Skin thickness in preterm neonates: relationship with skin bilirubin and predicted mortality.

This study investigates the relationship between the thickness of skin in preterm infants and its link with bilirubin and mortality, as this may help understanding the potential deleterious effects of phototherapy. Observational, prospective cohort study enrolling preterm neonates needing phototherapy and admitted to a neonatal intensive care unit. Transcutaneous bilirubin (TcB) and blood bilirubin were simultaneously measured before the onset of phototherapy, if any. The skin depth was measured by high-frequency point-of-care ultrasound. Mortality risk was estimated using the critical risk index for babies-II. Correlations and multivariate regressions (adjusting for several confounders) were applied to study the relationship between skin depth, TcB, and predicted mortality. One hundred fifty-nine neonates were studied. There was a positive and steady correlation between skin depth and TcB (r = 0.402 (95%CI: 0.206; 0.568), p < 0.001) and inverse correlation between skin depth and predicted mortality (r = -0.503 (95%CI: -0.61; -0.37), p < 0.001) as well as between TcB and predicted mortality (r = -0.303 (95%CI: -0.49; -0.09), p = 0.005). Multivariate analyses showed skin depth to be the strongest risk factors associated with both increasing TcB (ß = 198 (59;338), p < 0.001) and decreasing risk of death (ß = -24 (-46;2), p = 0.049). Blood bilirubin and gestational age were also associated with TcB and predicted mortality, respectively.   Conclusion: In NICU-admitted preterm infants, thicker skin is associated with higher TcB levels irrespective of gestational age. Greater skin depth is also associated with lower predicted mortality irrespective of blood bilirubin. What is Known: • In preterm infants, phototherapy may improve neuro-developmental outcomes but, particularly in the smallest and sickest ones, may increase mortality. • Mechanisms behind this effect are unclear but could involve the small thickness of preterm skin. This however has never been studied in relationship with bilirubin and mortality. What is New: • In NICU-admitted preterm infants, thicker skin is associated with higher levels of transcutaneous bilirubin, irrespective of gestational age and with lower predicted mortality, irrespective of blood bilirubin. • These data suggest that a thinner skin may contain less bilirubin to be photoisomerised and protect internal tissues less efficiently.

The Multifaceted Burden of Respiratory Syncytial Virus (RSV) Infections in Young Children on the Family: A European Study.

INTRODUCTION: Since the majority of hospitalisations due to RSV occur in young children, the illness profoundly influences the entire family. However, comprehensive evidence regarding its overall effects remains limited. The ResQ Family study aims to investigate the burden of RSV-induced pediatric hospitalisation on affected families. METHODS: Spanning the 2022-2023 RSV season, an interdisciplinary, observational study was conducted in Germany, France, Italy and Sweden. Using an online questionnaire, parents and caregivers of children (< 24 months of age) with an RSV-induced hospitalisation were recruited. Information was gathered on topics related to RSV and parental health-related quality of life (HRQoL) during the acute infection phase (t0) and 6 weeks later (t1). Descriptive evaluations of the data set were performed during t0 and regarding a potential change over the observation period (t0 vs. t1). Subgroup analysis aimed to further identify differences across the countries. RESULTS: A total set of 138 affected parents/caregivers were included in the study, with 59 participants responding to the follow-up survey (t1). Particularly during the acute infection phase, parental HRQoL was shown to be negatively influenced by the child's RSV infection [total score (p < 0.001, d = 0.54), parent HRQoL summary score (p < 0.001, d = 0.67) and family functioning summary score (p = 0.007, d = 0.33)]. Significant disparities in disease awareness and support structures were observed across Europe, with France and Sweden showing notably higher levels. CONCLUSION: The ResQ Family study provides convincing evidence that RSV-associated hospitalisations in young children across Europe generate a multifaced burden for the entire family, partly even beyond the acute infection phase. Standardised approaches for disease prevention at societal, educational and policy levels are needed to guarantee every newborn the best possible start into life. TRIAL REGISTRATION: ClinicalTrials.gov, identifier, NCT05550545.

Global and regional heterogeneity of lung aeration in neonates with different respiratory disorders: a physiological, observational study.

