Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension: Basing Care on Physiology.

Bronchopulmonary dysplasia (BPD) is the heterogeneous chronic lung developmental disease of prematurity, which is often accompanied by multisystem comorbidities. Pulmonary vascular disease and pulmonary hypertension (PH) contribute significantly to the pathogenesis and pathophysiology of BPD and dramatically influence the outcomes of preterm infants with BPD. When caring for those patients, clinicians should consider the multitude of phenotypic presentations that fall under the "BPD-PH umbrella," reflecting the need for matching therapies to specific physiologies to improve short- and long-term outcomes. Individualized management based on the patient's prenatal and postnatal risk factors, clinical course, and cardiopulmonary phenotype needs to be identified and prioritized to provide optimal care for infants with BPD-PH.

Brain Network Characterization of Preterm Infants With Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) affects the microstructure of white matter in preterm infants, but its influence on the changes of the brain structural network has not been elaborated. This study aims to investigate the connectivity characteristics of the brain structural network of BPD by using diffusion tensor imaging. METHODS: Thirty-three infants with BPD and 26 infants without BPD were enrolled in this study. Brain structural networks were constructed utilizing automated anatomic labeling mapping by tracing the fibers between each pair of regions in individual space. We calculated network metrics such as global efficiency, local efficiency, clustering coefficients, characteristic path length, and small-worldness. Then we compared the network metrics of these infants with those of 57 healthy term infants of comparable postmenstrual age at magnetic resonance imaging scan. Finally, network-based statistics was used to analyze the differences in brain network connectivity between the groups with and without BPD. RESULTS: Preterm infants with BPD had higher local efficiency and clustering coefficient, lower global efficiency, and longer characteristic path length. Also, preterm infants with BPD had decreased strength of limbic connections mainly in four brain regions: the left lingual gyrus, the left calcarine fissure and surrounding cortex, the right parahippocampal gyrus, and the left precuneus. CONCLUSIONS: Our findings suggest that preterm infants with BPD have lower network integration and higher segregation at term-equivalent age, which may reflect a compensatory mechanism. In addition, BPD affects brain regions involved in visual as well as cognitive functions; these findings provide a new approach to diagnose potential brain damage in preterm infants with BPD.

Respiratory and chest wall mechanics in very preterm infants.

Data on static compliance of the chest wall (Ccw) in preterm infants are scarce. We characterized the static compliance of the lung (CL) and Ccw to determine their relative contribution to static compliance of the respiratory system (Crs) in very preterm infants at 36 wk postmenstrual age (PMA). We also aimed to investigate how these compliances were influenced by the presence of bronchopulmonary dysplasia (BPD) and impacted breathing variables. Airway opening pressure, esophageal pressure, and tidal volume (VT) were measured simultaneously during a short apnea evoked by the Hering-Breuer reflex. We computed tidal breathing variables, airway resistance (R), and dynamic lung compliance (CL,dyn), inspiratory capacity (IC), and Crs, CL, and Ccw. Functional residual capacity was assessed by the multiple breath washout technique (FRCmbw). Breathing variables, compliances, and lung volumes were adjusted for body weight. Twenty-three preterm infants born at 27.2 ± 2.0 wk gestational age (GA) were studied at 36.6 ± 0.6 wk PMA. Median and interquartile range (IQR) Crs/kg is 0.69 (0.6), CL/kg 0.95 (1.0), and Ccw/kg 3.0 (2.4). Infants with BPD (n = 11) had lower Crs/kg (P = 0.013), CL/kg (P = 0.019), and Ccw/kg (P = 0.027) compared with infants without BPD. Ccw/CL ratio was equal between groups. FRCmbw/kg (P = 0.044) and IC/kg (P = 0.005) were decreased in infants with BPD. Infants with BPD have reduced static compliance of the respiratory system, the lungs, and chest wall. Decreased Crs, CL, and Ccw in infants with BPD explain the lower FRC and IC seen in these infants.NEW & NOTEWORTHY Data on chest wall compliance in very preterm infants in the postsurfactant era are scarce. To our knowledge, we are the first group to report data on static respiratory system compliance (Crs), lung compliance (CL), and chest wall compliance (Ccw) in preterm infants with and without bronchopulmonary dysplasia (BPD) in the postsurfactant era.

Relationships of Severity of Bronchopulmonary Dysplasia with Adverse Neurodevelopmental Outcomes and Poor Respiratory Function at 7-8 Years of Age.

