Use of neonatal lung ultrasound in European neonatal units: a survey by the European Society of Paediatric Research.

OBJECTIVE: Regarding the use of lung ultrasound (LU) in neonatal intensive care units (NICUs) across Europe, to assess how widely it is used, for what indications and how its implementation might be improved. DESIGN AND INTERVENTION: International online survey. RESULTS: Replies were received from 560 NICUs in 24 countries between January and May 2023. LU uptake varied considerably (20%-98% of NICUs) between countries. In 428 units (76%), LU was used for clinical indications, while 34 units (6%) only used it for research purposes. One-third of units had <2 years of experience, and only 71 units (13%) had >5 years of experience. LU was mainly performed by neonatologists. LU was most frequently used to diagnose respiratory diseases (68%), to evaluate an infant experiencing acute clinical deterioration (53%) and to guide surfactant treatment (39%). The main pathologies diagnosed by LU were pleural effusion, pneumothorax, transient tachypnoea of the newborn and respiratory distress syndrome. The main barriers for implementation were lack of experience with technical aspects and/or image interpretation. Most units indicated that specific courses and an international guideline on neonatal LU could promote uptake of this technique. CONCLUSIONS: Although LU has been adopted in neonatal care in most European countries, the uptake is highly variable. The main indications are diagnosis of lung disease, evaluation of acute clinical deterioration and guidance of surfactant. Implementation may be improved by developing courses and publishing an international guideline.

Active versus restrictive ligation strategy for patent ductus arteriosus - A retrospective two-center study of extremely preterm infants born between 22 + 0 and 25 + 6 weeks of gestational age.

BACKGROUND: Patent ductus arteriosus (PDA) in premature infants is associated with adverse clinical outcomes. Mode and timing of treatment are still controversial. Data are limited in the most extremely premature infants <26 weeks of gestational age (GA), where clinical problems are most significant and patients are most vulnerable. AIMS: To investigate whether different approaches to surgical closure of PDA in two large Swedish centers has an impact on clinical outcomes including mortality in extremely preterm infants born <26 weeks GA. STUDY DESIGN: Retrospective, two-center, cohort study. SUBJECTS: Infants born at 22+0-25+6 weeks GA between 2010 and 2016 at Uppsala University Children's Hospital (UUCH; n = 228) and Queen Silvia Children's Hospital Gothenburg (QSCHG; n = 220). MAIN OUTCOME MEASURES: Survival, bronchopulmonary dysplasia (BPD), and retinopathy of prematurity (ROP). RESULTS: Surgical closure of PDA was more common and performed earlier at QSCHG (50 % vs 16 %; median age 11 vs 44 days; p < 0.01). Survival was similar in both centres. There was a higher incidence of severe BPD and longer duration of mechanical ventilation at UUCH (p < 0.01). There was a higher incidence of ROP, IVH and sepsis at QSCH (p < 0.05, p < 0.01 and p < 0.01). A sub-group analysis matching all surgically treated infants at QSCHG with infants at UUCH with the same GA showed similar results as the total cohort. CONCLUSION: Earlier and higher rate of surgical PDA closure in this cohort of extremely preterms born <26 weeks GA did not impact mortality but was associated with lower rates of severe BPD and higher rates of severe ROP.

Collagen type IV alpha 1 chain (COL4A1) expression in the developing human lung.

BACKGROUND: Collagen type IV alpha 1 chain (COL4A1) in the basement membrane is an important component during lung development, as suggested from animal models where COL4A1 has been shown to regulate alveolarization and angiogenesis. Less is known about its role in human lung development. Our aim was to study COL4A1 expression in preterm infants with different lung maturational and clinical features. METHODS: COL4A1 expression in 115 lung samples from newborn infants (21-41 weeks' gestational age; 0-228 days' postnatal age [PNA]) was studied by immunohistochemistry combined with digital image analysis. Cluster analysis was performed to find subgroups according to immunohistologic and clinical data. RESULTS: Patients were automatically categorized into 4 Groups depending on their COL4A1 expression. Expression of COL4A1 was mainly extracellular in Group 1, low in Group 2, intracellular in Group 3, and both extra- and intracellular in Group 4. Intracellular/extracellular ratio of COL4A1 expression related to PNA showed a distinctive postnatal maturational pattern on days 1-7, where intracellular expression of COL4A1 was overrepresented in extremely preterm infants. CONCLUSIONS: COL4A1 expression seems to be highly dynamic during the postnatal life due to a possible rapid remodeling of the basement membrane. Intracellular accumulation of COL4A1 in the lungs of extremely premature infants occurs more frequently between 1 and 7 postnatal days than during the first 24 hours. In view of the lung arrest described in extremely preterm infants, the pathological and/or developmental role of postnatally increased intracellular COL4A1 as marker for basement membrane turnover, needs to be further investigated.

