Increased end-expiratory pressures improve lung function in near-term newborn rabbits with elevated airway liquid volume at birth

Approximately 53% of near-term newborns admitted to intensive care experience respiratory distress. These newborns are commonly delivered by cesarean section and have elevated airway liquid volumes at birth, which can cause respiratory morbidity. We investigated the effect of providing respiratory support with a positive end-expiratory pressure (PEEP) of 8 cmH(2)O on lung function in newborn rabbit kittens with elevated airway liquid volumes at birth. Near-term rabbits (30 days; term = 32 days) with airway liquid volumes that corresponded to vaginal delivery (similar to 7 mL/kg, control, n = 11) or cesarean section (similar to 37 mL/kg; elevated liquid (EL), n = 11] were mechanically ventilated (tidal volume= 8 mL/kg). The PEEP was changed after lung aeration from 0 to 8 to 0 cmH(2)O (control, n = 6; EL, n = 6), and in a separate group of kittens, PEEP was changed after lung aeration from 8 to 0 to 8 cmH(2)O (control, n = 5; EL, n = 5). Lung function (ventilator parameters, compliance, lung gas volumes, and distribution of gas within the lung) was evaluated using plethysmography and synchrotron-based phase-contrast X-ray imaging. EL kittens initially receiving 0 cmH(2)O PEEP had reduced functional residual capacities and lung compliance, requiring higher inflation pressures to aerate the lung compared with control kittens. Commencing ventilation with 8 cmH(2)O PEEP mitigated the adverse effects of EL, increasing lung compliance, functional residual capacity, and the uniformity and distribution of lung aeration, but did not normalize aeration of the distal airways. Respiratory support with PEEP supports lung function in near-term newborn rabbits with elevated airway liquid volumes at birth who are at a greater risk of suffering respiratory distress.NEW & NOTEWORTHY Term babies born by cesarean section have elevated airway liquid volumes, which predisposes them to respiratory distress. Treatments targeting molecular mechanisms to clear lung liquid are ineffective for term newborn respiratory distress. We showed that respiratory support with an end-expiratory pressure supports lung function in near-term rabbits with elevated airway liquid volumes at birth. This study provides further physiological understanding of lung function in newborns with elevated airway liquid volumes at risk of respiratory distress.Developmen

Validation of disease-specific biomarkers for the early detection of bronchopulmonary dysplasia

OBJECTIVE: To demonstrate and validate the improvement of current risk stratification for bronchopulmonary dysplasia (BPD) early after birth by plasma protein markers (sialic acid-binding lg-like lectin 14 (SIGLEC-14), basal cell adhesion molecule (BCAM), angiopoietin-like 3 protein (ANGPTL-3)) in extremely premature infants.METHODS AND RESULTS: Proteome screening in first-week-of-life plasma samples of n- 52 preterm infants <32 weeks gestational age (GA) on two proteomic platforms (SomaLogic (R), Olink-Proteomics (R)) confirmed three biomarkers with significant predictive power: BCAM, SIGLEC-14, and ANGPTL-3. We demonstrate high sensitivity (0.92) and specificity (0.86) under consideration of GA, show the proteins' critical contribution to the predictive power of known clinical risk factors, e.g., birth weight and GA, and predicted the duration of mechanical ventilation, oxygen supplementation, as well as neonatal intensive care stay. We confirmed significant predictive power for BPD cases when switching to a clinically applicable method (enzyme-linked immunosorbent assay) in an independent sample set (n = 25, p < 0.001) and demonstrated disease specificity in different cohorts of neonatal and adult lung disease.CONCLUSION: While successfully addressing typical challenges of clinical biomarker studies, we demonstrated the potential of BCAM, SIGLEC-14, and ANGPTL-3 to inform future clinical decision making in the preterm infant at risk for BPD.Analytical BioScience

Increasing Respiratory Effort With 100% Oxygen During Resuscitation of Preterm Rabbits at Birth

