divergences across Europe. Some areas of assistance, like UC management and DR ventilation strategies, would benefit of standardization. • Clinicians and stakeholders should consider this information when allocating resources and planning European perinatal programs.

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.

Peripheral Saturation and Perfusion Index on the First Day of Life Play a Role in Early Discharge of Healthy Term Newborns.

Introduction: Pulse oximetry screening is a safe, feasible test, effective in identifying congenital heart diseases in otherwise well-appearing newborns. Uncertainties still persist on the most effective algorithm to be used and the timing of screening. The aim of this study was to evaluate the role of the pulse oximetry screening associated with the peripheral perfusion index performed in the first 24 hours of life for the early detection of congenital heart diseases and noncongenital heart diseases in the newborns. Materials and Methods: A prospective observational cohort study was conducted. The enrollment criteria were as follows: term newborns with an APGAR score >8 at 5 minutes. The exclusion criteria were as follows: clinical signs of prenatal/perinatal asphyxia or known congenital malformations. Four parameters of pulse oximetry screening were utilized: saturation less than 90% (screening 1), saturation of less than 95% in one or both limbs (screening 2), difference of more than 3% between the limbs (screening 3), and preductal peripheral perfusion index or postductal peripheral perfusion index below 0.70 (screening 4). The likelihood ratio, sensibility, specificity, and positive and negative predictive values for identification of congenital heart diseases or noncongenital heart diseases (suspicion of perinatal infection and any respiratory diseases) were evaluated. Results: The best predictive results for minor congenital heart disease were obtained combining screening 3 and screening 4 (χ 2 (1) = 15,279; p < 0.05; OR = 57,900 (9,465-354,180)). Screening 2, screening 3, and screening 4 were predictive for noncongenital heart diseases (χ 2 (1) = 11,550; p < 0.05; OR = 65,744 (10,413-415,097)). Combined screenings 2-4 were predictive for both congenital heart disease and noncongenital heart disease (χ 2 (1) = 22,155; p < 0.05; OR = 117,685 (12,972-1067,648)). Conclusions: Combining peripheral saturation with the peripheral perfusion index in the first 24 hours of life shows a predictive role in the detection of minor congenital heart diseases and neonatal clinical conditions whose care needs attention.

Pediatric Multisystem Syndrome Associated with SARS-CoV-2 (MIS-C): The Interplay of Oxidative Stress and Inflammation.

Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (MIS-C) is characterized by persistent fever and evidence of single or multiorgan dysfunction, and laboratory evidence of inflammation, elevated neutrophils, reduced lymphocytes, and low albumin. The pathophysiological mechanisms of MIS-C are still unknown. Proinflammatory mediators, including reactive oxygen species and decreased antioxidant enzymes, seems to play a central role. Virus entry activates NOXs and inhibits Nrf-2 antioxidant response inducing free radicals. The biological functions of nonphagocytic NOXs are still under study and appear to include: defense of epithelia, intracellular signaling mechanisms for growth regulation and cell differentiation, and post-translational modifications of proteins. This educational review has the aim of analyzing the newest evidence on the role of oxidative stress (OS) in MIS-C. Only by relating inflammatory mediators to OS evaluation in children following SARS-CoV-2 infection will it be possible to achieve a better understanding of these mechanisms and to reduce long-term morbidity. The link between inflammation and OS is key to developing effective prevention strategies with antioxidants to protect children.

Management of pain in newborn circumcision: a systematic review.

