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.

Effect of different CPAP levels on ultrasound-assessed lung aeration and gas exchange in neonates.

BACKGROUND: Respiratory distress syndrome (RDS) and transient tachypnoea (TTN) are the two commonest neonatal respiratory disorders. The optimal continuous positive airway pressure (CPAP) to treat them is unknown. We aim to clarify the effect of different CPAP levels on lung aeration and gas exchange in patients with RDS and TTN. METHODS: Prospective, observational, pragmatic, physiological cohort study. CPAP was sequentially increased from 4 to 6 and 8 cmH2O and backwards, with interposed wash-out periods. Lung aeration was assessed with a validated neonatal lung ultrasound score. Gas exchange was non-invasively evaluated with transcutaneous monitoring. Ultrasound score and PtcO2/FiO2 ratio were the co-primary outcomes. PtcCO2 and other oxygenation metrics were the secondary outcomes. RESULTS: 30 neonates with RDS and 30 with TTN were studied. Each CPAP increment significantly (overall always p < 0.001) improved both lung aeration and oxygenation, but the increase from 6 to 8 cmH2O achieved a small absolute benefit. In RDS patients, the absolute improvements were small and the diagnosis of TTN was significantly associated with greater improvement of lung aeration (ß= -1.4 (95%CI: -2.4; -0.3), p = 0.01) and oxygenation (ß = 39.6 (95%CI: 4.1; 75.1), p = 0.029). Aeration improved in 16 (53.3%) and 27 (90%) patients in the RDS and TTN groups, respectively (p = 0.034). Lung aeration showed significant hysteresis in TTN patients. Secondary outcomes gave similar results. CONCLUSIONS: Increasing CPAP from 4 to 8 cmH2O improves ultrasound-assessed lung aeration and oxygenation in RDS and TTN. The absolute improvements are small when CPAP is beyond 6 cmH2O or for RDS patients.

Global and Regional Heterogeneity of Lung Aeration in Neonates with Different Respiratory Disorders: A Physiologic Observational Study.

BACKGROUND: Aeration heterogeneity affects lung stress and influences outcomes in adults with acute respiratory distress syndrome (ARDS). The authors 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: This was an observational prospective study. Neonates with respiratory distress syndrome, transient tachypnea of the neonate, evolving bronchopulmonary dysplasia, and neonatal ARDS were enrolled. Quantitative lung ultrasound and transcutaneous blood gas measurements were simultaneously performed. Global aeration heterogeneity (with its intra- and interpatient components) and regional aeration heterogeneity were primary outcomes; oxygenation metrics were the secondary outcomes. RESULTS: A total of 230 (50 respiratory distress syndrome, transient tachypnea of the neonate or evolving bronchopulmonary dysplasia, and 80 neonatal ARDS) patients were studied. Intrapatient aeration heterogeneity was higher in transient tachypnea of the neonate (mean ± SD, 61 ± 33%) and evolving bronchopulmonary dysplasia (mean ± SD, 57 ± 20%; P < 0.001), with distinctive aeration distributions. Interpatient aeration heterogeneity was high for all disorders (Gini-Simpson index, between 0.6 and 0.72) except respiratory distress syndrome (Gini-Simpson index, 0.5), whose heterogeneity was significantly lower than all others (P < 0.001). Neonatal ARDS and evolving bronchopulmonary dysplasia had the most diffuse injury and worst gas exchange metrics. Regional aeration heterogeneity was mostly localized in the upper anterior and posterior zones. Aeration heterogeneity and total lung aeration had an exponential relationship (P < 0.001; adj-R2 = 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-R2 = 0.83) and better oxygenation metrics upon multivariable analyses. CONCLUSIONS: Global aeration heterogeneity and regional aeration heterogeneity differ among neonatal respiratory disorders. Transient tachypnea of the neonate and evolving bronchopulmonary dysplasia have the highest intrapatient aeration heterogeneity. Transient tachypnea of the neonate, evolving bronchopulmonary dysplasia, and neonatal ARDS have the highest interpatient 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.

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.

Early life surfactant protein-D levels in bronchoalveolar lavage fluids of extremely preterm neonates.

