The role of nutritional interventions in the prevention and treatment of chronic lung disease of prematurity.

Chronic lung disease of prematurity or bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Nutrition may affect incidence and severity of BPD. In this context, the Section on Nutrition, Gastroenterology and Metabolism, the Pulmonary Section of the European Society for Paediatric Research (ESPR) and SPR have joined forces to review the current knowledge on nutritional issues related to BPD. The aim of this narrative review is to discuss the clinical implications for nutritional practice. Nutrient deficiencies may influence pathogenesis of BPD. Adequate nutrition and growth can play a crucial role in the prevention of and recovery from BPD. Optimal nutrition strategy is an important principle, especially in the early postnatal period. As optimal energy intake in infants at risk of BPD or with evolving BPD is not yet defined, further research with well-designed studies on nutritional strategies for preterm infants with BPD is urgently needed. IMPACT: Based on current evidence it seems reasonable to recommend that BPD diagnosed infants should receive an energy supply ranging from 120 to 150 Kcal/kg/d. Exclusive MOM feed with adequate fortification should be encouraged as this is associated with a significant reduction in the risk of BPD. Suboptimal nutritional delivery is often seen in preterm infants with BPD compared to controls.

Evolution of Ultrasound-Assessed Lung Aeration and Gas Exchange in Respiratory Distress Syndrome and Transient Tachypnea of the Neonate.

OBJECTIVE: To use clinical, lung ultrasound, and gas exchange data to clarify the evolution of lung aeration and function in neonates with respiratory distress syndrome (RDS) and transient tachypnea of the neonate (TTN), the most common types of neonatal respiratory failure. STUDY DESIGN: In this prospective observational cohort study, lung aeration and function were measured with a semiquantitative lung ultrasound score (LUS) and transcutaneous blood gas measurement performed at 1 hour (time point 0), 6 hours (time point 1), 12 hours (time point 2), 24 hours (time point 3) and 72 hours (time point 4) of life. Endogenous surfactant was estimated using lamellar body count (LBC). LUS, oxygenation index (OI), oxygen saturation index (OSI), and transcutaneous pressure of carbon dioxide (PtcCO2) were the primary outcomes. All results were adjusted for gestational age. RESULTS: Sixty-nine neonates were enrolled in the RDS cohort, and 58 neonates were enrolled in the TTN cohort. LUS improved over time (within-subjects, P < .001) but was worse for the RDS cohort than for the TTN cohort at all time points (between-subjects, P < .001). Oxygenation improved over time (within-subjects, P = .011 for OI, P < .001 for OSI) but was worse for the RDS cohort than for the TTN cohort at all time points (between-subjects, P < .001 for OI and OSI). PtcCO2 improved over time (within-subjects, P < .001) and was similar in the RDS and TTN cohorts at all time points. Results were unchanged after adjustment for gestational age. LBC was associated with RDS (ß = -0.2 [95% CI, -0.004 to -0.0001]; P = .037) and LUS (ß = -3 [95% CI, -5.5 to -0.5]; P = .019). CONCLUSIONS: For the first 72 hours of life, the RDS cohort had worse lung aeration and oxygenation compared with the TTN cohort at all time points. CO2 clearance did not differ between the cohorts, whereas both lung aeration and function improved in the first 72 hours of life.

Who Needs a Second Dose of Exogenous Surfactant?

OBJECTIVE: To identify prenatal and postnatal risk factors associated with surfactant redosing. STUDY DESIGN: Retrospective, single-regional center study including all infants born from 24 + 0 to 31 + 6 weeks of gestation in the Marche Region, Italy, and admitted to a single level III regional NICU from January 1, 2004, to February 28, 2021. Clinical factors associated with surfactant redosing were identified through logistic regression analysis. RESULTS: Of 1615 consecutive admissions, 662 infants were treated with exogenous surfactant: 462 (70%) received a single dose and 200 (30%) received more than 1 dose (25.5% two doses and 4.5% three doses). Risk of redosing was higher for infants born to mothers with hypertension in pregnancy (OR 3.95, P < .001), for small for gestational age (SGA) infants (OR 3.93, P < .001) and when the first surfactant dose was 100 mg/kg instead of 200 mg/kg (OR 4.56/4.61, P < .001). Infants with greater GA, delayed first surfactant administration, and milder respiratory distress syndrome had reduced risk of redosing. Infants who required multiple surfactant doses had a higher rate of bronchopulmonary dysplasia and mortality, as well as longer duration of respiratory support than patients that received 1 dose. CONCLUSIONS: Hypertension in pregnancy and SGA status were found to be statistically and clinically significant predictors of surfactant redosing. Understanding the pathophysiology of these conditions requires further investigation.

