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S(+)‐ibuprofen (S‐IBU) and R(−)‐ibuprofen (R‐IBU) concentrations were measured in 16 neonates with patent ductus arteriosus during a cycle of therapy (three intravenous doses of 10–5–5 mg kg−1 at 24‐h intervals), at the end of the first infusion and 6, 24, 48, and 72 h later. Data were analyzed with a PK model that included enantiomer elimination rate constants and the R‐ to S‐IBU conversion rate constant. The T½ of S‐IBU in the newborn was much longer than in adults (41.8 vs. ≈2 h), whereas the T½ of R‐IBU appeared to be the same (2.3 h). The mean fraction of R‐ to S‐IBU conversion was much the same as in adults (0.41 vs. ≈0.60). S‐IBU concentrations measured 6 h after the first dose were higher than at the end of the infusion in 10 out of 16 cases, and in five cases, they remained higher even after 24 h. This behavior is unprecedented and may be attributable to a rapid R‐to‐S conversion overlapping with a slow S‐IBU elimination rate. In 13 of the 16 neonates, S‐IBU concentrations at 48 and/or 72 h were lower than expected, probably due to the rapid postnatal maturation of the newborn's liver metabolism.

This study aimed to prospectively evaluate the association between the appearance and evolution of retinopathy of prematurity (ROP) and selected blood parameters, focusing on platelets count. In total, 157 preterm consecutive babies screened for ROP were included and classified in: ROP necessitating treatment (group ROP1), ROP regressed without therapy (group ROP2) and no ROP (group no-ROP), divided in two phases for each group depending on gestational age. Blood parameters were weekly gathered and referred to postmenstrual age, ROP severity and phase. Platelet count mean values were statistically lower (p &lt, 0.001) during both phases in ROP1 group (179 × 109/L vs. 213 × 109/L in phase 1 and 2, respectively) vs. other groups (ROP2: 286 × 109/L vs. 293 × 109/L, no ROP: 295 × 109/L vs. 313 × 109/L). Platelet count at birth &lt, 181 × 109 was statistically associated with Type 1 ROP development and evolution (sensibility = 76.47%, 95% confidence interval 60.0–87.6, specificity = 66.12%, 95% confidence interval 57.3–73.9). In ROP 1 group, a platelets count mean value “spike” (392.6 × 109/L) was documented at 36 weeks of corrected gestational age, preceding the need for treatment performed at a median of 38.1 ± 3.2 weeks. Early birth thrombocytopenia is confirmed as a biomarker of development and progression of ROP requiring treatment. The increase of platelets count at 35–37 weeks of corrected gestational age can be considered a possible clinical biomarker anticipating Type 1 ROP progression in preterm infants.

To the Editor We read with interest the recent network meta-analysis by Ramaswamy et al1 comparing different corticosteroid regimens for preventing bronchopulmonary dysplasia (BPD) and the accompanying editorial by Parikh.2 The main result lies in the authors’ suggestion that moderately early (8 to 14 days) medium cumulative doses (2 to 4 mg/kg) of dexamethasone may be the most appropriate regimen for preventing BPD and mortality.1 Randomized clinical trials with dexamethasone administered in the first postnatal week were excluded from analysis. As the authors said, although the evidence is still of low quality, their findings are very useful to neonatologists in clinical practice. Our attention was drawn to a core question of how to treat preterm newborns at risk of BPD. All but one of the studies including dexamethasone in their analysis concerned infants treated with mechanical ventilation. The target population of the meta-analysis was infants who were very ill from birth with early persistent pulmonary deterioration. However, most preterm infants (even those with extremely low birth weight) are currently treated with noninvasive ventilation strategies from birth or after early extubation,3 and this has become a cornerstone of BPD prevention. A sizable proportion (51%) of neonates with mild respiratory disease at birth who are treated with noninvasive respiratory support are nonetheless still at risk of needing progressively increased oxygen supply and at risk of developing BPD.4 Should preterm neonates who are treated with noninvasive ventilation and who are at risk of BPD be considered eligible for a postnatal corticosteroid regimen like the one proposed by the authors of this network meta-analysis?1

Objectives To compare the efficacy of intra‐tracheal (IT) surfactant/budesonide (SB) with that of surfactant alone (S) in reducing the rate of bronchopulmonary dysplasia (BPD) at 36 weeks post‐menstrual age (PMA), we included extremely preterm very low birth weight (VLBW) infants with severe respiratory distress syndrome (RDS) in our tertiary neonatal level of care unit (Padua, Italy). Study Design A retrospective chart review of two cohorts of extremely preterm VLBW neonates (