Surfactant protein-D (SP-D) is a hydrophilic protein with multiple crucial anti-inflammatory and immunological functions. It might play a role in the development and course of pulmonary infections, acute respiratory distress syndrome, and other respiratory disorders. Only few small neonatal studies have investigated SP-D: we aimed to investigate the links between this protein, measured in the first hours of life in extremely preterm neonates, and clinical outcomes, as well its relationship with pulmonary secretory phospholipase A2 (sPLA2). Bronchoalveolar lavage fluids were obtained within the first 3 h of life. SP-D and sPLA2 were measured with ELISA and radioactive method, respectively; epithelial lining fluid concentrations were estimated with urea ratio. Clinical data were prospectively collected. One hundred extremely preterm neonates were nonconsecutively studied. SP-D was significantly raised with increasing gestational age (24-26 wk: 68 [0-1,694], 27 or 28 wk: 286 [0-1,328], 29 or 30 wk: 1,401 [405-2,429] ng/mL, overall P = 0.03). SP-D was significantly higher in cases with clinical chorioamnionitis with fetal involvement (1,138 [68-3,336]) than in those without clinical chorioamnionitis with fetal involvement (0 [0-900] ng/mL, P < 0.001). SP-D was lower in infants with bronchopulmonary dysplasia (BPD) (251 [0-1,550 ng/mL]) compared with those without bronchopulmonary dysplasia (BPD) or who died before its diagnosis (977 [124-5,534 ng/mL], P = 0.05) and this was also significant upon multivariate analysis [odds ration (OR): 0.997 (0.994-0.999), P = 0.024], particularly in neonates between 27- and 28-wk gestation. SP-D significantly correlated with the duration of hospital stay (ρ = -0.283, P = 0.002), invasive ventilation (ρ = -0.544, P = 0.001), and total sPLA2 activity (ρ = 0.528, P = 0.008). These findings help understanding the role of SP-D early in life and support further investigation about the role of SP-D in developing BPD.NEW & NOTEWORTHY Surfactant protein-D increases with gestational age and is inversely associated with BPD development. These results have been obtained in the first hours of life of extremely preterm neonates with optimal perinatal care.

Neonatal outcomes for women at risk of preterm delivery given half dose versus full dose of antenatal betamethasone: a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial.

BACKGROUND: Antenatal betamethasone is recommended before preterm delivery to accelerate fetal lung maturation. However, reports of growth and neurodevelopmental dose-related side-effects suggest that the current dose (12 mg plus 12 mg, 24 h apart) might be too high. We therefore investigated whether a half dose would be non-inferior to the current full dose for preventing respiratory distress syndrome. METHODS: We designed a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial in 37 level 3 referral perinatal centres in France. Eligible participants were pregnant women aged 18 years or older with a singleton fetus at risk of preterm delivery and already treated with the first injection of antenatal betamethasone (11·4 mg) before 32 weeks' gestation. We used a computer-generated code producing permuted blocks of varying sizes to randomly assign (1:1) women to receive either a placebo (half-dose group) or a second 11·4 mg betamethasone injection (full-dose group) 24 h later. Randomisation was stratified by gestational age (before or after 28 weeks). Participants, clinicians, and study staff were masked to the treatment allocation. The primary outcome was the need for exogenous intratracheal surfactant within 48 h after birth. Non-inferiority would be shown if the higher limit of the 95% CI for the between-group difference between the half-dose and full-dose groups in the primary endpoint was less than 4 percentage points (corresponding to a maximum relative risk of 1·20). Four interim analyses monitoring the primary and the secondary safety outcomes were done during the study period, using a sequential data analysis method that provided futility and non-inferiority stopping rules and checked for type I and II errors. Interim analyses were done in the intention-to-treat population. This trial was registered with ClinicalTrials.gov, NCT02897076. FINDINGS: Between Jan 2, 2017, and Oct 9, 2019, 3244 women were randomly assigned to the half-dose (n=1620 [49·9%]) or the full-dose group (n=1624 [50·1%]); 48 women withdrew consent, 30 fetuses were stillborn, 16 neonates were lost to follow-up, and 9 neonates died before evaluation, so that 3141 neonates remained for analysis. In the intention-to-treat analysis, the primary outcome occurred in 313 (20·0%) of 1567 neonates in the half-dose group and 276 (17·5%) of 1574 neonates in the full-dose group (risk difference 2·4%, 95% CI -0·3 to 5·2); thus non-inferiority was not shown. The per-protocol analysis also did not show non-inferiority (risk difference 2·2%, 95% CI -0·6 to 5·1). No between-group differences appeared in the rates of neonatal death, grade 3-4 intraventricular haemorrhage, stage ≥2 necrotising enterocolitis, severe retinopathy of prematurity, or bronchopulmonary dysplasia. INTERPRETATION: Because non-inferiority of the half-dose compared with the full-dose regimen was not shown, our results do not support practice changes towards antenatal betamethasone dose reduction. FUNDING: French Ministry of Health.