Enteral Nutrition in Preterm Infants (2022): A Position Paper From the ESPGHAN Committee on Nutrition and Invited Experts.

OBJECTIVES: To review the current literature and develop consensus conclusions and recommendations on nutrient intakes and nutritional practice in preterm infants with birthweight <1800 g. METHODS: The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee of Nutrition (CoN) led a process that included CoN members and invited experts. Invited experts with specific expertise were chosen to represent as broad a geographical spread as possible. A list of topics was developed, and individual leads were assigned to topics along with other members, who reviewed the current literature. A single face-to-face meeting was held in February 2020. Provisional conclusions and recommendations were developed between 2020 and 2021, and these were voted on electronically by all members of the working group between 2021 and 2022. Where >90% consensus was not achieved, online discussion meetings were held, along with further voting until agreement was reached. RESULTS: In general, there is a lack of strong evidence for most nutrients and topics. The summary paper is supported by additional supplementary digital content that provide a fuller explanation of the literature and relevant physiology: introduction and overview; human milk reference data; intakes of water, protein, energy, lipid, carbohydrate, electrolytes, minerals, trace elements, water soluble vitamins, and fat soluble vitamins; feeding mode including mineral enteral feeding, feed advancement, management of gastric residuals, gastric tube placement and bolus or continuous feeding; growth; breastmilk buccal colostrum, donor human milk, and risks of cytomegalovirus infection; hydrolyzed protein and osmolality; supplemental bionutrients; and use of breastmilk fortifier. CONCLUSIONS: We provide updated ESPGHAN CoN consensus-based conclusions and recommendations on nutrient intakes and nutritional management for preterm infants.

Effect of preoperative pulmonary hemodynamic and cardiopulmonary bypass on lung function in children with congenital heart disease.

In children with congenital heart disease (CHD), pulmonary blood flow (Qp) contributes to alterations of pulmonary mechanics and gas exchange, while cardiopulmonary bypass (CPB) induces lung edema. We aimed to determine the effect of hemodynamics on lung function and lung epithelial lining fluid (ELF) biomarkers in biventricular CHD children undergoing CPB. CHD children were classified as high Qp (n = 43) and low Qp (n = 17), according to preoperative cardiac morphology and arterial oxygen saturation. We measured ELF surfactant protein B (SP-B) and myeloperoxidase activity (MPO) as indexes of lung inflammation and ELF albumin as index of alveolar capillary leak in tracheal aspirate (TA) samples collected before surgery and in 6 hourly intervals within 24 h after surgery. At the same time points, we recorded dynamic compliance and oxygenation index (OI). The same biomarkers were measured in TA samples collected from 16 infants with no cardiorespiratory diseases at the time of endotracheal intubation for elective surgery. Preoperative ELF biomarkers in CHD children were significantly increased than those found in controls. In the high Qp, ELF MPO and SP-B peaked 6 h after surgery and tended to decrease afterward, while they tended to increase within the first 24 h in the low Qp. ELF albumin peaked 6 h after surgery and decreased afterwards in both CHD groups. Dynamic compliance/kg and OI significantly improved after surgery only in the High Qp.  Conclusion: In CHD children, lung mechanics, OI, and ELF biomarkers were significantly affected by CPB, according to the preoperative pulmonary hemodynamics. What is Known: • Congenital heart disease children, before cardiopulmonary run, exhibit changes in respiratory mechanics, gas exchange, and lung inflammatory biomarkers that are related to the preoperative pulmonary hemodynamics. • Cardiopulmonary bypass induces alteration of lung function and epithelial lining fluid biomarkers according to preoperative hemodynamics. What is New: • Our findings can help to identify children with congenital heart disease at high risk of postoperative lung injury who may benefit of tailored intensive care strategies, such as non-invasive ventilation techniques, fluid management, and anti-inflammatory drugs that can improve cardiopulmonary interaction in the perioperative period.

