Oxidative stress - Related spontaneous preterm delivery challenges in causality determination, prevention and novel strategies in reduction of the sequelae

Spontaneous preterm birth (PTB) is one of the major complications of pregnancy and the main cause of neonatal mortality and morbidity. Despite the efforts devoted to the understanding of this obstetrical syndrome and improved medical care, there has been a tendency for the PTB rate to increase in the last decades globally. The costs of the screening for spontaneous PTB, its management, and treatment of the sequelae represent a major burden to the health service economy of high-income countries. In this scenario, it has been widely acknowledged that oxidative stress (OS) plays an important role in the pathogenicity of human disease in wide range of areas of medicine. There is an emerging evidence that an imbalance between pro-and-antioxidants may be associated with spontaneous PTB. However, there are still many controversies on the mechanisms by which OS are involved in the pathogenesis of prematurity. Moreover, the crucial question whether the OS is the cause or consequence of the disease is yet to be answered. The purpose of this article is to briefly summarize the current knowledge and controversies on oxidative stress-related spontaneous PTB and to give a critical approach on future perspectives on this topic as a classical example of translational medicine. Placenta-mediated pregnancy adverse outcome associated with OS leading to iatrogenic PTB (e.g. pre-eclampsia, intrauterine growth restriction, gestational diabetes) will not be discussed.Peer reviewe

A Review of Oxygen Use During Chest Compressions in Newborns—A Meta-Analysis of Animal Data

Background: International consensus statements for resuscitation of newborn infants recommend provision of 100% oxygen once chest compressions are required. However, 100% oxygen exacerbates reperfusion injury and reduces cerebral perfusion in newborn babies.Objective: We aimed to establish whether resuscitation with air during chest compression is feasible and safe in newborn infants compared with 100% oxygen.Methods: Systematic search of PubMed, Google Scholar and CINAHL for articles examining variable oxygen concentrations during chest compressions in term newborns.Results: Overall, no human studies but eight animal studies (n = 323 animals) comparing various oxygen concentrations during chest compression were identified. The pooled analysis showed no difference in mortality rates for animals resuscitated with air vs. 100% oxygen (risk ratio 1.04 [0.35, 3.08], I2 = 0%, p = 0.94). ROSC was also similar between groups with a mean difference of −3.8 [−29.7–22] s, I2 = 0%, p = 0.77. No difference in oxygen damage or adverse events were identified between groups.Conclusions: Air had similar time to ROSC and mortality as 100% oxygen during neonatal chest compression. A large randomized controlled clinical trial comparing air vs. 100% oxygen during neonatal chest compression is warranted

Reference ranges for SpO2, respiratory rate, and tidal volume in term newborn infants after birth: a narrative review

Background and Objective: Post-natal adaptation implies respiratory and hemodynamic changes that contribute to the successful switching from transplacental to lung-based respiration and from serial to parallel circulation after cord clamping. Initial respiratory efforts extrude lung fluid to the interstitial space, facilitate alveolar aeration, and alveolar-capillary gas exchange contributing to an increase in the arterial partial pressure of oxygen (paO2). Consequently, there is a decrease in pulmonary vascular resistance and the closure of the intra-and-extracardiac shunts. The establishment of a functional residual capacity contributes to the stabilization of the respiratory rate (RR) and the arterial paO2. This study sought to update the reference ranges for respiratory function, oxygen saturation, and heart rate (HR) to guide neonatologists in the stabilization and/or resuscitation of newborn infants in the delivery room (DR). Methods: Data on the respiratory function and oxygenation pattern of normal term infants in the stabilization period during the first minutes after birth were retrieved and stored by employing continuous pre-ductal pulse oximetry and respiratory function monitoring. The electronic databases searched included MEDLINE, Embase, CINAHL, and Scopus. Statistical methods were employed to establish the percentile curves for each parameter. Key Content and Findings: We provide data of HR and oxygen saturation measured by pulse oximetry and RR and tidal volume (VT) measured by a respiratory function monitor and recorded during the first 10 minutes after birth in healthy term infants. Post-natal respiratory and cardiorespiratory adaptation in healthy term babies is enhanced by delayed cord clamping. HR and oxygen saturation achieved values of 140–160 bpm and 90–95% in the first 2–3 minutes after birth, respectively, and a VT and RR between 5–10 minutes. Conclusions: Updated reference ranges for clinical parameters in the DR constitute a useful tool for guiding neonatologists in the stabilization of newborn infants.M Vento received PI20/00964 and RD16/0022/0001 grants, and the ILC CM20/00187 grant from the Health Research Institute Carlos III (Ministry of Science and Innovation; Kingdom of Spain).Medicin