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

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

Systematic review and synthesis of stillbirths and late miscarriages following SARS-CoV-2 infections.

OBJECTIVE: This study aimed to describe the characteristics of fetal demise after SARS-CoV-2 infections and clarify whether it is associated with clinical severity, placental lesions, or malformations or due to actual fetal infections. DATA SOURCES: PubMed and Web of Science databases were searched between December 1, 2019, and April 30, 2022. STUDY ELIGIBILITY CRITERIA: Cohort, cross-sectional, and case-control studies and case series or case reports describing stillbirths or late miscarriages (ie, pregnancy loss occurring between 14 and 22 weeks of gestation, before and after the onset of labor) from mothers with SARS-CoV-2 infection during pregnancy (demonstrated by at least 1 positive real-time reverse transcription-polymerase chain reaction from nasopharyngeal swabs and/or SARS-CoV-2 placental infection). No language restriction was applied; cases with other causes possibly explaining the fetal demise were excluded. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis Of Observational Studies in Epidemiology guidelines were followed. The quality of the case series and case reports was evaluated using the specific Mayo Clinic Evidence-Based Practice Center tool. Maternal and clinical fetal data and placental and fetal virology and histology findings were collected. Data were summarized with descriptive statistics using the World Health Organization criteria to classify disease severity and fetal-neonatal infections. RESULTS: Data from 184 mothers and 190 fetuses were analyzed. No clear link to maternal clinical severity or fetal malformation was evident. Approximately 78% of fetal demise cases occurred during the second and third trimesters of pregnancy, approximately 6 to 13 days after the diagnosis of SARS-CoV-2 infection or the onset of symptoms. Most placentas (88%) were positive for SARS-CoV-2 or presented the histologic features of placentitis (massive fibrin deposition and chronic intervillositis) previously observed in transplacentally transmitted infections (85%-91%). Of note, 11 fetuses (5.8%) had a confirmed in utero transmitted SARS-CoV-2 infection, and 114 fetuses (60%) had a possible in utero transmitted SARS-CoV-2 infection. CONCLUSION: The synthesis of available data showed that fetal demise generally occurs a few days after the infection with histologic placental inflammatory lesions associated with transplacental SARS-CoV-2 transmission and eventually causing placental insufficiency.

CARPEDIEM® for continuous kidney replacement therapy in neonates and small infants: a French multicenter retrospective study.

BACKGROUND: The Cardio-Renal Pediatric Dialysis Emergency Machine (CA.R.P.E.D.I.E.M.®) device is a continuous kidney replacement therapy (CKRT) equipment dedicated to neonates and small infants. This study aimed to assess the effectiveness, feasibility, outcomes, and technical considerations relating to CARPEDIEM® use. METHODS: This retrospective multicenter study included 19 newborns and six infants receiving CARPEDIEM® in five French pediatric and neonatal intensive care units. Laboratory parameters were collected at the initiation and end of the first CARPEDIEM® session. Results are presented as median [IQR] (range). RESULTS: At initiation, age was 4 days [2-13] (1-1134) with a body weight of 3.3 kg [2.5-4] (1.3-11.1). Overall, 131 sessions and 2125 h of treatment were performed. Treatment duration per patient was 42 h [24-91] (8-557). Continuous veno-venous hemofiltration (CVVH) was performed in 20 children. Blood flow rate was 8 mL/kg/min [6-9] (3-16). The effluent flow rate for CVVH was 74 mL/kg/h [43-99] (28-125) and net ultrafiltration (UF) 6 mL/kg/h [2-8] (1-12). In the five children treated by hemodialysis, the blood and dialysate flow rates were 6 mL/kg/min [5-7] (4-7) and 600 mL/h [300-600] (120-600), respectively, while session duration was 8 h [6-12] (2-24). Most infants required a catheter between 4.5 and 6.5 French. Hemodynamic instability with a need for volume replacement occurred in 31 sessions (23%). Thrombocytopenia was observed in 29 sessions (22%). No hemorrhage occurred; all the patients survived the sessions, but only eight patients (32%) were alive at hospital discharge. CONCLUSIONS: These data confirm that the use of CARPEDIEM® is safe and effective in critically ill neonates and infants. A higher resolution version of the Graphical abstract is available as Supplementary information.