OBJECTIVE: To clarify the relationships of 3 definitions of severity of bronchopulmonary dysplasia (BPD) with adverse neurodevelopmental and respiratory outcomes at early school-age. STUDY DESIGN: Participants comprised 218 consecutive survivors to 7-8 years of age born either <28 weeks' gestation or weighing <1000 g in Victoria, Australia, in 2005. BPD was classified as none, grade 1 (mild), grade 2 (moderate), or grade 3 (severe), using 2 commonly accepted definitions: 1) Jobe2001, and 2) Higgins2018, and our own 3) Victorian Infant Collaborative Study (VICS) 2005, adapted from Jensen2019. Outcomes included major neurodevelopmental disability, low IQ and academic achievement, poor motor function, and poor respiratory function as assessed by spirometry. Outcomes for children with each grade of BPD were compared with children with no BPD. RESULTS: Of the 218 survivors, 132 (61%) had BPD on Jobe2001 criteria, and 113 (52%) had BPD on both Higgins2018 and VICS2005 criteria. Grade 1 on any criteria was not associated with any adverse neurodevelopmental outcomes. Grade 1 on both Higgins2018 and VICS2005 was associated with reduced spirometry, grade 2 on both Higgins2018 and VICS2005, and grade 3 on all criteria were associated with increased risk for both adverse neurodevelopmental and respiratory outcomes. CONCLUSIONS: Compared with no BPD, receiving additional oxygen up to 29% but no positive pressure support at 36 weeks' postmenstrual age increased the risk of abnormal respiratory function but not adverse neurodevelopment. Receiving ≥30% oxygen or any positive pressure support at 36 weeks increased the risk of both adverse outcomes.

The emerging role of extracellular vesicles in bronchopulmonary dysplasia.

Extracellular vesicle (EV) biology in neonatal lung development and disease is a rapidly growing area of investigation. Although EV research in the neonatal population lags behind EV research in adult lung diseases, recent discoveries demonstrate promise in furthering our understanding of the pathophysiology of bronchopulmonary dysplasia and the potential use of EVs in the clinical setting, as both biomarkers and therapeutic agents. This review article explores some of the recent advances in this field and our evolving knowledge of the role of EVs in bronchopulmonary dysplasia.

Measurement of lung oxygenation by near-infrared spectroscopy in preterm infants with bronchopulmonary dysplasia.

INTRODUCTION: It has recently been reported that it is possible to monitor lung oxygenation (rSO2L) by near-infrared spectroscopy (NIRS) in preterm infants with respiratory distress syndrome (RDS). Thus, our aim was to assess the possibility of monitoring rSO2L in infants with evolving and established bronchopulmonary dysplasia (BPD) and to evaluate if rSO2L correlates with BPD severity and other oxygenation indices. METHODS: We studied 40 preterm infants with gestational age ≤30 weeks at risk for BPD. Patients were continuously studied for 2 h by NIRS at 28 ± 7 days of life and 36 weeks ± 7 days of postmenstrual age. RESULTS: rSO2L was similar at the first and second NIRS recordings (71.8 ± 7.2 vs. 71.4 ± 4.2%) in the overall population, but it was higher in infants with mild than in those with moderate-to-severe BPD at both the first (73.3 ± 3.1 vs. 71.2 ± 3.2%, p = .042) and second (72.3 ± 2.8 vs. 70.5 ± 2.8, p = .049) NIRS recording. A rSO2L cutoff value of 71.6% in the first recording was associated with a risk for moderate-to-severe BPD with a sensitivity of 66% and a specificity of 60%. Linear regression analysis demonstrated a significant positive relationship between rSO2L and SpO2/FiO2 ratio (p = .013) and a/APO2 (p = .004). CONCLUSIONS: Monitoring of rSO2L by NIRS in preterm infants with evolving and established BPD is feasible and safe. rSO2L was found to be higher in infants with mild BPD, and predicts the risk for developing moderate-to-severe BPD and correlates with other indices of oxygenation.

Blood pressure in preterm infants with bronchopulmonary dysplasia in the first three months of life.