Early postnatal weight loss does not affect the 2-year neurodevelopment in preterm infants of less than 32 weeks.

AIM: It is still unclear if the magnitude of early postnatal weight loss (PWL) could be associated with neurodevelopmental outcomes in preterm infants. We studied the association between PWL and neurodevelopment at 2-year corrected age in preterm infants. METHODS: We retrospectively reviewed data of preterm infants with a gestational age between 24 + 0 and 31 + 6 weeks/days, admitted at the G.Salesi Children's Hospital, Ancona, Italy, between 1 January 2006 and 31 December 2019. Infants with PWL greater than or equal to 10% (PWL ≥ 10%) were compared with those with PWL of less than 10% (PWL < 10%). A matched cohort analysis was also performed using gestational age and birth weight as matching variables. RESULTS: We analysed 812 infants: 471 (58%) PWL ≥ 10% and 341 (42%) PWL < 10%. A subgroup of 247 PWL ≥ 10% was closely match-paired with 247 PWL < 10% infants. There were no differences in amino acid and energy intakes from birth to day 14 of life and from birth to 36 weeks. Although at 36 weeks, body weight and total length were lower in PWL ≥ 10% than PWL < 10%, anthropometry and neurodevelopment at 2 years were similar between groups. CONCLUSION: Given similar amino acid and energy intakes on PWL ≥ 10% and PWL < 10% preterm infants of less than 32 + 0 weeks/days, PWL does not affect 2-year neurodevelopment.

DHA turnover in pregnant women using the natural abundance variation of 13C: a pilot study.

The importance of DHA intake to support fetal development and maternal health is well established. In this pilot study we applied the natural abundance approach to determine the contribution of 200 mg/day of DHA supplement to the plasma DHA pool in 19 healthy pregnant women on a free diet.Women received DHA, from pregnancy week 20 until delivery, from an algal source (N=13, Algae group) or from fish oil (N=6, Fish group) with slightly different content of 13C.We measured plasma phospholipids DHA 13C:12C ratio (reported as δ13C) prior to supplementation (T0), after 10 (T1) and 90 days (T2) and prior to delivery (T3).The δ13C of DHA in algae and fish supplements were -15.8±0.2 mUr and -25.3±0.2 mUr (p<0.001).DHA δ13C in the Algae group increased from -27.7±1.6 mUr (T0) to -21.9±2.2 mUr (T3) (p<0.001), whereas there were not significant changes in the Fish group (-27.8±0.9 mUr at T0 and -27.3±1.1 mUr at T3, p=0.09).In the Algae group 200 mg/day of DHA contributed to the plasma phospholipid pool by a median value of 53% (31-75% minimum and maximum). This estimation was not possible in the fish group.Our results demonstrate the feasibility of assessing the contribution of DHA from an algal source to the plasma DHA pool in pregnant women by the natural abundance approach. Plasma δ13C DHA did not change when consuming DHA of fish origin, with almost the same δ13C value of that of the pre-supplementation plasma δ13C DHA.

Lung Ultrasound to Monitor Extremely Preterm Infants and Predict Bronchopulmonary Dysplasia. A Multicenter Longitudinal Cohort Study.