Male circumcision (MC) is one of the most common surgical procedures performed on neonates. In the last decades, there have been consistent advances in the understanding of pain mechanisms in newborns, and analgesia has become a fundamental part of neonatal care. MC is still often performed with inappropriate analgesic methods, and there is still great variability among the various centers about surgical and anesthethic techniques to do it. The purpose of this review is to summarize the findings in the literature about pain management and analgesia during newborn MC. We performed a systematic review of neonatal MC studies published in the last 20 years. The most effective technique appeared to be the combination of pharmacological and non-pharmacological methods of analgesia.Conclusion: Combining local anesthesia with non-pharmacological analgesic strategies appears to be effective preventing procedural pain during MC. However, a standardized protocol for analgesia during MC is yet to be determined. Sensorial saturation appeared to help when used in conjunction with the local anesthesia techniques. What is Known: • Male circumcision is a painful procedure and it is frequently performed with inappropriate analgesic methods. • A gold standard practice in analgesia during male circumcision is still lacking and there is a great variability in the modus operandi between centers. What is New: • The combination of RB + EMLA + sucrose appears to be an analgesic strategy superior to other approaches. • We advocate for the integration of sensorial saturation during male circumcision in order to improve the efficacy of current analgesic practices.

The challenge to define the optimal prophylactic regimen for vitamin K deficiency bleeding in infants.

Infants are at risk of vitamin K deficiency that may lead to vitamin K deficiency bleeding (VKDB). Although many vitamin K prophylactic regimens have been developed throughout the years, still cases of late form VKBD may occur. The introduction of combined prophylactic strategy with prolonged oral prophylaxes after the intramuscular dose at birth has showed a decrease of the late severe VKDB incidence. Nevertheless, there is still lack of consensus about the administration scheme after the first dose at birth. CONCLUSION: Late form VKBD is not eradicated, and the best prophylactic regimen in term and preterm infants is still an open debate.

Review of guidelines and recommendations from 17 countries highlights the challenges that clinicians face caring for neonates born to mothers with COVID-19.

AIM: This review examined how applicable national and regional clinical practice guidelines and recommendations for managing neonates born to mothers with COVID-19 mothers were to the evolving pandemic. METHODS: A systematic search and review identified 20 guidelines and recommendations that had been published by May 25, 2020. We analysed documents from 17 countries: Australia, Brazil, Canada, China, France, India, Italy, Japan, Saudi Arabia, Singapore, South Africa, South Korea, Spain, Sweden, Switzerland, the UK and the United States. RESULTS: The documents were based on expert consensus with limited evidence and were of variable, low methodological rigour. Most did not provide recommendations for delivery methods or managing symptomatic infants. None provided recommendations for post-discharge assimilation of potentially infected infants into the community. The majority encouraged keeping mothers and infants together, subject to infection control measures, but one-third recommended separation. Although breastfeeding or using breastmilk was widely encouraged, two countries specifically prohibited this. CONCLUSION: The guidelines and recommendations for managing infants affected by COVID-19 were of low, variable quality and may be unsustainable. It is important that transmission risks are not increased when new information is incorporated into clinical recommendations. Practice guidelines should emphasise the extent of uncertainty and clearly define gaps in the evidence.

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 are 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 hour 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 hours 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.

Identification of a panel of cytokines in neonates with hypoxic ischemic encephalopathy treated with hypothermia.

PURPOSE: Inflammation is a crucial but understudied mechanism of neuronal injury after hypoxia-ischemia. The aim was to identify a panel of cytokines involved in brain injury in neonates with hypoxic ischemic encephalopathy (HIE). METHODS: Ten newborns with HIE undergoing to therapeutic hypothermia (TH, HIE Group) and 8 healthy newborns (CTRL Group) were enrolled. For the HIE group, 5 samples were collected: between 0 and 6 h of life (time 1), 12 h (time 2), 24 h (time 3), 48 h (time 4) and 96 h of life (time 5). For the CTRL group, one sample was collected. A panel of 48 inflammatory cytokines was determined in all samples. Data were analyzed using multivariate statistical analysis (Principal component analysis, PCA) RESULTS: 17 cytokines, among 48 analyzed, were found to be significantly different, initially, between the CTRL and HIE groups: 12 with reported pro-inflammatory effects and 5 with reported anti-inflammatory effects. In the HIE group cytokines showed a decreasing trend during the TH and at the end of treatment comparable to the CTRL group. IL-18 did demonstrate a slight increase at time 3 during HT but decreased steadily at sampling times, 4 and 5. CONCLUSIONS: Our data demonstrates that many pathways of the inflammatory cascade are activated following hypoxic-ischemic injury. This information will increase our understanding of changes in cytokines over time in neonates with HIE undergoing TH.