Opinion Paper: Rationale for Supra-National Training in Neonatology

Introduction: Clinical training in neonatology takes place where neonates are cared for, at the cot-side, in neonatal units. Neonatal units vary widely in size, specialization, resources, staffing and academic level. Among them, small units make up a large proportion which have more difficulties to offer structured training courses on site, local expertise on all relevant neonatal topics, and appropriate exposition of the trainee to high-risk cases. Although evidence-based medicine is widely accepted, training of physicians, including neonatologists, often follows ineffective learning methods, or even less favorable, learning by doing. When looking at the national training requirements and standards within Europe, there are large differences between countries. Some countries have training requirements, standards and national training courses in place other countries have none of this. Therefore, it is worthwhile to create a supra-regional or even supra-national training program that complements local clinical work on an individual basis to provide structured training and evidence-based education anywhere and anytime. The European Society for Paediatric Research (ESPR) has long been committed to the education and training of medical doctors specializing in neonatology. Together with the European Board of Neonatology (EBN), which is a substructure of ESPR devoted to the design and implementation of a syllabus that comprises the theoretical and practical needs for the European Training in Neonatology, the European Training Requirements (ETR) in Neonatology has been developed. The 2021 updated syllabus, the current ETR in Neonatology, is based on the previous 2007 syllabus version and has been approved by the Union of European Medicine Specialist (EAMS) in April 2021. Interestingly, the 2021 syllabus content was updated by the EBN members, but also critically incorporated and comments suggestions of national representatives of 30 European countries following two sequential surveys and face to face meetings. Each country pertaining to the EBN has a different national training curriculum to achieve the training standards required to exert as neonatologists. The aim of the ETR in Neonatology has been to harmonize training requirements within Europe to achieving a basic and reliable standard of quality in theoretical knowledge and practical skills alongside the European countries. We present an online training concept that meets the needs of neonatal training situations and implements the latest effective didactic elements

Expired Tidal Volume and Respiratory Rate During Postnatal Stabilization of Newborn Infants Born at Term via Cesarean Delivery

Objective To retrieve evolving respiratory measures in the first minutes after birth in normal neonates born at term using a respiratory function monitor. Study design We evaluated newborn babies delivered at term via cesarean after uncomplicated pregnancies. Immediately after birth, a respiratory function monitor with an adapted flowmeter and a face mask were applied at 2, 5, and 10 minutes after birth for 90 seconds in each period. We analyzed expired and inspired tidal volume, respiratory rate (RR), percentage of leakage, and number of analyzed breaths in each individual infant’s recording using a respiratory research software. Results A total of 243 infants completed the study. The final data set included 59 058 (48.35%) valid observations for each of the variables representing the analysis of 32 801 breaths. With these data, we constructed a reference range with 10th, 25th, 50th, 75th, and 90th percentiles for expired tidal volume and RR. Tidal volumes plateaued earlier in female than in male infants. No correlation with delayed cord clamping, gestational age, maternal morbidity, or indication for cesarean delivery were established. Conclusions We have constructed a reference range with percentiles for inspired and expired tidal volumes and RR in newborn babies born at term for the first 10 minutes after birth. Reference ranges can be employed for research and can be useful in the clinical setting to guide positive pressure ventilation in the delivery room.Enfermerí

Protein Oxidation Biomarkers and Myeloperoxidase Activation in Cerebrospinal Fluid in Childhood Bacterial Meningitis

The immunological response in bacterial meningitis (BM) causes the formation of reactive oxygen and nitrogen species (ROS, RNS) and activates myeloperoxidase (MPO), an inflammatory enzyme. Thus, structural oxidative and nitrosative damage to proteins and DNA occurs. We aimed to asses these events in the cerebrospinal fluid (CSF) of pediatric BM patients. Phenylalanine (Phe), para-tyrosine (p-Tyr), nucleoside 2'-deoxiguanosine (2dG), and biomarkers of ROS/RNS-induced protein and DNA oxidation: ortho-tyrosine (o-Tyr), 3-chlorotyrosine (3Cl-Tyr), 3-nitrotyrosine (3NO(2)-Tyr) and 8-oxo-2'-deoxyguanosine (8OHdG), concentrations were measured by liquid chromatography coupled to tandem mass spectrometry in the initial CSF of 79 children with BM and 10 without BM. All biomarkers, normalized with their corresponding precursors, showed higher median concentrations (p <0.0001) in BM compared with controls, except 8OHdG/2dG. The ratios o-Tyr/Phe, 3Cl-Tyr/p-Tyr and 3NO(2)-Tyr/p-Tyr were 570, 20 and 4.5 times as high, respectively. A significantly higher 3Cl-Tyr/p-Tyr ratio was found in BM caused by Streptococcus pneumoniae, than by Haemophilus influenzae type b, or Neisseria meningitidis (p = 0.002 for both). In conclusion, biomarkers indicating oxidative damage to proteins distinguished BM patients from non-BM, most clearly the o-Tyr/Phe ratio. The high 3Cl-Tyr/p-Tyr ratio in pneumococcal meningitis suggests robust inflammation because 3Cl-Tyr is a marker of MPO activation and, indirectly, of inflammation.Peer reviewe

