Plasma Proteome Profiles Associated with Early Development of Lung Injury in Extremely Preterm Infants.

The biological mediators which initiate lung injury in extremely preterm infants during early postnatal life remain largely unidentified, limiting opportunities for early treatment and diagnosis. This exploratory study used SWATH-mass spectrometry to identify bronchopulmonary dysplasia (BPD)-specific changes in protein abundance in plasma samples obtained in the first 72 hours of life from extremely preterm infants and bioinformatic analysis to identify BPD-related biological categories and pathways. Lasty, binary logistic regression analysis was used to test the BPD predictive potential of a base model alone (gestational age, birth weight, sex) and with the protein biomarker added, with bootstrap resampling used to internally validate protein predictors and adjust for overoptimism. We observed disturbance of key processes including coagulation, complement activation, development and extracellular matrix organisation in the first days of life in extremely preterm infants who were later diagnosed with BPD. In the BPD prediction analysis, 49 plasma proteins were identified which when each singularly was combined with birth characteristics had a C-index of 0.65-0.84 (optimism-adjusted C-index) suggesting predictive potential for BPD outcomes. Taken together, this study demonstrates that alterations in plasma proteins can be detected from 4 hours of age in extremely preterm infants who later develop BPD and that protein biomarkers when combined with three birth characteristics have the potential to predict BPD development within the first 72 hours of life.

Factors that determine first intubation attempt success in high-risk neonates.

BACKGROUND: Approximately 50% of all neonatal endotracheal intubation attempts are unsuccessful and associated with airway injury and cardiorespiratory instability. The aim of this study was to describe intubation practice at a high-risk Neonatal Intensive Care Unit (NICU) and identify factors associated with successful intubation at the first attempt. METHODS: Retrospective cohort study of all infants requiring intubation within the Royal Children's Hospital NICU over three years. Data was collected from the National Emergency Airway Registry for Neonates (NEAR4NEOS). Outcomes were number of attempts, level of operator training, equipment used, difficult airway grade, and clinical factors. Univariate and multivariate analysis were performed to determine factors independently associated with first attempt success. RESULTS: Three hundred and sixty intubation courses, with 538 attempts, were identified. Two hundred and twenty-five (62.5%) were successful on first attempt, with similar rates at subsequent attempts. On multivariate analysis, increasing operator seniority increased the chance of first attempt success. Higher glottic airway grades were associated with lower chance of first attempt success, but neither a known difficult airway nor use of a stylet were associated with first attempt success. CONCLUSION: In a NICU with a high rate of difficult airways, operator experience rather than equipment was the greatest determinant of intubation success. IMPACT: Neonatal intubation is a high-risk lifesaving procedure, and this is the first report of intubation practices at a quaternary surgical NICU that provides regional referral services for complex medical and surgical admissions. Our results showed that increasing operator seniority and lower glottic airway grades were associated with increased first attempt intubation success rates, while factors such as gestational age, weight, stylet use, and known history of difficult airway were not. Operator factors rather than equipment factors were the greatest determinants of first attempt success, highlighting the importance of team selection for neonatal intubations in a high-risk cohort of infants.

Lung ultrasound detects regional aeration inhomogeneity in ventilated preterm lambs.

