Megan O'Reilly

Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis

Objective To assess the role of nasal continuous positive airway pressure (CPAP) initiated at birth for prevention of death and bronchopulmonary dysplasia in very preterm infants. Design Systematic review. Data sources PubMed, Embase, the Cochrane Central Register of Controlled Trials, and online Pediatric Academic Society abstracts from the year of inception to June 2013. Eligibility criteria for selecting studies Randomised controlled trials evaluating the effect of nasal CPAP compared with intubation in preterm infants born at less than 32 weeks’ gestation and presenting the outcomes of either death or bronchopulmonary dysplasia, or both (defined as the need for oxygen support or mechanical ventilation at 36 weeks corrected gestation), during hospital stay. Results Four randomised controlled trials (2782 participants) met the inclusion criteria, with 1296 infants in the nasal CPAP group and 1486 in the intubation group. All the trials reported bronchopulmonary dysplasia independently at 36 weeks corrected gestation, with borderline significance in favour of the nasal CPAP group (relative risk 0.91, 95% confidence interval 0.82 to 1.01, risk difference −0.03, 95% confidence interval −0.07 to 0.01). No difference in death was observed (relative risk 0.88, 0.68 to 1.14, risk difference −0.02, −0.04 to 0.01, respectively). Pooled analysis showed a significant benefit for the combined outcome of death or bronchopulmonary dysplasia, or both, at 36 weeks corrected gestation for babies treated with nasal CPAP (relative risk 0.91, 0.84 to 0.99, risk difference −0.04, -0.07 to 0.00), number needed to treat of 25). Conclusion One additional infant could survive to 36 weeks without bronchopulmonary dysplasia for every 25 babies treated with nasal CPAP in the delivery room rather than being intubated.

Animal models of bronchopulmonary dysplasia. The term rat models

Bronchopulmonary dysplasia (BPD) is the chronic lung disease of prematurity that affects very preterm infants. Although advances in perinatal care have enabled the survival of infants born as early as 23-24 wk of gestation, the challenge of promoting lung growth while protecting the ever more immature lung from injury is now bigger. Consequently, BPD remains one of the most common complications of extreme prematurity and still lacks specific treatments. Progress in our understanding of BPD and the potential of developing therapeutic strategies have arisen from large (baboons, sheep, and pigs) and small (rabbits, rats, and mice) animal models. This review focuses specifically on the use of the rat to model BPD and summarizes how the model is used in various research studies and the advantages and limitations of this particular model, and it highlights recent therapeutic advances in BPD by using this rat model.

Sustained inflation versus positive pressure ventilation at birth: a systematic review and meta-analysis

Context Sustained inflation (SI) has been advocated as an alternative to intermittent positive pressure ventilation (IPPV) during the resuscitation of neonates at birth, to facilitate the early development of an effective functional residual capacity, reduce atelectotrauma and improve oxygenation after the birth of preterm infants. Objective The primary aim was to review the available literature on the use of SI compared with IPPV at birth in preterm infants for major neonatal outcomes, including bronchopulmonary dysplasia (BPD) and death. Data source MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials, until 6 October 2014. Study selection Randomised clinical trials comparing the effects of SI with IPPV at birth in preterm infants for neonatal outcomes. Data extraction and synthesis Descriptive and quantitative information was extracted; data were pooled using a random effects model. Heterogeneity was assessed using the Q statistic and I2. Results Pooled analysis showed significant reduction in the need for mechanical ventilation within 72 h after birth (relative risk (RR) 0.87 (0.77 to 0.97), absolute risk reduction (ARR) −0.10 (−0.17 to −0.03), number needed to treat 10) in preterm infants treated with an initial SI compared with IPPV. However, significantly more infants treated with SI received treatment for patent ductus arteriosus (RR 1.27 (1.05 to 1.54), ARR 0.10 (0.03 to 0.16), number needed to harm 10). There were no differences in BPD, death at the latest follow-up and the combined outcome of death or BPD among survivors between the groups. Conclusions Compared with IPPV, preterm infants initially treated with SI at birth required less mechanical ventilation with no improvement in the rate of BPD and/or death. The use of SI should be restricted to randomised trials until future studies demonstrate the efficacy and safety of this lung aeration manoeuvre.