Breast milk in neonate oral care: oropharyngeal effects in extremely preterm infants.

Ventilator-associated pneumonia (VAP) is a frequent nosocomial infection in neonatal intensive care units (NICU). Extremely preterm infants are at highest risk of developing VAP. Several studies indicate that oral care included in a preventive protocol effectively reduces neonatal VAP incidence. We investigated the effects of oral care with breast milk on oral immune defenses and microbiota in extremely preterm infants. Thirty infants born ≤ 30 weeks gestation hospitalized at our NICU were selected and divided into three groups: oral care with breast milk, formula, or sterile water. Effects on oral immune defenses in vivo were studied using ELISA to measure lactoferrin (LF) and secretory immunoglobulin A (sIgA) in pharyngeal aspirates before and after oral care. Different LF concentrations were tested in vitro to assess their effects on loads of selected bacterial species by culture. Effects on selected bacteria potentially responsible for VAP in vivo were studied by real-time PCR detection in pharyngeal aspirates before and after oral care. Oral care with breast milk significantly increases LF concentrations to 69.8 × 103 ng/ml (p = 0.012) and sIgA to 36.8 × 103 ng/ml (p = 0.017) in vivo. These LF concentrations considerably reduce loads of E. coli, S. epidermidis, S. aureus, and P. aeruginosa, in vitro. However, contrary to our expectation, no effect on colonization of bacteria most commonly responsible for VAP was found in vivo. CONCLUSION: In extremely preterm infants, oral care with breast milk increases local immune defense markers (LF, sIgA), which combat bacterial infections. Further clinical trials should be conducted to evaluate their effects on VAP prevention in neonates. WHAT IS KNOWN: • The population at higher risk to develop VAP are preterm infants. • Several studies indicate oral care within a preventive bundle is effective in reducing neonatal VAP incidence. WHAT IS NEW: • In extremely premature infants, oral care with breast milk causes a significant increase in local immune defences in terms of lactoferrin (LF) and secretory immunoglobulin A (sIgA). • LF concentrations obtained after oral care with breast milk decreased loads of bacteria most commonly responsible for VAP in premature infants under experimental in-vitro.

Multisystemic involvement of post-traumatic fat embolism at a Pediatric Trauma Center: a clinical series and literature review.

Post-traumatic fat embolism syndrome (FES) is a severe complication consequent to bone fractures. The authors describe its clinical features and management in a population of teenagers by detailing demographics, organ involvement, laboratory, and imaging findings, as well as outcome. Moreover, a systematic review of pediatric published case reports of post-traumatic FES is provided. First, a series of eight episodes of post-traumatic FES that occurred in seven patients (median age 16.0 years, IQR 16.0-17.5) admitted to a pediatric intensive care unit (PICU) in an 8-year period was analyzed through a retrospective chart review. Secondly, a systematic research was performed on PUBMED database. Trauma patients ≤ 18 years without comorbidities in a 20-year period (2002-2022) were included in the review. Neurological impairment was present in five out of seven patients, and a patent foramen ovale was found in four cases. Hemodynamic instability requiring vasoactive drugs was recorded in four patients. A severe form of acute respiratory distress syndrome (ARDS) occurred in five cases, with the evidence of hemorrhagic alveolitis in three of them. In the literature review, eighteen cases were examined. Most cases refer to adolescents (median age 17.0 years). More than half of patients experienced two or more long bone fractures (median: 2 fractures). Both respiratory and neurological impairment were common (77.8% and 83.3%, respectively). 88.9% of patients underwent invasive mechanical ventilation and 33.3% of them required vasoactive drugs support. Neurological sequelae were reported in 22.2% of patients. CONCLUSION: Post-traumatic FES is an uncommon multi-faceted condition even in pediatric trauma patients, requiring a high level of suspicion. Prognosis of patients who receive prompt support in an intensive care setting is generally favorable. WHAT IS KNOWN: •Post-traumatic fat embolism syndrome is a severe condition complicating long bone or pelvic fractures. •Little is known about clinical features and management in pediatric age. WHAT IS NEW: •Post-traumatic fat embolism syndrome can cause multiple organ failure, often requiring an intensive care management. •Prompt supportive care contributes to a favorable prognosis.