BACKGROUND: Inhomogeneous lung aeration is a significant contributor to preterm lung injury. EIT detects inhomogeneous aeration in the research setting. Whether LUS detects inhomogeneous aeration is unknown. The aim was to determine whether LUS detects regional inhomogeneity identified by EIT in preterm lambs. METHODS: LUS and EIT were simultaneously performed on mechanically ventilated preterm lambs. LUS images from non-dependent and dependent regions were acquired and reported using a validated scoring system and computer-assisted quantitative LUS greyscale analysis (Q-LUSMGV). Regional inhomogeneity was calculated by observed over predicted aeration ratio from the EIT reconstructive model. LUS scores and Q-LUSMGV were compared with EIT aeration ratios using one-way ANOVA. RESULTS: LUS was performed in 32 lambs (~125d gestation, 128 images). LUS scores were greater in upper anterior (non-dependent) compared to lower lateral (dependent) regions of the left (3.4 vs 2.9, p = 0.1) and right (3.4 vs 2.7, p < 0.0087). The left and right upper regions also had greater LUS scores compared to right lower (3.4 vs 2.7, p < 0.0087) and left lower (3.7 vs 2.9, p = 0.1). Q-LUSMGV yielded similar results. All LUS findings corresponded with EIT regional differences. CONCLUSION: LUS may have potential in measuring regional aeration, which should be further explored in human studies. IMPACT: Inhomogeneous lung aeration is an important contributor to preterm lung injury, however, tools detecting inhomogeneous aeration at the bedside are limited. Currently, the only tool clinically available to detect this is electrical impedance tomography (EIT), however, its use is largely limited to research. Lung ultrasound (LUS) may play a role in monitoring lung aeration in preterm infants, however, whether it detects inhomogeneous lung aeration is unknown. Visual LUS scores and mean greyscale image analysis using computer assisted quantitative LUS (Q-LUSMGV) detects regional lung aeration differences when compared to EIT. This suggests LUS reliably detects aeration inhomogeneity warranting further investigation in human trials.

Mechanical power made simple: validating a simplified calculation of mechanical power in preterm lungs.

BACKGROUND: The incidence of chronic lung disease is increasing, suggesting a need to explore novel ways to understand ventilator induced lung injury (VILI) in preterm infants. Mechanical power (MP) is a unifying measure of energy transferred to the respiratory system and a proposed determinant of VILI. The gold-standard method for calculating MP (geometric method) is not feasible in the clinical setting. This has prompted the derivation of simplified equations for calculating MP. OBJECTIVE: To validate the agreement between a simplified calculation of MP (MPSimple) and the true MP calculated using the geometric method (MPRef). METHODS: MPSimple and MPRef was calculated in mechanically ventilated preterm lambs (n = 71) and the agreement between both measures was determined using intraclass correlation coefficients (ICC), linear regression, and Bland-Altman analysis. RESULTS: A strong linear relationship (adjusted R2 = 0.98), and excellent agreement (ICC = 0.99, 95% CI = 0.98-0.99) between MPSimple and MPRef was demonstrated. Bland-Altman analysis demonstrated a negligible positive bias (mean difference = 0.131 J/min·kg). The 95% limits of agreement were -0.06 to 0.32 J/min·kg. CONCLUSIONS: In a controlled setting, there was excellent agreement between MPSimple and gold-standard calculations. MPSimple should be validated and explored in preterm neonates to assess the cause-effect relationship with VILI and neonatal outcomes. IMPACT STATEMENT: Mechanical power (MP) unifies the individual components of ventilator induced lung injury (VILI) and provides an estimate of total energy transferred to the respiratory system during mechanical ventilation. As gold-standard calculations of mechanical power at the bedside are not feasible, alternative simplified equations have been proposed. In this study, MP calculated using a simplified equation had excellent agreement with true MP in mechanically ventilated preterm lambs. These results lay foundations to explore the role of MP in neonatal VILI and determine its relationship with short and long term respiratory outcomes.

Inflating Pressure and Not Expiratory Pressure Initiates Lung Injury at Birth in Preterm Lambs.

Rationale: Inflation is essential for aeration at birth, but current inflating pressure settings are without an evidence base. Objectives: To determine the role of inflating pressure (ΔP), and its relationship with positive end-expiratory pressure (PEEP), in initiating early lung injury pathways in the preterm lamb lung. Methods: Preterm (124 to 127 d) steroid-exposed lambs (n = 45) were randomly allocated (8-10 per group) to 15 minutes of respiratory support with placental circulation and 20 or 30 cm H2O ΔP, with an initial high PEEP (maximum, 20 cm H2O) recruitment maneuver known to facilitate aeration (dynamic PEEP), and compared with dynamic PEEP with no ΔP or 30 cm H2O ΔP and low (4 cm H2O) PEEP. Lung mechanics and aeration were measured throughout. After an additional 30 minutes of apneic placental support, lung tissue and bronchoalveolar fluid were analyzed for regional lung injury, including proteomics. Measurements and Main Results: The 30 cm H2O ΔP and dynamic PEEP strategies resulted in quicker aeration and better compliance but higher tidal volumes (often >8 ml/kg, all P < 0.0001; mixed effects) and injury. ΔP 20 cm H2O with dynamic PEEP resulted in the same lung mechanics and aeration, but less energy transmission (tidal mechanical power), as ΔP 30 cm H2O with low PEEP. Dynamic PEEP without any tidal inflations resulted in the least lung injury. Use of any tidal inflating pressures altered metabolic, coagulation and complement protein pathways within the lung. Conclusions: Inflating pressure is essential for the preterm lung at birth, but it is also the primary mediator of lung injury. Greater focus is needed on strategies that identify the safest application of pressure in the delivery room.

