Extracellular Vesicle ASC: A Novel Mediator for Lung-Brain Axis in Preterm Brain Injury.

Bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI) are among the most common morbidities affecting preterm infants. Although BPD is a predictor of poor NDI, it is currently uncertain how BPD contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are involved in inter-organ communication in diverse pathological processes. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is pivotal in inflammasome assembly and activation of inflammatory response. We assessed expression profiles of alveolar macrophage (AM) markers, CD11b, CD11c, and CD206, and ASC in EVs isolated from the plasma of preterm infants at risk for BPD at 1 week of age. We found that infants on higher fraction inspired oxygen (FiO2) therapy (HO2, ≥30%) had increased levels of AM-derived EV-ASC compared with infants on lower FiO2 (LO2, <30%). To assess the function of these EVs, we performed adoptive transfer experiments by injecting them into the circulation of newborn mice. We discovered that mice that received EVs from infants on HO2 had increased lung inflammation, decreased alveolarization, and disrupted vascular development, the hallmarks of BPD. Importantly, these EVs crossed the blood-brain barrier and the EVs from infants on HO2 caused inflammation, reduced cell survival, and increased cell death with features of pyroptosis and necroptosis in the hippocampus. These results highlight a novel role for AM-derived EV-ASC in mediating the lung-to-brain crosstalk that is critical in the pathogenesis of BPD and brain injury and identify potential novel targets for preventing and treating BPD and brain injury in preterm infants.

Cardiorespiratory Monitoring Data to Predict Respiratory Outcomes in Extremely Preterm Infants.

Rationale: Immature control of breathing is associated with apnea, periodic breathing, intermittent hypoxemia, and bradycardia in extremely preterm infants. However, it is not clear if such events independently predict worse respiratory outcome. Objectives: To determine if analysis of cardiorespiratory monitoring data can predict unfavorable respiratory outcomes at 40 weeks postmenstrual age (PMA) and other outcomes, such as bronchopulmonary dysplasia at 36 weeks PMA. Methods: The Prematurity-related Ventilatory Control (Pre-Vent) study was an observational multicenter prospective cohort study including infants born at <29 weeks of gestation with continuous cardiorespiratory monitoring. The primary outcome was either "favorable" (alive and previously discharged or inpatient and off respiratory medications/O2/support at 40 wk PMA) or "unfavorable" (either deceased or inpatient/previously discharged on respiratory medications/O2/support at 40 wk PMA). Measurements and Main Results: A total of 717 infants were evaluated (median birth weight, 850 g; gestation, 26.4 wk), 53.7% of whom had a favorable outcome and 46.3% of whom had an unfavorable outcome. Physiologic data predicted unfavorable outcome, with accuracy improving with advancing age (area under the curve, 0.79 at Day 7, 0.85 at Day 28 and 32 wk PMA). The physiologic variable that contributed most to prediction was intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <90%. Models with clinical data alone or combining physiologic and clinical data also had good accuracy, with areas under the curve of 0.84-0.85 at Days 7 and 14 and 0.86-0.88 at Day 28 and 32 weeks PMA. Intermittent hypoxemia with oxygen saturation as measured by pulse oximetry <80% was the major physiologic predictor of severe bronchopulmonary dysplasia and death or mechanical ventilation at 40 weeks PMA. Conclusions: Physiologic data are independently associated with unfavorable respiratory outcome in extremely preterm infants.

Changes in Patent Ductus Arteriosus Treatment Strategy and Respiratory Outcomes in Premature Infants.

OBJECTIVE: To evaluate whether change in patent ductus arteriosus (PDA) management strategies over time had an impact on respiratory outcomes in premature infants. STUDY DESIGN: Prospectively collected data were included from all preterm infants born at 23-30 weeks gestational age with PDA admitted to the Children's Hospital of the University of Miami/Jackson Memorial Medical Center from January 1, 2005 to December 31, 2007 (epoch 1) and January 1, 2011 to December 31, 2015 (epoch 2). The 2 epochs were compared for approach with PDA diagnosis and subsequent management strategies and respiratory outcomes. RESULTS: Significantly fewer infants were treated for PDA in epoch 2 (54%) compared with epoch 1 (90%). Multivariable logistic regression analysis demonstrated that infants in epoch 2, with later PDA diagnosis and less frequent PDA treatment, had greater odds of bronchopulmonary dysplasia (BPD), composite of BPD or death, and more treatment with postnatal steroids than in epoch 1. CONCLUSIONS: The change in approach to diagnosis and management of PDA, from a more proactive and aggressive approach during the earlier epoch 1 to a more expectant approach during the subsequent epoch 2, was associated with worse respiratory outcomes, including increase in BPD and in BPD or death.

