Preterm Lung Research Articles

Trials of antenatal corticosteroids for preterm fetal lung maturity: a review of the potential for selective outcome reporting

ObjectiveTo measure the extent to which the evidence underpinning prenatal corticosteroids for preterm fetal lung maturity is at risk of bias due to selective outcome reporting. Study designFive biomedical databases (Medline, ClinicalTrials.gov, Embase, OVID and HMIC) were searched for trials published between February 2016 and September 2017.Randomised trials of prenatal steroids for women at risk of preterm birth were identified. For each, we recorded the registration status and timing, and whether the registered primary outcome had been reported. For unregistered trials, we estimated the potential for selective outcome reporting indirectly by tabulating all reported outcomes and by comparing the first outcome reported in the methods to the first in the results section. ResultsTwenty seven trials were identified. Only three (11%) trials had been registered. All three reported their pre-specified primary outcome. Among the unregistered trials, thirteen (54%) had different first reported outcomes in the methods and results sections, and among all trials many different outcomes were reported suggesting considerable potential for selective reporting. However, the single outcome of respiratory distress syndrome, albeit defined in different ways, was reported in all but two trials. This is reassuring evidence that the beneficial effect of steroids on this outcome has not been exaggerated by selective outcome reporting. ConclusionWe conclude that the evidence that steroids reduce respiratory distress syndrome is secure.

Repeat Antenatal Betamethasone and Cardiometabolic Outcomes

(Abstracted from Pediatrics 2018;142(1):e20180522) Antenatal corticosteroid therapy is one of the most effective interventions for preterm birth, resulting in rapid maturation of fetal organ systems. The Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) revealed that neonatal benefit is greatest when antenatal corticosteroids are administered in repeat doses, which can be used to reduce the incidence and severity of preterm lung disease and other serious neonatal morbidity, with absolute benefits similar to that of an initial course of antenatal corticosteroids.

Plasma proteomics reveals gestational age-specific responses to mechanical ventilation and identifies the mechanistic pathways that initiate preterm lung injury

The preterm lung is particularly vulnerable to ventilator-induced lung injury (VILI) as a result of mechanical ventilation. However the developmental and pathological cellular mechanisms influencing the changing patterns of VILI have not been comprehensively delineated, preventing the advancement of targeted lung protective therapies. This study aimed to use SWATH-MS to comprehensively map the plasma proteome alterations associated with the initiation of VILI following 60 minutes of standardized mechanical ventilation from birth in three distinctly different developmental lung states; the extremely preterm, preterm and term lung using the ventilated lamb model. Across these gestations, 34 proteins were differentially altered in matched plasma samples taken at birth and 60 minutes. Multivariate analysis of the plasma proteomes confirmed a gestation-specific response to mechanical ventilation with 79% of differentially-expressed proteins altered in a single gestation group only. Six cellular and molecular functions and two physiological functions were uniquely enriched in either the extremely preterm or preterm group. Correlation analysis supported gestation-specific protein-function associations within each group. In identifying the gestation-specific proteome and functional responses to ventilation we provide the founding evidence required for the potential development of individualized respiratory support approaches tailored to both the developmental and pathological state of the lung.

Computer simulation analysis of source‐detector position for percutaneously measured O2‐gas signal in a three‐dimensional preterm infant lung

Further improvements in the clinical care of our most vulnerable patients-preterm infants-are needed. Novel diagnostic and surveillance tools facilitate such advances. The GASMAS technique has shown potential to become a tool to, noninvasively, monitor gas in the lungs of preterm infants, by placing a laser source and a detector on the chest wall skin. It is believed that this technology will become a valuable clinical diagnostic tool for monitoring the lung function of these patients. Today, the technology is, for this application, in an early stage and further investigations are needed. In the present study, a three-dimensional computer model of the thorax of an infant is constructed, from a set of CT images. Light transport simulations are performed to provide information about the position dependence of the laser- and detector probe on the thorax of the infant. The result of the simulations, based on the study method and the specified model used in this work, indicates that measurement geometries in front and on the side of the lung are favorable in order to obtain a good gas absorption signal.