Classifying multicenter approaches to invasive mechanical ventilation for infants with bronchopulmonary dysplasia using hierarchical clustering analysis.

INTRODUCTION: Evidence-based ventilation strategies for infants with severe bronchopulmonary dysplasia (BPD) remain unknown. Determining whether contemporary ventilation approaches cluster as specific BPD strategies may better characterize care and enhance the design of clinical trials. The objective of this study was to test the hypothesis that unsupervised, multifactorial clustering analysis of point prevalence ventilator setting data would classify a discrete number of physiology-based approaches to mechanical ventilation in a multicenter cohort of infants with severe BPD. METHODS: We performed a secondary analysis of a multicenter point prevalence study of infants with severe BPD treated with invasive mechanical ventilation. We clustered the cohort by mean airway pressure (MAP), positive end expiratory pressure (PEEP), set respiratory rate, and inspiratory time (Ti) using Ward's hierarchical clustering analysis (HCA). RESULTS: Seventy-eight patients with severe BPD were included from 14 centers. HCA classified three discrete clusters as determined by an agglomerative coefficient of 0.97. Cluster stability was relatively strong as determined by Jaccard coefficient means of 0.79, 0.85, and 0.77 for clusters 1, 2, and 3, respectively. The median PEEP, MAP, rate, Ti, and PIP differed significantly between clusters for each comparison by Kruskall-Wallis testing (p < 0.0001). CONCLUSIONS: In this study, unsupervised clustering analysis of ventilator setting data identified three discrete approaches to mechanical ventilation in a multicenter cohort of infants with severe BPD. Prospective trials are needed to determine whether these approaches to mechanical ventilation are associated with specific severe BPD clinical phenotypes and differentially modify respiratory outcomes.

Paneth cell proteins DEFA6 and GUCA2A as tissue markers in necrotizing enterocolitis.

Previous studies suggest that Paneth cells are involved in NEC development. Defensin alpha 6 (DEFA6) and guanylate cyclase activator 2A (GUCA2A) are selective protein markers of Paneth cells. The objective was to explore DEFA6 and GUCA2A expression in intestinal tissue samples from newborn infants with and without NEC. Tissue samples from histologically intact intestine were analyzed from 70 infants: 43 underwent bowel resection due to NEC and 27 controls were operated due to conditions such as intestinal atresia, dysmotility, aganglionosis, pseudo-obstruction or volvulus. Each tissue sample was immunohistochemically stained for DEFA6 and GUCA2A. Semi-automated digital image analysis was performed to determine protein expression. Clinical data and protein expressions were compared between the groups. DEFA6 expression was lower in the NEC group (p = 0.006). Low DEFA6 correlated with risk of developing NEC in a logistic regression analysis, independently of gestational age and birth weight (OR 0.843 [CI 0.732-0.971]; p = 0.018). GUCA2A expression did not differ between the two groups. CONCLUSION: Lower expression of DEFA6 together with intact GUCA2A expression indicates that NEC patients have well-defined Paneth cells but diminished defensin activity. Our results suggest that DEFA6 could be used as a biomarker for NEC. WHAT IS KNOWN: • Previous studies of defensin activity in NEC have been inconsistent, showing that defensin levels may be increased or diminished in NEC. GUCA2A has to our knowledge never been studied in NEC. WHAT IS NEW: • This study benchmarks two specific Paneth cell markers (DEFA6 and GUCA2A) and their activity in individuals with and without NEC. • The key finding is that the NEC group had a lower DEFA6 expression compared to the Controls, while the expression of GUCA2A did not differ between the groups.