Effects of early nutrition and growth on brain volumes, white matter microstructure, and neurodevelopmental outcome in preterm newborns.

BackgroundThis study aimed to investigate the effect of nutrition and growth during the first 4 weeks after birth on cerebral volumes and white matter maturation at term equivalent age (TEA) and on neurodevelopmental outcome at 2 years' corrected age (CA), in preterm infants.MethodsOne hundred thirty-one infants born at a gestational age (GA) <31 weeks with magnetic resonance imaging (MRI) at TEA were studied. Cortical gray matter (CGM) volumes, basal ganglia and thalami (BGT) volumes, cerebellar volumes, and total brain volume (TBV) were computed. Fractional anisotropy (FA) in the posterior limb of internal capsule (PLIC) was obtained. Cognitive and motor scores were assessed at 2 years' CA.ResultsCumulative fat and enteral intakes were positively related to larger cerebellar and BGT volumes. Weight gain was associated with larger cerebellar, BGT, and CGM volume. Cumulative fat and caloric intake, and enteral intakes were positively associated with FA in the PLIC. Cumulative protein intake was positively associated with higher cognitive and motor scores (all P<0.05).ConclusionOur study demonstrated a positive association between nutrition, weight gain, and brain volumes. Moreover, we found a positive relationship between nutrition, white matter maturation at TEA, and neurodevelopment in infancy. These findings emphasize the importance of growth and nutrition with a balanced protein, fat, and caloric content for brain development.

Changes in brain morphology and microstructure in relation to early brain activity in extremely preterm infants.

Background and ObjectiveTo investigate the relation of early brain activity with structural (growth of the cortex and cerebellum) and white matter microstructural brain development.MethodsA total of 33 preterm neonates (gestational age 26±1 weeks) without major brain abnormalities were continuously monitored with electroencephalography during the first 48 h of life. Rate of spontaneous activity transients per minute (SAT rate) and inter-SAT interval (ISI) in seconds per minute were calculated. Infants underwent brain magnetic resonance imaging ∼30 (mean 30.5; min: 29.3-max: 32.0) and 40 (41.1; 40.0-41.8) weeks of postmenstrual age. Increase in cerebellar volume, cortical gray matter volume, gyrification index, fractional anisotropy (FA) of posterior limb of the internal capsule, and corpus callosum (CC) were measured.ResultsSAT rate was positively associated with cerebellar growth (P=0.01), volumetric growth of the cortex (P=0.027), increase in gyrification (P=0.043), and increase in FA of the CC (P=0.037). ISI was negatively associated with cerebellar growth (P=0.002).ConclusionsIncreased early brain activity is associated with cerebellar and cortical growth structures with rapid development during preterm life. Higher brain activity is related to FA microstructural changes in the CC, a region responsible for interhemispheric connections. This study underlines the importance of brain activity for microstructural brain development.

Rooming-in Reduces Salivary Cortisol Level of Newborn.

BACKGROUND: Rooming-in practice improves breastfeeding and reduces newborn stress reactivity. When this modality is not available, partial rooming-in after birth can be considered. Salivary cortisol levels (SCLs) are considered reliable biomarkers to indicate stress. OBJECTIVE: To test the hypothesis that rooming-in duration impacts neonatal stress response in hospitalized newborns. DESIGN/METHODS: Forty term newborns, enrolled in the Neonatology and Obstetrics Nursing, C.G. Ruesch, Naples, Italy, were divided, according to the mother's choice, into the study (SG; n = 20) and control (CG; n = 20) groups if they received full (24 hs) or partial (14 hs) rooming-in care, respectively. Saliva samples were collected from all babies between 7:00 a.m. and 8:00 a.m. of the 3rd day of life by using oral swab. Salivary cortisol levels were measured using an enzyme immunoassay kit (Salimetrics LLC, PA, USA). RESULTS: A statistically significant difference in the SCLs between SG and CG was found (median: 258 ng/dl versus 488.5 ng/dl; p = 0.048). CONCLUSIONS: Data support the practice of full rooming-in care compared with partial rooming-in. The rooming-in duration clearly reduces SCLs and likely neonatal stress. These lower SCLs may have long-term positive effects reducing the risk of metabolic syndrome, high blood pressure, and cognitive and behavioural changes.

