Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial.

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.

The role of nutrition in promoting growth in pre-term infants with bronchopulmonary dysplasia: a prospective non-randomised interventional cohort study.

BACKGROUND: Pre-term infants who develop bronchopulmonary dysplasia (BPD) are at risk of postnatal growth failure. It has been reported that energy expenditure is higher in infants with BPD than in those without BPD. The aim of the study was to evaluate whether increasing the enteral energy intake of pre-term infants with BPD can improve post-natal growth. METHODS: This prospective, non-randomised interventional cohort study was designed to assess growth in 57 preterm infants with BPD (gestational age <32 weeks, birth weight <1500 g, and persistent oxygen dependency for up to 28 days of life) fed individually tailored fortified breast milk and/or preterm formula, and a historical control group of 73 pre-term infants with BPD fed breast milk fortified in accordance with the instructions of the manufacturer and/or pre-term formula. Between-group differences in the continuous variables were analysed using Student's t test or the Mann-Whitney test; the discrete variables were compared using the chi-squared test. Linear regression analysis was used to investigate the independent contribution of enteral energy intake to weight gain velocity. RESULTS: The duration of parenteral nutrition was similar in the historical and intervention groups (43.7 ± 30.9 vs 39.6 ± 17.4 days). After the withdrawal of parenteral nutrition, enteral energy intake was higher in the infants in the intervention group with mild or moderate BPD (131 ± 6.3 vs 111 ± 4.6 kcal/kg/day; p < 0.0001) and in those with severe BPD (126 ± 5.3 vs 105 ± 5.1 kcal/kg/day; p < 0.0001), whereas enteral protein intake was similar (3.2 ± 0.27 vs 3.1 ± 0.23 g/kg/day).Weight gain velocity was greater in the infants in the intervention group with mild or moderate BPD (14.7 ± 1.38 vs 11.5 ± 2 g/kg/day, p < 0.0001) and in those with severe BPD (11.9 ± 2.9 vs 8.9 ± 2.3 g/kg/day; p < 0.007). The percentage of infants with post-natal growth retardation at 36 weeks of gestational age was higher in the historical group (75.3 vs 47.4; p = 0.02). CONCLUSIONS: On the basis of the above findings, it seems that improved nutritional management promotes post-natal ponderal growth in pre-term infants with BPD.

Calcium signaling-related proteins are associated with broncho-pulmonary dysplasia progression.

Broncho-pulmonary dysplasia (BPD) is a chronic pulmonary disorder that follows premature birth. It is preceded by respiratory distress syndrome (RDS), characterized by acute respiratory failure due to deficiency of surfactant at birth. Clinical characteristics of infants affected by BPD have widely changed in the last decades: they are extraordinarly immature, with impaired alveolar and vascular lung development. To build up new therapeutic strategies for BPD babies, it is necessary to understand the pathogenic mechanisms, which are complicated by environmental risk factors and genetic predisposition. Therefore, the aim of this study was to highlight protein changes in the broncho-alveolar lavage fluid (BALF), thus providing an appropriate picture on what is happening in the locus of injury. We analyzed BALF samples from preterm babies, born at different stages of lung development. We confirmed that gestational age is relevant for BPD progression, but we also detected few de-regulated proteins in the younger babies; we discovered less abundant calcium signaling-related proteins, consistent with BPD severity, comparing severe to mild BPD babies with matched gestational age. In conclusion, this study suggests a subset of proteins to be investigated to better treat BPD babies and facilitate the definition of potential drug targets for novel therapies. BIOLOGICAL SIGNIFICANCE: Pulmonary biomarkers are needed to predict the clinical course of lung disease, status, progression and response to treatment. A key aspect in biomarker discovery is uncovering molecules that appear early during disease initiation, when the natural history of the disease can be modified. Using a proteomic-based approach we compared broncho-alveolar lavage fluid (BALF) protein profile from preterm neonates at different postmenstrual ages, to have a molecular description of broncho-pulmonary dysplasia (BPD) progression. BALF provided a snapshot of local molecular changes, which are relevant for early diagnosis, assessment and characterization of lung disorders. We showed that even if the studied patients had similar clinical phenotype (they all developed severe BPD and they were all cured in the same way in terms of mechanical ventilation, surfactant administration, antenatal steroid treatment and ibuprofen treatment for patent ductus arteriosus), however their BALF protein profiling displayed significant differences in a subset of proteins, which could be exploited to facilitate the development of novel effective therapies, distinct for age and severity of the disease.

Differentiation and migration properties of human foetal umbilical cord perivascular cells: potential for lung repair.

