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AIM: The aim of this study was to assess the resuscitators' opinions of the usefulness and clinical value of using a respiratory function monitor (RFM) when resuscitating extremely preterm infants with positive pressure ventilation. METHODS: The link to an online survey was sent to 106 resuscitators from six countries who were involved in a multicentre trial that compared the percentage of inflations within a predefined target range with and without the RFM. The resuscitators were asked to assess the usefulness and clinical value of the RFM. The survey was online for 4 months after the trial ended in May 2019. RESULTS: The survey was completed by 74 (70%) resuscitators of which 99% considered the RFM to be helpful during neonatal resuscitation and 92% indicated that it influenced their decision-making. The majority (76%) indicated that using the RFM improved their practice and made resuscitation more effective, even when the RFM was not available. Inadequate training was the key issue that limited the effectiveness of the RFM: 45% felt insufficiently trained, and 78% felt more training in using and interpreting the RFM would have been beneficial. CONCLUSION: Resuscitators considered the RFM to be helpful to guide neonatal resuscitation, but sufficient training was required to achieve the maximum benefit.

Infants with moderate and severe neonatal encephalopathy (NE) frequently suffer from long-term adverse outcomes. We hypothesize that the urinary metabolome of newborns with NE reflects the evolution of injury patterns observed with magnetic resonance imaging (MRI).Eligible patients were newborn infants with perinatal asphyxia evolving to NE and qualifying for therapeutic hypothermia (TH) included in the HYPOTOP trial. MRI was employed for characterizing brain injury. Urine samples of 55 infants were collected before, during, and after TH. Metabolic profiles of samples were recorded employing three complementary mass spectrometry-based assays, and the alteration of detected metabolic features between groups was assessed.The longitudinal assessment revealed significant perturbations of the urinary metabolome. After 24 h of TH, a stable disease pattern evolved characterized by the alterations of 4-8% of metabolic features related to lipid metabolism, metabolism of cofactors and vitamins, glycan biosynthesis and metabolism, amino acid metabolism, and nucleotide metabolism. Characteristic metabolomic fingerprints were observed for different MRI injury patterns.This study shows the potential of urinary metabolic profiles for the noninvasive monitoring of brain injury of infants with NE during TH.A comprehensive approach for the study of the urinary metabolome was employed involving a semi-targeted capillary electrophoresis-time-of-flight mass spectrometry (TOFMS) assay, an untargeted ultra-performance liquid chromatography (UPLC)-quadrupole TOFMS assay, and a targeted UPLC-tandem MS-based method for the quantification of amino acids. The longitudinal study of the urinary metabolome identified dynamic metabolic changes between birth and until 96 h after the initiation of TH. The identification of altered metabolic pathways in newborns with pathologic MRI outcomes might offer the possibility of developing noninvasive monitoring approaches for personalized adjustment of the treatment and for supporting early outcome prediction.

AIM: To determine whether the use of a respiratory function monitor (RFM) during PPV of extremely preterm infants at birth, compared with no RFM, leads to an increase in percentage of inflations with an expiratory tidal volume (Vte) within a predefined target range. METHODS: Unmasked, randomised clinical trial conducted October 2013 - May 2019 in 7 neonatal intensive care units in 6 countries. Very preterm infants (24-27 weeks of gestation) receiving PPV at birth were randomised to have a RFM screen visible or not. The primary outcome was the median proportion of inflations during manual PPV (face mask or intubated) within the target range (Vte 4-8 mL/kg). There were 42 other prespecified monitor measurements and clinical outcomes. RESULTS: Among 288 infants randomised (median (IQR) gestational age 26+2 (25+3-27+1) weeks), a total number of 51,352 inflations were analysed. The median (IQR) percentage of inflations within the target range in the RFM visible group was 30.0 (18.0-42.2)% vs 30.2 (14.8-43.1)% in the RFM non-visible group (p = 0.721). There were no differences in other respiratory function measurements, oxygen saturation, heart rate or FiO2. There were no differences in clinical outcomes, except for the incidence of intraventricular haemorrhage (all grades) and/or cystic periventricular leukomalacia (visible RFM: 26.7% vs non-visible RFM: 39.0%; RR 0.71 (0.68-0.97); p = 0.028). CONCLUSION: In very preterm infants receiving PPV at birth, the use of a RFM, compared to no RFM as guidance for tidal volume delivery, did not increase the percentage of inflations in a predefined target range. TRIAL REGISTRATION: Dutch Trial Register NTR4104, clinicaltrials.gov NCT03256578.