Rationale: Lung ultrasound is useful in critically ill patients with acute respiratory failure. Given its characteristics, it could also be useful in extremely preterm infants with evolving chronic respiratory failure, as we lack accurate imaging tools to monitor them. Objectives: To verify if lung ultrasound can monitor lung aeration and function and has good reliability to predict bronchopulmonary dysplasia in extremely preterm neonates. Methods: A multicenter, international, prospective, longitudinal, cohort, diagnostic accuracy study consecutively enrolling inborn neonates with gestational age 30+6 weeks or younger. Lung ultrasound was performed on the 1, 7, 14, and 28 days of life, and lung ultrasound scores were calculated and correlated with simultaneous blood gases and work of breathing score. Gestational age-adjusted lung ultrasound scores were created, verified in multivariate models, and subjected to receiver operator characteristics (ROC) analyses to predict bronchopulmonary dysplasia at 36 weeks postmenstrual age. Measurements and Main Results: Mean lung ultrasound scores are different between infants developing (n = 72) or not developing (n = 75) bronchopulmonary dysplasia (P < 0.001 at any time point). Lung ultrasound scores significantly correlate with oxygenation metrics and work of breathing at any time point (P always < 0.0001). Gestational age-adjusted lung ultrasound scores significantly predict bronchopulmonary dysplasia at 7 (area under ROC curve, 0.826-0.833; P < 0.0001) and 14 (area under ROC curve, 0.834-0.858; P < 0.0001) days of life. Bronchopulmonary dysplasia severity and gestational age-adjusted lung ultrasound scores are significantly correlated at 7 and 14 days (P always < 0.0001). Conclusions: Lung ultrasound scores allow monitoring of lung aeration and function in extremely preterm infants. Gestational age-adjusted scores significantly predict the occurrence of bronchopulmonary dysplasia, starting from the seventh day of life.

Is low cerebral near infrared spectroscopy oximetry associated with neurodevelopment of preterm infants without brain injury?

OBJECTIVES: To evaluate the association between low regional cerebral oxygen saturation (rScO2) and neurodevelopment in preterm infants classified as no brain injury (NBI). METHODS: We retrospectively reviewed data of rScO2 monitoring during the first 3 days of life of infants with a gestational age (GA)<28 weeks or birth weight (BW)<1,000 g, with and without brain injury (BI). BI was defined as intraventricular haemorrhage, cystic periventricular leukomalacia or cerebellar haemorrhage. Univariate and multivariate analyses were used to study the association of rScO2<55% for more than 10 h in the first 3 days of life (NIRS<55%>10H) and the 24 months neurodevelopment. RESULTS: Of the 185 patients who met the inclusion criteria, 31% were classified as BI infants and 69% NBI. BI compared to NBI infants had a significantly lower GA and a higher incidence of complications of prematurity. Mean rScO2 in the first 72 h of life was significantly lower in BI than NBI. NIRS<55%>10H in NBI patients was negatively associated with neurodevelopmental scores both at the univariate and multivariate analysis (p<0.05). NBI infants with NIRS<55%>10H were found to have lower systemic oxygenation than their counterparts with rScO2<55% for less than 10 h. CONCLUSIONS: NIRS<55%>10H in NBI small preterm infants was found to be an independent predictor of neurodevelopment at 24 months and it was associated with low systemic saturation values.

Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia.

BACKGROUND: The long-term effects on neurodevelopment of the use of inhaled glucocorticoids in extremely preterm infants for the prevention or treatment of bronchopulmonary dysplasia are uncertain. METHODS: We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to receive early (within 24 hours after birth) inhaled budesonide or placebo. The prespecified secondary long-term outcome was neurodevelopmental disability among survivors, defined as a composite of cerebral palsy, cognitive delay (a Mental Development Index score of <85 [1 SD below the mean of 100] on the Bayley Scales of Infant Development, Second Edition, with higher scores on the scale indicating better performance), deafness, or blindness at a corrected age of 18 to 22 months. RESULTS: Adequate data on the prespecified composite long-term outcome were available for 629 infants. Of these infants, 148 (48.1%) of 308 infants assigned to budesonide had neurodevelopmental disability, as compared with 165 (51.4%) of 321 infants assigned to placebo (relative risk, adjusted for gestational age, 0.93; 95% confidence interval [CI], 0.80 to 1.09; P=0.40). There was no significant difference in any of the individual components of the prespecified outcome. There were more deaths in the budesonide group than in the placebo group (82 [19.9%] of 413 infants vs. 58 [14.5%] of 400 infants for whom vital status was available; relative risk, 1.37; 95% CI, 1.01 to 1.86; P=0.04). CONCLUSIONS: Among surviving extremely preterm infants, the rate of neurodevelopmental disability at 2 years did not differ significantly between infants who received early inhaled budesonide for the prevention of bronchopulmonary dysplasia and those who received placebo, but the mortality rate was higher among those who received budesonide. (Funded by the European Union and Chiesi Farmaceutici; ClinicalTrials.gov number, NCT01035190 .).