Pre-Vent: the prematurity-related ventilatory control study.

BACKGROUND: The increasing incidence of bronchopulmonary dysplasia in premature babies may be due in part to immature ventilatory control, contributing to hypoxemia. The latter responds to ventilation and/or oxygen therapy, treatments associated with adverse sequelae. This is an overview of the Prematurity-Related Ventilatory Control Study which aims to analyze the under-utilized cardiorespiratory continuous waveform monitoring data to delineate mechanisms of immature ventilatory control in preterm infants and identify predictive markers. METHODS: Continuous ECG, heart rate, respiratory, and oxygen saturation data will be collected throughout the NICU stay in 500 infants < 29 wks gestation across 5 centers. Mild permissive hypercapnia, and hyperoxia and/or hypoxia assessments will be conducted in a subcohort of infants along with inpatient questionnaires, urine, serum, and DNA samples. RESULTS: Primary outcomes will be respiratory status at 40 wks and quantitative measures of immature breathing plotted on a standard curve for infants matched at 36-37 wks. Physiologic and/or biologic determinants will be collected to enhance the predictive model linking ventilatory control to outcomes. CONCLUSIONS: By incorporating bedside monitoring variables along with biomarkers that predict respiratory outcomes we aim to elucidate individualized cardiopulmonary phenotypes and mechanisms of ventilatory control contributing to adverse respiratory outcomes in premature infants.

Maternal preeclampsia and respiratory outcomes in extremely premature infants.

BACKGROUND: Preeclampsia (PE) is a pregnancy complication characterized by an anti-angiogenic environment. This can affect fetal pulmonary vascular and alveolar development but data of the impact of PE on respiratory outcome in extremely premature infants are inconclusive. The objective of this study was to determine if PE is associated with an increased risk for severe respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in extremely premature infants. METHODS: Prospectively collected single center data from a cohort of infants born at 23-28 w gestational age between January 2005 and December 2015 were analyzed. Logistic regression analysis and generalized estimating equations were used to model the association between PE and severe RDS (≥30% supplemental oxygen on d1), BPD and severe BPD [supplemental oxygen and ≥30% oxygen at 36 w postmenstrual age (PMA), respectively]. RESULTS: The cohort included 1218 infants of whom 23% were exposed to PE. PE was associated with increased risk for severe RDS as well as severe BPD among infants alive at 36w PMA. CONCLUSION: Exposure to preeclampsia is independently associated with an increased risk for severe RDS and adverse respiratory outcome in extreme premature infants. The mechanisms behind these associations need to be investigated.

The Impact of Late Onset Arterial Hypotension on Respiratory Outcome in Extremely Premature Infants.

BACKGROUND: In extremely premature infants, arterial hypotension in the first days after birth has been associated with an increased risk for bronchopulmonary dysplasia (BPD). Some infants present with hypotension at a later postnatal age, but the relationship between late onset hypotension (LOH) and BPD has not been evaluated. OBJECTIVE: To evaluate the association between LOH and BPD and to identify pre- and postnatal factors associated with LOH. METHODS: Prospectively collected data from a cohort of 23-28 weeks gestational age (GA) infants born during years 2005-2015 and alive at day 28 were analyzed. LOH was defined as the receipt of vasopressor treatment during days 8-28. BPD was defined as need for oxygen at 36 weeks postmenstrual age. Late mortality was defined as death after day 28. RESULTS: Of 1,058 infants in the cohort, 90 (9%) had LOH during days 8-28. Infants with LOH had a higher incidence of BPD than normotensive infants (55 vs. 21%, p < 0.001). Multivariate logistic regression analysis (LRA) showed that LOH was associated with an increased risk for BPD (OR 1.87, 95% CI 1.10-3.17). LOH was also associated with an increased risk for late mortality. LRA showed the risk for LOH increased with lower GA, sepsis and patent ductus arteriosus during days 8-28. CONCLUSIONS: In this cohort of extremely premature infants, LOH was associated with an increased the risk for BPD. This association could be secondary to underlying factors that predispose to LOH and BPD or to the deleterious effects of LOH or its treatments on the lung. Further investigation is needed to assess causality.

