EXPRESS: Sildenafil for bronchopulmonary dysplasia and pulmonary hypertension: a meta-analysis.
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ABSTRACT:
SUBMITTER: van der Graaf M
PROVIDER: S-EPMC6681505 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
Publications
EXPRESS: Sildenafil for bronchopulmonary dysplasia and pulmonary hypertension: a meta-analysis.
van der Graaf Marissa M Rojer Leonne Arindah LA Helbing Willem W Reiss Irwin I Etnel Jonathan Richard Gregory JRG Bartelds Beatrijs B
Pulmonary circulation 20190226
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Project description:Bronchopulmonary dysplasia (BPD) is a major complication in prematurely born infants. Pulmonary hypertension (PH) associated with BPD (BPD-PH) is characterized by alveolar diffusion impairment, abnormal vascular remodeling, and rarefication of pulmonary vessels (vascular growth arrest), which lead to increased pulmonary vascular resistance and right heart failure. About 25% of infants with moderate to severe BPD develop BPD-PH that is associated with high morbidity and mortality. The recent evolution of broader PH-targeted pharmacotherapy in adults has opened up new treatment options for infants with BPD-PH. Sildenafil became the mainstay of contemporary BPD-PH therapy. Additional medications, such as endothelin receptor antagonists and prostacyclin analogs/mimetics, are increasingly being investigated in infants with PH. However, pediatric data from prospective or randomized controlled trials are still sparse. We discuss comprehensive diagnostic and therapeutic strategies for BPD-PH and briefly review the relevant differential diagnoses of parenchymal and interstitial developmental lung diseases. In addition, we provide a practical framework for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH from the 2018 World Symposium on Pulmonary Hypertension, and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies. Finally, current gaps of knowledge and future research directions are discussed. IMPACT: PH in BPD substantially increases mortality. Treatment of BPD-PH should be conducted by an interdisciplinary team and follow our new treatment algorithm while still kept tailored to the individual patient. We discuss recent developments in BPD-PH, make recommendations on diagnosis, monitoring and treatment of PH in BPD, and address current gaps of knowledge and potential research directions. We provide a practical framework, including a new treatment algorithm, for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH (2018 WSPH) and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies for BPD-PH.
| S-EPMC7979539 | biostudies-literature
Project description:ObjectiveTo quantify and compare levels of potential biomarkers in neonates with (i) Bronchopulmonary dysplasia (BPD); (ii) BPD-associated pulmonary hypertension (BPD-PH); (iii) PH without BPD; and (iv) neonates without lung disease at ~36 weeks postmenstrual age.Study designMultiple potential biomarkers were measured in plasma samples of 90 patients using a multi-spot enzyme-linked immunosorbent assay. Statistical tests done included one-way ANOVA to compare levels of biomarkers between different groups.ResultsHigher levels of ICAM-1 were present in infants with BPD and correlated with its severity. Infants with BPD have significantly higher levels of ANG-2 and lower levels of ANG-1. Infants with PH have higher levels of: IL-6, IL-8, IL-10, and TNF-α. Infants with BPD-PH have significantly lower levels of MCP-1 and higher levels of IL-1β than infants with PH without BPD.ConclusionICAM-1 may be used as a specific biomarker for diagnosis of BPD and its severity.