The efficacy of antenatal steroid therapy is dependent on the duration of low-concentration fetal exposure: evidence from a sheep model of pregnancy

Antenatal corticosteroids are among the most important and widely used interventions to improve outcomes for preterm infants. Antenatal corticosteroid dosing regimens remain unoptimized and without maternal weight-adjusted dosing. We, and others, have hypothesized that, once a low concentration of maternofetal steroid exposure is achieved and maintained, the duration of the steroid exposure determines treatment efficacy. Using a sheep model of pregnancy, we tested the relationship among steroid dose, duration of exposure, and treatment efficacy. The study was conducted to investigate the relative importance of duration and magnitude of fetal corticosteroid exposure to mature the preterm fetal ovine lung. Ewes with single fetuses at 120 days gestation received an intravenous bolus (loading dose) followed by a maintenance infusion of betamethasone phosphate to target 12-hour fetal plasma betamethasone concentrations of (1) 20 ng/mL, (2) 10 ng/mL, or (3) 2ng/mL. In a subsequent experiment, fetal plasma betamethasone concentrations were targeted at 2 ng/mL for 26 hours. Negative control animals received sterile saline solution. Positive control animals received 2 intramuscular injections of 0.25 mg/kg Celestone Chronodose (betamethasone phosphate+ betamethasone acetate) spaced at 24 hours. Preterm lambs were delivered surgically and ventilated 48 hours after treatment commenced. Maternal and fetal plasma betamethasone concentrations were confirmed by mass spectrometry in a parallel study of chronically catheterized, corticosteroid-treated ewes and fetuses. The loading and maintenance doses were achieved and maintained the desired fetal plasma betamethasone concentrations of approximately 20, 10, and 2 ng/mL for 12 hours. Compared with the 12-hour infusion-treated animals, lambs from the positive control (2intramuscular doses of 0.25 mg/kg Celestone Chronodose) group had the greatest functional lung maturation (compliance, gas exchange, arterial pH) and molecular evidence of maturation (glucocorticoid receptor signaling activation), despite having maximum fetal plasma betamethasone concentrations 2.5 times lower than animals in the 20 ng/mL betamethasone infusion group. Lambs from the 12-hour 2-ng/mL betamethasone infusion group had little functional lung maturation. In contrast, lambs from the 26-hour 2-ng/mL betamethasone infusion group had functional lung maturation equivalent to lambs from the positive control group. In preterm lambs that were exposed to antenatal corticosteroids, high maternofetal plasma betamethasone concentrations did not correlate with improved lung maturation. The largest and most consistent improvements in lung maturation were in animals that were exposed to either the clinical course of Celestone Chronodose or a low-dose betamethasone phosphate infusion to achieve a fetal plasma betamethasone concentration of approximately 2 ng/mL for 26 hours. The duration of low-concentration maternofetal steroid exposure, not total dose or peak drug exposure, is a key determinant for antenatal corticosteroids efficacy. These findings underscore the need to develop an optimized steroid dosing regimen that may improve both the efficacy and safety of antenatal corticosteroids therapy.

Effects of budesonide and surfactant in preterm fetal sheep.

Mechanical ventilation causes lung injury and systemic inflammatory responses in preterm sheep and is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Budesonide added to surfactant decreased BPD by 20% in infants. We wanted to determine the effects of budesonide and surfactant on injury from high tidal volume (VT) ventilation in preterm lambs. Ewes at 125 ± 1 days gestational age had fetal surgery to expose fetal head and chest with placental circulation intact. Lambs were randomized to 1) mechanical ventilation with escalating VT to target 15 ml/kg by 15 min or 2) continuous positive airway pressure (CPAP) of 5 cmH2O. After the 15-min intervention, lambs were given surfactant 100 mg/kg with saline, budesonide 0.25 mg/kg, or budesonide 1 mg/kg. The fetuses were returned to the uterus for 24 h and then delivered and ventilated for 30 min to assess lung function. Budesonide levels were low in lung and plasma. CPAP groups had improved oxygenation, ventilation, and decreased injury markers compared with fetal VT lambs. Budesonide improved ventilation in CPAP lambs. Budesonide decreased lung weights and lung liquid and increased lung compliance and surfactant protein mRNA. Budesonide decreased proinflammatory and acute-phase responses in lung. Airway thickness increased in animals not receiving budesonide. Systemically, budesonide decreased monocyte chemoattractant protein-1 mRNA and preserved glycogen in liver. Results with 0.25 and 1 mg/kg budesonide were similar. We concluded that budesonide with surfactant matured the preterm lung and decreased the liver responses but did not improve lung function after high VT injury in fetal sheep.