Background Among infants needing urgent transfer after birth, very preterm infants are a high-risk sub-group requiring special attention. This study aimed to assess trends in early respiratory management in a large series of very preterm infants undergoing postnatal transfer. Methods Trends in patient characteristics and early respiratory management were assessed in 798 very preterm infants who were transferred by the Eastern Veneto Neonatal Emergency Transport Service in 2000-2019. Trends were analyzed using joinpoint regression analysis and summarized as annual percentage changes (APCs). Results Proportion of neonates with birth weight less than 1 kg decreased from 33% to 16% (APC -3.82%). Use of nasal-continuous-positive-airway pressure increased (at call: APC 15.39%; during transfer: APC 15.60%), while use of self-inflating bag (at call: APC -12.09%), oxygen therapy (at call: APC -13.00%; during transfer: APC -23.77%) and mechanical ventilation (at call: APC -2.71%; during transfer: APC -2.99%) decreased. Use of oxygen concentrations at 21% increased (at call: APC 6.26%; during transfer: APC 7.14%), while oxygen concentrations above 40% decreased (at call: APC -5.73%; at transfer APC -8.89%). Surfactant administration at call increased (APC 3%-10%), while surfactant administration when arriving at referring hospital remained around 7-11% (APC 2.55%). Conclusion Relevant trends toward "gentle" approaches in early respiratory management of very preterm infants undergoing postnatal transfer occurred during the last twenty years. In addition, the proportion of transferred extremely low birth weight infants halved. Clinicians and stakeholders should consider such information when allocating assets to both hospitals and transfer services and planning regional perinatal programs.

Background and Objective: Placing an endotracheal tube (ETT) in neonates is challenging and currently requires timely radiographic confirmation of correct tip placement. The objective was to establish the reliability of ultrasound (US) for assessing ETT position in the neonatal intensive care unit (NICU), time needed to do so, and patients’ tolerance. Methods: A prospective study on 71 newborns admitted to our NICU whose ETT placement was evaluated with US (ETT-echo) and confirmed on chest X-rays (CXR). Data were collected by 3 operators (2 neonatologists and a resident in pediatrics). The right pulmonary artery (RPA) was used as a landmark for US. The distance between the tip of the ETT and the upper margin of the RPA was measured using US and compared with the distance between the tube’s tip and the carina on the CXR. Results: Seventy-one intubated newborns were included in the study (n = 34 < 1,000 g, n = 18 1,000–2,000 g, n = 19 > 2,000 g). Statistical analysis (Bland-Altman plot and Lin’s concordance correlation coefficient) showed an excellent consistency between ETT positions identified on US and chest X-ray. The 2 measures (ETT-echo and CXR) were extremely concordant both in the whole sample and in the subgroups. Minimal changes in patients’ vital signs were infrequently observed during US, confirming the tolerability of ETT-echo. The mean time to perform US was 3.2 min (range 1–13). Conclusions: ETT-echo seems to be a rapid, tolerable, and highly reliable method worth further investigating for future routine use in neonatology with a view to reducing radiation exposure.

The neonatal Hub and Spoke (HandS) ECMO approach provides emergent ECMO implantation to support neonates in severe cardio-respiratory life-threatening conditions at secondary (Spoke) centers, and a safe transfer to the ECMO center (Hub). We report a retrospective review of 11 neonates fom January 2014 to January 2020, presenting with life-threatening conditions and treated by HandS ECMO team in Spoke hospitals. Protocols and checklists were arranged by a local group of ECMO experts and shared with all the hospitals located in North-Eastern Italy. At the emergent call, all patients were cared for at the Spoke hospitals, receiving maximal respiratory and cardiovascular support (including high frequency oscillatory ventilation, inhaled nitric oxide, and major inotropic intravenous infusion). All but 3 patients were affected by life-threatening meconium aspiration syndrome. Median duration of ECMO support and hospitalization were 4 days (range 2-32) and 30 days ( range 8-50), respectively. All but 2 patients with congenital diaphragmatic hernia, were weaned off ECMO and discharged home without complications. At a median follow up of 14.4 months (1.3-74.8), all survivors were alive and in good clinical conditions, without medications, and normal somatic growth. All but one had normal neuropsychological development. We conclude that HandS ECMO model for treating neonates in life-threatening conditions is effective and successful. A specialized multidisciplinary team and common organizational protocols shared between Hub and Spoke centers are the key-points for success. While excellent results occur with MAS (100% survival), treatment was not successful in CDH, in which other that HandS ECMO issues are implied. Lessons learned from our experience are presented and discussed in this article.

