Search

Abstract Background Non-invasive delivery of nebulized surfactant has been a neonatology long-pursued goal. Nevertheless, the clinical efficacy of nebulized surfactant remains inconclusive, in part, due to the great technical challenges of depositing nebulized drugs in the lungs of preterm infants. The aim of this study was to investigate the feasibility of delivering nebulized surfactant (poractant alfa) in vitro and in vivo with an adapted, neonate-tailored aerosol delivery strategy. Methods Particle size distribution of undiluted poractant alfa aerosols generated by a customized eFlow-Neos nebulizer system was determined by laser diffraction. The theoretical nebulized surfactant lung dose was estimated in vitro in a clinical setting replica including a neonatal continuous positive airway pressure (CPAP) circuit, a cast of the upper airways of a preterm neonate, and a breath simulator programmed with the tidal breathing pattern of an infant with mild respiratory distress syndrome (RDS). A dose-response study with nebulized surfactant covering the 100–600 mg/kg nominal dose-range was conducted in RDS-modelling, lung-lavaged spontaneously-breathing rabbits managed with nasal CPAP. The effects of nebulized poractant alfa on arterial gas exchange and lung mechanics were assessed. Exogenous alveolar disaturated-phosphatidylcholine (DSPC) in the lungs was measured as a proxy of surfactant deposition efficacy. Results Laser diffraction studies demonstrated suitable aerosol characteristics for inhalation (mass median diameter, MMD = 3 μm). The mean surfactant lung dose determined in vitro was 13.7% ± 4.0 of the 200 mg/kg nominal dose. Nebulized surfactant delivered to spontaneously-breathing rabbits during nasal CPAP significantly improved arterial oxygenation compared to animals receiving CPAP only. Particularly, the groups of animals treated with 200 mg/kg and 400 mg/kg of nebulized poractant alfa achieved an equivalent pulmonary response in terms of oxygenation and lung mechanics as the group of animals treated with instilled surfactant (200 mg/kg). Conclusions The customized eFlow-Neos vibrating-membrane nebulizer system efficiently generated respirable aerosols of undiluted poractant alfa. Nebulized surfactant delivered at doses of 200 mg/kg and 400 mg/kg elicited a pulmonary response equivalent to that observed after treatment with an intratracheal surfactant bolus of 200 mg/kg. This bench-characterized nebulized surfactant delivery strategy is now under evaluation in Phase II clinical trial (EUDRACT No.:2016–004547-36).

Objectives: Pancreatic cystic neoplasms (PCNs), particularly intraductal papillary mucinous neoplasms (IPMNs), present a challenge for their potential malignancy. Despite promising biomarkers like CEA, amylase, and glucose, our study investigates whether metabolic indices in blood and cystic fluids (CFs), in addition to lymphocyte subsets and hematopoietic stem/progenitor cells (HSPCs), can effectively differentiate between high- and low-risk PCNs. Materials and Methods: A total of 26 patients (11 males, mean age 69.5 ± 9 years) undergoing Endoscopic Ultrasound-guided Fine Needle Aspiration were consecutively enrolled. Analyses included blood, serum, and CF, assessing glucose, CEA, cholesterol (total, HDL, and LDL), and total proteins. Flow cytometry examined immunophenotyping in peripheral blood and cystic fluids. Mass spectrometry was used for the metabolomic analysis of CF. Sensitivity, specificity, and ROC analyses evaluated discriminatory power. Results: A total of 25 out of 26 patients had IPMN. Patients were categorized as low or high risk based on multidisciplinary evaluation of clinical, radiological, and endoscopic data. High-risk patients showed lower CF total proteins and LDL cholesterol ( p = 0.005 and p = 0.031), with a marked reduction in CF lymphocytes ( p = 0.005). HSCPs were absent in CF. In blood, high-risk patients showed increased non-MHC-restricted cytotoxic T cells ( p = 0.019). The metabolomic analysis revealed significantly reduced middle and long-chain acyl carnitines (AcCa) and tryptophan metabolites in high-risk patients. ROC curves indicated comparable discriminant abilities for CF lymphocytes (AUC 0.868), CF total proteins (AUC 0.859), and CF LDL cholesterol (AUC 0.795). The highest performance was achieved by the AcCa 14:2 and 16:0 (AUC: 0.9221 and 0.8857, respectively). Conclusions: CF levels of glucose, CEA, LDL cholesterol, and total proteins together with lymphocyte counts are easy translational biomarkers that may support risk stratification of PCNs in IPMN patients and might be endorsed by metabolomic analysis. Further studies are required for potential clinical integration.