Mesenchymal stem cells (MSC) have been derived from different cultured human tissues, including bone marrow, adipose tissue, amniotic fluid and umbilical cord blood. Only recently it was suggested that MSC descended from perivascular cells, the latter being defined as CD146⁺ neuro-glial proteoglycan (NG)2⁺ platelet-derived growth factor-Rß⁺ ALP⁺ CD34⁻ CD45⁻ von Willebrand factor (vWF)⁻ CD144⁻. Herein we studied the properties of perivascular cells from a novel source, the foetal human umbilical cord (HUC) collected from pre-term newborns. By immunohistochemistry and flow cytometry we show that pre-term/foetal HUCs contain more perivascular cells than their full-term counterparts (2.5%versus 0.15%). Moreover, foetal HUC perivascular cells (HUCPC) express the embryonic cell markers specific embryonic antigen-4, Runx1 and Oct-4 and can be cultured over the long term. To further confirm the MSC identity of these cultured perivascular cells, we also showed their expression at different passages of antigens that typify MSC. The multilineage differentiative capacity of HUCPC into osteogenic, adipogenic and myogenic cell lineages was demonstrated in culture. In the perspective of a therapeutic application in chronic lung disease of pre-term newborns, we demonstrated the in vitro ability of HUCPC to migrate towards an alveolar type II cell line damaged with bleomycin, an anti-cancer agent with known pulmonary toxicity. The secretory profile exhibited by foetal HUCPC in the migration assay suggested a paracrine effect that could be exploited in various clinical conditions including lung disorders.

The role of laparoscopy in newborns affected by NEC.

INTRODUCTION: For many years, laparoscopic procedures have been reported in the literature in pediatrics also. In this article, we report their experiences of the use of gasless laparoscopy in 8 newborns affected by necrotizing enterocolitis (NEC). MATERIALS AND METHODS: From January 2007 to May 2008, 8 patients affected by stage 1-2 NEC were treated at the Department of Pediatric Surgery, Fondazione Policlinico Milan (Milan, Italy). Of those, 3 patients presented with a birth weight below 1.5 kg. RESULTS: All patients were submitted at gasless laparoscopy. In 6 of 8 patients, a covered perforation was detected; in 5 cases, the perforation was on the posterior wall of the ascending colon, and in 1, a perforation of the transverse colon was detected. In these 6 of 8 patients, the procedure was converted to formal laparotomy, with colonic resection and primary anastomosis. In 2 of 8 patients, a diffuse necrotizing enteritis of the small bowel was reported, without evidence of perforation; two drains were placed and continued abdominal washout with antibiotics solution was maintained for 48 hours, associated with systemic therapy. All patients were maintained on systemic antibiotic therapy for 7 days with regression of sepsis; all patients survived and were discharged in good general condition. At follow-up of 3 months, none of the patients presented with complications. DISCUSSION: We believe that the decision to perform a laparoscopy, despite the very low weight of the patient, was crucial in the management of nondetected perforation at X-ray. Retrospectively, laparoscopy would be the best option to define the presence of NEC without a perforation, which may only require washout of the cavity that can be also managed with this technique. CONCLUSIONS: We believe that laparoscopy can be easily managed also in newborns and small for gestational age neonates, reducing the morbidity of laparotomy for suspicion of perforation in patients affected by NEC who do not respond to medical treatment.

Glutathione-S-transferase-P1 I105V polymorphism and response to antenatal betamethasone in the prevention of respiratory distress syndrome.

PURPOSE: The aim of this pilot study was to assess the association between polymorphisms in genes that encode for proteins involved in the pharmacokinetics/pharmacodynamics of glucocorticoids and the occurrence of respiratory distress syndrome (RDS) in preterm infants born to mothers treated with a complete course of betamethasone. METHODS: Sixty-two preterm infants were enrolled. The C1236T, G2677T, and C3435T polymorphisms in the ABCB1 gene, BclI, N363S and ER22/23EK in the NR3C1 gene, I105V in the GST-P1 gene and GST-M1 and GST-T1 deletions were analyzed, and their association with the occurrence of RDS was assessed. RESULTS: In univariate analysis, the heterozygous and homozygous presence of the I105V variant in the GST-P1 gene seemed to confer protection against the occurrence of RDS (P = 0.032), while no association for all other polymorphisms was observed. In multivariate analysis, selection from the reference model of independent variables based on AIC (Akaike information criteria) maintained three variables in the model: gestation, C3435T, and GST-P1 genotype. CONCLUSIONS: Polymorphisms of the GST-P1 gene may influence the effect of antenatal steroids on the newborn lung.