BACKGROUND.: Aeration heterogeneity affects lung stress and influences outcomes in adults with acute respiratory distress syndrome (ARDS). We hypothesize that aeration heterogeneity may differ between neonatal respiratory disorders and is associated with oxygenation, so its evaluation may be relevant in managing respiratory support. METHODS.: Observational, prospective study. Neonates with respiratory distress syndrome (RDS), transient tachypnea (TTN), evolving bronchopulmonary dysplasia (BPD) and neonatal ARDS (NARDS) were enrolled. Quantitative lung ultrasound and transcutaneous blood gas measurements were simultaneously performed. Global aeration heterogeneity (with its intra- and inter-patient components) and regional aeration heterogeneity were primary outcomes; oxygenation metrics were the secondary outcomes. RESULTS.: 230 (50 RDS, TTN or evolving BPD and 80 NARDS) patients were studied. Intra-patient aeration heterogeneity was higher in TTN (mean: 61% [standard deviation: 33%]) and evolving BPD (mean: 57% [standard deviation: 20%], p<0.001), with distinctive aeration distributions. Inter-patient aeration heterogeneity was high for all disorders (Gini-Simpson index: between 0.6 and 0.72) except RDS (Gini-Simpson index: 0.5) whose heterogeneity was significantly lower than all others (p<0.001). NARDS and evolving BPD had the most diffuse injury and worst gas exchange metrics. Regional aeration heterogeneity was mostly localized in upper anterior and posterior zones. Aeration heterogeneity and total lung aeration had an exponential relationship (p<0.001; adj-R 2=0.62). Aeration heterogeneity is associated with greater total lung aeration (i.e., higher heterogeneity means a relatively higher proportion of normally aerated lung zones, thus greater aeration; p<0.001; adj-R 2=0.83) and better oxygenation metrics upon multivariable analyses. CONCLUSIONS.: Global aeration heterogeneity and regional aeration heterogeneity differ amongst neonatal respiratory disorders. TTN and evolving BPD have the highest intra-patient aeration heterogeneity. TTN, evolving BPD and NARDS have the highest inter-patient aeration heterogeneity, but the latter two have the most diffuse injury and worst gas exchange. Higher aeration heterogeneity is associated with better total lung aeration and oxygenation.

NIV-NAVA versus non-invasive respiratory support in preterm neonates: a meta-analysis of randomized controlled trials.

OBJECTIVE: To analyze the clinical and physiological outcomes of NIV-NAVA in preterm infants compared with other non-invasive respiratory support. STUDY DESIGN: We conducted a meta-analysis of RCTs and randomized crossover studies comparing NIV-NAVA to other non-invasive strategies in preterm neonates. RESULTS: NIV-NAVA was superior to other non-invasive support in maximum EAdi (MD - 0.66 µV; 95% CI - 1.17 to -0.15; p = 0.01), asynchrony index (MD - 49.8%; 95% CI - 63.1 to -36.5; p < 0.01), and peak inspiratory pressure (MD - 2.2 cmH2O; 95% CI - 2.7 to -1.7; p < 0.01). However, there were no significant differences in the incidences of intubation (RR 0.91; 95% CI 0.56-1.48; p = 0.71), reintubation (RR 0.72; 95% CI 0.45-1.16; p = 0.18), or bronchopulmonary dysplasia (RR 0.77; 95% CI 0.37-1.60; p = 0.48). CONCLUSION: NIV-NAVA was associated with improvements in maximum Edi, asynchrony index, and peak inspiratory pressure relative to other non-invasive respiratory strategies, without significant differences in clinical outcomes between groups.

Maternal and neonatal outcomes of French prospective multicenter cohort study COVIPREG during the first two COVID-19 waves.

BACKGROUND: SARS-CoV-2 infection on pregnant women was the subject of many questions since the COVID-19 pandemic. METHODS: We aim to assess maternal and neonatal outcomes of SARS-CoV-2 infection contracted during 2nd and 3rd trimesters of pregnancy during the first two COVID-19 waves across a prospective French multicenter cohort study. Patients were included between April 2020 and January 2021 in 10 maternity hospitals in Paris area with two groups (i) pregnant women with a positive SARS-CoV-2 nasopharyngeal RT-PCR between [14WG; 37WG[(symptomatic infection), (ii) pregnant women with a negative serology (or equivocal) at delivery and without a positive SARS-CoV-2 nasopharyngeal RT-PCR at any time during pregnancy (G2 group) MAIN FINDINGS: 2410 pregnant women were included, of whom 310 had a positive SARS-CoV-2 nasopharyngeal RT-PCR and 217 between [14WG; 37WG[. Most infections occurred between 28 and 37 weeks of gestation (56 %). Most patients could be managed as outpatients, while 23 % had to be hospitalized. Among women with a positive RT-PCR, multiparous women were over-represented (OR = 2.45[1.52;3.87]); were more likely to deliver before 37 weeks of gestation (OR = 2.19[1.44;3.24]) and overall cesarean deliveries were significantly increased (OR = 1.53[1.09;2.13]). CONCLUSIONS: This study highlights the maternal, obstetrical, and neonatal burden associated with SARS-CoV-2 infections during the first two pandemic waves before availability of vaccines. TRIAL REGISTRATION: NCT04355234 (registration date: 21/04/2020).