Approaches to Interdisciplinary Care for Infants with Severe Bronchopulmonary Dysplasia: A Survey of the Bronchopulmonary Dysplasia Collaborative.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) remains the most common late morbidity for extremely premature infants. Care of infants with BPD requires a longitudinal approach from the neonatal intensive care unit to ambulatory care though interdisciplinary programs. Current approaches for the development of optimal programs vary among centers. STUDY DESIGN: We conducted a survey of 18 academic centers that are members of the BPD Collaborative, a consortium of institutions with an established interdisciplinary BPD program. We aimed to characterize the approach, composition, and current practices of the interdisciplinary teams in inpatient and outpatient domains. RESULTS: Variations exist among centers, including composition of the interdisciplinary team, whether the team is the primary or consult service, timing of the first team assessment of the patient, frequency and nature of rounds during the hospitalization, and the timing of ambulatory visits postdischarge. CONCLUSION: Further studies to assess long-term outcomes are needed to optimize interdisciplinary care of infants with severe BPD. KEY POINTS: · Care of infants with BPD requires a longitudinal approach from the NICU to ambulatory care.. · Benefits of interdisciplinary care for children have been observed in other chronic conditions.. · Current approaches for the development of optimal interdisciplinary BPD programs vary among centers..

An Update on Patent Ductus Arteriosus and What is Coming Next.

Patent ductus arteriosus is the most common cardiovascular condition in preterm infants. There is a significant uncertainty about when and how to close ductus arteriosus in preterm infants due to a high spontaneous closure rate even in very immature preterm infants. Diagnosis and management of patent ductus arteriosus remain a challenge for both neonatologists and pediatric cardiologists. Researchers have tried to define a balance between an expectant approach and active treatment in selected infants. This review aimed to focus on the pathophysiology and management of patent ductus arteriosus and to make suggestions about approaches that might eliminate the association of morbidities with patent ductus arteriosus.

Respiratory support of infants born at 22-24 weeks of gestational age.

Lung immaturity and acute respiratory failure are the major problems in the care of extremely preterm infants. Most infants with gestational age (GA) 22-24 weeks will need mechanical ventilation and many will depend on some type of respiratory support, invasive and non-invasive for extended periods. There is ongoing gap in knowledge regarding optimal respiratory support and applying strategies that are effective in more mature populations is not easy or even suitable because lung maturation differs in smaller infants. Better strategies on how to avoid lung damage and to promote growth and development of the immature lung are warranted since increased survival is accompanied by increasing rates of bronchopulmonary dysplasia and concerns over long-standing reductions in lung function. This review focuses on some aspects of respiratory care of infants born at 22-24 weeks of GA.

The Impact of Restricted versus Liberal Early Fluid Volumes on Plasma Sodium, Weight Change, and Short-Term Outcomes in Extremely Preterm Infants.

The optimal fluid requirements for extremely preterm infants are not fully known. We examined retrospectively the fluid intakes during the first week of life in two cohorts of extremely preterm infants born at 22-26 weeks of gestation before (n = 63) and after a change from a restrictive to a more liberal (n = 112) fluid volume allowance to improve nutrient provision. The cohorts were similar in gestational age and birth weight, but antenatal steroid exposure was more frequent in the second era. Although fluid management resulted in a cumulative difference in the total fluid intake over the first week of 87 mL/kg (p < 0.001), this was not reflected in a mean weight loss (14 ± 5% at a postnatal age of 4 days in both groups) or mean peak plasma sodium (142 ± 5 and 143 ± 5 mmol/L in the restrictive and liberal groups, respectively). The incidences of hypernatremia (>145 and >150 mmol/L), PDA ligation, bronchopulmonary dysplasia, and IVH were also similar. We conclude that in this cohort of extremely preterm infants a more liberal vs. a restricted fluid allowance during the first week had no clinically important influence on early changes in body weight, sodium homeostasis, or hospital morbidities.

Ventilatory Strategies in Infants with Established Severe Bronchopulmonary Dysplasia: A Multicenter Point Prevalence Study.

We performed a point prevalence study on infants with severe bronchopulmonary dysplasia (BPD), collecting data on type and settings of ventilatory support; 187 infants, 51% of whom were on invasive positive-pressure ventilation (IPPV), from 15 centers were included. We found a significant center-specific variation in ventilator modes.

Respiratory management for extremely premature infants born at 22 to 23 weeks of gestation in proactive centers in Sweden, Japan, and USA.