How best to capture the respiratory consequences of prematurity?

Chronic respiratory morbidity is a common complication of premature birth, generally defined by the presence of bronchopulmonary dysplasia, both clinically and in trials of respiratory therapies. However, recent data have highlighted that bronchopulmonary dysplasia does not correlate with chronic respiratory morbidity in older children born preterm. Longitudinally evaluating pulmonary morbidity from early life through to childhood provides a more rational method of defining the continuum of chronic respiratory morbidity of prematurity, and offers new insights into the efficacy of neonatal respiratory interventions. The changing nature of preterm lung disease suggests that a multimodal approach using dynamic lung function assessment will be needed to assess the efficacy of a neonatal respiratory therapy and predict the long-term respiratory consequences of premature birth. Our aim is to review the literature regarding the long-term respiratory outcomes of neonatal respiratory strategies, the difficulties of assessing dynamic lung function in infants, and potential new solutions.

Modelling Bronchopulmonary Dysplasia in Animals: Arguments for the Preterm Rabbit Model.

Bronchopulmonary dysplasia (BPD) remains a frequent and disabling consequence of preterm birth, despite the recent advances in neonatal intensive care. There is a need to further improve outcomes and many novel therapeutic or preventive strategies are therefore investigated in animal models. We discuss in this review the aspects of human BPD pathophysiology and phenotype, which ideally should be mimicked by an animal model for this disease. Prematurity remains the common denominator in the heterogeneous spectrum of human BPD, and preterm animal models thus have a clear translational advantage. Additional factors, like excessive oxygen, mechanical ventilation and infection, which frequently have been studied in animal models, can contribute to preterm lung injury however are not indispensable to develop BPD. The phenotype of human BPD is characterized by alveolar developmental arrest with extracellular matrix remodeling, signs of obstructive airway disease and pulmonary vascular disease. Many animal models mimic this phenotype and have their place in BPD research, but results should be interpreted bearing in mind the specific advantages and disadvantages of the model. Term mice and rats are well suited for basic explorative research on specific disease mechanisms, essential for the generation of new hypotheses, while the larger ventilated preterm baboons and lambs provide a good platform for the ultimate translation of these strategies towards clinical application. The preterm rabbit model seems a promising model as it the smallest model that includes a factor of prematurity and has a unique position between the small and large animal models.

Evidence for Role of Genital Mycoplasmas in Preterm Birth and Neonatal Lung Injury

Although the genital mycoplasmas are common commensals in the vaginal flora of up to 80% of women, these organisms have been associated with adverse perinatal outcomes. These outcomes include chorioamnionitis, preterm premature rupture of the membranes (pPROM), preterm birth, and altered lung development contributing to the development of bronchopulmonary dysplasia in preterm infants with respiratory infection. This review focuses on the current knowledge of the evidence supporting a causal role of these organisms in these adverse outcomes and controversies, including whether treatment of affected pregnant women or their infants is warranted.

Reactive Oxygen Species, Biomarkers of Microvascular Maturation and Alveolarization, and Antioxidants in Oxidative Lung Injury.

The lungs of extremely low gestational age neonates (ELGANs) are deficient in pulmonary surfactant and are incapable of efficient gas exchange necessary for successful transition from a hypoxic intrauterine environment to ambient air. To improve gas exchange and survival, ELGANs often receive supplemental oxygen with mechanical ventilation which disrupts normal lung developmental processes, including microvascular maturation and alveolarization. Factors that regulate these developmental processes include vascular endothelial growth factor and matrix metalloproteinases, both of which are influenced by generation of oxygen byproducts, or reactive oxygen species (ROS). ELGANs are also deficient in antioxidants necessary to scavenge excessive ROS. Thus, the accumulation of ROS in the preterm lungs exposed to prolonged hyperoxia, results in inflammation and development of bronchopulmonary dysplasia (BPD), a form of chronic lung disease (CLD). Despite advances in neonatal care, BPD/CLD remains a major cause of neonatal morbidity and mortality. The underlying mechanisms are not completely understood, and the benefits of current therapeutic interventions are limited. The association between ROS and biomarkers of microvascular maturation and alveolarization, as well as antioxidant therapies in the setting of hyperoxia-induced neonatal lung injury are reviewed in this article.