Objective: To evaluate the association between delivery mode and intraventricular hemorrhage (IVH) in infants with a gestational age (GA) < 32 weeks., Study Design: We retrospectively reviewed data of 1760 infants with a GA between 24 +0/7 and 31 +6/7  weeks/days born between 01.01.2004 and 31.12.2022. We excluded outborn, congenital malformations, infants born by complicated delivery and without antenatal corticosteroid administration. Exposure was the delivery mode: cesarean section (CS) versus vaginal delivery (VD). IVH within the first week of life was the primary outcome. Multiple regression analyses were used to evaluate the association between delivery mode and IVH. CS infants were also match-paired for GA and small for gestational age (SGA) with VD infants., Results: The incidence of IVH was lower in 1046 CS than in 144 VD study infants (IVH I-IV: 14 vs 29 %, p < 0.001; IVH I-II: 10 vs 22 %, p < 0.001; IVH III-IV: 3 vs 8 %, p = 0.008). CS was associated with a lower risk of IVH grades I-IV (aOR: 0.52, p = 0.012) after the adjustment for GA, year of birth, sex, singleton pregnancy, SGA, hypertensive disorders of pregnancy, pH ≤ 7.00 and/or standard base excess (SBE) ≤ -12 mmol/L at cord blood gas analysis, early-onset sepsis, hemodynamically significant patent ductus arteriosus, thrombocytopenia, need of blood transfusion, mechanical ventilation and inotropes/vasoactive amines., Conclusions: CS was associated with lower risk of IVH than VD in infants with a GA between 24 +0/7 and 31 +6/7 weeks/days, born by uncomplicated delivery and who have received antenatal corticosteroids., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The objective of this study is to evaluate whether early hypoglycemia is an independent risk factor for 2-year cognitive (COG) impairment in small for gestational age (SGA) preterm infants with gestational age (GA) < 32 weeks. We retrospectively reviewed data of 1364 preterm infants with a GA 24 +0/7 -31 +6/7  weeks. Infants were classified based on blood glucose concentrations within the first 6 h of life (HOL) as < or ≥ 40 mg/dL (Glyc < 40 [Birth-6HOL] and Glyc ≥ 40 [Birth-6HOL] , respectively) and subsequently by birth weight z-score as SGA or appropriate for gestational age (AGA). Propensity score matching analyses were conducted for each comparison. Multiple logistic regression was used to evaluate the association of Glyc < 40 [Birth-6HOL] with 2-year COG impairment, defined as a Bayley-III score < 85, in SGA infants. Out of the 747 preterm infants who met the inclusion criteria, 173 (23.2%) were classified as Glyc < 40 [Birth-6HOL] , and 574 (76.8%) as Glyc ≥ 40 [Birth-6HOL] . The proportion of SGA infants was significantly higher in Glyc < 40 [Birth-6HOL] than in Glyc ≥ 40 [Birth-6HOL] (25.4 vs 18.3%, p = 0.039). The incidence of 2-year COG impairment was significantly higher in SGA infants compared to matched AGA counterparts both in Glyc < 40 [Birth-6HOL] (+ 20%, p = 0.040) and Glyc ≥ 40 [Birth-6HOL] (+ 17%, p = 0.029). Neither in the entire cohort nor in the SGA infants, Glyc < 40 [Birth-6HOL] was significantly associated with 2-year COG impairment (aOR: 1.077, p = 0.768; 0.993, p = 0.935; respectively) after the adjustment for GA, sex, Apgar score at 5 min < 7, SGA status, complications of prematurity, duration of mechanical ventilator support > 7 days, cumulative energy intakes from birth to 36 weeks, and maternal university level., Conclusion:  Among SGA preterm infants with GA between 24 +0/7 and 31 +6/7  weeks/days, hypoglycemia within the first 6 HOL was not an independent risk factor for 2-year COG impairment., What Is Known: • Hypoglycemia is associated with poor neurodevelopmental outcomes in preterm infants. • Small for gestational age (SGA) preterm infants are more prone to cognitive (COG) impairment compared to AGA counterparts., What Is New: • In a large cohort of preterm infants < 32 weeks, the incidence of hypoglycemia within the first 6 hours of life (HOL) was higher in SGA compared to AGA. • Hypoglycemia within the first 6 HOL was not an independent risk factor for 2-year COG impairment in SGA preterm infants., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: A multicenter randomized clinical trial (RCT) showed a lung recruitment maneuver using high-frequency oscillatory ventilation just before surfactant administration (ie, intubate-recruit-surfactant-extubate [IN-REC-SUR-E]) improved the efficacy of treatment compared with the standard intubate-surfactant-extubate (IN-SUR-E) technique without increasing the risk of adverse neonatal outcomes., Objective: To examine follow-up outcomes at corrected postnatal age (cPNA) 2 years of preterm infants previously enrolled in an RCT and treated with IN-REC-SUR-E or IN-SUR-E in 35 tertiary neonatal intensive care units., Design, Setting, and Participants: This was a follow-up study of infants recruited into the primary RCT from 2015 to 2018 at 35 tertiary neonatal intensive care units (NICUs) in Italy. Follow-up examinations included neurodevelopmental, growth, and respiratory outcomes of these children at cPNA 2 years. Participants included spontaneously breathing extremely preterm neonates (24 0/7 to 27 6/7 weeks' gestation) reaching failure criteria for continuous positive airway pressure within the first 24 hours of life. Data were analyzed from April 2023 to January 2024., Intervention: Infants were randomly assigned (1:1) to IN-REC-SUR-E or IN-SUR-E and then followed up., Main Outcomes and Measures: The primary outcome was the occurrence of death after discharge or major disability at cPNA 2 years. Secondary outcomes were neurodevelopmental outcomes (major disability, cerebral palsy, cognitive impairment, visual deficit, or auditory deficit), anthropometric measurements (weight, length, and head circumference), and recurrent respiratory infections and hospitalizations because of respiratory causes at 2y cPNA., Results: A total of 137 extremely preterm infants (median [IQR] gestational age, 26.5 [25.3-27.5] weeks and 75 [54.7%] female), initially enrolled in the original RCT, were followed up at cPNA 2 years, including 64 infants in the IN-SUR-E group and 73 infants in the IN-REC-SUR-E group. There were no significant differences in the occurrence of death after discharge or major disability at cPNA 2 years (IN-SUR-E: 13 children [20.3%] vs IN-REC-SUR-E: 10 children [13.7%]; P = .36). There were no significant differences in incidence of disability, cerebral palsy, or cognitive impairment in the IN-REC-SUR-E group compared with the IN-SUR-E group. There were no significant differences in anthropometric measurements (weight, length, and head circumference) between groups. There were no significant differences in the incidence of recurrent respiratory infections or in hospitalizations because of respiratory causes between groups., Conclusions and Relevance: In this RCT of lung recruitment before surfactant vs standard care there were no significant differences between the 2 groups in death, neurodevelopmental outcomes, anthropometric measurements, or recurrent respiratory infections at the 2-year follow-up. These findings can aid clinicians in decision-making for the best strategy to administer surfactant, considering long-term outcomes.