Impact of preterm birth and bronchopulmonary dysplasia on the developing lung: Long-term consequences for respiratory health

Preterm birth affects 8–10% of human pregnancies and is a major cause of long‐term disability. Individuals who are born very preterm, especially if they develop bronchopulmonary dysplasia (BPD), have an increased risk of impaired lung function in infancy, childhood and adulthood, as well as an increased risk of respiratory illness. Our aim is to briefly review current understanding of the basis for long‐term impairments in lung function and respiratory health following preterm birth and BPD. Histopathology of the lungs of infants and children following preterm birth and BPD shows altered development of the lung parenchyma, conducting airways and pulmonary vasculature. Owing to improvements in the care of preterm infants, especially the use of exogenous surfactant and lower concentrations of administered oxygen, lung pathology following preterm birth and BPD is less severe than in the past. Recent studies indicate that very preterm birth and BPD can lead to hyperplasia of airway smooth muscle, impaired alveolarization, pulmonary inflammation and an increase in pulmonary artery muscularization. Imaging of adult lungs suggests that the deficit in alveoli can persist into later life. Long‐term lung injury apparently relates to the use of mechanical ventilation and the use of supplemental oxygen in infancy. Impaired lung function in later life is due to airway hyper‐reactivity and fewer alveoli, resulting in reductions in the surface area for gas exchange and physical support for bronchioles. Because the incidence of preterm birth is not declining, it will continue to be a major cause of respiratory ill‐health in adults.

Persistent bronchiolar remodeling following brief ventilation of the very immature ovine lung

Children and adults who were mechanically ventilated following preterm birth are at increased risk of reduced lung function, suggesting small airway dysfunction. We hypothesized that short periods of mechanical ventilation of very immature lungs can induce persistent bronchiolar remodeling that may adversely affect later lung function. Our objectives were to characterize the effects of brief, positive-pressure ventilation per se on the small airways in very immature, surfactant-deficient lungs and to determine whether the effects persist after the cessation of ventilation. Fetal sheep (0.75 of term) were mechanically ventilated in utero with room air (peak inspiratory pressure 40 cmH2O, positive end-expiratory pressure 4 cmH2O, 65 breaths/min) for 6 or 12 h, after which tissues were collected; another group was studied 7 days after 12-h ventilation. Age-matched unventilated fetuses were controls. The mean basement membrane perimeter of airways analyzed was 548.6+/-8.5 microm and was not different between groups. Immediately after ventilation, 21% of airways had epithelial injury; in airways with intact epithelium, there was more airway smooth muscle (ASM) and less collagen, and the epithelium contained more mucin-containing and apoptotic cells and fewer proliferating cells. Seven days after ventilation, epithelial injury was absent but the epithelium was thicker, with greater cell turnover; there were increased amounts of bronchiolar collagen and ASM and fewer alveolar attachments. The increase in ASM was likely due to cellular hypertrophy rather than hyperplasia. We conclude that brief mechanical ventilation of the very immature lung induces remodeling of the bronchiolar epithelium and walls that lasts for at least 7 days; such changes could contribute to later airway dysfunction.