Regional differences of hypothermia on oxidative stress following hypoxia-ischemia: a study of DHA and hypothermia on brain lipid peroxidation in newborn piglets.

Background Oxidative stress plays an important part in the pathophysiology of hypoxic-ischemic encephalopathy (HIE) and is reliably measured through prostanoids following lipid peroxidation of polyunsaturated fatty acids (PUFAs). The aim of the study is to measure oxidative stress in the prefrontal cortex, white matter and hippocampus in the brains of hypoxic-ischemic piglets treated with docosahexaenoic acid (DHA) and therapeutic hypothermia (TH) and investigate the additive effects of DHA on hypothermia by factorial design. Methods Fifty-five piglets were randomized as having severe global hypoxia (n=48) or not (sham, n=7). Hypoxic piglets were further randomized: vehicle (VEH), DHA, VEH+hypothermia (HT) or HT+DHA. A total of 5 mg/kg DHA was given intravenously 210 min after the end of hypoxia. Brain tissues were analyzed using liquid chromatography triple quadrupole mass spectrometry technique (LC-MS). A two-way analysis of variance (ANOVA) was performed with DHA and HT as main effects. Results In the white matter, we found main effects of DHA on DH-isoprostanes (P=0.030) and a main effect of HT on F4-neuroprostanes (F4-NeuroPs) (P=0.007), F2-isoprostanes (F2-IsoPs) (P=0.043) and DH-isoprostanes (P=0.023). In the cortex, the ANOVA analysis showed the interactions of main effects between DHA and HT for neurofuranes (NeuroFs) (P=0.092) and DH-isoprostanes (P=0.015) as DHA significantly reduced lipid peroxidation in the absence of HT. DHA compared to VEH significantly reduced NeuroFs (P=0.019) and DH-isoprostanes (P=0.010). No differences were found in the hippocampus. Conclusion After severe hypoxia, HT reduced lipid peroxidation in the white matter but not in the cortical gray matter. HT attenuated the reducing effect of DHA on lipid peroxidation in the cortex. Further studies are needed to determine whether DHA can be an effective add-on therapy for TH.

Rapid modulation of the silent information regulator 1 by melatonin after hypoxia-ischemia in the neonatal rat brain.

Increasing evidence indicates that melatonin possesses protective effects toward different kinds of damage in various organs, including the brain. In a neonatal model of hypoxia-ischemia (HI), melatonin was neuroprotective and preserved the expression of the silent information regulator 1 (SIRT1) 24 hours after the insult. This study aimed to gain more insight into the role of SIRT1 in the protective effect of melatonin after HI by studying the early (1 hour) modulation of SIRT1 and its downstream targets, and the consequences on necrosis, apoptosis, autophagy, and glial cell activation. We found that melatonin administered 5 minutes after the ischemic insult significantly reduced necrotic cell death assessed 1 hour after its administration. In parallel, we found a reduced activation of the early phases of intrinsic apoptosis, detected by reduced BAX translocation to the mitochondria and preservation of the mitochondrial expression of cytochrome C, indicating a reduced outer mitochondrial membrane permeabilization in the melatonin-treated ischemic animals. These effects were concomitant to increased expression and activity of SIRT1, reduced expression and acetylation of p53, and increased autophagy activation. Melatonin also reduced HI-induced glial cells activation. SIRT1 was expressed in neurons after HI and melatonin but not in reactive glial cells expressing GFAP. Colocalization between SIRT1 and GFAP was found in some cells in control conditions. In summary, our results provide more insight into the connection between SIRT1 and melatonin in neuroprotection. The possibility that melatonin-induced SIRT1 activity might contribute to differentiate neuronal progenitor cells during the neurodegenerative process needs to be further investigated.

Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial.

BACKGROUND: Retinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1). METHODS: A multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23-32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations. DISCUSSION: Propranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014-005472-29.

Oxidative Stress Biomarkers: Establishment of Reference Values for Isoprostanes, AOPP, and NPBI in Cord Blood.

Oxidative stress (OS) is a common pathogenic factor involved in the onset of several diseases in humans, from immunologic disorders to malignancy, being a serious public health problem. In perinatal period, OS has been associated with adverse outcome of pregnancy and neonatal diseases. Dangerous effects of OS are mediated by increased production of free radicals (FRs) following various mechanisms, such as hypoxia, ischemia reperfusion, hyperoxia, inflammation, mitochondrial dysfunction, Fenton chemistry, and prostaglandin metabolism. FRs have short half-life, and their measurement in vivo is faced with many challenges. However, oxyradical derivatives are stable and thus may be measured and monitored repeatedly. The quantification of OS is based on the measurement of specific biomarkers in biologic fluids and tissues, which reflect induced oxidative damage to lipids, proteins, and DNA. Prostanoids, non-protein-bound iron (NPBI), and advanced oxidation protein products (AOPP) are actually considered truly specific and reliable for neonatal injury. Defining reference values for these biomarkers is necessary to investigate their role in neonatal diseases or also to evaluate the success of treatments. In this work, we wanted to define laboratory reference values for biomarkers of OS in a healthy population of term newborns.

Melatonin Secretion Is Increased in Children with Severe Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability in children. Oxidative stress plays a significant role in brain damage and melatonin exhibits both direct and indirect antioxidant effects. The primary aim of the present study was to evaluate serum melatonin levels in children with severe TBI in comparison to critically ill children admitted to the Pediatric Intensive Care Unit for conditions other than TBI. METHODS: Twenty-four children were evaluated, equally divided into severe TBI and no-TBI. Blood samples for serum melatonin analysis were collected at 22:00, 01:00, 03:00, 05:00, 08:00, and 12:00. RESULTS: Mean serum melatonin peaks in children of the TBI group were higher compared to the values of no-TBI critically ill children (495 ± 102 vs. 294 ± 119 pg/mL, p = 0.0002). Furthermore, the difference was even more significant in comparison to values reported in literature for healthy age-matched children (495 ± 102 vs. 197 ± 71 pg/mL, p < 0.0001). CONCLUSION: This study has shown that endogenous serum melatonin levels dramatically increase in children after severe TBI. This elevation is likely to represent a response to oxidative stress and/or inflammation due to severe head injury.

Melatonin Pharmacokinetics Following Oral Administration in Preterm Neonates.

Melatonin possesses potential efficacy in perinatal brain injuries, and has been proposed as adjunctive pharmacological therapy in combination with hypothermia in the clinical setting. However, the pharmacokinetics of melatonin in preterm and term newborns is still unknown. The aim of this study was to analyze the pharmacokinetics of melatonin after intragastric administration in preterm infants. Preterm newborns were enrolled 24-72 h after birth, and randomly assigned to three groups receiving a single bolus of 0.5 mg·kg-1 melatonin, or 3 boluses of 1 or 5 mg·kg-1 of melatonin at 24-h intervals. Blood samples were collected before and at selective times after melatonin administration. The half-life of melatonin in plasma ranged from 7.98 to 10.94 h, and the area under the curve (AUC) from 10.48 to 118.17 µg·mL-1·h-1. Our results indicate a different pharmacokinetic profile in premature newborns, compared to adults and experimental animals. The high peak plasma concentrations and the long half-life indicate that in the neonatal clinical setting, it is possible to obtain and maintain high serum concentrations using a single administration of melatonin repeated every 12/24 h.