Point-of-care ultrasound (POCUS) protocol for systematic assessment of the crashing neonate-expert consensus statement of the international crashing neonate working group.

Sudden unexpected clinical deterioration or cardiorespiratory instability is common in neonates and is often referred as a "crashing" neonate. The established resuscitation guidelines provide an excellent framework to stabilize and evaluate these infants, but it is primarily based upon clinical assessment only. However, clinical assessment in sick neonates is limited in identifying underlying pathophysiology. The Crashing Neonate Protocol (CNP), utilizing point-of-care ultrasound (POCUS), is specifically designed for use in neonatal emergencies. It can be applied both in term and pre-term neonates in the neonatal intensive care unit (NICU). The proposed protocol involves a stepwise systematic assessment with basic ultrasound views which can be easily learnt and reproduced with focused structured training on the use of portable ultrasonography (similar to the FAST and BLUE protocols in adult clinical practice). We conducted a literature review of the evidence-based use of POCUS in neonatal practice. We then applied stepwise voting process with a modified DELPHI strategy (electronic voting) utilizing an international expert group to prioritize recommendations. We also conducted an international survey among a group of neonatologists practicing POCUS. The lead expert authors identified a specific list of recommendations to be included in the proposed CNP. This protocol involves pre-defined steps focused on identifying the underlying etiology of clinical instability and assessing the response to intervention.Conclusion: To conclude, the newly proposed POCUS-based CNP should be used as an adjunct to the current recommendations for neonatal resuscitation and not replace them, especially in infants unresponsive to standard resuscitation steps, or where the underlying cause of deterioration remains unclear. What is known? • Point-of-care ultrasound (POCUS) is helpful in evaluation of the underlying pathophysiologic mechanisms in sick infants. What is new? • The Crashing Neonate Protocol (CNP) is proposed as an adjunct to the current recommendations for neonatal resuscitation, with pre-defined steps focused on gaining information regarding the underlying pathophysiology in unexplained "crashing" neonates. • The proposed CNP can help in targeting specific and early therapy based upon the underlying pathophysiology, and it allows assessment of the response to intervention(s) in a timely fashion.

Continuous Venovenous Hemofiltration Performed by Neonatologists With Cardio-Renal Pediatric Dialysis Emergency Machine to Treat Fluid Overload During Multiple Organ Dysfunction Syndrome: A Case Series.