Background: Spontaneous breathing is essential for successful non-invasive respiratory support delivered by a facemask at birth. As hypoxia is a potent inhibitor of spontaneous breathing, initiating respiratory support with a high fraction of inspired O2 may reduce the risk of hypoxia and increase respiratory effort at birth. Methods: Preterm rabbit kittens (29 days gestation, term ~32 days) were delivered and randomized to receive continuous positive airway pressure with either 21% (n = 12) or 100% O2 (n = 8) via a facemask. If apnea occurred, intermittent positive pressure ventilation (iPPV) was applied with either 21% or 100% O2 in kittens who started in 21% O2, and remained at 100% O2 for kittens who started the experiment in 100% O2. Respiratory rate (breaths per minute, bpm) and variability in inter-breath interval (%) were measured from esophageal pressure recordings and functional residual capacity (FRC) was measured from synchrotron phase-contrast X-ray images. Results: Initially, kittens receiving 21% O2 had a significantly lower respiratory rate and higher variability in inter-breath interval, indicating a less stable breathing pattern than kittens starting in 100% O2 [median (IQR) respiratory rate: 16 (4–28) vs. 38 (29–46) bpm, p = 0.001; variability in inter-breath interval: 33.3% (17.2–50.1%) vs. 27.5% (18.6–36.3%), p = 0.009]. Apnea that required iPPV, was more frequently observed in kittens in whom resuscitation was started with 21% compared to 100% O2 (11/12 vs. 1/8, p = 0.001). After recovering from apnea, respiratory rate was significantly lower and variability in inter-breath interval was significantly higher in kittens who received iPPV with 21% compared to 100% O2. FRC was not different between study groups at both timepoints. Conclusion: Initiating resuscitation with 100% O2 resulted in increased respiratory activity and stability, thereby reducing the risk of apnea and need for iPPV after birth. Further studies in human preterm infants are mandatory to confirm the benefit of this approach in terms of oxygenation. In addition, the ability to avoid hyperoxia after initiation of resuscitation with 100% oxygen, using a titration protocol based on oxygen saturation, needs to be clarified

Langzeitentwicklung von Kindern nach Extra Corporaler Membran Oxygenierung (ECMO).

Hintergrund Nach neonatalem Lungenversagen und insbesondere nach einer ECMO-Therapie können verschiedenste Langzeitmorbiditäten auftreten. Das Follow-up dieser schwer kranken Neugeborenen ist als Qualitätskriterium für ein ECMO-Zentrum unverzichtbar und sie besitzt einen hohen Stellenwert in der Beratung von Eltern. Da ECMO-Zentren ein großes Einzugsgebiet haben, ist eine feste Anbindung der Patienten an das Zentrum oft schwierig. Methode Nachsorgeuntersuchung und Entwicklungsscreening einer Kohorte (n=41) ehemaliger Neugeborener und Säuglinge mit schweren Lungenversagen auf Langzeitmorbiditäten durch eine Fragebogenerhebung sowie eine systematische, z.T. computergestützte Recherche mittels Arztbriefen und Telefonbefragung. Ergebnisse An 28 von 31 Familien überlebender Kinder konnten Fragebögen versendet werden. 23 Fragebögen wurden zurückgesandt, einer Rücklaufquote von 82% entsprechend. Vier Kinder hatten auffällige Fragebogenergebnisse, d. h. sie lagen unter der 90ten Perzentile der altersentsprechenden Werte und besaßen damit ein Risiko für eine Entwicklungsauffälligkeit. Davon waren 3 Kinder im Alter von 2 Jahren und waren im Rahmen ihres Lungenversagens konventionell behandelt worden. Ein Kind im Alter von 6 Jahren hatte eine ECMO-Therapie erhalten. Schlussfolgerung Die von uns erstmals an Kindern mit einem schweren neonatalen Lungenversagen eingesetzten Fragebögen können der Detektion einer Entwicklungsauffälligkeit dienen. In der klinischen Praxis sind sie als Entwicklun

Intrapulmonary instillation of perflurooctylbromide improves lung growth, alveolarization, and lung mechanics in a fetal rabbit model of diaphragmatic hernia.