The aim of this randomized, double-blind, controlled trial was to examine the effects of infant formula on the growth, stool consistency, and bone strength of infants ( n  = 120) over a period of 4 months. The investigational group was fed an A2 β-casein cow's milk infant formula containing casein phosphopeptides (CPP) and high sn-2 palmitate (54% of total palmitate at sn-2). The control group was fed a standard cow's milk formula without CPP and with low sn-2 palmitate (29% of total palmitate at sn-2). The third group was fed human milk (HM) ( n  = 60). All three groups had similar baseline characteristics, and maintained similar BMI, sleep habits, and growth rates in body weight and length throughout the study. However, compared to the control group, infants in the investigational and human milk groups had significantly: (i) greater body length at 90, 120, and 150 days of age; (ii) greater growth rate in head circumference from 30 to 60 days of age, with larger head circumference at 60 days of age; (iii) larger daily stool frequency at 60, 90, and 120 days of age; (iv) softer stool at 60, 90, and 120 days of age; (v) higher bone quality index and bone speed of sound at 150 days of age; (vi) fewer hours of crying at 60 and 90 days of age; (vii) less abdominal distention, burp, and flatus at 60, 90, and 120 days of age; and (viii) less constipation at 90 days of age. At other time points, no significant differences were observed between the three groups. No serious adverse events (AEs) related to the study products were reported, and significantly fewer infants in the investigational and HM groups experienced at least one AE compared to the control group. The study suggests that the A2 β-casein formula with high sn-2 palmitate and CPP supports adequate growth, is well tolerated, and may have beneficial effects on stool consistency, gastrointestinal comfort, crying duration, and bone density, comparable to HM. Clinical trial registration: https://clinicaltrials.gov/, NCT04749290., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sheng, Mi, Yuan, Liu, Carnielli, Ning and Einerhand.)