BACKGROUND: Neonatal hypertension is common in preterm infants with bronchopulmonary dysplasia (BPD). Our study aimed to examine blood pressure variation in the first three months of life in preterm BPD patients. METHODS: We conducted a retrospective, single-centre study at the Neonatal Intensive Care Unit of the University of Szeged, Hungary. We collected blood pressure data from 26 preterm infants (born at < 30 weeks gestation) with moderate or severe BPD over three years (2019-2021). We calculated the BPD group's daily average blood pressure values and used previously defined normal blood pressure values from a preterm patient group born at < 30 weeks gestation as a reference. We used 19,481 systolic, diastolic and mean blood pressure measurement data separately to calculate daily average blood pressures. RESULTS: We found a statistically significant correlation between the blood pressure values of the BPD patient group and the reference data. The difference between the blood pressure curve of the group with BPD and that of the reference group was also statistically significant. We also analysed individual patients' daily average blood pressure values and found that 11 patients (42%) had hypertensive blood pressure values for three or more days within the first 90 days of life. Within this group, our statistical analysis showed a 25% chance of acute kidney injury. CONCLUSION: The blood pressure of the BPD group not only correlated with but also significantly differed from the reference data. Hypertension lasting three or more days occurred more frequently in patients with acute kidney injury accompanied by BPD.

Expiratory airflow limitation in adults born extremely preterm: A systematic review and meta-analysis.

Extreme preterm (EP) birth, denoting delivery before the onset of the third trimester, interrupts intrauterine development and causes significant early-life pulmonary trauma, thereby posing a lifelong risk to respiratory health. We conducted a systematic review and meta-analysis to investigate adult lung function following EP birth (gestational age <28 weeks); comparing forced expiratory volume in first second (FEV1), forced vital capacity (FVC), and FEV1/FVC to reference values. Subgroup differences were explored based on timing of birth relative to surfactant use (1991) and bronchopulmonary dysplasia (BPD) status. Systematic searches were performed in Medline, EMBASE, Web of Science and Cochrane Central. Quality assessments were carried out using a modified Newcastle-Ottawa Scale for cohort studies. Sixteen studies encompassing 1036 EP-born adults were included, with 14 studies (n = 787) reporting data as %predicted, and 11 (n = 879) as z-score (not mutually exclusive). Overall mean [95 % confidence interval (CI)] %FEV1 was 85.30 (82.51; 88.09), %FVC was 94.33 (91.74; 96.91), and FEV1/FVC was 79.54 (77.71 to 81.38), all three with high heterogeneity. Overall mean (95 %CI) zFEV1 was -1.05 (-1.21; -0.90) and zFVC was. -0.45 (-0.59; -0.31), both with moderate heterogeneity. Subgroup analyses revealed no difference in FEV1 before versus after widespread use of surfactant, but more impairments after neonatal BPD. This meta-analysis revealed significant airflow limitation in EP-born adults, mostly explained by those with neonatal BPD. FEV1 was more reduced than FVC, and FEV1/FVC was at the lower limit of normal. Although at a group level, most adult EP-born individuals do not meet COPD criteria, these findings are concerning.

Flow-resistive loading and diaphragmatic muscle function in term and preterm infants.

PURPOSE: We aimed to assess diaphragmatic function in term and preterm infants with and without history of bronchopulmonary dysplasia (BPD), before and after the application of inspiratory flow resistive loading. METHODS: Forty infants of a median (range) gestational age of 34 (25-40) weeks were studied. BPD was defined as supplemental oxygen requirement for >28 days of life. Seventeen infants were term, 17 preterm without history of BPD, and six preterm with a history of BPD. The diaphragmatic pressure-time index (PTIdi) was calculated as the mean to maximum trans-diaphragmatic pressure ratio times the inspiratory duty cycle. The PTIdi was calculated before and after the application of an inspiratory-flow resistance for 120 s. Airflow was measured by a pneumotachograph and the transdiaphragmatic pressure by a dual pressure catheter. RESULTS: The median (interquartile range [IQR]) pre-resistance PTIdi was higher in preterm infants without BPD (0.064 [0.050-0.077]) compared with term infants (0.052 [0.044-0.062], p = .029) and was higher in preterm infants with BPD (0.119 [0.086-0.132]) compared with a subgroup of preterm infants without BPD (0.062 [0.056-0.072], p = .004). The median (IQR) postresistance PTIdi was higher in preterm infants without BPD (0.101 [0.084-0.132]) compared with term infants (0.067 [0.055-0.083], p < .001) and was higher in preterm infants with BPD [0.201(0.172-0.272)] compared with the preterm subgroup without BPD (0.091 [0.081-0.108],p = .004). The median (IQR) percentage change of the PTIdi after the application of the resistance was higher in preterm infants without BPD (65 [51-92] %) compared with term infants (34 [20-39] %, p < .001). CONCLUSIONS: Preterm infants, especially those recovering from BPD, are at increased risk of diaphragmatic muscle fatigue under conditions of increased inspiratory loading.