Chorioamnionitis alters lung surfactant lipidome in newborns with respiratory distress syndrome.

BACKGROUND: Chorioamnionitis is associated with preterm delivery and morbidities; its role in lung disease is controversial. The aim of this study is to assess the effect of chorioamnionitis on metabolite and lipid profiles of epithelial lining fluid in preterm newborns with respiratory distress syndrome (RDS). METHODS: The study involved 30 newborns with RDS, born from mothers with or without histological chorioamnionitis (HCA): HCA+, N = 10; HCA-, N = 20. Patients had a gestational age ≤30 weeks; the groups were matched for age and birth weights. Tracheal aspirates were collected within 24 h after birth and analyzed using liquid chromatography/mass spectrometry-based untargeted lipidomics. RESULTS: According to Mann-Whitney U tests, 570 metabolite features had statistically significantly higher or lower concentrations (p < 0.05) in tracheal aspirates of HCA+ compared to HCA-, and 241 metabolite features were putatively annotated and classified. The most relevant changes involved higher levels of glycerophospholipids (fold change 2.42-17.69) and sphingolipids, with lower concentration of all annotated sphingomyelins in HCA+ (fold change 0.01-0.50). CONCLUSIONS: Untargeted lipidomics of tracheal aspirates suggested the production of lipid mediators in the context of an ongoing inflammatory status in HCA+ babies. However, the effect of chorioamnionitis on epithelial lining fluid composition deserves further investigations on a larger group of infants. IMPACT: Our lipidomics investigation on tracheal aspirates of preterm newborns at birth suggested that exposure to maternal histological chorioamnionitis may cause changes in epithelial lining fluid composition. This is the first description of epithelial lining fluid lipidomic profiles in preterm infants with and without exposition to chorioamnionitis. These results could provide novel link between placental membrane inflammation and newborns' respiratory outcome.

Surfactant lung delivery with LISA and InSurE in adult rabbits with respiratory distress.

BACKGROUND: In preterm infants, InSurE (Intubation-Surfactant-Extubation) and LISA (less invasive surfactant administration) techniques allow for exogenous surfactant administration while reducing lung injury associated with mechanical ventilation. We compared the acute pulmonary response and lung deposition of surfactant by LISA and InSurE in surfactant-depleted adult rabbits. METHODS: Twenty-six spontaneously breathing surfactant-depleted adult rabbits (6-7 weeks old) with moderate RDS and managed with nasal continuous positive airway pressure were randomized to 3 groups: (1) 200 mg/kg of surfactant by InSurE; (2) 200 mg/kg of surfactant by LISA; (3) no surfactant treatment (Control). Gas exchange and lung mechanics were monitored for 180 min. After that, surfactant lung deposition and distribution were evaluated monitoring disaturated-phosphatidylcholine (DSPC) and surfactant protein C (SP-C), respectively. RESULTS: No signs of recovery were found in the untreated animals. After InSurE, oxygenation improved more rapidly compared to LISA. However, at 180' LISA and InSurE showed comparable outcomes in terms of gas exchange, ventilation parameters, and lung mechanics. Neither DSPC in the alveolar pool nor SP-C signal distributions in a frontal lung section were significantly different between InSurE and LISA groups. CONCLUSIONS: In an acute setting, LISA demonstrated efficacy and surfactant lung delivery similar to that of InSurE in surfactant-depleted adult rabbits. IMPACT: Although LISA technique is gaining popularity, there are still several questions to address. This is the first study comparing LISA and InSurE in terms of gas exchange, ventilation parameters, and lung mechanics as well as surfactant deposition and distribution. In our animal study, three hours post-treatment, LISA method seems to be as effective as InSurE and showed similar surfactant lung delivery. Our findings provide some clarifications on a fair comparison between LISA and InSurE techniques, particularly in terms of surfactant delivery. They should reassure some of the concerns raised by the clinical community on LISA adoption in neonatal units.

Surfactant-secreted phospholipase A2 interplay and respiratory outcome in preterm neonates.