Extremely preterm fetal sheep lung responses to antenatal steroids and inflammation

The efficacy of antenatal steroids for fetal lung maturation in the periviable period is not fully understood. We sought to determine the lung maturational effects of antenatal steroids and inflammation in early gestation sheep fetuses, similar to the periviable period in human beings. Date-mated ewes with singleton fetuses were randomly assigned to 1 of 4 treatment groups (n= 8/group): (1) maternal intramuscular injection of betamethasone; (2) intraamniotic lipopolysaccharide; (3) betamethasone+ lipopolysaccharide; and (4) intraamniotic+ intramuscular saline (controls). Fetuses were delivered surgically 48 hours later at 94 days' gestation (63% term gestation) for comprehensive evaluations of lung maturation, and lung and systemic inflammation. Relative to controls, first, betamethasone increased the fetal lung air space to mesenchymal area ratio by 47% but did not increase the messenger RNAs for the surfactant proteins-B and -C that are important for surfactant function or increase the expression of pro-surfactant protein-C in the alveolar type II cells. Second, betamethasone increased expression of 1 of the 4 genes in surfactant lipid synthetic pathways. Third, betamethasone increased genes involved in epithelium sodium channel transport, but not sodium-potassium adenosine triphosphatase or Aquaporin 5. Fourth, lipopolysaccharide increased proinflammatory genes in the lung but did not effectively recruit activated inflammatory cells. Last, betamethasone incompletely suppressed lipopolysaccharide-induced lung inflammation. In the liver, betamethasone when given alone increased the expression of serum amyloid A3 and C-reactive protein messenger RNAs. Compared the more mature 125-day gestation sheep, antenatal steroids do not induce pulmonary surfactants during the periviable period, indicating a different response.

Pulmonary vascular changes in extremely preterm sheep after intra-amniotic exposure to Ureaplasma parvum and lipopolysaccharide.

BackgroundChorioamnionitis can induce pulmonary inflammation and promote bronchopulmonary dysplasia development, distinguished by alveolar simplification and impaired vascular growth. Chorioamnionitis is more common during the extremely preterm canalicular lung stage (crucial for vascular development); and increases the risk for subsequent sepsis. We hypothesized that single/combined exposure to chronic and/or acute inflammation induces pulmonary inflammatory responses and vascular changes.MethodsOvine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 24 days (d) before extreme preterm delivery at 94d (term 147d) and/or to lipopolysaccharide (LPS) 7 or 2d before delivery. Pulmonary inflammation, vascular remodeling and angiogenic factors were assessed.ResultsLPS exposure increased CD3-positive and myeloperoxidase-positive cells. Combined UP-LPS exposure increased pulmonary inflammation compared with 2d LPS or UP groups. The UP+2d LPS group had an increased adventitial fibrosis score when compared with UP-treated animals. A reduced wall-to-lumen ratio was found in the 7d LPS animals when compared to the 2d LPS-treated animals. Exposure to UP+2d LPS reduced VEGF and VEGFR-2 levels compared with 2d LPS-treated animals. Angiopoietin-1 (Ang1) and tunica interna endothelial cell kinase 2 (Tie-2) levels were decreased after UP+7d LPS as well as after 7d LPS, but not with UP alone.ConclusionChronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single hit-exposed animals.

