The Impact of Pulmonary Hypertension in Preterm Infants with Severe Bronchopulmonary Dysplasia through 1 Year.
ABSTRACT: OBJECTIVES:To assess the effect of pulmonary hypertension on neonatal intensive care unit mortality and hospital readmission through 1 year of corrected age in a large multicenter cohort of infants with severe bronchopulmonary dysplasia. STUDY DESIGN:This was a multicenter, retrospective cohort study of 1677 infants born <32 weeks of gestation with severe bronchopulmonary dysplasia enrolled in the Children's Hospital Neonatal Consortium with records linked to the Pediatric Health Information System. RESULTS:Pulmonary hypertension occurred in 370 out of 1677 (22%) infants. During the neonatal admission, pulmonary hypertension was associated with mortality (OR?3.15, 95% CI 2.10-4.73, P?
Project description:BACKGROUND:Assessment of pulmonary hemodynamics is critical in the diagnosis and management of cardiopulmonary disease of premature infants, but reliable noninvasive indices of pulmonary hemodynamics in preterm infants are lacking. Because pulmonary artery acceleration time (PAAT) is a validated noninvasive method to assess right ventricular (RV) afterload in infants and children, the aim of this study was to investigate the maturational changes of PAAT measures in preterm infants over the first year of age and to discern the impact of typical cardiopulmonary abnormalities on these measures. METHODS:In a prospective multicenter study of 239 preterm infants (<29 weeks at birth), PAAT was assessed at days 1, 2, and 5 to 7, at 32 and 36 weeks' postmenstrual age, and at 1-year corrected age. To account for heart rate variability, PAAT was adjusted for RV ejection time. Premature infants who developed bronchopulmonary dysplasia or had echocardiographic findings of pulmonary hypertension were analyzed separately. Intra- and interobserver reproducibility analysis was performed. RESULTS:PAAT was feasible in 95% of the image acquisitions, and there was high intra- and interobserver agreement (intraclass correlation coefficients > 0.9 and coefficients of variation < 6%). In uncomplicated preterm infants (n = 103 [48%]) PAAT and PAAT adjusted for RV ejection time increased longitudinally from birth to 1-year corrected age (P < .001) and were linearly associated with gestational age at birth (r = 0.81 and r = 0.82, P < .001) and increasing postnatal weight and postnatal age (r > 0.81, P < .001). PAAT measures were significantly reduced (P < .001) in infants with bronchopulmonary dysplasia and/or pulmonary hypertension (n = 119 [51%]) beyond 1 week of age. CONCLUSIONS:PAAT measures increase in preterm infants from birth to 1-year corrected age, reflective of the physiologic postnatal drop in RV afterload. Bronchopulmonary dysplasia and pulmonary hypertension have a negative impact on PAAT measures. By demonstrating excellent reliability and establishing reference patterns of PAAT in preterm infants, this study suggests that PAAT and PAAT adjusted for RV ejection time can be used as complementary parameters to assess physiologic and pathologic changes in pulmonary hemodynamics in neonates.
Project description:OBJECTIVE:To test the hypothesis that echocardiographic markers of pulmonary vascular disease (PVD) exist in asymptomatic infants born preterm at 1-year corrected age. STUDY DESIGN:We conducted a prospective cohort study of 80 infants born preterm (<29 weeks of gestation) and 100 age- and weight-matched infants born at term and compared broad-based conventional and quantitative echocardiographic measures of pulmonary hemodynamics at 1-year corrected age. Pulmonary artery acceleration time (PAAT), a validated index of pulmonary vascular resistance, arterial pressure, and compliance, was used to assess pulmonary hemodynamics. Lower PAAT is indicative of PVD. Subanalyses were performed in infants with bronchopulmonary dysplasia (BPD, n?=?48, 59%) and/or late-onset pulmonary hypertension (n?=?12, 15%). RESULTS:At 1 year, there were no differences between conventional measures of pulmonary hypertension in the infants born at term and preterm. All infants born preterm had significantly lower values of PAAT than infants born at term (73?±?8 milliseconds vs 98?±?5?milliseconds, P?<?.001). Infants born preterm with BPD had even lower PAAT than those without BPD (69?±?5 milliseconds vs 79?±?4?milliseconds, P?<?.01). The degree of PVD at 1-year corrected age was inversely related to gestation in all infants born preterm. Data analysis included adjustment for ventricular function and other confounding factors. CONCLUSIONS:In comparison with infants born at term, infants born preterm exhibit abnormal PAAT at 1-year corrected age irrespective of neonatal lung disease status, suggesting the existence of PVD beyond infancy. PAAT measurements offer a reliable, noninvasive tool for screening and longitudinal monitoring of pulmonary hemodynamics in infants.