Critical care of severe bronchiolitis during shortage of ICU resources.

Large seasonal outbreaks of bronchiolitis put pressure on healthcare systems and particularly on intensive care units (ICUs). ICU admission is necessary to provide respiratory support to the severest cases, otherwise bronchiolitis can result in substantial mortality. ICU resources are often insufficient and there is scant evidence to guide the ICU clinical management. Most available studies do not cover the ICU-admitted cases and do not consider the associated public health issues. We review this topic through a multidisciplinary approach from both the clinical and public health perspectives, with an analysis based on pathophysiology and cost-effectiveness. We suggest ways to optimise respiratory care, minimise ICU stay, "protect" ICU beds and, whenever possible, make them available for other critically ill children. We also provide guidance on how to prepare ICUs to work under stressful conditions due to outbreaks and to reduce the risk of nosocomial cross-contamination, particularly in ICUs caring for high-risk children. Funding: None.

Inspiratory-expiratory variation of pleural line thickness in neonates with and without acute respiratory failure.

BACKGROUND: There are relatively few data about the ultrasound evaluation of pleural line in patients with respiratory failure. We measured the pleural line thickness during different phases of the respiratory cycle in neonates with and without acute respiratory failure as we hypothesized that this can significantly change. METHODS: Prospective, observational, cohort study performed in an academic tertiary neonatal intensive care unit recruiting neonates with transient tachypnoea of the neonate (TTN), respiratory distress syndrome (RDS) or neonatal acute respiratory distress syndrome (NARDS). Neonates with no lung disease (NLD) were also recruited as controls. Pleural line thickness was measured with high-frequency ultrasound at end-inspiration and end-expiration by two different raters. RESULTS: Pleural line thickness was slightly but significantly higher at end-expiration (0.53 [0.43-0.63] mm) than at end-inspiration (0.5 [0.4-0.6] mm; p = 0.001) for the whole population. End-inspiratory (NLD: 0.45 [0.38-0.53], TTN: 0.49 [0.43-0.59], RDS: 0.53 [0.41-0.62], NARDS: 0.6 [0.5-0.7] mm) and -expiratory (NLD: 0.47 [0.42-0.56], TTN: 0.48 [0.43-0.61], RDS: 0.53 [0.46-0.65], NARDS: 0.61 [0.54-0.72] mm) thickness were significantly different (overall p = 0.021 for both), between the groups although the absolute differences were small. The inter-rater agreement was optimal (ICC: 0.95 (0.94-0.96)). Coefficient of variation was 2.8% and 2.5% for end-inspiratory and end-expiratory measurements, respectively. These findings provide normative data of pleural line thickness for the most common forms of neonatal acute respiratory failure and are useful to design future studies to investigate possible clinical applications.

International Online Survey on the Management of Patent Ductus Arteriosus.

INTRODUCTION: There is uncertainty and lack of consensus regarding optimal management of patent ductus arteriosus (PDA). We aimed to determine current clinical practice in PDA management across a range of different regions internationally. MATERIALS AND METHODS: We surveyed PDA management practices in neonatal intensive care units using a pre-piloted web-based survey, which was distributed to perinatal societies in 31 countries. The survey was available online from March 2018 to March 2019. RESULTS: There were 812 responses. The majority of clinicians (54%) did not have institutional protocols for PDA treatment, and 42% reported variable management within their own unit. Among infants <28 weeks (or <1,000 g), most clinicians (60%) treat symptomatically. Respondents in Australasia were more likely to treat PDA pre-symptomatically (44% vs. 18% all countries [OR 4.1; 95% CI 2.6-6.5; p < 0.001]), and respondents from North America were more likely to treat symptomatic PDA (67% vs. 60% all countries [OR 2.0; 95% CI 1.5-2.6; p < 0.001]). In infants ≥28 weeks (or ≥1,000 g), most clinicians (54%) treat symptomatically. Respondents in North America were more likely to treat PDAs in this group of infants conservatively (47% vs. 38% all countries [OR 2.3; 95% CI 1.7-3.2; p < 0.001]), and respondents from Asia were more likely to treat the PDA pre-symptomatically (21% vs. 7% all countries [OR 5.5; 95% CI 3.2-9.8; p < 0.001]). DISCUSSION/CONCLUSION: There were marked international differences in clinical practice, highlighting ongoing uncertainty and a lack of consensus regarding PDA management. An international conglomeration to coordinate research that prioritises and addresses these areas of contention is indicated.