Regional Volume Characteristics of the Preterm Infant Receiving First Intention Continuous Positive Airway Pressure

To determine whether applying nasal continuous positive airway pressure (CPAP) using systematic changes in continuous distending pressure (CDP) results in a quasi-static pressure-volume relationship in very preterm infants receiving first intention CPAP in the first 12-18 hours of life. Twenty infants at <32 weeks' gestation with mild respiratory distress syndrome (RDS) managed exclusively with nasal CPAP had CDP increased from 5 to 8 to 10 cmH2O, and then decreased to 8 cmH2O and returned to baseline CDP. Each CDP was maintained for 20 min. At each CDP, relative impedance change in end-expiratory thoracic volume (ΔZEEV) and tidal volume (ΔZVT) were measured using electrical impedance tomography. Esophageal pressure (Poes) was measured as a proxy for intrapleural pressure to determine transpulmonary pressure (Ptp). Overall, there was a relationship between Ptp and global ΔZEEV representing the pressure-volume relationship in the lungs. There were regional variations in ΔZEEV, with 13 infants exhibiting hysteresis with the greatest gains in EEV and tidal volume in the dependent lung with no hemodynamic compromise. Seven infants did not demonstrate hysteresis during decremental CDP changes. It was possible to define a pressure-volume relationship of the lung and demonstrate reversal of atelectasis by systematically manipulating CDP in most very preterm infants with mild RDS. This suggests that CDP manipulation can be used to optimize the volume state of the preterm lung.

Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs

Erythropoietin (EPO) is being trialed in preterm neonates for neuroprotection. We have recently demonstrated that a single high bolus dose (5,000 IU/kg) of recombinant human EPO amplified preterm lung and brain ventilation-induced injury. We aimed to determine the optimal dose of EPO to reduce ventilation-induced cerebral white matter inflammation and injury in preterm lambs. Lambs (0.85 gestation) were ventilated with an injurious strategy for 15 min followed by conventional ventilation for 105 min. Lambs were randomized to no treatment (VENT; n = 8) or received a bolus dose of EPO (EPREX®): 300 IU/kg (EPO 300; n = 5), 1,000 IU/kg (EPO 1,000; n = 5), or 3,000 IU/kg (EPO 3,000; n = 5). Physiological parameters were measured throughout the study. After 2 h, brains were collected for analysis; real-time quantitative polymerase chain reaction and immunohistochemistry were used to assess inflammation, cell death, and vascular leakage in the periventricular and subcortical white matter (PVWM; SCWM). Molecular and histological inflammatory indices in the PVWM were not different between groups. EPO 300 lambs had higher IL-6 (p = 0.006) and caspase-3 (p = 0.025) mRNA expression in the SCWM than VENT lambs. Blood-brain barrier (BBB) occludin mRNA levels were higher in EPO 3,000 lambs in the PVWM and SCWM than VENT lambs. The number of blood vessels with protein extravasation in the SCWM was lower in EPO 1,000 (p = 0.010) and EPO 3,000 (p = 0.025) lambs compared to VENT controls but not different between groups in the PVWM. Early administration of EPO at lower doses neither reduced nor exacerbated cerebral white matter inflammation or injury. 3,000 IU/kg EPO may provide neuroprotection by improving BBB integrity.

Quantitative Ultrasound Texture Analysis for Differentiating Preterm From Term Fetal Lungs.

To differentiate preterm (<37 weeks' gestation) from term (≥37 weeks' gestation) fetal lungs by using quantitative texture analysis of ultrasound images. This study retrospectively evaluated singleton gestations with valid dating at 20 weeks' gestational age (GA) or later between January 2015 and December 2015. Images were obtained from Voluson E8 ultrasound systems (GE Healthcare, Milwaukee, WI). A region of interest was selected in each fetal lung image at the level of the 4 heart chambers from an area that appeared most representative of the overall lung tissue and had the least shadow. Ultrasonic tissue heterogeneity (heterogeneity index) based on dynamic range calculation was determined for all lung images. This quantification was performed with a custom-made software program that used a dithering technique based on the Floyd-Steinberg algorithm, in which the pixels are transformed into a binary map. Regression analysis was used to determine the correlation and functional association between the heterogeneity index and GA. A receiver operating characteristic curve was used to identify the optimal heterogeneity index cutoff point for differentiating preterm from term fetal lungs. A total of 425 fetal lung ultrasound images (313 preterm and 112 term) were analyzed. Quantitative texture analysis predicted GA with sensitivity and specificity of 87.9% and 92.0%, respectively, based on the optimal receiver operating characteristic cutoff point. Quantitative ultrasound texture analysis of fetal lung tissue can differentiate preterm fetal lungs from term fetal lungs. Our data suggest that decreased fetal lung heterogeneity on ultrasound imaging is associated with preterm fetuses.