Altered Small Airways in Aged Mice following Neonatal Exposure to Hyperoxic Gas

Background: Supplemental oxygen is necessary in the respiratory support of very preterm infants, but it may contribute to bronchopulmonary dysplasia and an increased risk of poor lung function in later life. It is well established that hyperoxia can inhibit alveolarization, but effects on the developing conducting airways, which are important determinants of lung function, are poorly understood. It is possible that prolonged exposure of the immature lung to hyperoxic gas alters the development of small conducting airways (bronchioles), and that these effects may persist throughout life. Objectives: To examine the effects of neonatal inhalation of hyperoxic gas on the bronchiolar walls in adulthood. Methods: Neonatal mice (C57BL/6J) born at term inhaled 65% O2 from birth until postnatal day 7; thereafter, they were raised in room air until 10 months postnatal age (P10mo), which is advanced adulthood. Age-matched controls inhaled room air from birth. We investigated small conducting airways with a diameter between 105-310 µm. Results: At P10mo, bronchiolar walls of hyperoxia-exposed mice contained ∼18% more smooth muscle than controls (p < 0.05), although there was no effect on bronchiolar epithelium or collagen. Neonatal hyperoxia resulted in significantly fewer bronchiolar-alveolar attachments at P10mo (p < 0.05); this was accompanied by persistent simplification of the lung parenchyma, as indicated by greater mean linear intercept and less parenchymal tissue (p < 0.05). Conclusions: Neonatal exposure to hyperoxia induces remodeling of the bronchiolar walls and loss of bronchiolar-alveolar attachments in adulthood, both of which could contribute to impaired lung function and airway hyper-reactivity.

Exhaled carbon dioxide can be used to guide respiratory support in the delivery room

Respiratory support in the delivery room remains challenging. Assessing chest rise is imprecise, and mask leak and airway obstruction are common problems. We describe recordings of respiratory signals during delivery room resuscitations and discuss guidance on positive‐pressure ventilation using respiratory parameters and exhaled carbon dioxide (ECO2) during neonatal resuscitations.

The promise of stem cells in bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity, which affects very preterm infants. Advances in perinatal care have enabled the survival of infants born as early as 23-24 weeks of gestation, but make the task more challenging of protecting injury to an ever more immature lung. Currently, there is no specific treatment for BPD. Recent advances in our understanding of stem/progenitor cells and their potential to repair damaged organs offer the possibility of cell-based treatments for neonatal lung injury. This review summarizes the recent advances in our understanding of lung stem cells during normal and impaired lung growth and the exciting pre-clinical data using mesenchymal stromal cells to prevent/repair impaired alveolar growth in experimental models of BPD.

Cell-Based Strategies to Reconstitute Lung Function in Infants with Severe Bronchopulmonary Dysplasia

Recent advances in our understanding of stem/progenitor cells and their potential to repair damaged organs offer the possibility of cell-based treatments for neonatal lung injury. This review summarizes basic concepts of stem/progenitor cell biology and discusses the recent advances and challenges of cell-based therapies for lung diseases, with a particular focus on bronchopulmonary dysplasia (BPD), a form of chronic lung disease that primarily affects very preterm infants. Despite advances in perinatal care, BPD still remains the most common complication of extreme prematurity, and there is no specific treatment.

Bronchiolar remodeling in adult mice following neonatal exposure to hyperoxia: relation to growth

Preterm infants who receive supplemental oxygen for prolonged periods are at increased risk of impaired lung function later in life. This suggests that neonatal hyperoxia induces persistent changes in small conducting airways (bronchioles). Although the effects of neonatal hyperoxia on alveolarization are well documented, little is known about its effects on developing bronchioles. We hypothesized that neonatal hyperoxia would remodel the bronchiolar walls, contributing to altered lung function in adulthood. We studied three groups of mice (C57BL/6J) to postnatal day 56 (P56; adulthood) when they either underwent lung function testing or necropsy for histological analysis of the bronchiolar wall. One group inhaled 65% O2 from birth until P7, after which they breathed room air; this group experienced growth restriction (HE+GR group). We also used a group in which hyperoxia‐induced GR was prevented by dam rotation (HE group). A control group inhaled room air from birth. At P56, the bronchiolar epithelium of HE mice contained fewer Clara cells and more ciliated cells, and the bronchiolar wall contained ∼25% less collagen than controls; in HE+GR mice the bronchiolar walls had ∼13% more collagen than controls. Male HE and HE+GR mice had significantly thicker bronchiolar epithelium than control males and altered lung function (HE males: greater dynamic compliance; HE+GR males: lower dynamic compliance). We conclude that neonatal hyperoxia remodels the bronchiolar wall and, in adult males, affects lung function, but effects are altered by concomitant growth restriction. Our findings may partly explain the reports of poor lung function in ex‐preterm children and adults. Anat Rec, 297:758–769, 2014.