Objective: To evaluate the association between mother's own milk (MOM) and bronchopulmonary dysplasia (BPD) in appropriate for gestational age (AGA) preterm infants <32 weeks., Methods: Clinical data of AGA preterm infants (24 +0/7 -31 +6/7 weeks) were reviewed. Infants with ≥66% of cumulative prescribed enteral volumes as MOM from birth to 36 weeks were allocated to the high provision of MOM group (H-MOM), whereas those with <66% were assigned to the low provision of MOM group (L-MOM). Multiple regressions were used to assess the association of H-MOM with BPD and oxygen saturation to fraction inspired oxygen ratio (SFR) at 36 weeks., Results: A total of 1041 infants met the inclusion criteria, with a median provision of cumulative enteral nutrition volumes of 5721 (IQR 2616) mL/kg. Among them, 517 (49.7%) were H-MOM and 524 (50.3%) L-MOM infants. H-MOM showed a reduction in the incidence of BPD to 31.6% compared to L-MOM infants. H-MOM had a lower risk of BPD than L-MOM infants after the adjustment for gestational age, sex, cesarean section, mean SFR at the first hours of life, surfactant administration, patent ductus arteriosus, sepsis, prolonged ventilatory supports/oxygen exposure, and cumulative energy intakes from birth to 36 weeks [aOR: 0.613, p = 0.047]. H-MOM was also associated with a lower risk of SFR in the first quartile at 36 weeks [aOR: 0.616, p = 0.028] than L-MOM., Conclusion: A high provision (≥66%) of enteral volume as MOM from birth to 36 weeks is associated with a reduced risk of both BPD and low SFR at 36 weeks in AGA preterm infants <32 weeks., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