Project description:INTRODUCTION:Prematurity impacts myocardial development and may determine long-term outcomes. The objective of this study was to test the hypothesis that preterm neonates develop right ventricle dysfunction and adaptive remodelling by 32 weeks post-menstrual age that persists through 1 year corrected age. MATERIALS AND METHODS:A subset of 80 preterm infants (born <29 weeks) was selected retrospectively from a prospectively enrolled cohort and measures of right ventricle systolic function and morphology by two-dimensional echocardiography were assessed at 32 weeks post-menstrual age and at 1 year of corrected age. Comparisons were made to 50 term infants at 1 month and 1 year of age. Sub-analyses were performed in preterm-born infants with bronchopulmonary dysplasia and/or pulmonary hypertension. RESULT:In both term and preterm infants, right ventricle function and morphology increased over the first year (p < 0.01). The magnitudes of right ventricle function measures were lower in preterm-born infants at each time period (p < 0.01 for all) and right ventricle morphology indices were wider in all preterm infants by 1 year corrected age, irrespective of lung disease. Measures of a) right ventricle function were further decreased and b) morphology increased through 1 year in preterm infants with bronchopulmonary dysplasia and/or pulmonary hypertension (p < 0.01). CONCLUSION:Preterm infants exhibit abnormal right ventricle performance with remodelling at 32 weeks post-menstrual age that persists through 1 year corrected age, suggesting a less developed intrinsic myocardial function response following preterm birth. The development of bronchopulmonary dysplasia and pulmonary hypertension leave a further negative impact on right ventricle mechanics over the first year of age.
Project description:Premature birth and bronchopulmonary dysplasia (BPD) are risk factors for the development of echocardiographic signs of pulmonary hypertension (PH) and are associated with changes in cardiac structure and function. It is unclear whether this association persists beyond early infancy. The aims of this study are to prospectively investigate the prevalence of PH in children with severe BPD and to investigate the effect of BPD and PH on myocardial structure and function at six months corrected age. Preterm infants (gestational age???32 weeks) with severe BPD were included. Echocardiography was used to define PH and to measure speckle tracking derived longitudinal and circumferential strain of the left ventricle (LV) and right ventricle (RV). Sixty-nine infants with a median (interquartile range [IQR]) gestational age of 25.6 (24.9-26.4) weeks and a median birthweight of 770 (645-945) gram were included. Eight (12%) infants had signs of PH at six months corrected age. RV fractional area change was lower in infants with severe BPD and PH at six months compared to infants without PH (35%?±?9% vs. 43%?±?9%, P?=?0.03). RV mean longitudinal systolic strain was lower in infants with severe BPD and PH compared to infants without PH (17.6% [-19.5%/-16.1%] vs. -20.9% [-25.9%/-17.9%], P?=?0.04). RV size and LV longitudinal and circumferential strain in children with BPD with or without PH were similar. Signs of PH were found in 12% of infants with severe BPD at six months corrected age and the presence of PH is associated with reduced RV systolic function.