OBJECTIVES: A new device is available for neonates needing extracorporeal renal replacement therapy. We reviewed the use of this device (in continuous venovenous hemofiltration [CVVH] mode) in term or preterm neonates affected by multiple organ dysfunction syndrome (MODS) with fluid overload. DESIGN: Case series. SETTING: Academic specialized referral neonatal ICU (NICU) with expertise on advanced life support and monitoring. PATIENTS: Neonates with MODS and fluid overload despite conventional treatments and receiving at least one CVVH session. INTERVENTION: CVVH with the Cardio-Renal Pediatric Dialysis Emergency Machine. MEASUREMENTS AND MAIN RESULTS: Ten (three preterm) neonates were treated using 18 consecutive CVVH sessions. All patients were in life-threatening conditions and successfully completed the CVVH treatments, which almost always lasted 24 hr/session, without major side effects. Three neonates survived and were successfully discharged from hospital with normal follow-up. CVVH reduced fluid overload (before versus after represented as a weight percentage: 23.5% [12-34%] vs 14.6% [8.2-24.1%]; p = 0.006) and lactate (before versus after: 4.6 [2.9-12.1] vs 2.9 mmol/L [2.3-5.5 mmol/L]; p = 0.001). CVVH also improved the Pa o2 to Fio2 (before vs after: 188 mm Hg [118-253 mm Hg] vs 240 mm Hg [161-309 mm Hg]; p = 0.003) and oxygenation index (before vs after: 5.9 [3.8-14.6] vs 4 [2.9-11]; p = 0.002). The average cost of CVVH in these patients was minor (≈3%) in comparison with the median total cost of NICU care per patient. CONCLUSIONS: We have provided CVVH to critically ill term and preterm neonates with MODS. CVVH improved fluid overload and oxygenation. The cost of CVVH was minimal compared with the overall cost of neonatal intensive care.

Ultrasound-assessed lung aeration, oxygenation and respiratory care in neonatal bile acid pneumonia: A nested case-control study.

AIM: Neonatal bile acid pneumonia (NBAP) occurs in neonates following obstetric cholestasis. We aimed to study the lung aeration and respiratory support of NBAP. METHODS: Nested, case/control study enrolling age-matched neonates with NBAP, respiratory distress syndrome (RDS) or transient tachypnoea (TTN). Lung aeration and oxygenation were assessed with lung ultrasound score, oxygenation index and SpO2 /FiO2 . RESULTS: Nineteen, 22 and 25 neonates with NBAP, RDS and TTN, respectively were studied (mean gestational age = 33 (2.2) weeks, 30 (45.5%) males). Upon admission, RDS patients had the worst lung ultrasound score (p = 0.022) and oxygenation index (p = 0.001), while NBAP and TTN neonates had similar values. At the worst time-point, NBAP and RDS patients showed similar oxygenation index (NBAP: 4.6 [2], RDS: 5.7 [3]) and SpO2 /FiO2 (NBAP: 3.1 [1.1], RDS: 2.7 [1]) which were worse than those of TTN patients (oxygenation index: p = 0.015, SpO2 /FiO2 : p = 0.001). RDS neonates needed the longest continuous positive airway pressure and highest mean airway pressure, but NBAP neonates needed invasive ventilation (26.3%, p = 0.01) and surfactant (31.6%, p = 0.003) more often than TTN patients who never needed these. CONCLUSION: NBAP was a mild disorder in the first hours of life but subsequently worsened and became similar to RDS.

Transcriptome Sequencing of the Diatom Asterionellopsis thurstonii and In Silico Identification of Enzymes Potentially Involved in the Synthesis of Bioactive Molecules.

Microalgae produce a plethora of primary and secondary metabolites with possible applications in several market sectors, including cosmetics, human nutrition, aquaculture, biodiesel production and treatment/prevention of human diseases. Diatoms, in particular, are the most diversified microalgal group, many species of which are known to have anti-cancer, anti-oxidant, anti-diabetes, anti-inflammatory and immunomodulatory properties. Compounds responsible for these activities are often still unknown. The aim of this study was to de novo sequence the full transcriptome of two strains of the diatom Asterionellopsis thurstonii, sampled from two different locations and cultured in both control and phosphate starvation conditions. We used an RNA-sequencing approach to in silico identify transcripts potentially involved in the synthesis/degradation of compounds with anti-cancer and immunomodulatory properties. We identified transcript coding for L-asparaginase I, polyketide cyclase/dehydrase, bifunctional polyketide phosphatase/kinase, 1-deoxy-D-xylulose-5-phosphate synthase (fragment), inositol polyphosphate 5-phosphatase INPP5B/F, catechol O-Methyltransferase, digalactosyldiacylglycerol synthase (DGD1), 1,2-diacylglycerol-3-beta-galactosyltransferase and glycerolphosphodiester phosphodiesterase. Differential expression analysis also allowed to identify in which culturing condition these enzymes are more expressed. Overall, these data give new insights on the annotation of diatom genes, enzymatic pathways involved in the generation of bioactive molecules and possible exploitation of Asterionellopsis thurstonii.