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., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: The effect of different neonatal anthropometric charts on the incidence and neurodevelopmental outcomes at two years (Y) corrected age of small-for-gestational-age (SGA) preterm infants has still not been fully explored., Methods: All preterm infants with a gestational age (GA) between 24.0 and 31.6 weeks (W), born from Jan-2004 to Dec-2017 in the Marche region (Italy) were studied. Intergrowth-21 st , Beeby, Fenton, and Bertino anthropometric charts were used to classify infants with a birth weight less than 10 th centile as SGA. Disabilities and neurodevelopmental scores assessed by Bayley-III Test were recorded at the 2Y follow-up visit., Results: One thousand one hundred forty-seven preterm infants were evaluated. The incidence of SGA was significantly different among the study charts (from 12.9 to 17.5%). Nine hundred and twenty-seven study infants were assessed for neurodevelopmental outcomes at 2Y corrected age. The incidence of SGA with moderate cognitive impairment (COG Score: 70-84) and mild neurodevelopmental disability (NDD) were significantly different between the Intergrowth-21 st and Bertino charts (31.7% vs. 19.6%, P=0.042; 30.8 vs. 19.2%, P=0.036; respectively). A statistically significant difference in COG Score was found between SGA preterm infants overlapping in all study charts and those classified as SGA only by the Intergrowth-21 st chart (89.1±15.7 vs. 99.2±19.8; P=0.038)., Conclusions: In a large cohort of preterm infants with a GA between 24.0 and 31.6W, the incidence and neurodevelopmental outcomes at 2Y corrected age of SGAs were significantly different depending on the anthropometric charts. These differences, albeit small, should be considered both in clinical practice and trials on SGA preterm infants.

Background: Small-for-gestational-age (SGA) preterm infants are at increased risk of developing bronchopulmonary dysplasia (BPD). There is limited information on pulmonary oxygen diffusion of SGA preterm infants, particularly in those without BPD., Objective: To compare the pulmonary oxygen diffusion of SGA to that of appropriate-for-gestational-age (AGA) preterm infants without BPD., Study Design: Preterm infants with a gestational age (GA) between 24.0 and 31.6 weeks were studied. The oxygen saturation (SpO 2 ), fraction to inspired oxygen (FiO 2 ), and the SpO 2 to FiO 2 ratio (SFR) were compared between SGA and AGA infants. The association between SGA and SFR at 36 weeks was assessed using a multiple regression analysis. In the subgroup without BPD, SGA were match-paired for GA and gender with AGA infants., Results: We analyzed 1189 infants surviving at 36 weeks: 194 (16%) were SGA and 995 (84%) AGA. The incidence of BPD was significantly higher in SGA than AGA infants (32% vs. 13%; p = .000). Out of the 995 infants without BPD, 132 (13%) were SGA and 863 (87%) AGA. SGA was negatively associated with the SFR value at 36 weeks, independently from BPD. SGA infants without BPD had significantly higher (better) SFR at birth, but lower (worse) SpO 2 and SFR and from 33 to 36 weeks than their matched AGA counterpart. At 36 weeks, median SpO 2 and SFR values were 97.7 versus 98.4 (p = .006) and 465 versus 468 (p = .010) in match-paired SGA and AGA, respectively., Conclusion: Among preterm infants of less than 32 weeks and without BPD, SGA infants had a reduced pulmonary oxygen diffusion at 36 weeks in comparison with AGA infants., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

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., Competing Interests: Declaration of Competing Interest The authors do not have conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (© 2023. The Author(s).)

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., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

The need for high quality evidence is recognized for optimizing practices of parenteral nutrition (PN). The purpose of the present systematic review is to update the available evidence and investigate the effect of standardized PN (SPN) vs. individualized PN (IPN) on protein intake, immediate morbidities, growth, and long-term outcome in preterm infants. A literature search was performed on articles published in the period from 1/2015 to 11/2022 in PubMed and Cochrane database for trials on parenteral nutrition in preterm infants. Three new studies were identified. All new identified trials were nonrandomized observational trials using historical controls. SPN may increase weight and occipital frontal circumference gain and lower the value of maximum weight loss. More recent trials suggest that SPN may easily increase early protein intake. SPN may reduce the sepsis incidence, but overall, no significant effect was found. There was no significant effect of standardization of PN on mortality or stage ≥2 necrotizing enterocolite (NEC) incidence. In conclusion SPN may improve growth through higher nutrient (especially protein) intake and has no effect on sepsis, NEC, mortality, or days of PN.