Secreted phospholipase A2 hydrolyzes surfactant phospholipids and is crucial for the inflammatory cascade; preterm neonates are treated with exogenous surfactant, but the interaction between surfactant and phospholipase is unknown. We hypothesize that this interplay is complex and the enzyme plays a relevant role in neonates needing surfactant replacement. We aimed to: 1) identify phospholipases A2 isoforms expressed in preterm lung; 2) study the enzyme role on surfactant retreatment and function and the effect of exogenous surfactant on the enzyme system; and 3) verify whether phospholipase A2 is linked to respiratory outcomes. In bronchoalveolar lavages of preterm neonates, we measured enzyme activity (alone or with inhibitors), enzyme subtypes, surfactant protein-A, and inflammatory mediators. Surfactant function and phospholipid profile were also tested. Urea ratio was used to obtain epithelial lining fluid concentrations. Follow-up data were prospectively collected. Subtype-IIA is the main phospholipase isoform in preterm lung, although subtype-IB may be significantly expressed. Neonates needing surfactant retreatment have higher enzyme activity (P = 0.021) and inflammatory mediators (P always ≤ 0.001) and lower amounts of phospholipids (P always < 0.05). Enzyme activity was inversely correlated to surfactant adsorption (ρ = -0.6; P = 0.008; adjusted P = 0.009), total phospholipids (ρ = -0.475; P = 0.05), and phosphatidylcholine (ρ = -0.622; P = 0.017). Exogenous surfactant significantly reduced global phospholipase activity (P < 0.001) and subtype-IIA (P = 0.005) and increased dioleoylphosphatidylglycerol (P < 0.001) and surfactant adsorption (P < 0.001). Enzyme activity correlated with duration of ventilation (ρ = 0.679, P = 0.005; adjusted P = 0.04) and respiratory morbidity score at 12 mo postnatal age (τ-b = 0.349, P = 0.037; adjusted P = 0.043) but was not associated with mortality, bronchopulmonary dysplasia, or other long-term respiratory outcomes.

Low socio-economic conditions and prematurity-related morbidities explain healthcare use and costs for 2-year-old very preterm children.

AIM: To estimate healthcare use and related costs for 2-year-old very preterm (VP) children after discharge from the neonatal unit. METHODS: As part of a European project, we recruited an area-based cohort including all VP infants born in three Italian regions (Lazio, Emilia-Romagna and Marche) in 2011-2012. At 2 years corrected age, parents completed a questionnaire on their child health and healthcare use (N = 732, response rate 75.6%). Cost values were assigned based on national reimbursement tariffs. We used multivariable analyses to identify factors associated with any rehospitalisation and overall healthcare costs. RESULTS: The most frequently consulted physicians were the paediatrician (85% of children), the ophthalmologist (36%) and the neurologist/neuropsychiatrist (26%); 38% of children were hospitalised at least once after the initial discharge, for a total of 513 admissions and over one million euros cost, corresponding to 75% of total healthcare costs. Low maternal education and parental occupation index, congenital anomalies and postnatal prematurity-related morbidities significantly increased the risk of rehospitalisation and total healthcare costs. CONCLUSION: Rehospitalisation and outpatient care are frequent in VP children, confirming a substantial health and economic burden. These findings should inform the allocation of resources to preventive and rehabilitation services for these children.

Inhaled nitric oxide (iNO) for preventing prematurity-related bronchopulmonary dysplasia (BPD): 7-year follow-up of the European Union Nitric Oxide (EUNO) trial.

OBJECTIVES: Most studies of inhaled nitric oxide (iNO) for prevention of bronchopulmonary dysplasia (BPD) in premature infants have focused on short-term mortality and morbidity. Our aim was to determine the long-term effects of iNO. METHODS: A 7-year follow-up was undertaken of infants entered into a multicenter, double-blind, randomized, placebo-controlled trial of iNO for prevention of BPD in premature infants born between 24 and 28 weeks plus six days of gestation. At 7 years, survival and hospital admissions since the 2-year follow-up, home oxygen therapy in the past year, therapies used in the previous month and growth assessments were determined. Questionnaires were used to compare general health, well-being, and quality of life. RESULTS: A total of 305 children were assessed. No deaths were reported. Rates of hospitalization for respiratory problems (6.6 vs. 10.5%, iNO and placebo group, respectively) and use of respiratory medications (6.6 vs. 9.2%) were similar. Two patients who received iNO and one who received placebo had received home oxygen therapy. There were no significant differences in any questionnaire-documented health outcomes. CONCLUSIONS: iNO for prevention of BPD in very premature infants with respiratory distress did not result in long-term benefits or adverse long-term sequelae. In the light of current evidence, routine use of iNO cannot be recommended for prevention of BPD in preterm infants.