Impact of tidal volume strategy at birth on initiating lung injury in preterm lambs.

Tidal ventilation is essential in supporting the transition to air-breathing at birth, but excessive tidal volume (VT) is an important factor in preterm lung injury. Few studies have assessed the impact of specific VT levels on injury development. Here, we used a lamb model of preterm birth to investigate the role of different levels of VT during positive pressure ventilation (PPV) in promoting aeration and initiating early lung injury pathways. VT was delivered as 1) 7 mL/kg throughout (VTstatic), 2) begun at 3 mL/kg and increased to a final VT of 7 mL/kg over 3 min (VTinc), or 3) commenced at 7 mL/kg, decreased to 3 mL/kg, and then returned to 7 mL/kg (VTalt). VT, inflating pressure, lung compliance, and aeration were similar in all groups from 4 min, as was postmortem histology and lung lavage protein concentration. However, transient decrease in VT in the VTalt group caused increased ventilation heterogeneity. Following TMT-based quantitative mass spectrometry proteomics, 1,610 proteins were identified in the lung. Threefold more proteins were significantly altered with VTalt compared with VTstatic or VTinc strategies. Gene set enrichment analysis identified VTalt specific enrichment of immune and angiogenesis pathways and VTstatic enrichment of metabolic processes. Our finding of comparable lung physiology and volutrauma across VT groups challenges the paradigm that there is a need to rapidly aerate the preterm lung at birth. Increased lung injury and ventilation heterogeneity were identified when initial VT was suddenly decreased during respiratory support at birth, further supporting the benefit of a gentle VT approach.NEW & NOTEWORTHY There is little evidence to guide the best tidal volume (VT) strategy at birth. In this study, comparable aeration, lung mechanics, and lung morphology were observed using static, incremental, and alternating VT strategies. However, transient reduction in VT was associated with ventilation heterogeneity and inflammation. Our results suggest that rapidly aerating the preterm lung may not be as clinically critical as previously thought, providing clinicians with reassurance that gently supporting the preterm lung maybe permissible at birth.

Estimating Preterm Lung Volume: A Comparison of Lung Ultrasound, Chest Radiography, and Oxygenation.

OBJECTIVE: To determine the relationship between lung ultrasound (LUS) examination, chest radiograph (CXR), and radiographic and clinical evaluations in the assessment of lung volume in preterm infants. STUDY DESIGN: In this prospective cohort study LUS was performed before CXR on 70 preterm infants and graded using (1) a LUS score, (2) an atelectasis score, and (3) measurement of atelectasis depth. Radiographic diaphragm position and radio-opacification were used to determine global and regional radiographic atelectasis. The relationship between LUS, CXR, and oxygenation was assessed using receiver operator characteristic and correlation analysis. RESULTS: LUS scores, atelectasis scores, and atelectasis depth did not correspond with radiographic global atelectasis (area under receiver operator characteristics curves, 0.54 [95% CI, 0.36-0.71], 0.49 [95% CI, 0.34-0.64], and 0.47 [95% CI, 0.31-0.64], respectively). Radiographic atelectasis of the right upper, right lower, left upper, and left lower quadrants was predicted by LUS scores (0.75 [95% CI, 0.59-0.92], 0.75 [95% CI, 0.62-0.89], 0.69 [95% CI, 0.56-0.82], and 0.63 [95% CI, 0.508-0.751]) and atelectasis depth (0.66 [95% CI, 0.54-0.78], 0.65 [95% CI, 0.53-0.77], 0.63 [95% CI, 0.50-0.76], and 0.56 [95% CI, 0.44-0.70]). LUS findings were moderately correlated with oxygen saturation index (ρ = 0.52 [95% CI, 0.30-0.70]) and saturation to fraction of inspired oxygen ratio (ρ = -0.63 [95% CI, -0.76 to -0.46]). The correlation between radiographic diaphragm position, the oxygenation saturation index, and peripheral oxygen saturation to fraction of inspired oxygen ratio was very weak (ρ = 0.36 [95% CI, 0.11-0.59] and ρ = -0.32 [95% CI, -0.53 to -0.07], respectively). CONCLUSIONS: LUS assessment of lung volume does not correspond with radiographic diaphragm position preterm infants. However, LUS predicted radiographic regional atelectasis and correlated with oxygenation. The relationship between radiographic diaphragm position and oxygenation was very weak. Although LUS may not replace all radiographic measures of lung volume, LUS more accurately reflects respiratory status in preterm infants. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12621001119886.