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., Competing Interests: N.D.E. reports receipt of research grant supports from National Institutes for Health Research (UK), Prolacta Bioscience (US), Danone Early Life Nutrition, Medical Research Council, and Action Medical Research; payment/honorarium for lectures from Nestle Nutrition Institute, Astarte Medical. S.J.M. reports receipt of research support from DSM Nutritional Products and payment/honorarium for lectures from Baxter. A.L. reports receipt of lecture fees and/or nonfinancial support from Baxter, Fresenius, Nestle, and Mead Johnson Nutrition. C.H.P.v.d.A. reports receipt of speakers and consultancy honoraria from Nestlé Nutrition Institute, Nutricia Early Life Nutrition, and Baxter. V.C. reports speaker fees from Baxter and Chiesi Pharma. C.F. reports receipt of lecture fees from Nestle Nutrition Institute, Medela, Prolacta, and Neobiomics and consultancy fees for Medela, Baxter, Hipp, and Nutricia. K.G. reports receipt of research grants, speakers and consultancy fees and hospitality from Nestle Health Sciences, Nutricia-Danone, Baxter, Mylan, Dr. Falk Pharma, Abbott, Servier, and Janssen. J.B.v.G. reports a research grant from Nutrinia and FP7/Danone. Founder & Director of Dutch National Human Milk Bank and council member of National Health Council. N.H. reports consulting fees from Medis, MAM, Baxter, and Nestle and speaker fees from Nestle, Baxter, Danone, and Hipp outside the submitted work. M.J.J. reports research grants from NeoKare UK Ltd. S.M. reports research support from Nestle Health Science. L.N. reports consultancy advice for Takaeda and Nestle. J.B. reports personal fees and nonfinancial support from AbbVie, Nutricia, and Biocodex, personal fees from MSD, Nestlé, and Ferring. F.I. reports receipt of payment/honorarium for lectures from Biogaia, Nestle, Danone, and Abbot, and consultancy fees from Biogaia. E.V. reports grant/research support from Nutricia Italia Spa, Nestle Health Science – Vitaflo Italy, FoodAR srl Italy, PIAM Pharma, and Integrative Care. M.D. reports a research grant from Prolacta and speaker fees from Semper, Baxter, Mead Johnson, and Nestlé. The remaining authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

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., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Stable isotope tracing can be safely used for metabolic studies in animals and humans. The endogenous biosynthesis of lipids (lipogenesis) is a key process throughout the entire life but especially during brain and lung growth. Adequate synthesis of pulmonary surfactant lipids is indispensable for life. With this study, we report the use of deuterium-depleted water (DDW), suitable for human consumption, as metabolic precursor for lipogenesis. We studied 13 adult rabbits for 5 days. Four rabbits drank tap water (TW) and served as controls; in four animals, DDW was substituted to drinking water, whereas five drank deuterium-enriched water (DEW). After 5 days, a blood sample and a bronchoalveolar lavage (BAL) sample were collected. The 2 H/ 1 H (δ 2 H) of BAL palmitic acid (PA) desaturated phosphatidylcholine (DSPC), the major phospholipid of pulmonary surfactant, and of plasma water was determined by high-resolution mass spectrometry. We found that the δ 2 H values of DDW, DEW and TW were -984 ± 2‰, +757 ± 2‰ and -58 ± 1‰, respectively. After 5 days, plasma water values were -467 ± 87‰, +377 ± 56‰ and -53 ± 6‰, and BAL DSPC-PA was -401 ± 27‰, -96 ± 38‰ and -249 ± 9‰ in the DDW, DEW and TW, respectively. With this preliminary study, we demonstrated the feasibility of using DDW to label pulmonary surfactant lipids. This novel approach can be used in animals and in humans, and we speculate that it could be associated with more favourable study compliance than DEW in human studies., (© 2022 The Authors. Journal of Mass Spectrometry published by John Wiley & Sons Ltd.)