Urinary metabolomics reveals kynurenine pathway perturbation in newborns with transposition of great arteries after surgical repair.

INTRODUCTION: Transposition of the great arteries (TGA) is a cyanotic congenital heart defect that requires surgical correction, with the use of cardiopulmonary-bypass (CPB), usually within 3 weeks of life. The use of CPB in open heart surgery results in brain hypoperfusion and in a powerful systemic inflammatory response and oxidative stress. OBJECTIVE: We aimed to develop a novel untargeted metabolomics approach to detect early postoperative changes in metabolic profile following neonatal cardiac surgery. METHODS: We studied 14 TGA newborns with intact ventricular septum undergoing arterial switch operation with the use of CPB. Urine samples were collected preoperatively and at the end of the surgery and were analyzed using an untargeted metabolomics approach based on UHPLC-high resolution mass spectrometry. RESULTS: Since post surgery metabolic spectra were heavily contaminated by metabolites derived from administered drugs, we constructed a list of drugs used during surgery and their related metabolites retrieved from urine samples. This library was applied to our samples and 1255 drugs and drug metabolites were excluded from the analysis. Afterward, we detected over 39,000 unique compounds and 371 putatively annotated metabolites were different between pre and post-surgery samples. Among these metabolites, 13 were correctly annotated or identified. Metabolites linked to kynurenine pathway of tryptophan degradation displayed the highest fold change. CONCLUSIONS: This is the first report on metabolic response to cardiac surgery in TGA newborns. We developed an experimental design that allowed the identification of perturbed metabolic pathways and potential biomarkers of brain damage, limiting drugs interference in the analysis.

Tracing exogenous surfactant in vivo in rabbits by the natural variation of 13C.

BACKGROUND: Respiratory Distress Syndrome (RDS) is a prematurity-related breathing disorder caused by a quantitative deficiency of pulmonary surfactant. Surfactant replacement therapy is effective for RDS newborns, although treatment failure has been reported. The aim of this study is to trace exogenous surfactant by 13C variation and estimate the amount reaching the lungs at different doses of the drug. METHODS: Forty-four surfactant-depleted rabbits were obtained by serial bronchoalveolar lavages (BALs), that were merged into a pool (BAL pool) for each animal. Rabbits were in nasal continuous positive airway pressure and treated with 0, 25, 50, 100 or 200 mg/kg of poractant alfa by InSurE. After 90 min, rabbits were depleted again and a new pool (BAL end experiment) was collected. Disaturated-phosphatidylcholine (DSPC) was measured by gas chromatography. DSPC-Palmitic acid (PA) 13C/12C was analyzed by isotope ratio mass spectrometry. One-way non-parametric ANOVA and post-hoc Dunn's multiple comparison were used to assess differences among experimental groups. RESULTS: Based on DSPC-PA 13C/12C in BAL pool and BAL end experiment, the estimated amount of exogenous surfactant ranged from 61 to 87% in dose-dependent way (p < 0.0001) in animals treated with 25 up to 200 mg/kg. Surfactant administration stimulated endogenous surfactant secretion. The percentage of drug recovered from lungs did not depend on the administered dose and accounted for 31% [24-40] of dose. CONCLUSIONS: We reported a risk-free method to trace exogenous surfactant in vivo. It could be a valuable tool for assessing, alongside the physiological response, the delivery efficiency of surfactant administration techniques.

Hypertriglyceridemia and Intravenous Lipid Titration During Routine Parenteral Nutrition in Small Preterm Infants.