Retrospective study of serial polysomnograms of bronchopulmonary dysplasia patients with oxygen dependence.

INTRODUCTION: This retrospective study describes characteristics of serial polysomnograms (PSGs) of BPD patients on home oxygen therapy and describes PSG parameters associated with discontinuation of supplemental oxygen. METHODS: A single-center study was performed at Children's Hospital Los Angeles, where serial PSGs for 44 patients with BPD infants discharged on home oxygen therapy were extracted for maximum of five PSGs or until oxygen discontinuation. Clinical and polysomnography data was collected. Characteristics of PSG1 were compared amongst the patients who were weaned from oxygen after PSG2 and PSG3. RESULTS: Of 44 patients, 68.2% of patients were males with median birth gestational age of 26 weeks (IQR: 24.6-28.1), median birthweight of 777.5 g (IQR: 632.5-1054 g) and 77.3% of the cohort had severe BPD. A total of 138 PSGs were studied between all 44 patients serially. When comparing PSG1 and PSG2 parameters, statistically significant improvement was noted in multiple parameters. Median baseline SpO2, peak RR, and average PETCO2 were found to be potential predictors of prolonged oxygen use. Gestational age and birth weight were not associated with prolonged oxygen use after PSG3. The median age of oxygen discontinuation was calculated to be about 2 years of age. CONCLUSIONS: The severity of hypoxia and tachypnea on initial infant PSG are associated with prolonged oxygen therapy past 2 years of age. Growth and development of lungs with maturation of control of breathing help improve these parameters over time regardless of BPD severity. The study may inform discussions between providers and parents for patients discharged home on oxygen therapy.

Postnatal diuretics, weight gain and home oxygen requirement in extremely preterm infants.

OBJECTIVES: Diuretics are often given to infants with evolving/established bronchopulmonary dysplasia (BPD) with the hope of improving their pulmonary outcomes. We aimed to determine if diuretic use in preterm infants was associated with improved pulmonary outcomes, but poorer weight gain. METHODS: An observational study over a 5 year period was undertaken of all infants born at less than 29 weeks of gestation and alive at discharge in all neonatal units in England who received consecutive diuretic use for at least 7 days. Postnatal weight gain and home supplementary oxygen requirement were the outcomes. A literature review of randomised controlled trials (RCTs) and crossover studies was undertaken to determine if diuretic usage was associated with changes in lung mechanics and oxygenation, duration of supplementary oxygen and requirement for home supplementary oxygen. RESULTS: In the observational study, 9,457 infants survived to discharge, 44.6% received diuretics for at least 7 days. Diuretic use was associated with an increased probability of supplementary home oxygen of 0.14 and an increase in weight gain of 2.5 g/week. In the review, seven of the 10 studies reported improvements only in short term lung mechanics. There was conflicting evidence regarding whether diuretics resulted in short term improvements in oxygenation. CONCLUSIONS: Diuretic use was not associated with a reduction in requirement for supplemental oxygen on discharge. The literature review highlighted a lack of RCTs assessing meaningful long-term clinical outcomes. Randomised trials are needed to determine the long-term risk benefit ratio of chronic diuretic use.

Función pulmonar: función pulmonar en pacientes con displasia broncopulmonar / Pulmonary function: pulmonary function in patients with bronchopulmonary dysplasia

La displasia broncopulmonar (DBP) es una complicación frecuente en los prematuros extremos. La detención de la alveolarización determina menor volumen pulmonar total, el cual se recupera al menos parcialmente en el trayecto de la vida. La vía aérea se ve afectada en su crecimiento en mayor proporción que los alvéolos, y en los pacientes con displasia severa va a existir hasta la etapa adulta una limitación al flujo aéreo debido a su menor calibre. En este artículo, se describirá el origen, hallazgos característicos y evolución de las alteraciones en la función pulmonar, especialmente, en los pacientes con la nueva DBP.