Aeration strategy at birth does not impact carotid haemodynamics in preterm lambs.

BACKGROUND: The impact of different respiratory strategies at birth on the preterm lung is well understood; however, concerns have been raised that lung recruitment may impede cerebral haemodynamics. This study aims to examine the effect of three different ventilation strategies on carotid blood flow, carotid artery oxygen content and carotid oxygen delivery. METHODS: 124-127-day gestation apnoeic intubated preterm lambs studied as part of a larger programme primarily assessing lung injury were randomised to positive pressure ventilation with positive end-expiratory pressure (PEEP) 8 cmH2O (No-RM; n = 12), sustained inflation (SI; n = 15) or dynamic PEEP strategy (DynPEEP; maximum PEEP 14 or 20 cmH2O, n = 41) at birth, followed by 90 min of standardised ventilation. Haemodynamic data were continuously recorded, with intermittent arterial blood gas analysis. RESULTS: Overall carotid blood flow measures were comparable between strategies. Except for mean carotid blood flow that was significantly lower for the SI group compared to the No-RM and DynPEEP groups over the first 3 min (p < 0.0001, mixed effects model). Carotid oxygen content and oxygen delivery were similar between strategies. Maximum PEEP level did not alter cerebral haemodynamic measures. CONCLUSIONS: Although there were some short-term variations in cerebral haemodynamics between different PEEP strategies and SI, these were not sustained. IMPACT: Different pressure strategies to facilitate lung aeration at birth in preterm infants have been proposed. There is minimal information on the effect of lung recruitment on cerebral haemodynamics. This is the first study that compares the effect of sustained lung inflation and dynamic and static positive end-expiratory pressure on cerebral haemodynamics. We found that the different ventilation strategies did not alter carotid blood flow, carotid oxygen content or carotid oxygen delivery. This preclinical study provides some reassurance that respiratory strategies designed to focus on lung aeration at birth may not impact cerebral haemodynamics in preterm neonates.

Quantitative lung ultrasound detects dynamic changes in lung recruitment in the preterm lamb.

BACKGROUND: Lung ultrasound (LUS) may not detect small, dynamic changes in lung volume. Mean greyscale measurement using computer-assisted image analysis (Q-LUSMGV) may improve the precision of these measurements. METHODS: Preterm lambs (n = 40) underwent LUS of the dependent or non-dependent lung during static pressure-volume curve mapping. Total and regional lung volumes were determined using the super-syringe technique and electrical impedance tomography. Q-LUSMGV and gold standard measurements of lung volume were compared in 520 images. RESULTS: Dependent Q-LUSMGV moderately correlated with total lung volume (rho = 0.60, 95% CI 0.51-0.67) and fairly with right whole (rho = 0.39, 0.27-0.49), central (rho = 0.38, 0.27-0.48), ventral (rho = 0.41, 0.31-0.51) and dorsal regional lung volumes (rho = 0.32, 0.21-0.43). Non-dependent Q-LUSMGV moderately correlated with total lung volume (rho = 0.57, 0.48-0.65) and fairly with right whole (rho = 0.43, 0.32-0.52), central (rho = 0.46, 0.35-0.55), ventral (rho = 0.36, 0.25-0.47) and dorsal lung volumes (rho = 0.36, 0.25-0.47). All correlation coefficients were statistically significant. Distinct inflation and deflation limbs, and sonographic pulmonary hysteresis occurred in 95% of lambs. The greatest changes in Q-LUSMGV occurred at the opening and closing pressures. CONCLUSION: Q-LUSMGV detected changes in total and regional lung volume and offers objective quantification of LUS images, and may improve bedside discrimination of real-time changes in lung volume. IMPACT: Lung ultrasound (LUS) offers continuous, radiation-free imaging that may play a role in assessing lung recruitment but may not detect small changes in lung volume. Mean greyscale image analysis using computer-assisted quantitative LUS (Q-LUSMGV) moderately correlated with changes in total and regional lung volume. Q-LUSMGV identified opening and closing pressure and pulmonary hysteresis in 95% of lambs. Computer-assisted image analysis may enhance LUS estimation of lung recruitment at the bedside. Future research should focus on improving precision prior to clinical translation.