Pulmonary surfactant is a complex lipoprotein mixture secreted into the alveolar lumen by type 2 pneumocytes, which is composed by tens of different lipids (approximately 90% of its entire mass) and surfactant proteins (approximately 10% of the mass). It is crucially involved in maintaining lung homeostasis by reducing the values of alveolar liquid surface tension close to zero at end-expiration, thereby avoiding the alveolar collapse, and assembling a chemical and physical barrier against inhaled pathogens. A deficient amount of surfactant or its functional inactivation is directly linked to a wide range of lung pathologies, including the neonatal respiratory distress syndrome. This paper reviews the main biophysical concepts of surfactant activity and its inactivation mechanisms, and describes the past, present and future roles of surfactant replacement therapy, focusing on the exogenous surfactant preparations marketed worldwide and new formulations under development. The closing section describes the pulmonary surfactant in the context of drug delivery. Thanks to its peculiar composition, biocompatibility, and alveolar spreading capability, the surfactant may work not only as a shuttle to the branched anatomy of the lung for other drugs but also as a modulator for their release, leading to innovative therapeutic avenues for the treatment of several respiratory diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Preterm infants' spontaneous motility is a valuable diagnostic and prognostic index of motor and cognitive impairments. Despite being recognized as crucial, preterm infant's movement assessment is mostly based on clinicians' visual inspection. The aim of this work is to present a 2D dense convolutional neural network (denseCNN) to detect preterm infant's joints in depth images acquired in neonatal intensive care units. The denseCNN allows to improve the performance of our previous model in the detection of joints and joint connections, reaching a median recall value equal to 0.839. With a view to monitor preterm infants in a scenario where computational resources are scarce, we tested the architecture on a mid-range laptop. The prediction occurs in real-time (0.014 s per image), opening up the possibility of integrating such monitoring system in a domestic environment.

Computer-assisted tools for preterm infants' movement monitoring in neonatal intensive care unit (NICU) could support clinicians in highlighting preterm-birth complications. With such a view, in this work we propose a deep-learning framework for preterm infants' pose estimation from depth videos acquired in the actual clinical practice. The pipeline consists of two consecutive convolutional neural networks (CNNs). The first CNN (inherited from our previous work) acts to roughly predict joints and joint-connections position, while the second CNN (Asy-regression CNN) refines such predictions to trace the limb pose. Asy-regression relies on asymmetric convolutions to temporally optimize both the training and predictions phase. Compared to its counterpart without asymmetric convolutions, Asy-regression experiences a reduction in training and prediction time of 66% , while keeping the root mean square error, computed against manual pose annotation, merely unchanged. Research mostly works to develop highly accurate models, few efforts have been invested to make the training and deployment of such models time-effective. With a view to make these monitoring technologies sustainable, here we focused on the second aspect and addressed the problem of designing a framework as trade-off between reliability and efficiency.