Alexandrium spp.: From Toxicity to Potential Biotechnological Benefits.

Many dinoflagellates of the genus Alexandrium are well known for being responsible for harmful algal blooms (HABs), producing potent toxins that cause damages to other marine organisms, aquaculture, fishery, tourism, as well as induce human intoxications and even death after consumption of contaminated shellfish or fish. In this review, we summarize potential bioprospecting associated to the genus Alexandrium, including which Alexandrium spp. produce metabolites with anticancer, antimicrobial, antiviral, as well as anti-Alzheimer applications. When available, we report their mechanisms of action and targets. We also discuss recent progress on the identification of secondary metabolites with biological properties favorable to human health and aquaculture. Altogether, this information highlights the importance of studying which culturing conditions induce the activation of enzymatic pathways responsible for the synthesis of bioactive metabolites. It also suggests considering and comparing clones collected in different locations for toxin monitoring and marine bioprospecting. This review can be of interest not only for the scientific community, but also for the entire population and industries.

Bile acid-induced lung injury: update of reverse translational biology.

The presence of bile acids in lung tissue is associated with some clinical features observed in various medical specialties, but it took time to understand that these are due to a "bile acid-induced lung injury" since specific translational studies and cross-disciplinary awareness were lacking. We used a reverse translational approach to update and summarize the current knowledge about the mechanisms of bile acid-induced lung injury. This has been done in a cross-disciplinary fashion since these conditions may occur in patients of various ages and in different medical fields. We here define these clinical conditions, then we review the physiopathology of these conditions and the animal models used to mimic them, and, finally, their pathobiology. Mechanisms of bile acid-induced lung injury have been partially clarified over time and are represented by 1) the interaction with secretory phospholipase A2 pathway, 2) the effect on surfactant function and structure, 3) the biological effects on inflammation and local immunity, and 4) the direct cellular toxicity. These mechanisms are schematically illustrated and histological comparisons between acute respiratory distress syndrome (ARDS) induced by bile acids and other triggers are also provided. Based on these mechanisms, we propose possible direct therapeutic applications and, finally, we discuss further research steps to improve the understanding of processes that generate pathological clinical conditions.

Secretory phospholipase A2 expression and activity in preterm clinical chorioamnionitis with fetal involvement.

Secretory phospholipase A2 (sPLA2) regulates the first step of inflammatory cascade and is involved in several pathological processes. sPLA2 also plays a role in preterm labor and parturition, since they are triggered by inflammatory mediators such as prostaglandins. Interestingly, chorioamnionitis (i.e., the presence of intrauterine inflammation) is also often associated with preterm birth. We aimed to verify if chorioamnionitis with fetal involvement modifies sPLA2 activity and expression profile in mothers and neonates delivered prematurely. We collected maternal plasma and amniotic fluid, as well as bronchoalveolar lavage fluid from preterm neonates born to mothers with or without clinical chorioamnionitis with fetal involvement. We measured concentrations of sPLA2 subtype-IIA and -IB, total enzyme activity, and proteins. Urea ratio was used to obtain epithelial lining fluid concentrations. Enzyme activity measured in maternal plasma (P < 0.001) and amniotic fluid (P < 0.001) was higher in chorioamnionitis cases than in controls. This was mainly due to the increased production of sPLA2-IIA, as the subtype -IB was present in a smaller amount and was similar between the two groups; sPLA2-IIA was increased in epithelial lining fluid (P = 0.045) or increased, although without statistical significance, in maternal plasma (P = 0.06) and amniotic fluid (P = 0.08) of chorioamnionitis cases. Cytokines that are known to increase sPLA2-IIA expression (TNF-α and IL-1ß) or whose expression was increased by sPLA2-IIA (IL-8) were higher in histologically confirmed chorioamnionitis [TNF-α (P = 0.028), IL-1ß (P < 0.001), and IL-8 (P = 0.038)]. These data represent the basis for future studies on sPLA2-IIA inhibition to prevent deleterious consequences of chorioamnionitis and preterm birth.