Current and emerging technologies for the timely screening and diagnosis of neonatal jaundice.

Neonatal jaundice is one of the most common clinical conditions affecting newborns. For most newborns, jaundice is harmless, however, a proportion of newborns develops severe neonatal jaundice requiring therapeutic interventions, accentuating the need to have reliable and accurate screening tools for timely recognition across different health settings. The gold standard method in diagnosing jaundice involves a blood test and requires specialized hospital-based laboratory instruments. Despite technological advancements in point-of-care laboratory medicine, there is limited accessibility of the specialized devices and sample stability in geographically remote areas. Lack of suitable testing options leads to delays in timely diagnosis and treatment of clinically significant jaundice in developed and developing countries alike. There has been an ever-increasing need for a low-cost, simple to use screening technology to improve timely diagnosis and management of neonatal jaundice. Consequently, several point-of-care (POC) devices have been developed to address this concern. This paper aims to review the literature, focusing on emerging technologies in the screening and diagnosing of neonatal jaundice. We report on the challenges associated with the existing screening tools, followed by an overview of emerging sensors currently in pre-clinical development and the emerging POC devices in clinical trials to advance the screening of neonatal jaundice. The benefits offered by emerging POC devices include their ease of use, low cost, and the accessibility of rapid response test results. However, further clinical trials are required to overcome the current limitations of the emerging POC's before their implementation in clinical settings. Hence, the need for a simple to use, low-cost POC jaundice detection technology for newborns remains an unsolved challenge globally.

Dynamic positive end-expiratory pressure strategies using time and pressure recruitment at birth reduce early expression of lung injury in preterm lambs.

Positive end-expiratory pressure (PEEP) is critical to the preterm lung at birth, but the optimal PEEP level remains uncertain. The objective of this study was to determine the effect of maximum PEEP levels at birth on the physiological and injury response in preterm lambs. Steroid-exposed preterm lambs (124-127 days gestation; n = 65) were randomly assigned from birth to either 1) positive pressure ventilation (PPV) at 8 cmH2O PEEP or 3-min dynamic stepwise PEEP strategy (DynPEEP), with either 2) 20 cmH2O maximum PEEP (10 PEEP second steps) or 3) 14 cmH2O maximum PEEP (20-s steps), all followed by standardized PPV for 90 min. Lung mechanics, gas exchange, regional ventilation and aeration (electrical impedance tomography), and histological and molecular measures of lung injury were compared between groups. Dynamic compliance was greatest using a maximum 20 cmH2O (DynPEEP). There were no differences in gas exchange, end-expiratory volume, and ventilator requirements. Regional ventilation became more uniform with time following all PEEP strategies. For all groups, gene expression of markers of early lung injury was greater in the gravity nondependent lung, and inversely related to the magnitude of PEEP, being lowest in the 20 cmH2O DynPEEP group overall. PEEP levels had no impact on lung injury in the dependent lung. Transient high maximum PEEP levels using dynamic PEEP strategies may confer more lung protection at birth.

Respiratory strategy at birth initiates distinct lung injury phenotypes in the preterm lamb lung.