Nadph oxidase and epithelial sodium channels regulate neonatal mouse lung development

Background: Epithelial sodium channels (ENaC) play critically important roles in lung fluid clearance at birth. We have previously shown that Nadph oxidase (NOX)-derived reactive oxygen species signaling activates ENaC and promotes alveolar fluid clearance. In this study, we examined a new physiological role for NOX-mediated ENaC activity in mouse lung development. Methods: NOX isoform and ENaC subunit mRNA levels were evaluated in preterm and neonatal C57Bl6 mouse lung using real-time PCR analysis. Newborn mice were intra-nasally treated with 1 mM amiloride, 100 mM NSC 23766, or 300 mM apocynin during postnatal days 1–15 to study development. Lung development was assessed using hematoxylin and eosin (H&E) staining, coupled with radial alveolar counts (RAC) and mean linear intercept (MLI) measurements. Results: ENaC subunits and NOX1-4 mRNA were detected in mouse lung during late gestation, birth, and postnatally. Inhibition of Rac-1-mediated-NOX signaling indicates functional (Rac-dependent) NOX1-3 isoforms in newborn lung, determined by dihydroethidium (DHE) detection of reactive oxygen species production in postnatal (PN) day 7 mouse lung. Amiloride inhibition of ENaC activity, NSC 23766 inhibition of Rac1, and apocynin inhibition of pan NOX activity attenuated normal alveolar development in mouse lung. Conclusion: NOX and ENaC play important roles in mouse lung development.

Bronchopulmonary Dysplasia andUreaplasma: What Do We Know So Far?

Bronchopulmonary dysplasia (BPD) is the most common morbidity of prematurity. BPD is a chronic respiratory disease related to lung-injury during the primary course of critical lung disease such as respiratory distress syndrome or when abnormal development of the preterm lung occurs. Abnormal lung development not only results from primary lung injury in the first days after birth, but also secondary injury through abnormal repair resulting in arrested and abnormal alveolarization, fibrosis and pulmonary vascular dysgenesis. Chorioamnionitis is a risk factor that plays an important role in the development of BPD. Ureaplasma subspecies (spp.) are the most common isolated organisms from chorioamniotic tissue after premature births. Therefore Ureaplasma spp. appear to play an important role in the development of BPD, and treatment or prophylactic treatment of these infections or colonization may reduce the incidence, morbidity and mortality of BPD. Ureaplasma spp. infections are challenging not only to treat, but also to diagnosis in a timely manner. This review summarizes the current state of treatment and new developments in the treatment of Ureaplasma exposure in premature infants.

Anti-inflammatory effects of the new generation synthetic surfactant CHF5633 on Ureaplasma-induced cytokine responses in human monocytes

ABSTRACTBackground: Synthetic surfactants represent a promising alternative to animal-derived preparations in the treatment of neonatal respiratory distress syndrome. The synthetic surfactant CHF5633 has proven biophysical effectiveness and, moreover, demonstrated anti-inflammatory effects in LPS-stimulated monocytes. With ureaplasmas being relevant pathogens in preterm lung inflammation, the present study addressed immunomodulatory features on Ureaplasma-induced monocyte cytokine responses.Methods: Ureaplasma parvum-stimulated monocytes were exposed to CHF5633. TNF-α, IL-1β, IL-8, IL-10, TLR2 and TLR4 expression were analyzed using qPCR and flow cytometry.Results: CHF5633 did not induce pro-inflammation, and did not aggravate Ureaplasma-induced pro-inflammatory cytokine responses. It suppressed U. parvum-induced intracellular TNF-α (p < 0.05) and IL-1β (p < 0.05) in neonatal monocytes and inhibited Ureaplasma-induced TNF-α mRNA (p < 0.05), TNF-α protein (p < 0.001), and IL-1β (p = 0.05) in adult monocytes. Ureaplasma-modulated IL-8, IL-10, TLR2 and TLR4 were unaffected.Conclusion: CHF5633 does neither act pro-apoptotic nor pro-inflammatory in native and Ureaplasma-infected monocytes. Suppression of Ureaplasma-induced TNF-α and IL-1β underlines anti-inflammatory features of CHF5633.