Background and Objectives: Therapeutic interventions to improve the efficacy of whole-body cooling for hypoxic-ischemic encephalopathy (HIE) are desirable. Topiramate has been effective in reducing brain damage in experimental studies. However, in the clinical setting information is limited to a small number of feasibility trials. We launched a randomized controlled double-blinded topiramate/placebo multicenter trial with the primary objective being to reduce the antiepileptic activity in cooled neonates with HIE and assess if brain damage would be reduced as a consequence. Study Design: Neonates were randomly assigned to topiramate or placebo at the initiation of hypothermia. Topiramate was administered via a nasogastric tube. Brain electric activity was continuously monitored. Topiramate pharmacokinetics, energy-related and Krebs’ cycle intermediates, and lipid peroxidation biomarkers were determined using liquid chromatography-mass spectrometry and MRI for assessing brain damage. Results: Out of 180 eligible patients 110 were randomized, 57 (51.8%) to topiramate and 53 (48.2%) to placebo. No differences in the perinatal or postnatal variables were found. The topiramate group exhibited less seizure burden in the first 24 h of hypothermia (topiramate, n = 14 [25.9%] vs. placebo, n = 22 [42%]); needed less additional medication, and had lower mortality (topiramate, n = 5 [9.2%] vs. placebo, n = 10 [19.2%]); however, these results did not achieve statistical significance. Topiramate achieved a therapeutic range in 37.5 and 75.5% of the patients at 24 and 48 h, respectively. A significant association between serum topiramate levels and seizure activity (p < 0.016) was established. No differences for oxidative stress, energy-related metabolites, or MRI were found. Conclusions: Topiramate reduced seizures in patients achieving therapeutic levels in the first hours after treatment initiation; however, they represented only a part of the study population. Our results warrant further studies with higher loading and maintenance dosing of topiramate.

Therapeutic hypothermia (TH) initiated within 6 h from birth is the most effective therapeutic approach for moderate to severe hypoxic-ischemic encephalopathy (HIE). However, underlying mechanisms and effects on the human metabolism are not yet fully understood. This work aims at studying the evolution of several energy related key metabolites in newborns with HIE undergoing TH employing gas chromatography - mass spectrometry. The method was validated following stringent FDA requirements and applied to 194 samples from a subgroup of newborns with HIE (N = 61) enrolled in a multicenter clinical trial (HYPOTOP) for the determination of lactate, pyruvate, ketone bodies and several Krebs cycle metabolites at different sampling time points. The analysis of plasma samples from newborns with HIE revealed a decrease of lactate, pyruvate and β-hydroxybutyrate concentrations, whereas rising malate concentrations were observed. In healthy control newborns (N = 19) significantly lower levels of pyruvate and lactate were found in comparison to age-matched newborns with HIE undergoing TH, whereas acetoacetate and β-hydroxybutyrate levels were clearly increased. Access to a validated analytical method and a controlled cohort of newborns with HIE undergoing hypothermia treatment for the first time allowed the in-depth study of the evolution of key metabolites of metabolic junctions in this special population., MV acknowledges the EC11-244 grant from the Instituto Carlos III. ANR acknowledges a research contract by the Spanish Maternal, Neonatal and Developmental Network SAMID RETICS funded by the PN 2018–2011 (Spain), ISCIII-Sub-Directorate General for Research Assessment and Promotion and the European Regional Development Fund (FEDER), reference RD12/0026. JK, MCe and ASI are grateful for their personal grants from the Instituto Carlos III (grant numbers CP16/00034, JR16/00038 and FI16/00380, respectively). APL acknowledges her personal grant from the Health Research Institute La Fe (CPR2015/0371)

Aims Pulmonary interstitial emphysema is a severe complication of mechanical ventilation in preterm infants that leads to air leakage and, or, chronic lung disease. We determined the associated risk factors. Methods This was a retrospective case-control study from 2005-2014 at a regional referral centre in Valencia, Spain. The cases were 54 preterm infants up to 30 weeks’ gestation and, or, born weighing less than 1,500g, who were diagnosed with pulmonary interstitial emphysema (PIE). The 54 controls were preterm infants without PIE matched by gestational age. Univariate analysis and multivariate analysis were performed to assess the independent predicting factors. Results Infants with PIE had been resuscitated with higher mean fractional inspired oxygen concentration (FiO2) (p=0.008), had received higher peak mean positive end expiratory pressure (p=0.00) and higher mean airway pressure (p=0.026) 24 hours before diagnosis. PIE patients also received more surfactant (p=0.00) and had higher mortality (p=0.034). A Cox regression model identified that independent risk factors were the total amount of surfactant administered and the mean FiO2 during the 24 hours before diagnosis. Conclusion Independent risk factors for pulmonary interstitial emphysema in preterm infants were higher oxygen during resuscitation and a higher need for surfactant and ventilatory pressures before diagnosis. This article is protected by copyright. All rights reserved.

International audience; Pasteurized donor human milk (DHM) is the preferred alternative for infant nutrition when own mother's milk (OMM) is unavailable. Whether DHM is an efficient means for protecting preterm infants from oxidative stress remains unknown. We quantified a panel of oxidative stress biomarkers in urine samples from preterm infants (≤32 weeks of gestation and a birth weight ≤1500 g) receiving ≥80% of feeding volume as either DHM or OMM. The noninvasive in vivo assessment of oxidative stress showed no statistically significant difference between both groups at the time when full enteral nutrition (150 mL/kg body weight) was achieved and until hospital discharge. In addition, the changes of urinary biomarker levels with time were assessed. This is the first longitudinal study on oxidative stress levels in preterm infants fed with DHM in comparison with OMM. There is no statistically significant difference in urinary oxidative stress levels of preterm infants from both groups indicating that despite the effects of pasteurization, DHM is a valid alternative when OMM is not available. Based on the results, we raise the hypothesis that pasteurized DHM protects preterm infants from oxidative stress as good as OMM, and consequently, its use could prevent oxidative stress-related diseases. Antioxid. Redox Signal. 31, 791-799.