| S-EPMC7664991 | biostudies-literature
Project description:ImportanceBronchopulmonary dysplasia (BPD) is often associated with pulmonary vascular disease and secondary pulmonary hypertension (PH). The pathogenesis of BPD-associated PH (BPD-PH) is complex and involves prenatal and postnatal factors that disrupt pulmonary vascular development, and patent ductus arteriosus (PDA) is a factor potentially associated with risk of BPD-PH that has been identified in very recent studies.ObjectiveTo explore the association of PDA with BPD-PH using a bayesian model-averaged (BMA) meta-analysis of studies.Data sourcesPubMed and Embase were searched up to April 2023. Key search terms included BPD and PH.Study selectionStudies examining infants with gestational age 32 weeks or less and reporting data on PDA and risk of BPD-PH.Data extraction and synthesisThis study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Meta-Analysis of Observational Studies in Epidemiology reporting guidelines. Two independent reviewers extracted data, with a third reviewer checking for accuracy and completeness. Data pooling and effect size calculations were performed by BMA.Main outcomes and measuresThe primary outcome was BPD-PH. BMA was used to calculate Bayes factors (BFs). The BF10 is the ratio of the probability of the data under the alternative hypothesis (H1, association of PDA with BPD-HP) over the probability of the data under the null hypothesis (H0).ResultsA total of 32 studies (8513 infants) were included. BMA showed that the evidence in favor of H1 was weak for any PDA (BF10 = 2.90; 10 studies), moderate for hemodynamically significant PDA (BF10 = 3.77; 3 studies), and extreme for surgically ligated or catheter-occluded PDA (BF10 = 294.9; 16 studies). In contrast, the evidence in favor of H0 was weak for medically treated PDA (BF10 = 0.55; 6 studies). In addition, BMA found strong evidence in favor of H1 when prolonged exposure to PDA was analyzed as a dichotomous variable (BF10 = 11.80; 6 studies) and extreme evidence (BF10 = 113.60; 3 studies) when PDA exposure time was analyzed as a continuous variable.Conclusions and relevanceIn this bayesian meta-analysis, the data suggest that prolonged exposure to PDA might be associated with increased risk of pulmonary vascular disease in extremely preterm infants. This highlights the need to monitor for PH in high-risk preterm infants with prolonged exposure to PDA and to incorporate PH risk into clinical decisions regarding PDA management.
| S-EPMC10685885 | biostudies-literature
Project description:To evaluate pulmonary hemodynamics in patients who had been followed up for bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) in the mid-term by right heart catheterization (RHC). A retrospective study was conducted among 56 patients who were born at a gestational age < 28 weeks during 2018-2020, and the consecutive patients complicated by BPD and ultrasound-defined PH (n = 10, 18%), of whom 7 patients were treated with sildenafil, were examined by RHC in the mid-term follow-up (median age: 25 months [IQR: 19-32]). Ultrasound study at RHC showed improvement in PH as represented by left ventricular end-systolic eccentricity index (median [IQR], 1.05 [IQR: 1.03-1.06] vs. 1.18 [IQR: 1.15-1.33]), pulmonary artery acceleration time (PAAT) (mean ± SD, 97.3 ± 18.2 vs. 55.2 ± 10.1) and a ratio of PAAT to right ventricular ejection time (0.35 ± 0.05 vs. 0.25 ± 0.04) compared with those at 40 weeks of postmenstrual age (PMA) (p < 0.05, respectively). RHC (mean pulmonary artery [PA] pressure: 21 [19-22] mmHg; pulmonary vascular resistance index [PVRi]: 2.63 [1.95-2.94] Wood Units·m2) revealed that 5 infants (50%) had mild PH (21-24 mmHg) and reduced peripheral PAs by pulmonary wedge angiography. The presence of emphysema on chest CT at 40 weeks of PMA and moderate/marked reduction of contrast filling in peripheral PAs on angiography were correlated with increased PVRi (p < 0.05, respectively).ConclusionWe observed that even after apparent resolution of ultrasound-defined PH, half of patients had catheterization-defined PH and vasculopathy at 2 years of age. These findings warrant long-term follow-up studies of BPD-associated PH.What is known• Pulmonary hypertension (PH) is associated with increased mortality in infants with bronchopulmonary dysplasia (BPD). Mortality in patients with BPD-associated PH predominantly occurs within the first 6 months of life and most patients who survive beyond 6 months show resolution of PH on echocardiography by 2 to 3 years of age.What is new• Even after the resolution of echocardiography-derived PH in infants with BPD-associated PH in the mid-term, the majority of such patients have abnormal pulmonary vasculature with PH or mildly elevated pulmonary artery pressure on right heart catheterization (RHC), indicating that echocardiography is insufficient and RHC may be necessary to follow up this population of patients.