Ultrasound-assessed lung aeration correlates with respiratory system compliance in adults and neonates with acute hypoxemic restrictive respiratory failure: an observational prospective study.

BACKGROUND: Lung ultrasound allows lung aeration to be assessed through dedicated lung ultrasound scores (LUS). Despite LUS have been validated using several techniques, scanty data exist about the relationships between LUS and compliance of the respiratory system (Crs) in restrictive respiratory failure. Aim of this study was to investigate the relationship between LUS and Crs in neonates and adults affected by acute hypoxemic restrictive respiratory failure, as well as the effect of patients' age on this relationship. METHODS: Observational, cross-sectional, international, patho-physiology, bi-center study recruiting invasively ventilated, adults and neonates with acute respiratory distress syndrome (ARDS), neonatal ARDS (NARDS) or respiratory distress syndrome (RDS) due to primary surfactant deficiency. Subjects without lung disease (NLD) and ventilated for extra-pulmonary conditions were recruited as controls. LUS, Crs and resistances (Rrs) of the respiratory system were measured within 1 h from each other. RESULTS: Forty adults and fifty-six neonates were recruited. LUS was higher in ARDS, NARDS and RDS and lower in control subjects (overall p < 0.001), while Crs was lower in ARDS, NARDS and RDS and higher in control subjects (overall p < 0.001), without differences between adults and neonates. LUS and Crs were correlated in adults [r = - 0.86 (95% CI - 0.93; - 0.76), p < 0.001] and neonates [r = - 0.76 (95% CI - 0.85; - 0.62), p < 0.001]. Correlations remained significant among subgroups with different causes of respiratory failure; LUS and Rrs were not correlated. Multivariate analyses confirmed the association between LUS and Crs both in adults [B = - 2.8 (95% CI - 4.9; - 0.6), p = 0.012] and neonates [B = - 0.045 (95% CI - 0.07; - 0.02), p = 0.001]. CONCLUSIONS: Lung aeration and compliance of the respiratory system are significantly and inversely correlated irrespective of patients' age. A restrictive respiratory failure has the same ultrasound appearance and mechanical characteristics in adults and neonates.

Noninvasive Ventilation in a Pediatric Trauma Center: A Cohort Study.

OBJECTIVE: To determine whether non-invasive ventilation (NIV) can avoid the need for tracheal intubation and/or reduce the duration of invasive ventilation (IMV) in previously intubated patients admitted to the pediatric intensive care unit (PICU) and developing acute hypoxemic respiratory failure (AHRF) after major traumatic injury. STUDY DESIGN: A single center observational cohort study. SETTING: Pediatric ICU in a University Hospital (tertiary referral Pediatric Trauma Centre). POPULATION: During the 48-month study period, 276 patients (median age 6.4 years) with trauma were admitted to PICU; among 86 of them, who suffered from AHRF and received ventilation (IMV and/or NIV) for more than 12 hrs, 32 patients (median age 8.5 years) were treated with NIV. INCLUSION/EXCLUSION CRITERIA: Inclusion criteria: at least 12 hours of NIV; exclusion criteria: patients with facial trauma or congenital malformations; patients receiving IMV <12 hours or perioperative ventilation. MEASUREMENTS AND RESULTS: Among NIV patients, 27 (84,3%) were previously on IMV, while 5 (15,6%) could be managed exclusively with NIV. In patients with post-extubation respiratory distress, NIV was successful in 88.4% of cases. Before starting NIV, P/F ratio was 242.7 ± 71. After 8 hours of NIV treatment, a significant oxygenation improvement (PaO2/FiO2 = 354.3 ± 81; p = 0.0002) was found, with no significant changes in carbon dioxide levels. A trend toward increasing ventilation-free time has been evidenced; NIV resulted feasible and generally well tolerated. CONCLUSIONS: AHRF in trauma patients is multifactorial and may be due to many reasons, such as lung contusion, aspiration of blood or gastric contents. Systemic inflammatory response and transfusions may also contribute to hypoxia. Our pilot study strongly suggests that NIV can be applied in post-traumatic AHRF: it may successfully reduce the time of both invasive ventilation and deep sedation. Further data from controlled studies are needed to assess the advantage of NIV in pediatric trauma.