Byproducts of arachidonic (AA) and docosahexaenoic acid (DHA) oxidation are highly relevant for the study of free radical associated conditions in the perinatal period. Plasma metabolites can provide the clinician with a snapshot of the oxidant status of patients before and after specific clinical interventions (e.g.: supplementation with oxygen). We describe a new andreliable ultra-performance liquid mass spectrometry method to determine F2-isoprostanes and other byproducts (isoprostanes, isofurans, neuroprostanes, neurofurans) in newborn serum samples. Cord blood samples were obtained from severely depressed newborn infants (Apgar score 1 min < 3; arterial cord pH < 7.00), and aliquoted for serum determination and stored at -80 degrees C. AUHPLC-MS/MS method was employed. It has a series of technical advantages: simple sample treatment; reduced sample volume (100 mu L) which is essential for preterm neonates with low circulating blood volume, high throughput of sample analysis (96 samples in less than 24 h) and high selectivity for different isoprostanes isomers. Excellent sensitivity was achieved within limits of detection between 0.06 and 4.2 nmol L-1, which renders this method suitable to monitoranalyte concentration in newborn samples. The method's precision was satisfactory; with coefficients of variation around 5-12% (intra-day) and 7-17% (inter-day). The reliability of the described method was assessed by analysis of spiked serum samples obtaining recoveries between 70% and 120%. The proposed method has rendered suitable for serum determination for newborn babies at risk of oxygen free radical associated conditions. (C) 2015 Elsevier B.V. All rights reserved.

Background: The therapeutic decision to close patent ductus arteriosus in preterm infants entails great uncertainty. Near-infrared spectroscopy is a noninvasive bedside technique used to monitor mixed regional oxygen saturation. We hypothesized that near-infrared spectroscopy could identify preterm infants at risk of mesenteric hypoperfusion associated with hemodynamically significant ductus arteriosus. Methods: This is a prospective observational study including consecutively admitted preterm infants with a gestational age Results: A total of 72 preterm infants were enrolled. The daily mean regional oxygen saturation for preterm infants was determined both in mesenteric and cerebral regions and plotted against time. We identified a differential temporary baseline. Hemodynamic significant ductus arteriosus was associated with lower blood pressures and lower regional splanchnic oxygenation. There was a significant relationship between reversal diastolic flow in the descending aorta and the regional oxygen saturation, which remained significant after controlling for ductal size and nil per os. Conclusions: The simultaneous monitoring of splanchnic near-infrared spectroscopy and echocardiography could identify low mesenteric perfusion in the presence of hemodynamic ductus arteriosus.

Objectives To determine whether the amount of oxygen provided during postnatal stabilization changes the DNA methylome in preterm infants. Study design This prospective, observational study included 32 preterm infants 500 mLO(2)/kg changed the methylation pattern of the selected CpGs. Genes associated with these CpGs were "enriched" in KEGG pathways involved in cell cycle progression, DNA repair, and oxidative stress. Conclusions The oxygen load provided upon resuscitation modified the DNA methylome. Differential methylation may lead to altered expression of genes related to cell cycle progression, oxidative stress, and DNA repair. The reversibility of these early epigenetic changes is unknown but merits further study.

Intra-amniotic infection/inflammation (IAI) is associated with preterm birth, short and long-term adverse clinical outcomes and oxidative stress. The diagnosis of IAI is based on histological and clinical findings; however, often these results are unspecific. Therefore, efforts have been directed towards validating reliable methods for patients lacking overt clinical symptoms. In this study, amniotic fluid (AF) samples were prospectively collected from 23 women grouped into two categories (with or without IAI) following clinical, microbiological and histological criteria. AFs were analyzed using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for the determination of the following biomarkers: oxidized and nitrated tyrosines (Tyr), 8-hydroxy-2'-deoxyguanosine (8OHdG), oxidized glutathione (GSSG) and glutathione sulfonamide (GSA). 3-NO2-Tyrosine (3NO2-Tyr) and GSSG concentrations in AF were not identified as significantly relevant biomarkers in the presence of IAI. However, inflammatory biomarkers such as GSA (p=0.002) and 3-Chloro-Tyrosine [3Cl-Tyr (p=0.049)], and oxidative stress biomarker 8OHdG (p=0.021) were significantly increased in AF with IAI as compared to normal controls. Biomarkers of inflammation and oxidative stress determined in AF samples could represent a new approach towards an early diagnosis of IAI and subsequent chorioamnionitis in the clinical setting.