Survival of preterm newborn infants have increased steadily since the introduction of surfactant treatment and antenatal steroids. In the absence of randomized controlled trials on ventilatory strategies in extremely preterm infants, we present ventilatory strategies applied during the initial phase and the continued ventilatory care as applied in three centers with proactive prenatal and postnatal management and well documented good outcomes in terms of mortality and morbidity in this cohort of infants.

Early Postnatal Comprehensive Biomarkers Cannot Identify Extremely Preterm Infants at Risk of Developing Necrotizing Enterocolitis.

Background: Necrotizing enterocolitis (NEC) is a fatal disease where current diagnostic tools are insufficient for preventing NEC. Early predictive biomarkers could be beneficial in identifying infants at high risk of developing NEC. Objective: To explore early biomarkers for predicting NEC in extremely preterm infants (EPIs). Methods: Blood samples were collected on day 2 (median 1.7; range 1.5-2.0) from 40 EPI (median 25 gestational weeks; range 22-27): 11 developed NEC and 29 did not (controls). In each infant, 189 inflammatory, oncological, and vascular proteomic biomarkers were quantified through Proximity Extension Assay. Biomarker expression and clinical data were compared between the NEC group and Controls. Based on biomarker differences, controls were sorted automatically into three subgroups (1, 2, and 3) by a two-dimensional hierarchical clustering analysis. Results: None of the biomarkers differed in expression between all controls and the NEC group. Two biomarkers were higher in Control 1, and 16 biomarkers were lower in Control group 2 compared with the NEC group. No biomarker distinguished Control 3 from the NEC group. Perinatal data were similar in the whole population. Conclusions: Early postnatal comprehensive biomarkers do not identify EPIs at risk of developing NEC in our study. Future studies of predictors of NEC should include sequential analysis of comprehensive proteomic markers in large cohorts.

Early extubation is associated with shorter duration of mechanical ventilation and lower incidence of bronchopulmonary dysplasia.

INTRODUCTION: Respiratory care of extremely preterm infants remains a challenge. The majority require invasive mechanical ventilation (MV), which is a contributing factor in developing bronchopulmonary dysplasia (BPD). It is important to keep MV to a minimum but there have been concerns that attempting extubation too early increases the risk for atelectasis, re-intubation, and further lung trauma. The aim of this study was to compare two different approaches to extubation. METHODS: Single-center, retrospective cohort study including infants born at 22 + 0-25 + 6 weeks during 2005-2009 and 2011-2015, before and after implementing guidelines recommending delayed extubation. Primary outcomes were BPD, duration of MV and length of hospital stay. RESULTS: Eighty-eight infants in the early era and 102 infants in the late era were included. Infants in the first period were younger at first extubation attempt, and a higher number of infants were extubated within 24 h, 72 h, and one week after birth. The number of infants re-intubated and postnatal age at re-intubation did not differ between the groups. The incidence of severe BPD was 28% in the early period compared to 48% in the later (p < 0.01). Infants in the late period had longer duration of MV (17 vs 27 days, p < 0.01) but similar length of hospital stay (118 vs 123, p = 0.21). CONCLUSION: After implementing guidelines recommending delayed extubation, the incidence of severe BPD was higher and the duration of MV was longer. This supports the strategy to attempt extubation early even in extremely preterm infants.

The value of autopsy in preterm infants at a Swedish tertiary neonatal intensive care unit 2002-2018.

Reliable data on causes of death (COD) in preterm infants are needed to assess perinatal care and current clinical guidelines. In this retrospective observational analysis of all deceased preterm infants born < 37 weeks' gestational age (n = 278) at a Swedish tertiary neonatal intensive care unit, we compared preliminary COD from Medical Death Certificates with autopsy defined COD (2002-2018), and assessed changes in COD between two periods (period 1:2002-2009 vs. period 2:2011-2018; 2010 excluded due to centralized care and seasonal variation in COD). Autopsy was performed in 73% of all cases and was more than twice as high compared to national infant autopsy rates (33%). Autopsy revised or confirmed a suspected preliminary COD in 34.9% of the cases (23.6% and 11.3%, respectively). Necrotizing enterocolitis (NEC) as COD increased between Period 1 and 2 (5% vs. 26%). The autopsy rate did not change between the two study periods (75% vs. 71%). We conclude that autopsy determined the final COD in a third of cases, while the incidence of NEC as COD increased markedly during the study period. Since there is a high risk to determine COD incorrectly based on clinical findings in preterm infants, autopsy remains a valuable method to obtain reliable COD.