BACKGROUND: A lack of clear trial evidence often hampers clinical decision-making during support of the preterm lung at birth. Protein biomarkers have been used to define acute lung injury phenotypes and improve patient selection for specific interventions in adult respiratory distress syndrome. The objective of the study was to use proteomics to provide a deeper biological understanding of acute lung injury phenotypes resulting from different aeration strategies at birth in the preterm lung. METHODS: Changes in protein abundance against an unventilated group (n = 7) were identified via mass spectrometry in a biobank of gravity dependent and non-dependent lung tissue from preterm lambs managed with either a Sustained Inflation (SI, n = 20), Dynamic PEEP (DynPEEP, n = 19) or static PEEP (StatPEEP, n = 11). Ventilation strategy-specific pathways and functions were identified (PANTHER and WebGestalt Tool) and phenotypes defined using integrated analysis of proteome, physiological and clinical datasets (MixOmics package). RESULTS: 2372 proteins were identified. More altered proteins were identified in the non-dependent lung, and in SI group than StatPEEP and DynPEEP. Different inflammation, immune system, apoptosis and cytokine pathway enrichment were identified for each strategy and lung region. Specific integration maps of clinical and physiological outcomes to specific proteins could be generated for each strategy. CONCLUSIONS: Proteomics mapped the molecular events initiating acute lung injury and identified detailed strategy-specific phenotypes. This study demonstrates the potential to characterise preterm lung injury by the direct aetiology and response to lung injury; the first step towards true precision medicine in neonatology.

Epidemiology of Neonatal Acute Respiratory Distress Syndrome: Prospective, Multicenter, International Cohort Study.

OBJECTIVES: Age-specific definitions for acute respiratory distress syndrome (ARDS) are available, including a specific definition for neonates (the "Montreux definition"). The epidemiology of neonatal ARDS is unknown. The objective of this study was to describe the epidemiology, clinical course, treatment, and outcomes of neonatal ARDS. DESIGN: Prospective, international, observational, cohort study. SETTING: Fifteen academic neonatal ICUs. PATIENTS: Consecutive sample of neonates of any gestational age admitted to participating sites who met the neonatal ARDS Montreux definition criteria. MEASUREMENTS AND MAIN RESULTS: Neonatal ARDS was classified as direct or indirect, infectious or noninfectious, and perinatal (≤ 72 hr after birth) or late in onset. Primary outcomes were: 1) survival at 30 days from diagnosis, 2) inhospital survival, and 3) extracorporeal membrane oxygenation (ECMO)-free survival at 30 days from diagnosis. Secondary outcomes included respiratory complications and common neonatal extrapulmonary morbidities. A total of 239 neonates met criteria for the diagnosis of neonatal ARDS. The median prevalence was 1.5% of neonatal ICU admissions with male/female ratio of 1.5. Respiratory treatments were similar across gestational ages. Direct neonatal ARDS (51.5% of neonates) was more common in term neonates and the perinatal period. Indirect neonatal ARDS was often triggered by an infection and was more common in preterm neonates. Thirty-day, inhospital, and 30-day ECMO-free survival were 83.3%, 76.2%, and 79.5%, respectively. Direct neonatal ARDS was associated with better survival outcomes than indirect neonatal ARDS. Direct and noninfectious neonatal ARDS were associated with the poorest respiratory outcomes at 36 and 40 weeks' postmenstrual age. Gestational age was not associated with any primary outcome on multivariate analyses. CONCLUSIONS: Prevalence and survival of neonatal ARDS are similar to those of pediatric ARDS. The neonatal ARDS subtypes used in the current definition may be associated with distinct clinical outcomes and a different distribution for term and preterm neonates.

Transmission of Oscillatory Volumes into the Preterm Lung during Noninvasive High-Frequency Ventilation.