Background and aims Preterm newborns undergo hemodynamic challenges in the postnatal period. The aim of this study was to investigate myocardial mechanics changes in the postnatal period in preterm infants using speckle tracking echocardiography (STE). Material and methods Thirty-nine preterm infants ≤34 weeks' gestation underwent cardiac ultrasound evaluation during the first 96 hours of life. A repeated echocardiogram at 3 weeks of age was performed. Echocardiographic assessment involved left ventricular ejection fraction, mitral E/A ratio, S' and E' velocities, E/E' ratio, tricuspid annular plane systolic excursion (TAPSE), left atrium-to-aorta ratio, ductal diameter and ductal shunt pattern. Left ventricular longitudinal, circumferential and radial strain, apex-basal rotation and twist were measured from the apical 4-chamber and short-axis views using STE. Results The mean gestational age was 30 ± 2.7 weeks with a mean birth weight of 1318 ± 485 g. Apical segments demonstrated higher longitudinal strain than basal and mid-ones. In all gestational ages, endocardial longitudinal strain was higher than the epicardial. Epicardial longitudinal strain significantly increased during the first 3 weeks, resulting in the change in basal rotation from counterclockwise to clockwise and thus in the acquisition of twist. Deformation parameters were higher in infants with a hemodynamic significant patents ductus arteriosus. Conclusions Echocardiographic assessment of myocardial deformation parameters is feasible in preterm infants. Our data suggest that the maturational process of the myocardium is due to the development of the epicardial layer after birth, which allows the acquisition of the twist.

Preterm infants are exposed to a higher risk of developing Metabolic Bone Disease (MBD) with an increased bone fragility, a higher fracture risk and a long-term reduced linear growth and childhood height. Monitoring bone growth has become mandatory in neonatology. Several risk factors have been identified among the population of extremely low birth weight infants, but we still do not know which is the real incidence of MBD since its evaluation is not routinely performed worldwide. The aim of this study was to evaluate the incidence of MBD in preterm infants and in those suffering from bronchopulmonary dysplasia (BPD).Prospective evaluation of patients who developed BPD (BPD group) versus infants who did not develop it (no-BPD group). We examined, in preterms1.250 g, the metacarpus bone transmission time (mc-BTT) at birth, 21 days and 36 weeks of gestational age (GA) together with biochemical markers of bone status.We included 135 patients, 55 with BPD. BPD patients received less total proteins in the first two weeks and less energy in the first month of life (p = 0.007 and p 0.001 respectively). BPD patients had a worse growth velocity at two weeks of age (12.36 ± 7.86 vs 16.59 ± 7.05 g/kg/day, p = 0.001). At 21 days, BPD patients had lower phosphatemia (1.65 ± 0.031 mmol/L vs 1.85 ± 0.034 mmol/L, p = 0.007) and higher alkaline phosphatase levels (411.62 ± 135.31 IU/l vs 338.98 ± 102.20 IU/l, p = 0.005). BPD patients had significantly worse mc-BTT at 36 weeks GA (0.45 ± 0.06 vs 0.50 ± 0.08 μsec, p 0.001) and a higher incidence of MBD (60% vs 34%; p = 0.012).BPD infants are a special subset of patients among preterms who receive, in the first month of life, a lower energy intake than patients without BPD. BPD patients have a suboptimal bone growth and a higher incidence of MBD. Monitoring growth, bone status and optimizing nutritional intakes need to be further improved in preterm infants with BPD.

Monocyte-macrophages have a role in host defense and tissue remodeling. Classically activated (M1) and alternatively activated (M2) macrophages from preterm newborns are analyzed, and the role in acute respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) is evaluated. Observational study was conducted on the blood samples (BSs) and tracheal aspirates (TAs) collected at 48 to 72 hours of life in preterm newborns. Flow-cytometry was performed to identify monocytes and M1 or M2. Prenatal factors, gestational age, birth weight, acute RDS and BPD were assessed and related to the M1 and M2 levels and M2/M1. One hundred nine subjects were included, and 100 were followed up. M1 and M2 increase and decrease, respectively, according to the gestational age and birth weight. Higher M2 and lower M1 levels in TAs were found after maternal chorioamnionitis. BPD patients have low M1 with high M2 in blood samples (BSs), as well as in tracheal aspirates (TAs). No relation was found between activation pattern and prenatal variables or the RDS grade. The correlation between gestational age or birth weight and M1 could reflect a more mature macrophage system, capable to push undifferentiated macrophages toward the classical pathway. We speculate that adequate early classical macrophage activation could be crucial to protect lungs from post-natal injuries, preventing the development of BPD.

Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective. Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial. Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297– 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment. Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a β-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results. Clinical Trial Registration The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.

Bronchopulmonary dysplasia (BPD) is a major complication of premature birth that significantly affects mortality and long-term morbidity in numerous immature infants. Corticosteroids are particularly suitable for treating BPD, as lung inflammation is central to its pathogenesis. Corticosteroids have considerable, fast beneficial effects on lung function in premature infants with lung disease, but they are also associated with several serious adverse effects, which may have a detrimental impact on long-term outcome. Dexamethasone is the most often used corticosteroid for systemic administration. Despite its value in preventing and treating BPD, its use is associated with several alarming short-term effects and, worst of all, with an increased rate of cerebral palsy in the long term. Dexamethasone nonetheless remains an important therapeutic option for infants with severe lung disease beyond the second to third week of life. Hydrocortisone is an important alternative to dexamethasone, as its use does not appear to be associated with any neurotoxic effects. Its efficacy in the prevention and treatment of BPD has yet to be clearly demonstrated, however. Inhaled corticosteroids might reduce lung inflammation with fewer systemic adverse effects; however, a recent, large randomized trial showed that inhaled budesonide was associated with an excess mortality, despite its beneficial respiratory effects. In another study, instilling budesonide together with surfactant in the trachea of intubated infants with severe respiratory distress appeared safe and achieved a significant reduction in the rate of BPD at 36 postmenstrual weeks. This important finding needs to be confirmed in a larger trial currently underway.

Acylcarnitines are biomarkers of fatty acid metabolism, and examining their patterns in preterm newborn may reveal metabolic changes associated with particular conditions related to prematurity. Isomeric acylcarnitines in dried blood spots (DBS) and plasma have never been assessed in preterm infants. We studied 157 newborn divided into four groups by weeks of gestational age (GA), as follows: 22–27 wk in group 1; 28–31 wk in group 2; 32–36 wk in group 3; and 37–42 wk in group 4. Samples were collected on the third day of life. Acylcarnitines were separated and quantified using ultra-performance liquid chromatography tandem mass spectrometry. Acylcarnitine concentrations correlated significantly with GA and birth weight in both DBS and plasma samples. Concentrations were lower in preterm newborn, except for acylcarnitines derived from branched-chain amino acids, which were higher and correlated with enteral feeding. On day 3 of life, no correlations emerged with gender, respiratory distress syndrome, bronchopulmonary dysplasia, surfactant administration, or mechanical ventilation. We established GA-based reference ranges for isomeric acylcarnitine concentrations in preterm newborn, which could be used to assess nutritional status and the putative neuroprotective role of acylcarnitines.

Elevated Tricuspid Regurgitant Velocity (TRV) has been related to higher mortality in adults and to hemolysis, lower oxygen saturation during 6-minute walk test and acute chest syndrome (ACS) in children with sickle cell disease (SCD). Hydroxyurea (HU) has reduced TRV value in children and adults. We describe a three year old HbSS child with recurrent ACS, hypoperfusion of the left lung, mild hemolysis and persistent TRV elevation. TRV did not normalize after HU, despite improvement in clinical conditions and in baseline laboratory parameters related to hemolysis and blood viscosity, but normalized after bone marrow transplantation (BMT). Our experience suggests that in young patients, TRV reduction can be a positive concomitant effect of BMT.

We describe successful rescue airway management with a laryngeal mask airway (LMA) by experienced users in rare ‘can't ventilate/can't intubate’ scenarios in three infants with normal airway anatomy.1 1. A male infant weighing 3.53 kg underwent surgical intervention for intestinal malrotation. Twenty-six hours after the intervention, fentanyl infusion was stopped; the patient was extubated to spontaneous breathing. Twenty minutes later, he presented with apnoea, desaturation and bradycardia. Face mask ventilation (FMV) failed. Therefore, a LMA was inserted obtaining immediate clinical improvement. Naloxone was administered. The LMA was removed 5 min later when the neonate became vigorous and would no longer tolerate it. No further complications were encountered. The patient was discharged in good clinical condition.