| S-EPMC11573848 | biostudies-literature
Project description:Rationale: Patients with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) have increased morbidity and mortality. Noninvasive assessment relies on echocardiograms (echos), which are technically challenging in this population. Improved assessment could augment decisions regarding PH therapies.Objectives: We hypothesized that neonatal cardiac magnetic resonance imaging (MRI) will correlate with BPD severity and predict short-term clinical outcomes, including need for PH therapies for infants with BPD.Methods: A total of 52 infants (31 severe BPD, 9 moderate BPD, and 12 with either mild or no BPD) were imaged between 39 and 47 weeks postmenstrual age on a neonatal-sized, neonatal ICU-sited 1.5-T magnetic resonance (MR) scanner. MR left ventricular eccentricity index (EI), main pulmonary artery-to-aorta (PA/AO) diameter ratio, and pulmonary arterial blood flow were determined. Echos obtained for clinical indications were reviewed. MRI and echo indices were compared with BPD severity and clinical outcomes, including length of stay (LOS), duration of respiratory support, respiratory support at discharge, and PH therapy.Measurements and Main Results: PA/AO ratio increased with BPD severity. Increased PA/AO ratio, MR-EI, and echo-EIs were associated with increased LOS and duration of respiratory support. No correlation was seen between pulmonary arterial blood flow and BPD outcomes. Controlling for gestational age, birth weight, and BPD severity, MR-EI was associated with LOS and duration of respiratory support. Increased PA/AO ratio and MR-EI were associated with PH therapy during hospitalization and at discharge.Conclusions: MRI can provide important image-based measures of cardiac morphology that relate to disease severity and clinical outcomes in neonates with BPD.
| S-EPMC6938152 | biostudies-literature
Project description:Clinical trials have failed to demonstrate an effective preventative or therapeutic strategy for bronchopulmonary dysplasia (BPD), a multifactorial chronic lung disease in preterm infants frequently complicated by pulmonary hypertension (PH). Mesenchymal stem cells (MSCs) and their secreted components have been shown to prevent BPD and pulmonary fibrosis in rodent models. We hypothesized that treatment with conditioned media (CM) from cultured mouse bone marrow-derived MSCs could reverse hyperoxia-induced BPD and PH. Newborn mice were exposed to hyperoxia (FiO(2)=0.75) for two weeks, were then treated with one intravenous dose of CM from either MSCs or primary mouse lung fibroblasts (MLFs), and placed in room air for two to four weeks. Histological analysis of lungs harvested at four weeks of age was performed to determine the degree of alveolar injury, blood vessel number, and vascular remodeling. At age six weeks, pulmonary artery pressure (PA acceleration time) and right ventricular hypertrophy (RVH; RV wall thickness) were assessed by echocardiography, and pulmonary function tests were conducted. When compared to MLF-CM, a single dose of MSC-CM-treatment (1) reversed the hyperoxia-induced parenchymal fibrosis and peripheral PA devascularization (pruning), (2) partially reversed alveolar injury, (3) normalized lung function (airway resistance, dynamic lung compliance), (4) fully reversed the moderate PH and RVH, and (5) attenuated peripheral PA muscularization associated with hyperoxia-induced BPD. Reversal of key features of hyperoxia-induced BPD and its long-term adverse effects on lung function can be achieved by a single intravenous dose of MSC-CM, thereby pointing toward a new therapeutic intervention for chronic lung diseases.
| S-EPMC3401871 | biostudies-literature
Project description:AimPulmonary 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.MethodsBronchopulmonary 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.ResultsCases 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.ConclusionThese 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.
| S-EPMC6226353 | biostudies-literature
Project description:This study evaluated whether early pulmonary hypertension (PH) in extremely preterm infants (EPIs) at 22-27 weeks of gestation detected clinically with echocardiography at 4-7 postnatal days (PND) is a risk factor for death before 36 weeks post-menstrual age (PMA) or late PH in moderate or severe (m/s) bronchopulmonary dysplasia (BPD) (BPD-PH). We analyzed risk factors for death before 36 weeks PMA or BPD-PH. Among 247 EPIs enrolled, 74 (30.0%) had early PH. Twenty-one (28.4%) infants with early PH and 18 (10.4%) without early PH died before 36 weeks PMA; 14 (18.9%) infants with early PH and 9 (5.2%) without early PH had BPD-PH at 36-38 weeks PMA. Multivariate analysis revealed that early PH (adjusted odds ratio, 6.55; 95% confidence interval, 3.10-13.82, P < 0.05), clinical chorioamnionitis (2.50; 1.18-5.31), intraventricular hemorrhage (grade 3-4) (3.43; 1.26-9.37), and late sepsis (6.76; 3.20-14.28) independently increased the risk of development of death before 36 weeks PMA or BPD-PH. Subgroup analysis among m/s BPD patients revealed that early PH (4.50; 1.61-12.58) and prolonged invasive ventilator care (> 28 days) (4.91; 1.02-23.68) increased the risk for late PH independently. In conclusion, EPIs with early PH at 4-7 PND should be monitored for BPD-associated late PH development.