Rationale: There is increasing evidence for a clinical benefit of noninvasive high-frequency oscillatory ventilation (nHFOV) in preterm infants. However, it is still unknown whether the generated oscillations are effectively transmitted to the alveoli.Objectives: To assess magnitude and regional distribution of oscillatory volumes (VOsc) at the lung level.Methods: In 30 prone preterm infants enrolled in a randomized crossover trial comparing nHFOV with nasal continuous positive airway pressure, electrical impedance tomography recordings were performed. During nHFOV, the smallest amplitude to achieve visible chest wall vibration was used, and the frequency was set at 8 hertz.Measurements and Main Results: Thirty consecutive breaths during artifact-free tidal ventilation were extracted for each of the 228 electrical impedance tomography recordings. After application of corresponding frequency filters, Vt and VOsc were calculated. There was a signal at 8 and 16 Hz during nHFOV, which was not detectable during nasal continuous positive airway pressure, corresponding to the set oscillatory frequency and its second harmonic. During nHFOV, the mean (SD) VOsc/Vt ratio was 0.20 (0.13). Oscillations were more likely to be transmitted to the non-gravity-dependent (mean difference [95% confidence interval], 0.041 [0.025-0.058]; P < 0.001) and right-sided lung (mean difference [95% confidence interval], 0.040 [0.019-0.061]; P < 0.001) when compared with spontaneous Vt.Conclusions: In preterm infants, VOsc during nHFOV are transmitted to the lung. Compared with the regional distribution of tidal breaths, oscillations preferentially reach the right and non-gravity-dependent lung. These data increase our understanding of the physiological processes underpinning nHFOV and may lead to further refinement of this novel technique.

Imaging the Respiratory Transition at Birth: Unraveling the Complexities of the First Breaths of Life.

Rationale: The transition to air breathing at birth is a seminal respiratory event common to all humans, but the intrathoracic processes remain poorly understood. Objectives: The objectives of this prospective, observational study were to describe the spatiotemporal gas flow, aeration, and ventilation patterns within the lung in term neonates undergoing successful respiratory transition. Methods: Electrical impedance tomography was used to image intrathoracic volume patterns for every breath until 6 minutes from birth in neonates born by elective cesearean section and not needing resuscitation. Breaths were classified by video data, and measures of lung aeration, tidal flow conditions, and intrathoracic volume distribution calculated for each inflation. Measurements and Main Results: A total of 1,401 breaths from 17 neonates met all eligibility and data analysis criteria. Stable FRC was obtained by median (interquartile range) 43 (21-77) breaths. Breathing patterns changed from predominantly crying (80.9% first min) to tidal breathing (65.3% sixth min). From birth, tidal ventilation was not uniform within the lung, favoring the right and nondependent regions; P < 0.001 versus left and dependent regions (mixed-effects model). Initial crying created a unique volumetric pattern with delayed midexpiratory gas flow associated with intrathoracic volume redistribution (pendelluft flow) within the lung. This preserved FRC, especially within the dorsal and right regions. Conclusions: The commencement of air breathing at birth generates unique flow and volume states associated with marked spatiotemporal ventilation inhomogeneity not seen elsewhere in respiratory physiology. At birth, neonates innately brake expiratory flow to defend FRC gains and redistribute gas to less aerated regions.

Mechanism of bilirubin elimination in urine: insights and prospects for neonatal jaundice.

Despite a century of research, bilirubin metabolism and the transport mechanisms responsible for homeostasis of bilirubin in serum remain controversial. Emerging evidence on the hepatic membrane transporters and inherited disorders of bilirubin metabolism have contributed to a greater understanding of the various steps involved in bilirubin homeostasis and its associated excretory pathways. We discuss these recent research findings on hepatic membrane transporters and evaluate their significance on the newborn bilirubin metabolism and excretion. New insights gained speculate that a proportion of conjugated bilirubin is excreted via the renal system, as an alternative to the intestinal excretion, even in normal physiological jaundice with no associated pathological concerns. Finally, this paper discusses the clinical relevance of targeting the altered renal excretory pathway, as bilirubin in urine may hold diagnostic importance in screening for neonatal jaundice.

Respiratory mechanics during initial lung aeration at birth in the preterm lamb.