Hydrocortisone in very preterm neonates for BPD prevention: meta-analysis and effect size modifiers.

OBJECTIVES: To clarify if systemic hydrocortisone, in protocols allowing to start it before the 15th day of life, prevents bronchopulmonary dysplasia (BPD) or other adverse outcomes in very preterm neonates, and to identify any possible effect size modifiers. STUDY DESIGN: Systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Additional analyses included meta-regressions and review of biological plausibility. RESULTS: Seven trials were included, they were of general good quality and accounted for a total of 2193 infants. Hydrocortisone treatment did not reduce BPD (risk ratio (RR) 0.84 (95% CI 0.64 to 1.04)), but heterogeneity was evident (I2=51.6%). The effect size for BPD is greatest for 10-12 days duration of treatment (ß=0.032 (0.01), p=0.007) and tended to be greater in patients with chorioamnionitis (ß=-1.5 (0.841), p=0.07). Hydrocortisone treatment may significantly reduce mortality (RR 0.75 (95% CI 0.59 to 0.91)), there is no heterogeneity (I2=0) and the reduction tended to be greater in males (ß=-0.06 (0.03), p=0.07). Hydrocortisone may significantly reduce necrotising enterocolitis (NEC; RR 0.72 (95% CI 0.53 to 0.92)); there is neither heterogeneity (I2=0%) nor any effect size modifiers. Hydrocortisone did not affect other adverse outcomes of prematurity. CONCLUSIONS: Systemic hydrocortisone may be considered, on a case-by-case evaluation, to reduce mortality and NEC, while it does not affect BPD. There are some potential effect size modifiers for mortality and BPD which should be addressed in future explanatory trials. PROSPERO REGISTRATION NUMBER: CRD42023400520.

Surfactant status assessment and personalized therapy for surfactant deficiency or dysfunction.

Surfactant is a pivotal neonatal drug used both for respiratory distress syndrome due to surfactant deficiency and for more complex surfactant dysfunctions (such as in case of neonatal acute respiratory distress syndrome). Despite its importance, indications for surfactant therapy are often based on oversimplified criteria. Lung biology and modern monitoring provide several diagnostic tools to assess the patient surfactant status and they can be used for a personalized surfactant therapy. This is desirable to improve the efficacy of surfactant treatment and reduce associated costs and side effects. In this review we will discuss these diagnostic tools from a pathophysiological and multi-disciplinary perspective, focusing on the quantitative or qualitative surfactant assays, lung mechanics or aeration measurements, and gas exchange metrics. Their biological and technical characteristics are described with practical information for clinicians. Finally, available evidence-based data are reviewed, and the diagnostic accuracy of the different tools is compared. Lung ultrasound seems the most suitable tool for assessing the surfactant status, while some other promising tests require further research and/or development.

Imaging of bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a multifactorial disease with many associated co-morbidities, responsible for most cases of chronic lung disease in childhood. The use of imaging exams is pivotal for the clinical care of BPD and the identification of candidates for experimental therapies and a closer follow-up. Imaging is also useful to improve communication with the family and objectively evaluate the clinical evolution of the patient's disease. BPD imaging has been classically performed using only chest X-rays, but several modern techniques are currently available, such as lung ultrasound, thoracic tomography, magnetic resonance imaging and electrical impedance tomography. These techniques are more accurate and provide clinically meaningful information. We reviewed the most recent evidence published in the last five years regarding these techniques and analyzed their advantages and disadvantages.

Perfluorocarbons in Research and Clinical Practice: A Narrative Review.