A randomized controlled trial of two nasal continuous positive airway pressure levels after extubation in preterm infants.

OBJECTIVE: To compare extubation failure rate with two ranges of nasal continuous positive airway pressure (NCPAP) in oxygen dependent preterm infants. STUDY DESIGN: Preterm infants of birth weight 500-1000 g and gestational age 23-30 weeks, extubated for the first time during the first 6 weeks while requiring fraction of inspired oxygen ≥ 0.25, were randomly assigned to a NCPAP range of 4-6 (low NCPAP) or 7-9 (high NCPAP) cmH2O. RESULTS: Infants were randomized to low (n = 47) or high NCPAP (n = 46) at day 16.3 ± 14.7 and 15.5 ± 12.4, respectively. Rates of extubation failure per criteria (24% vs 43%, P = .04, OR and 95% CI: 0.39 [0.16-0.96]) and re-intubation (17% vs 38%, P = .023, 0.33 [0.016-0.85]) within 96 hours were significantly lower in the high- compared with the low NCPAP group. This was mainly due to a strikingly lower failure rate in the 500-750 g birth weight strata. Duration of ventilation, bronchopulmonary dysplasia, or severe bronchopulmonary dysplasia did not differ significantly. No infant developed pneumothorax during 96 hours post-extubation. CONCLUSIONS: Extubation failure in preterm infants with residual lung disease was lower with NCPAP range of 7-9 compared with 4-6 cmH2O. These findings suggest the need for higher distending pressure post-extubation in the more immature infants who are still oxygen dependent.

Methods and evidence on volume-targeted ventilation in preterm infants.

PURPOSE OF REVIEW: Several modalities of volume-targeted ventilation have been developed for the premature infant or were adopted from those used in older populations. The article describes these modalities, their clinical application in preterm infants and reviews the evidence for the possible beneficial effects in this population. RECENT FINDINGS: Evidence from physiologic studies indicates increased stability of tidal volume and gas exchange while requiring less ventilatory support. Randomized trials of volume-targeted ventilation indicate faster weaning and shorter duration of mechanical ventilation, but this has not resulted in better respiratory outcome. SUMMARY: The proposed benefits of volume-targeted ventilation on respiratory outcome have not been fully confirmed by the existing data. Some trends suggest possible benefits, but these need to be further explored. The efficacy of volume-targeted ventilation may be method dependent and may also be influenced by the magnitude of the volume targeted.

Definitions and diagnostic criteria for bronchopulmonary dysplasia.

The changes in clinical presentation of bronchopulmonary dysplasia (BPD) in recent years have made many of the original definitions of BPD obsolete. The use of supplemental oxygen as a criterion for BPD diagnosis has many limitations. Supplemental oxygen is necessary to treat these infants, but at the same time it plays an important role in the pathogenesis of BPD. Because there are no accepted standards for supplemental oxygen administration, there are wide variations for its indications among different centers and this has a marked effect on the reported incidence of BPD. For this reason, it is essential to standardize the indications for supplemental oxygen when duration of oxygen therapy is used as the main criteria to diagnose BPD. Using supplemental oxygen need at specific time points does not necessarily reflect chronic lung damage and should be avoided as a single diagnostic criterion for BPD. A prolonged duration of supplemental oxygen is necessary to demonstrate the presence of chronic lung damage. The criteria based on supplemental oxygen at 36 weeks postmenstrual age has gained wide acceptance, but it is a less stringent criterion for the more mature infants. The longer the gestation, the shorter the time on oxygen that is required to meet this BPD criterion. None of the proposed criteria based on duration of oxygen therapy have shown a strong predictive value for long-term outcome. In view of all these shortcomings, it is essential to develop more objective physiologic tools to define the degree of lung damage and improve the prediction for long-term outcome in these infants.

Patent ductus arteriosus and respiratory outcome in premature infants.