| S-EPMC8160152 | biostudies-literature
Project description:BackgroundEchocardiography has poor accuracy in grading the severity of pulmonary hypertension (PH) compared to cardiac catheterization. However, the relationship between degree of PH and prognostic outcomes remains uncertain. Our primary objective was to determine whether echocardiogram-assessed PH severity is associated with mortality and hospital readmission in the first year of life.MethodsA retrospective cohort study of infants born less than 32 weeks of gestational age with bronchopulmonary dysplasia (BPD) underwent echocardiography was performed. Echocardiograms were performed at 36-38 weeks postmenstrual age. Data during hospitalization and post-discharge collected at 1-year age were analyzed with cox regression models and logistic regression models to identify the association of PH severity with mortality and readmission. Area under curve (AUC) was calculated to examine the accuracy of these models to reflect the likelihood of outcomes.ResultsFifty-six of 237 (23.6%) infants were diagnosed as PH. Moderate and severe PH was significantly associated with mortality during the first one year of life (moderate PH vs. none HR =26.58, 95% CI: 4.40-160.78, P<0.001; severe PH vs. none HR =36.49, 95% CI: 5.65-235.84, P<0.001). Male, preeclampsia and inhaled nitric oxide were also associated with mortality. Mild PH was significantly associated with readmission (OR =2.42, 95% CI: 1.12-5.26, P=0.025), but not associated with mortality (HR =2.09, 95% CI: 0.43-10.18, P=0.36). The PH severity model based on echocardiography accurately informed mortality (AUC 0.79).ConclusionsEchocardiogram-assessed PH severity is associated with prognostic outcomes, including mortality and readmission in very preterm infants with BPD. The severity of PH based on echocardiography is a potential predictor of mortality in the first year of life.
| S-EPMC7882291 | biostudies-literature
Project description:Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification, airway hyperreactivity, and pulmonary hypertension. In our BPD model, we have investigated the metabolism of the bronchodilator and pulmonary vasodilator GSNO (S-nitrosoglutathione). We have shown the GSNO catabolic enzyme encoded by adh5 (alcohol dehydrogenase-5), GSNO reductase, is epigenetically upregulated in hyperoxia. Here, we investigated the distribution of GSNO reductase expression in human BPD and created an animal model that recapitulates the human data. Blinded comparisons of GSNO reductase protein expression were performed in human lung tissues from infants and children with and without BPD. BPD phenotypes were evaluated in global (adh5-/-) and conditional smooth muscle (smooth muscle/adh5-/-) adh5 knockout mice. GSNO reductase was prominently expressed in the airways and vessels of human BPD subjects. Compared with controls, expression was greater in BPD smooth muscle, particularly in vascular smooth muscle (2.4-fold; P = 0.003). The BPD mouse model of neonatal hyperoxia caused significant alveolar simplification, airway hyperreactivity, and right ventricular and vessel hypertrophy. Global adh5-/- mice were protected from all three aspects of BPD, whereas smooth muscle/adh5-/- mice were only protected from pulmonary hypertensive changes. These data suggest adh5 is required for the development of BPD. Expression in the pulmonary vasculature is relevant to the pathophysiology of BPD-associated pulmonary hypertension. GSNO-mimetic agents or GSNO reductase inhibitors, both of which are currently in clinical trials for other conditions, could be considered for further study in BPD.
| S-EPMC8320118 | biostudies-literature