Progressive Vascular Functional and Structural Damage in a Bronchopulmonary Dysplasia Model in Preterm Rabbits Exposed to Hyperoxia.

Bronchopulmonary dysplasia (BPD) is caused by preterm neonatal lung injury and results in oxygen dependency and pulmonary hypertension. Current clinical management fails to reduce the incidence of BPD, which calls for novel therapies. Fetal rabbits have a lung development that mimics humans and can be used as a translational model to test novel treatment options. In preterm rabbits, exposure to hyperoxia leads to parenchymal changes, yet vascular damage has not been studied in this model. In this study we document the early functional and structural changes of the lung vasculature in preterm rabbits that are induced by hyperoxia after birth. Pulmonary artery Doppler measurements, micro-CT barium angiograms and media thickness of peripheral pulmonary arteries were affected after seven days of hyperoxia when compared to controls. The parenchyma was also affected both at the functional and structural level. Lung function testing showed higher tissue resistance and elastance, with a decreased lung compliance and lung capacity. Histologically hyperoxia leads to fewer and larger alveoli with thicker walls, less developed distal airways and more inflammation than normoxia. In conclusion, we show that the rabbit model develops pulmonary hypertension and developmental lung arrest after preterm lung injury, which parallel the early changes in human BPD. Thus it enables the testing of pharmaceutical agents that target the cardiovascular compartment of the lung for further translation towards the clinic.

Efficacy of a new technique - INtubate-RECruit-SURfactant-Extubate - "IN-REC-SUR-E" - in preterm neonates with respiratory distress syndrome: study protocol for a randomized controlled trial.

BackgroundAlthough beneficial in clinical practice, the INtubate-SURfactant-Extubate (IN-SUR-E) method is not successful in all preterm neonates with respiratory distress syndrome, with a reported failure rate ranging from 19 to 69 %. One of the possible mechanisms responsible for the unsuccessful IN-SUR-E method, requiring subsequent re-intubation and mechanical ventilation, is the inability of the preterm lung to achieve and maintain an “optimal” functional residual capacity. The importance of lung recruitment before surfactant administration has been demonstrated in animal studies showing that recruitment leads to a more homogeneous surfactant distribution within the lungs. Therefore, the aim of this study is to compare the application of a recruitment maneuver using the high-frequency oscillatory ventilation (HFOV) modality just before the surfactant administration followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate: IN-REC-SUR-E) with IN-SUR-E alone in spontaneously breathing preterm infants requiring nasal continuous positive airway pressure (nCPAP) as initial respiratory support and reaching pre-defined CPAP failure criteria.Methods/designIn this study, 206 spontaneously breathing infants born at 24+0–27+6 weeks’ gestation and failing nCPAP during the first 24 h of life, will be randomized to receive an HFOV recruitment maneuver (IN-REC-SUR-E) or no recruitment maneuver (IN-SUR-E) just prior to surfactant administration followed by prompt extubation. The primary outcome is the need for mechanical ventilation within the first 3 days of life. Infants in both groups will be considered to have reached the primary outcome when they are not extubated within 30 min after surfactant administration or when they meet the nCPAP failure criteria after extubation.DiscussionFrom all available data no definitive evidence exists about a positive effect of recruitment before surfactant instillation, but a rationale exists for testing the following hypothesis: a lung recruitment maneuver performed with a step-by-step Continuous Distending Pressure increase during High-Frequency Oscillatory Ventilation (and not with a sustained inflation) could have a positive effects in terms of improved surfactant distribution and consequent its major efficacy in preterm newborns with respiratory distress syndrome. This represents our challenge.Trial registrationClinicalTrials.gov identifier: NCT02482766. Registered on 1 June 2015.