Despite recent insights into the dynamic processes during lung aeration at birth, several aspects remain poorly understood. We aimed to characterize changes in lung mechanics during the first inflation at birth and their relationship to changes in lung volume. Intubated preterm lambs (gestational age, 124-127 days; n = 17) were studied at birth. Lung volume changes were measured by electrical impedance tomography (VLEIT). Respiratory system resistance (R5) and oscillatory compliance (Cx5) were monitored with the forced oscillation technique at 5 Hz. Lambs received 3-7 s of 8 cmH2O of continuous distending pressure (CDP) before delivery of a sustained inflation (SI) of 40 cmH2O. The SI was then applied until either Cx5 or the VLEIT or the airway opening volume was stable. CDP was resumed for 3-7 s before commencement of mechanical ventilation. The exponential increases with time of Cx5 and VLEIT from commencement of the SI were characterized by estimating their time constants (τCx5 and τVLEIT, respectively). During SI, a fast decrease in R5 and an exponential increase in Cx5 and VLEIT were observed. Cx5 and VLEIT provided comparable information on the dynamics of lung aeration in all lambs, with τCx5 and τVLEIT being highly linearly correlated (r2 = 0.87, P < 0.001). Cx5 and VLEIT decreased immediately after SI. Despite the standardization of the animal model, changes in Cx5 and R5 both during and after SI were highly variable. Lung aeration at birth is characterized by a fast reduction in resistance and a slower increase in oscillatory compliance, the latter being a direct reflection of the amount of lung aeration.

The EPICENTRE (ESPNIC Covid pEdiatric Neonatal Registry) initiative: background and protocol for the international SARS-CoV-2 infections registry.

The outbreak of SARS-CoV-2 is the worst healthcare emergency of this century, and its impact on pediatrics and neonatology is still largely unknown. The European Society for Pediatric and Neonatal Intensive Care (ESPNIC) launched the EPICENTRE (ESPNIC Covid pEdiatric Neonatal Registry) international, multicenter, and multidisciplinary initiative to study the epidemiology, clinical course, and outcomes of pediatric and neonatal SARS-CoV-2 infections. EPICENTRE background and aims are presented together with protocol details. EPICENTRE is open to centers all over the world, and this will allow to provide a pragmatic picture of the epidemic, with a particular attention to pediatric and neonatal critical care issues.Conclusions: EPICENTRE will allow researchers to clarify the epidemiology, clinical presentation, and outcomes of pediatric and neonatal SARS-CoV-2 infection, refining its clinical management and hopefully providing new insights for clinicians. What is Known: • COVID19 is the new disease caused by SARS-CoV-2 infection and is spreading around the globe. • Majority of data available about SARS-CoV-2 infections originates from adult patients. What is New: • EPICENTRE is the first international, multicenter, multidisciplinary, meta-data driven, hospital-based, online, prospective cohort registry dedicated to neonatal and pediatric SARS-CoV-2 infections. • EPICENTRE will allow to understand epidemiology and physiopathology of COVID19.

Gradual Aeration at Birth Is More Lung Protective Than a Sustained Inflation in Preterm Lambs.

Rationale: The preterm lung is susceptible to injury during transition to air breathing at birth. It remains unclear whether rapid or gradual lung aeration at birth causes less lung injury.Objectives: To examine the effect of gradual and rapid aeration at birth on: 1) the spatiotemporal volume conditions of the lung; and 2) resultant regional lung injury.Methods: Preterm lambs (125 ± 1 d gestation) were randomized at birth to receive: 1) tidal ventilation without an intentional recruitment (no-recruitment maneuver [No-RM]; n = 19); 2) sustained inflation (SI) until full aeration (n = 26); or 3) tidal ventilation with an initial escalating/de-escalating (dynamic) positive end-expiratory pressure (DynPEEP; n = 26). Ventilation thereafter continued for 90 minutes at standardized settings, including PEEP of 8 cm H2O. Lung mechanics and regional aeration and ventilation (electrical impedance tomography) were measured throughout and correlated with histological and gene markers of early lung injury.Measurements and Main Results: DynPEEP significantly improved dynamic compliance (P < 0.0001). An SI, but not DynPEEP or No-RM, resulted in preferential nondependent lung aeration that became less uniform with time (P = 0.0006). The nondependent lung was preferential ventilated by 5 minutes in all groups, with ventilation only becoming uniform with time in the No-RM and DynPEEP groups. All strategies generated similar nondependent lung injury patterns. Only an SI caused greater upregulation of dependent lung gene markers compared with unventilated fetal controls (P < 0.05).Conclusions: Rapidly aerating the preterm lung at birth creates heterogeneous volume states, producing distinct regional injury patterns that affect subsequent tidal ventilation. Gradual aeration with tidal ventilation and PEEP produced the least lung injury.