OBJECTIVES: In case of hypertriglyceridemia (HiTG) during parenteral nutrition (PN), the 2018 European Society of Paediatric Gastroenterology, Hepatology and Nutrition guidelines recommend an intravenous (IV) lipid titration, but its consequences in small preterm infants are largely unknown. We compared macronutrient and energy intakes, growth, diseases associated with prematurity, and neurodevelopment in small preterm infants on PN who developed (cases) or did not develop HiTG (controls, CNTR). METHODS: We retrospectively reviewed data of preterm infants with a birth weight (BW) <1250 g consecutively admitted to our neonatal intensive care unit (2004-2016) who received routine PN. HiTG infants were defined by at least 1 triglyceride (TG) measurement >250 mg/dL during the first 10 days of life. Patients with and without HiTG were match-paired for BW and gestational age. RESULTS: A total of 658 infants were analyzed and 196 (30%) had HiTG. One hundred thirty-six HiTG patients were matched with 136 CNTR. In the first 10 days of life, IV lipid, non-protein energy and total energy intakes, but not IV amino acids and carbohydrates, were significantly lower in HiTG infants. We found no differences between groups in diseases associated with prematurity. Anthropometry at 36 weeks (W), anthropometry at 2-year (Y) corrected age (CA), and neurodevelopment at 2Y CA were not different. CONCLUSIONS: Growth, diseases associated with prematurity, and neurodevelopment at 2Y CA in HiTG infants were similar to CNTR. This occurred despite a statistically significant albeit small reduction in IV lipid and non-protein energy intakes due to a strict TG monitoring and IV lipid titration at TG levels >250 mg/dL.

Early Inhaled Budesonide for the Prevention of Bronchopulmonary Dysplasia.

BACKGROUND: Systemic glucocorticoids reduce the incidence of bronchopulmonary dysplasia among extremely preterm infants, but they may compromise brain development. The effects of inhaled glucocorticoids on outcomes in these infants are unclear. METHODS: We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to early (within 24 hours after birth) inhaled budesonide or placebo until they no longer required oxygen and positive-pressure support or until they reached a postmenstrual age of 32 weeks 0 days. The primary outcome was death or bronchopulmonary dysplasia, confirmed by means of standardized oxygen-saturation monitoring, at a postmenstrual age of 36 weeks. RESULTS: A total of 175 of 437 infants assigned to budesonide for whom adequate data were available (40.0%), as compared with 194 of 419 infants assigned to placebo for whom adequate data were available (46.3%), died or had bronchopulmonary dysplasia (relative risk, stratified according to gestational age, 0.86; 95% confidence interval [CI], 0.75 to 1.00; P=0.05). The incidence of bronchopulmonary dysplasia was 27.8% in the budesonide group versus 38.0% in the placebo group (relative risk, stratified according to gestational age, 0.74; 95% CI, 0.60 to 0.91; P=0.004); death occurred in 16.9% and 13.6% of the patients, respectively (relative risk, stratified according to gestational age, 1.24; 95% CI, 0.91 to 1.69; P=0.17). The proportion of infants who required surgical closure of a patent ductus arteriosus was lower in the budesonide group than in the placebo group (relative risk, stratified according to gestational age, 0.55; 95% CI, 0.36 to 0.83; P=0.004), as was the proportion of infants who required reintubation (relative risk, stratified according to gestational age, 0.58; 95% CI, 0.35 to 0.96; P=0.03). Rates of other neonatal illnesses and adverse events were similar in the two groups. CONCLUSIONS: Among extremely preterm infants, the incidence of bronchopulmonary dysplasia was lower among those who received early inhaled budesonide than among those who received placebo, but the advantage may have been gained at the expense of increased mortality. (Funded by the European Union and Chiesi Farmaceutici; ClinicalTrials.gov number, NCT01035190.).

Surfactant Components and Tracheal Aspirate Inflammatory Markers in Preterm Infants with Respiratory Distress Syndrome.

In 93 preterm infants ≤32 weeks of gestational age and 12 control infants, epithelial lining fluid disaturated-phosphatidylcholine, surfactant protein A and B, albumin, and myeloperoxidase activity were assessed after intubation and before exogenous surfactant administration. We found that disaturated-phosphatidylcholine, surfactant protein B, and myeloperoxidase were significantly higher in preterms with chorioamnionitis.