Project description:AIM:Pulmonary hypertension significantly increases morbidity and mortality in infants with bronchopulmonary dysplasia. The frequency of single nucleotide polymorphisms in arginase-1 (ARG1 rs2781666) and dimethylarginine dimethylaminohydrolase-1 (DDAH1 rs480414) genes has been found to differ in a cohort of bronchopulmonary dysplasia patients with pulmonary hypertension (cases) and without pulmonary hypertension (controls). Therefore, we tested the hypothesis that combining these genotypes with phenotypic data would better predict pulmonary hypertension in bronchopulmonary dysplasia patients. METHODS:Bronchopulmonary dysplasia patients (n = 79) born at <35 weeks gestation were studied. Pulmonary hypertension was diagnosed by echocardiographic criteria (n = 20). ROC curves to predict pulmonary hypertension in bronchopulmonary dysplasia were generated from genotype and/or clinical data. RESULTS:Cases were born at an earlier gestation and weighed less at birth than did controls. ROC curves for rs2781666 had an AUC of 0.61, while rs480414 had an AUC of 0.66. Together, the AUC was 0.70. When clinical data were added to the genetic model, AUC was 0.73. CONCLUSION:These findings demonstrate that ROC predictive modelling of pulmonary hypertension in bronchopulmonary dysplasia improves with inclusion of both genotypic and phenotypic data. Further refinement of these types of models could facilitate the implementation of precision medicine approaches to pulmonary hypertension in bronchopulmonary dysplasia.
Project description:<h4>Background</h4>Pulmonary hypertension is a deadly complication of bronchopulmonary dysplasia, the most common pulmonary morbidity of prematurity. Despite these catastrophic consequences, no evidence-based therapies are available for the prevention of pulmonary hypertension in this population. Sildenafil is a potent pulmonary vasodilator approved by the US Food and Drug Administration for the treatment of pulmonary hypertension in adults. Preclinical models suggest a beneficial effect of sildenafil on premature lungs through improved alveolarization and preserved vascular development. Sildenafil may therefore prevent the development of pulmonary hypertension associated with lung disease of prematurity by reducing pulmonary vascular remodeling and lowering pulmonary vascular resistance; however, clinical trial evidence is needed. The present study, supported by the National Institutes of Health's National Heart Lung and Blood Institute, will generate safety, pharmacokinetics, and preliminary effectiveness data on sildenafil in a population of premature infants with severe bronchopulmonary dysplasia at risk for pulmonary hypertension.<h4>Methods</h4>We have designed a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety trial of sildenafil in premature infants with severe bronchopulmonary dysplasia. We will randomize 120 premature infants <?29?weeks gestational age with severe bronchopulmonary dysplasia at 32-40?weeks postmenstrual age in a dose-escalating approach 3:1 (sildenafil: placebo) sequentially into each of 3 cohorts at ~?30 clinical sites. Participants will receive up to 34?days of study drug, followed by 28?days of safety monitoring. The primary outcome will be safety as determined by incidence of hypotension. Secondary outcomes will include pharmacokinetics and preliminary effectiveness of sildenafil based on presence or absence of pulmonary hypertension diagnosed by echocardiography at the end of treatment period.<h4>Discussion</h4>Sildenafil is a promising intervention to prevent the development of pulmonary hypertension in premature infants with bronchopulmonary dysplasia. Clinical trials of sildenafil specifically designed for premature infants are urgently needed. The current study will make substantial contributions to scientific knowledge of the safety of sildenafil in premature infants at risk for pulmonary hypertension. Results from the study will be used by investigators to inform the design of a pivotal efficacy trial.<h4>Trial registration</h4>ClinicalTrials.gov NCT04447989 . Registered 25 June 2020.
Project description:BACKGROUND:The aim of this study was to determine the maturational changes in systolic ventricular strain mechanics by two-dimensional speckle-tracking echocardiography in extremely preterm neonates from birth to 1 year of age and discern the impact of common cardiopulmonary abnormalities on the deformation measures. METHODS:In a prospective multicenter study of 239 extremely preterm infants (<29 weeks gestation at birth), left ventricular (LV) global longitudinal strain (GLS) and global longitudinal systolic strain rate (GLSRs), interventricular septal wall (IVS) GLS and GLSRs, right ventricular (RV) free wall longitudinal strain and strain rate, and segmental longitudinal strain in the RV free wall, LV free wall, and IVS were serially measured on days 1, 2, and 5 to 7, at 32 and 36 weeks postmenstrual age, and at 1 year corrected age (CA). Premature infants who developed bronchopulmonary dysplasia or had echocardiographic findings of pulmonary hypertension were analyzed separately. RESULTS:In uncomplicated preterm infants (n = 103 [48%]), LV GLS and GLSRs remained unchanged from days 5 to 7 to 1 year CA (P = .60 and P = .59). RV free wall longitudinal strain, RV free wall longitudinal strain rate, and IVS GLS and GLSRs significantly increased over the same time period (P < .01 for all measures). A significant base-to-apex (highest to lowest) segmental longitudinal strain gradient (P < .01) was seen in the RV free wall and a reverse apex-to-base gradient (P < .01) in the LV free wall. In infants with bronchopulmonary dysplasia and/or pulmonary hypertension (n = 119 [51%]), RV free wall longitudinal strain and IVS GLS were significantly lower (P < .01), LV GLS and GLSRs were similar (P = .56), and IVS segmental longitudinal strain persisted as an RV-dominant base-to-apex gradient from 32 weeks postmenstrual age to 1 year CA. CONCLUSIONS:This study tracks the maturational patterns of global and regional deformation by two-dimensional speckle-tracking echocardiography in extremely preterm infants from birth to 1 year CA. The maturational patterns are ventricular specific. Bronchopulmonary dysplasia and pulmonary hypertension leave a negative impact on RV and IVS strain, while LV strain remains stable.