OBJECTIVES: Fetal tracheal occlusion of hypoplastic rabbit lungs results in lung growth and alveolarization although the surfactant protein messenger RNA expression is decreased and the transforming growth factor-&beta; pathway induced. The prenatal filling of healthy rabbit lungs with perfluorooctylbromide augments lung growth without suppression of surfactant protein synthesis. We hypothesizes that Intratracheal perfluorooctylbromide instillation improves lung growth, mechanics, and extracellular matrix synthesis in a fetal rabbit model of lung hypoplasia induced by diaphragmatic hernia. SETTING AND INTERVENTIONS: On day 23 of gestation, DH was induced by fetal surgery in healthy rabbit fetuses. Five days later, 0.8ml of perfluorooctylbromide (diaphragmatic hernia-perfluorooctylbromide) or saline (diaphragmatic hernia-saline) was randomly administered into the lungs of previously operated fetuses. After term delivery (day 31), lung mechanics, lung to body weight ratio, messenger RNA levels of target genes, assessment of lung histology, and morphological distribution of elastin and collagen were determined. Nonoperated fetuses served as controls. MEASUREMENTS AND MAIN RESULTS: Fetal instillation of perfluorooctylbromide in hypoplastic lungs resulted in an improvement of lung-to-body weight ratio (0.016 vs 0.013&thinsp;g/g; p = 0.05), total lung capacity (23.4 vs 15.4 &mu;L/g; p = 0.03), and compliance (2.4 vs 1.2&thinsp;mL/cm H2O; p = 0.007) as compared to diaphragmatic hernia-saline. In accordance with the results from lung function analysis, elastin staining of pulmonary tissue revealed a physiological distribution of elastic fiber to the tips of the secondary crests in the diaphragmatic hernia-perfluorooctylbromide group. Likewise, messenger RNA expression was induced in genes associated with extracellular matrix remodeling (matrix metalloproteinase-2, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2). Surfactant protein expression was similar in the diaphragmatic hernia-perfluorooctylbromide and diaphragmatic hernia-saline groups. Distal airway size, mean linear intercept, as well as airspace and tissue fractions were similar in diaphragmatic hernia-perfluorooctylbromide, diaphragmatic hernia-saline, and control groups. CONCLUSIONS: Fetal perfluorooctylbromide treatment improves lung growth, lung mechanics, and extracellular matrix remodeling in hypoplastic lungs, most probably due to transient pulmonary stretch, preserved fetal breathing movements, and its physical characteristics. Perfluorooctylbromide instillation is a promising approach for prenatal therapy of lung hypoplasia

In silico numerical simulation of ventilator settings during high-frequency ventilation in preterm infants.

Objective: Despite the routine use of antenatal steroids, exogenous surfactants, and different noninvasive ventilation methods, many extremely low gestational age neonates, preterm, and term infants eventually require invasive ventilation. In addition to prematurity, mechanical ventilation itself can induce ventilator-induced lung injury leading to lifelong pulmonary sequelae. Besides conventional mechanical ventilation, high-frequency oscillatory ventilation (HFOV) with tidal volumes below dead space and high ventilation frequencies is used either as a primary or rescue therapy in severe neonatal respiratory failure. Methods and Results: Applying a high-resolution computational lung modeling technique in a preterm infant, we studied three different high-frequency ventilation settings as well as conventional ventilation (CV) settings. Evaluating the computed oxygen delivery (OD) and lung mechanics (LM) we outline for the first time how changing ventilator settings from CV to HFOV lead to significant improvements in OD and LM. Conclusion: This personalized “digital twin” strategy advances our general knowledge of protective ventilation strategies in neonatal care and can support decisions on various modes of ventilatory therapy at high frequencies

Antenatal BAY 41-2272 reduces pulmonary hypertension in the rabbit model of congenital diaphragmatic hernia

Infants with congenital diaphragmatic hernia (CDH) fail to adapt at birth because of persistent pulmonary hypertension (PH), a condition characterized by excessive muscularization and abnormal vasoreactivity of pulmonary vessels. Activation of soluble guanylate cyclase by BAY 41-2272 prevents pulmonary vascular remodeling in neonatal rats with hypoxia-induced PH. By analogy, we hypothesized that prenatal administration of BAY 41-2272 would improve features of PH in the rabbit CDH model. Rabbit fetuses with surgically induced CDH at day 23 of gestation were randomized at day 28 for an intratracheal injection of BAY 41-2272 or vehicle. After term delivery (day 31), lung mechanics, right ventricular pressure, and serum NH2-terminal-pro-brain natriuretic peptide (NT-proBNP) levels were measured. After euthanasia, lungs were processed for biological or histological analyses. Compared with untouched fetuses, the surgical creation of CDH reduced the lung-to-body weight ratio, increased mean terminal bronchial density, and impaired lung mechanics. Typical characteristics of PH were found in the hypoplastic lungs, including increased right ventricular pressure, higher serum NT-proBNP levels, thickened adventitial and medial layers of pulmonary arteries, reduced capillary density, and lower levels of endothelial nitric oxide synthase. A single antenatal instillation of BAY 41-2272 reduced mean right ventricular pressure and medial thickness of small resistive arteries in CDH fetuses. Capillary density, endothelial cell proliferation, and transcripts of endothelial nitric oxide synthase increased, whereas airway morphometry, lung growth, and mechanics remained unchanged. These results suggest that pharmacological activation of soluble guanylate cyclase may provide a new approach to the prenatal treatment of PH associated with CDH.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Stimulating and maintaining spontaneous breathing during transition of preterm infants