High Oxygen Does Not Increase Reperfusion Injury Assessed with Lipid Peroxidation Biomarkers after Cardiac Arrest: A Post Hoc Analysis of the COMACARE Trial

The products of polyunsaturated fatty acid peroxidation are considered reliable biomarkers of oxidative injury in vivo. We investigated ischemia-reperfusion-related oxidative injury by determining the levels of lipid peroxidation biomarkers (isoprostane, isofuran, neuroprostane, and neurofuran) after cardiac arrest and tested the associations between the biomarkers and different arterial oxygen tensions (PaO2). We utilized blood samples collected during the COMACARE trial (NCT02698917). In the trial, 123 patients resuscitated from out-of-hospital cardiac arrest were treated with a 10–15 kPa or 20–25 kPa PaO2 target during the initial 36 h in the intensive care unit. We measured the biomarker levels at admission, and 24, 48, and 72 h thereafter. We compared biomarker levels in the intervention groups and in groups that differed in oxygen exposure prior to randomization. Blood samples for biomarker determination were available for 112 patients. All four biomarker levels peaked at 24 h; the increase appeared greater in younger patients and in patients without bystander-initiated life support. No association between the lipid peroxidation biomarkers and oxygen exposure either before or after randomization was found. Increases in the biomarker levels during the first 24 h in intensive care suggest continuing oxidative stress, but the clinical relevance of this remains unresolved

High Oxygen Does Not Increase Reperfusion Injury Assessed with Lipid Peroxidation Biomarkers after Cardiac Arrest: A Post Hoc Analysis of the COMACARE Trial

The products of polyunsaturated fatty acid peroxidation are considered reliable biomarkers of oxidative injury in vivo. We investigated ischemia-reperfusion-related oxidative injury by determining the levels of lipid peroxidation biomarkers (isoprostane, isofuran, neuroprostane, and neurofuran) after cardiac arrest and tested the associations between the biomarkers and different arterial oxygen tensions (PaO2). We utilized blood samples collected during the COMACARE trial (NCT02698917). In the trial, 123 patients resuscitated from out-of-hospital cardiac arrest were treated with a 10–15 kPa or 20–25 kPa PaO2 target during the initial 36 h in the intensive care unit. We measured the biomarker levels at admission, and 24, 48, and 72 h thereafter. We compared biomarker levels in the intervention groups and in groups that differed in oxygen exposure prior to randomization. Blood samples for biomarker determination were available for 112 patients. All four biomarker levels peaked at 24 h; the increase appeared greater in younger patients and in patients without bystander-initiated life support. No association between the lipid peroxidation biomarkers and oxygen exposure either before or after randomization was found. Increases in the biomarker levels during the first 24 h in intensive care suggest continuing oxidative stress, but the clinical relevance of this remains unresolved

The Impact of Postnatal Systemic Steroids on the Growth of Preterm Infants: A Multicenter Cohort Study

Postnatal steroids, often used to prevent and treat bronchopulmonary dysplasia, may influence the growth of preterm infants, although data are scarce in the literature. This is a multicenter cohort study including surviving preterm infants <32 weeks at birth (n = 17,621) from the Spanish Neonatal Network SEN1500 database, without major congenital malformations. Linear regression models were adjusted for postnatal steroids, respiratory severity course (invasive mechanical ventilation at 28 days), progression to moderate-severe bronchopulmonary dysplasia (O2 at 36 weeks), length of stay, sex, gestational age and z-scores at birth. A subgroup analysis depending on the timing of administration, ventilation status at 28 days and moderate-severe BPD diagnosis was also performed. Overall, systemic postnatal steroids were not independently associated with poorer weight gain (0.1; 95% CI: -0.05 to 0.2 g/kg/day), linear growth (0; 95% CI: -0.03 to 0.01 cm/week) or head circumference growth (-0.01; 95% CI: -0.02 to 0 cm/week). Patients who received steroids after 28 days or who were not O2 dependent at 36 weeks after having received steroids gained more weight (0.22; 95% CI: 0.04 to 0.4 and 0.2; 95% CI: 0.004 to 0.5 g/kg/day, respectively). Globally, systemic postnatal steroids had no significant adjusted effect on postnatal growth