Project description:Many infants with severe bronchopulmonary dysplasia (BPD) can be safely managed with oxygen at home. This review covers criteria for home oxygen therapy, monitoring, and weaning protocols for oxygen therapy in the outpatient setting. Although most infants with BPD are weaned from oxygen within a year, they continue to have pulmonary function abnormalities into adolescence. These infants also require evaluation for pulmonary hypertension, systemic hypertension, and a strong focus on adequate nutritional needs for growth.
Project description:The chemokine interleukin-8 is implicated in the development of bronchopulmonary dysplasia in preterm infants. The 77-amino acid isoform of interleukin-8 (interleukin-877) is a less potent chemoattractant than other shorter isoforms. Although interleukin-877 is abundant in the preterm circulation, its regulation in the preterm lung is unknown.To study expression and processing of pulmonary interleukin-877 in preterm infants who did and did not develop bronchopulmonary dysplasia.Total interleukin-8 and interleukin-877 were measured in bronchoalveolar lavage fluid from preterm infants by immunoassay. Neutrophil serine proteases were used to assess processing. Neutrophil chemotaxis assays and degranulation of neutrophil matrix metalloproteinase-9 were used to assess interleukin-8 function.Peak total interleukin-8 and interleukin-877 concentrations were increased in infants who developed bronchopulmonary dysplasia compared to those who did not. Shorter forms of interleukin-8 predominated in the preterm lung (96.3% No-bronchopulmonary dysplasia vs 97.1% bronchopulmonary dysplasia, p>0.05). Preterm bronchoalveolar lavage fluid significantly converted exogenously added interleukin-877 to shorter isoforms (p<0.001). Conversion was greater in bronchopulmonary dysplasia infants (p<0.05). This conversion was inhibited by ?-1 antitrypsin and antithrombin III (p<0.01). Purified neutrophil serine proteases efficiently converted interleukin-877 to shorter isoforms in a time- and dose-dependent fashion; shorter interleukin-8 isoforms were primarily responsible for neutrophil chemotaxis (p<0.001). Conversion by proteinase-3 resulted in significantly increased interleukin-8 activity in vitro (p<0.01).Shorter, potent, isoforms interleukin-8 predominate in the preterm lung, and are increased in infants developing bronchopulmonary dysplasia, due to conversion of interleukin-877 by neutrophil serine proteases and thrombin. Processing of interleukin-8 provides an attractive therapeutic target to prevent development of bronchopulmonary dysplasia.
Project description:More than 50 years after the first description of Bronchopulmonary dysplasia (BPD) by Northway, this chronic lung disease affecting many preterm infants is still poorly understood. Additonally, approximately 40% of preterm infants suffering from severe BPD also suffer from Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH), leading to a significant increase in total morbidity and mortality. Until today, there is no curative therapy for both BPD and BPD-PH available. It has become increasingly evident that growth factors are playing a central role in normal and pathologic development of the pulmonary vasculature. Thus, this review aims to summarize the recent evidence in our understanding of BPD-PH from a basic scientific point of view, focusing on the potential role of Fibroblast Growth Factor (FGF)/FGF10 signaling pathway contributing to disease development, progression and resolution.