Most preterm infants breathe at birth, but need additional respiratory support due to immaturity of the lung and respiratory control mechanisms. To avoid lung injury, the focus of respiratory support has shifted from invasive towards non-invasive ventilation. However, applying effective non-invasive ventilation is difficult due to mask leak and airway obstruction. The larynx has been overlooked as one of the causes for obstruction, preventing face mask ventilation from inflating the lung. The larynx remains mostly closed at birth, only opening briefly during a spontaneous breath. Stimulating and supporting spontaneous breathing could enhance the success of non-invasive ventilation by ensuring that the larynx remains open. Maintaining adequate spontaneous breathing and thereby reducing the need for invasive ventilation is not only important directly after birth, but also in the first hours after admission to the NICU. Respiratory distress syndrome is an important cause of respiratory failure. Traditionally, treatment of RDS required intubation and mechanical ventilation to administer exogenous surfactant. However, new ways have been implemented to administer surfactant and preserve spontaneous breathing while maintaining non-invasive support. In this narrative review we aim to describe interventions focused on stimulation and maintenance of spontaneous breathing of preterm infants in the first hours after birth.Developmen

Entwicklungsneurologie &ndash; vernetzte Medizin und neue Perspektiven.

Die Entwicklungsneurologie ist einer der gro&szlig;en Bereiche der Kinderneurologie. Sie hat u.&nbsp;a. die (gesetzliche) Aufgabe, mithilfe standardisierter Nachsorgeuntersuchungen die motorische, kognitive und psychosoziale Entwicklung von Fr&uuml;hgeborenen vor der 32.&nbsp;Schwangerschaftswoche (unter 1500&thinsp;g Geburtsgewicht), ebenso aber auch aller anderen Risikokinder engmaschig und standardisiert zu begleiten. Abweichungen von der &bdquo;normalen&ldquo; altersentsprechenden Entwicklung sollen durch eine fr&uuml;hestm&ouml;gliche Diagnosestellung zu einer fr&uuml;hen Therapieeinleitung (&bdquo;early intervention&ldquo;) f&uuml;hren und die Langzeitprognose der Patienten positiv beeinflussen. Die hierf&uuml;r zu Verf&uuml;gung stehenden Methoden mit Schwerpunkt auf aktuellen Neuentwicklungen werden beleuchtet. Mit einem Fokus auf Fr&uuml;herkennung wird besonders auf den pr&auml;diktiven Wert der &bdquo;general movements&ldquo; (GMs) eingegangen. Dabei wird die fortschreitende Entwicklung der automatisierten, markerlosen Bewegungsanalyse beispielhalft an drei Patienten (gesund vs. genetisches Syndrom vs. Zerebralparese) im Alter von 12&nbsp;Wochen mithilfe herk&ouml;mmlicher Tiefenbildkameras veranschaulicht und diskutiert

Abca3 haploinsufficiency is a risk factor for lung injury induced by hyperoxia or mechanical ventilation in a murine model.

Background:Heterozygous ABCA3 (ATP-binding-cassette sub-family A member3) mutations are associated with neonatal respiratory complications. We investigated in an adult murine model whether Abca3 haploinsufficiency is a predisposing factor for lung injury induced by hyperoxia or mechanical ventilation.Methods:Abca3 haploinsufficient (Abca3+/-) and wild-type (WT) mice were prospectively randomized to 25&thinsp;min of ventilation or 72 hours of hyperoxia or left unchallenged in air.Results:As compared to WT, unchallenged Abca3+/- mice had significantly decreased lung phosphatidylcholine (PC) and phosphatidylglycerol (PG) levels (p&lt;0.02) and decreased lung compliance (p&lt;0.05). When ventilated for 25&thinsp;min, Abca3+/- mice demonstrated a significantly greater increase in bronchoalveolar lavage (BAL) interleukins (p&lt;0.01) and lung wet to dry ratio (p&lt;0.005). Hyperoxia resulted in increased compliance (p&lt;0.05) and total lung capacity (TLC) (p=0.01) only in the Abca3+/- mice consistent with enlarged alveolar spaces. The ratio of PC to PG in BAL - relevant for surfactant dysfunction - was significantly elevated by oxygen exposure with the greatest increase in Abca3+/- mice.Conclusions:In a murine model, Abca3 haploinsufficiency results in an altered biochemical and lung mechanical phenotype as well as a greater lung injury induced by hyperoxia or mechanical ventilation. The inability to maintain a normal PC/PG ratio appears to play a key role