Bronchopulmonary dysplasia (BPD) is a frequent complication in extremely premature infants. The arrest of alveolarization determines a lower total lung volume, which recovers at least partially during life. The airway is affected in its growth to a greater extent than the alveoli, and in patients with severe dysplasia there will be airflow limitation until adulthood due to its smaller caliber. In this article, the origin, characteristic findings, and evolution of changes in lung function will be described, especially in patients with the new BPD.

Definición de displasia broncopulmonar propuesta por la Comisión Neo SOCHINEP / Definition of bronchopulmonary dysplasia proposed by the Neo SOCHINEP Commission

La displasia broncopulmonar (DBP) es la enfermedad crónica más frecuente del recién nacido prematuro. Los avances en su prevención y tratamiento han permitido una mayor sobrevida de prematuros más pequeños, pero su incidencia se ha mantenido estable en el tiempo, con una fisiopatología y presentación clínica que abarca un amplio espectro y que difiere de la DBP descrita originalmente hace más de 50 años. Aún existen controversias en su definición, la que se ha establecido en base al tratamiento, específicamente al requerimiento de soporte respiratorio. Las definiciones más utilizadas son el requerimiento de oxígeno por 28 días y a las 36 semanas de edad gestacional corregida (EGC). Recientemente se ha propuesto definirla en base al requerimiento de ventilación mecánica a las 36 semanas de EGC, lo que identificaría a los prematuros con DBP más grave y mayor probabilidad de complicaciones respiratorias y neurológicas en los 2 primeros años de vida. Nuestro objetivo en la comisión de Neo-SOCHINEP es el de recomendar la definición y clasificación que nos parece más adecuada para identificar a los prematuros portadores de DBP, considerando los aspectos fisiopatológicos, del compromiso de la función pulmonar y consecuencias prácticas de la definición en nuestro medio. También proponemos la definición del requerimiento de oxígeno en el prematuro cuando esta en neonatología, las condiciones e interpretación de la saturometría contínua cuando está pronto al alta y el seguimiento de la oxigenoterapia posterior al alta.

Bronchopulmonary dysplasia (BPD) is the most frequent chronic disease of the premature newborn. Advances in its prevention and treatment have allowed a greater survival of smaller preterm infants, but its incidence has remained stable over time, with a pathophysiology and clinical presentation that covers a wide spectrum and differs from the BPD originally described more than 50 years ago. There are still controversies in its definition, which has been established based on the treatment, specifically the requirement of respiratory support. The most used definitions are the oxygen requirement for 28 days and at 36 weeks of postmenstrual age (PMA). It has recently been proposed a definition based on the requirement of mechanical ventilation at 36 weeks of PMA, which would identify premature infants with more severe BPD and a greater probability of respiratory and neurological complications in the first 2 years of life. Our objective in the Neo-SOCHINEP commission is to recommend the definition and classification that we believe is most appropriate to identify premature infants with BPD, considering the pathophysiological aspects, the compromised lung function, and practical consequences of the definition in our medium. We also propose the definition of the oxygen requirement in premature infants when they are in neonatology, the conditions and interpretation of continuous saturation when they are soon discharged, and the follow-up of post-discharge oxygen therapy.

Impact of the definition of bronchopulmonary dysplasia on neurodevelopmental outcomes.

Understanding the short and long-term pulmonary and neurologic outcomes of neonates with bronchopulmonary dysplasia (BPD) is important in neonatal care for low-birth-weight infants. Different criteria for BPD may have different associations with long-term outcomes. Currently, two criteria for diagnosing BPD have been proposed by the NIH (2001) and NRN (2019) for preterm infants at a postmenstrual age (PMA) of 36 weeks. We investigated which BPD definition best predicts long-term outcomes. Korean nationwide data for preterm infants born between 24+0 and < 32+0 weeks gestation from January 2013 to December 2015 were collected. For long-term outcomes, severity based on the NRN criteria was significantly related to neurodevelopmental impairment (NDI) in a univariate analysis after other risk factors were controlled. For the admission rate for respiratory disorder, grade 3 BPD of the NRN criteria had the highest specificity (96%), negative predictive value (86%), and accuracy (83%). For predicting NDI at the 18-24 month follow-up, grade 3 BPD of the NRN criteria had the best specificity (98%), positive (64%) and negative (79%) predictive values, and accuracy (78%) while NIH severe BPD had the highest sensitivity (60%). The NRN definition was more strongly associated with poor 2-year developmental outcomes. BPD diagnosed by NRN definitions might better identify infants at high risk for NDI.