A persistent ductus arteriosus is a common event in preterm infants. The systemic-to-pulmonary shunting that occurs as the pulmonary vascular resistance decreases after birth can have significant cardiovascular and respiratory consequences. Acute pulmonary effects include pulmonary edema and hemorrhage, worsened lung mechanics and deterioration in gas exchange with hypoxemia and hypercapnia. The increased pulmonary blood flow can also produce damage to the capillary endothelium and trigger an inflammatory cascade. This, plus the need for longer and more aggressive mechanical ventilation, can explain the association between patent ductus arteriosus and an increased risk for bronchopulmonary dysplasia in extremely premature infants.

The association between early tracheal colonization and bronchopulmonary dysplasia.

OBJECTIVE: To evaluate the relationship between early tracheal colonization and bronchopulmonary dysplasia (BPD). STUDY DESIGN: This is a retrospective cohort study which included 308 inborn neonates admitted to the newborn intensive care unit at the University of Miami Jackson Memorial Medical Center between January 1997 and December 2000 with birthweight 500 to 1000 g, who required mechanical ventilation on the first day of life. Chorioamnionitis was diagnosed by maternal symptoms and histopathopathology. Tracheal cultures were obtained immediately after tracheal intubation. BPD was diagnosed in neonates who had supplemental oxygen requirement for more than 28 days. Pearson's chi(2) and Logistic Regression Analysis were used to evaluate the relationship between chorioamnionitis, positive initial tracheal cultures and BPD, after adjusting for confounding variables. RESULTS: In patients with chorioamnionitis, the incidence of early positive tracheal cultures was 41% compared to 16% in those without chorioamnionitis, (p < 0.00001). In patients with birthweight 700 to 1000 g, a positive early tracheal culture increased the risk of BPD (OR = 2.42, CI 1.05 to 5.62, p < 0.05). CONCLUSION: Preterm infants exposed to chorioamnionitis have an increased incidence of early tracheal colonization. This early tracheal colonization may predispose them to develop BPD.

Acute effects of inhaled nitric oxide on pulmonary and cardiac function in preterm infants with evolving bronchopulmonary dysplasia.

BACKGROUND: Inhaled nitric oxide (iNO) reduces pulmonary vascular resistance by preferential vasodilation in ventilated lung units. In experimental animals, iNO also reduces airway resistance by smooth muscle relaxation. Hence, there may be a therapeutic role for iNO in evolving bronchopulmonary dysplasia (BPD). OBJECTIVE: To evaluate the acute effects of low-dose iNO on lung mechanics, ventilation distribution, oxygenation, and cardiac function in preterm infants with evolving BPD. METHODS: Measurements of lung compliance (C(L)), airway resistance (R(L)), ventilation-distribution (N(2) clearance in multiple-breath washout), oxygenation (SpO(2)), left ventricular ejection fraction (LVEF) and right ventricular shortening fraction were obtained before and during 2 hours of iNO (10 ppm) in a group of ventilated preterm infants with evolving BPD. RESULTS: A total of 13 preterm infants with (mean+/-SD) BW: 663.8+/-116 g, GA: 24.9+/-1.2 weeks, age: 32+/-14 days, mean airway pressure: 6.7+/-0.9 cmH(2)O and fraction of inspired oxygen: 0.35+/-0.06 were studied. iNO did not affect C(L), R(L) or N(2) clearance. There was a small increase in LVEF. Mean SpO(2) remained unchanged, but the duration of spontaneous hypoxemic episodes increased during iNO. CONCLUSION: Low-dose iNO had no acute effects on lung function, cardiac function and oxygenation in evolving BPD.

Bronchopulmonary dysplasia: changes in pathogenesis, epidemiology and definition.

Bronchopulmonary dysplasia (BPD) continues to be one of the most common long-term complications associated with preterm birth. Its incidence is increasing as the survival of extreme premature infants improves, but its clinical presentation is milder than the original description of Northway and collaborators. In contrast to the classic BPD that was strongly related to mechanical injury and oxygen toxicity, current forms of the condition are more related to immaturity, perinatal infection and inflammation, persistent ductus arteriosus and disrupted alveolar and capillary development. Many different definitions of BPD have been proposed, most of which are based on the duration of supplemental oxygen requirement. The different definitions can produce strikingly different incidence figures, which may account for the wide variations in the condition reported in the literature. Some of the limitations of the criteria most commonly used to diagnose BPD are discussed in this article.