Perfluorocarbons (PFCs) are organic liquids derived from hydrocarbons in which some of the hydrogen atoms have been replaced by fluorine atoms. They are chemically and biologically inert substances with a good safety profile. They are stable at room temperature, easy to store, and immiscible in water. Perfluorocarbons have been studied in biomedical research since 1960 for their unique properties as oxygen carriers. In particular, PFCs have been used for liquid ventilation in unusual environments such as deep-sea diving and simulations of zero gravity, and more recently for drug delivery and diagnostic imaging. Additionally, when delivered as emulsions, PFCs have been used as red blood cell substitutes. This narrative review will discuss the multifaceted utilization of PFCs in therapeutics, diagnostics, and research. We will specifically emphasize the potential role of PFCs as red blood cell substitutes, as airway mechanotransducers during artificial placenta procedures, as a means to improve donor organ perfusion during the ex vivo assessment, and as an adjunct in cancer therapies because of their ability to reduce local tissue hypoxia.

Effectiveness of Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation vs Noninvasive High-Frequency Oscillatory Ventilation as Support After Extubation of Neonates Born Extremely Preterm or With More Severe Respiratory Failure: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The NASONE (Nasal Oscillation Post-Extubation) trial showed that noninvasive high-frequency oscillatory ventilation (NHFOV) slightly reduces the duration of invasive mechanical ventilation (IMV) in preterm infants, whereas NHFOV and noninvasive intermittent positive pressure ventilation (NIPPV) result in fewer reintubations than nasal continuous positive airway pressure (NCPAP). It is unknown whether NHFOV is similarly effective in extremely preterm neonates or in those with more severe respiratory failure (based on the duration of previous ventilation and CO2 levels). Objective: To clarify whether NHFOV is better than NIPPV and NCPAP in reducing the duration of IMV in extremely preterm neonates or those with severe respiratory failure. Design, Setting, and Participants: This study is a predefined secondary analyses of a multicenter randomized clinical trial that was performed at tertiary academic neonatal intensive care units (NICUs) in China. Participants included neonates enrolled in the NASONE trial between December 2017 and May 2021 and belonging to 3 predefined subgroups: (1) born at less than or equal to 28 weeks' (plus 6 days) gestation, (2) invasively ventilated for more than 1 week from birth, and (3) with CO2 greater than 50 mm Hg before or in the 24 hours after extubation. Data analysis was performed in August 2022. Intervention: NCPAP, NIPPV, or NHFOV since the first extubation and until NICU discharge, with airway pressure higher in NHFOV than in NIPPV and than in NCPAP. Main Outcomes and Measures: The co-primary outcomes were total duration of IMV during the NICU stay, need for reintubation, and ventilator-free days calculated as per the original trial protocol. Outcomes were analyzed on an intention-to-treat basis as for the whole trial, and subgroup analyses followed the original statistical plan. Results: Among 1137 preterm infants, 455 (279 boys [61.3%]) were born at 28 weeks' gestation or less, 375 (218 boys [58.1%]) underwent IMV for more than 1 week from birth, and 307 (183 boys [59.6%]) had CO2 greater than 50 mm Hg before or in the 24 hours after extubation. Both NIPPV and NHFOV were associated with significantly fewer reintubations (risk difference range, -28% [95% CI, -39% to -17%] to -15% [95% CI, -25% to -4%]; number needed to treat, 3-7 infants) and early reintubations (risk difference range, -24% [95% CI, -35% to -14%] to -20% [95% CI, -30% to -10%]) than NCPAP, and these reintubations were less frequently due to refractory hypoxemia. IMV was shorter in the NIPPV and NHFOV groups (mean difference range, -5.0 days [95% CI, -6.8 to -3.1 days] to -2.3 days [95% CI, -4.1 to -0.4 days]) than in the NCPAP group. Co-primary outcomes were not different between NIPPV and NHFOV; there was no significant interaction effect. Infants in the NHFOV group showed significantly less moderate-to-severe bronchopulmonary dysplasia than infants in the NCPAP group (range, -12% to -10%; number needed to treat, 8-9 infants) and better postextubation gas exchange in all subgroups. The 3 interventions were provided at different mean airway pressure and were equally safe. Conclusions and Relevance: The subgroup analyses of extremely preterm or more ill infants confirm the results obtained in the whole population: NIPPV and NHFOV appeared equally effective in reducing duration of IMV compared with NCPAP. Trial Registration: ClinicalTrials.gov Identifier: NCT03181958.