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., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Although short binasal prongs (SBP) are the most common interface for noninvasive ventilation, the "double-inspiratory loop cannulas" (DILC) have recently been introduced into many neonatal intensive care units. DILC show advantages over SBP, including reduced nasal trauma and increased comfort. However, their higher intrinsic resistance may compromise ventilation. Our aim was to test a new, low resistance DILC interface., Methods: A test lung was programmed to simulate preterm neonates (500-2000 g BW) with moderate-to-severe respiratory distress syndrome. The artificial nose was designed to keep prongs-to-nares leaks to around 30%. Giulia® ventilator (GINEVRI srl) was used to provide nasal continuous positive airway pressure (NCPAP) and flow synchronized nasal intermittent positive pressure ventilation (NIPPV). NCPAP was set at 4-10 cmH 2 O and synchronized-NIPPV (SNIPPV) at peak inspiratory pressure, 15-20-25 cmH 2 O; inspiratory time, 0.3-0.5 s; and positive end-expiratory pressure, 5-8 cmH 2 O. Four sizes of Sync-flow Cannula® (GINEVRI srl) were tested. The Sync-flow Cannula® was compared with Neotech RAM® cannula and Ginevri SBP®. The outcome measures were the flow/pressure relationship through the four Sync-flow Cannula® sizes, the difference in resistance, the drop in ventilator-alveoli pressure measured by the test lung and the system response time during flow-SNIPPV., Results: The smaller DILC sizes had the lowest flow-pressure ratio. The resistance of the RAM® cannula was significantly higher compared to the other interfaces (p < .001). With 30% leaks, there was a 4-38% ventilator-alveoli drop in pressure, depending on interface size. The system response time was excellent (~65-70 ms)., Conclusions: With about 30% leaks, the Sync-flow Cannula® interfaces result in good pressure transmission and give optimal performance for flow-SNIPPV. Clinical studies are needed to confirm the clinical relevance of these data., (© 2020 Wiley Periodicals LLC.)

Background: The importance of lung recruitment before surfactant administration has been shown in animal studies. Well designed trials in preterm infants are absent. We aimed to examine whether the application of a recruitment manoeuvre just before surfactant administration, followed by rapid extubation (intubate-recruit-surfactant-extubate [IN-REC-SUR-E]), decreased the need for mechanical ventilation during the first 72 h of life compared with no recruitment manoeuvre (ie, intubate-surfactant-extubate [IN-SUR-E])., Methods: We did a randomised, unblinded, controlled trial in 35 tertiary neonatal intensive care units in Italy. Spontaneously breathing extremely preterm neonates (24 + 0 to 27 + 6 weeks' gestation) reaching failure criteria for continuous positive airway pressure within the first 24 h of life were randomly assigned (1:1) with a minimisation algorithm to IN-REC-SUR-E or IN-SUR-E using an interactive web-based electronic system, stratified by clinical site and gestational age. The primary outcome was the need for mechanical ventilation in the first 72 h of life. Analyses were done in intention-to-treat and per-protocol populations, with a log-binomial regression model correcting for stratification factors to estimate adjusted relative risk (RR). This study is registered with ClinicalTrials.gov, NCT02482766., Findings: Of 556 infants assessed for eligibility, 218 infants were recruited from Nov 12, 2015, to Sept 23, 2018, and included in the intention-to-treat analysis. The requirement for mechanical ventilation during the first 72 h of life was reduced in the IN-REC-SUR-E group (43 [40%] of 107) compared with the IN-SUR-E group (60 [54%] of 111; adjusted RR 0·75, 95% CI 0·57-0·98; p=0·037), with a number needed to treat of 7·2 (95% CI 3·7-135·0). The addition of the recruitment manoeuvre did not adversely affect the safety outcomes of in-hospital mortality (19 [19%] of 101 in the IN-REC-SUR-E group vs 37 [33%] of 111 in the IN-SUR-E group), pneumothorax (four [4%] of 101 vs seven [6%] of 111), or grade 3 or worse intraventricular haemorrhage (12 [12%] of 101 vs 17 [15%] of 111)., Interpretation: A lung recruitment manoeuvre just before surfactant administration improved the efficacy of surfactant treatment in extremely preterm neonates compared with the standard IN-SUR-E technique, without increasing the risk of adverse neonatal outcomes. The reduced need for mechanical ventilation during the first 72 h of life might facilitate implementation of a non-invasive respiratory support strategy., Funding: None., (Copyright © 2021 Elsevier Ltd. All rights reserved.)