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Durlak W, Thébaud B. The vascular phenotype of BPD: new basic science insights-new precision medicine approaches. Pediatr Res 2024; 96:1162-1171. [PMID: 36550351 DOI: 10.1038/s41390-022-02428-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 10/27/2022] [Accepted: 11/23/2022] [Indexed: 12/24/2022]
Abstract
Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth. Up to 1/3 of children with BPD develop pulmonary hypertension (PH). PH increases mortality, the risk of adverse neurodevelopmental outcome and lacks effective treatment. Current vasodilator therapies address symptoms, but not the underlying arrested vascular development. Recent insights into placental biology and novel technological advances enabling the study of normal and impaired lung development at the single cell level support the concept of a vascular phenotype of BPD. Dysregulation of growth factor pathways results in depletion and dysfunction of putative distal pulmonary endothelial progenitor cells including Cap1, Cap2, and endothelial colony-forming cells (ECFCs), a subset of vascular progenitor cells with self-renewal and de novo angiogenic capacity. Preclinical data demonstrate effectiveness of ECFCs and ECFC-derived particles including extracellular vesicles (EVs) in promoting lung vascular growth and reversing PH, but the mechanism is unknown. The lack of engraftment suggests a paracrine mode of action mediated by EVs that contain miRNA. Aberrant miRNA signaling contributes to arrested pulmonary vascular development, hence using EV- and miRNA-based therapies is a promising strategy to prevent the development of BPD-PH. More needs to be learned about disrupted pathways, timing of intervention, and mode of delivery. IMPACT: Single-cell RNA sequencing studies provide new in-depth view of developmental endothelial depletion underlying BPD-PH. Aberrant miRNA expression is a major cause of arrested pulmonary development. EV- and miRNA-based therapies are very promising therapeutic strategies to improve prognosis in BPD-PH.
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Affiliation(s)
- Wojciech Durlak
- Regenerative Medicine Program, The Ottawa Hospital Research Institute (OHRI), Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Jagiellonian University Medical College, Krakow, Poland
| | - Bernard Thébaud
- Regenerative Medicine Program, The Ottawa Hospital Research Institute (OHRI), Ottawa, ON, Canada.
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
- Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario (CHEO) and CHEO Research Institute, Ottawa, ON, Canada.
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2
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Hernandez BS, Shinozaki RM, Grady RM, Drussa A, Jamro-Comer E, Wang J, Aggarwal M. Improvement in Echocardiographic and Diagnostic Biomarkers after Systemic Glucocorticoid Therapy in Infants with Pulmonary Hypertension. J Pediatr 2024; 273:114116. [PMID: 38815741 DOI: 10.1016/j.jpeds.2024.114116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 05/09/2024] [Accepted: 05/22/2024] [Indexed: 06/01/2024]
Abstract
OBJECTIVE To assess the effect of treating pulmonary hypertension (PH) in infants younger than 1 year of age with systemic glucocorticoids while using echocardiographic and diagnostic biomarkers as measures of efficacy. STUDY DESIGN A retrospective chart review was performed on 17 hospitalized infants younger than 1 year of age at St Louis Children's Hospital who received a 5- to 7-day course of systemic glucocorticoid treatment followed by a 3-week taper with no significant intracardiac shunts from January 1, 2017, to December 31, 2021. Quantitative echocardiographic indices for PH, N-terminal pro b-type natriuretic peptide, and/or b-type natriuretic peptide levels were collected before glucocorticoid treatment, after the glucocorticoid burst, and after the 21-day taper. RESULTS Mean (±SD) gestational age was 32.1 (±5.8) weeks, 5 infants were (29%) concomitantly treated with sildenafil, and 8 were male. Twelve were classified as World Health Organization group 3 PH (71%) and 5 as World Health Organization group 1 PH. There were significant improvements 30 days after glucocorticoid initiation in b-type natriuretic peptide levels (P = .008), PCO2 (P = .03), eccentricity index (P = .005), right ventricular ejection time (P = .04), pulmonary artery acceleration time (P = .002), and pulmonary artery acceleration time-to-right ventricular ejection time ratio (P = .02). Tricuspid regurgitation velocity was not able to be assessed. There were no mortalities during the study timeline. CONCLUSIONS In our retrospective study, systemic glucocorticoid therapy was well tolerated and appeared to be associated with significant improvement in cardiopulmonary function in infants with PH. Further prospective study in a larger sample is warranted.
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Affiliation(s)
- Brian S Hernandez
- Division of Pediatric Cardiology, Department of Pediatrics, Washington University School of Medicine, St Louis, MO
| | - Rod M Shinozaki
- Division of Pediatric Critical Care, Department of Pediatrics, Loma Linda University Children's Hospital, Loma Linda, CA
| | - R Mark Grady
- Division of Pediatric Cardiology, Department of Pediatrics, Washington University School of Medicine, St Louis, MO
| | - Andrea Drussa
- Division of Pediatric Cardiology, Department of Pediatrics, Washington University School of Medicine, St Louis, MO
| | - Erica Jamro-Comer
- Division of Biostatistics, Washington University in St Louis, St Louis, MO
| | - Jinli Wang
- Division of Biostatistics, Washington University in St Louis, St Louis, MO
| | - Manish Aggarwal
- Division of Pediatric Cardiology, Department of Pediatrics, Washington University School of Medicine, St Louis, MO.
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Pharande P, Sehgal A, Menahem S. Cardiovascular Sequelae of Bronchopulmonary Dysplasia in Preterm Neonates Born before 32 Weeks of Gestational Age: Impact of Associated Pulmonary and Systemic Hypertension. J Cardiovasc Dev Dis 2024; 11:233. [PMID: 39195141 DOI: 10.3390/jcdd11080233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 07/21/2024] [Accepted: 07/24/2024] [Indexed: 08/29/2024] Open
Abstract
Bronchopulmonary dysplasia (BPD) remains the most common respiratory disorder of prematurity for infants born before 32 weeks of gestational age (GA). Early and prolonged exposure to chronic hypoxia and inflammation induces pulmonary hypertension (PH) with the characteristic features of a reduced number and increased muscularisation of the pulmonary arteries resulting in an increase in the pulmonary vascular resistance (PVR) and a fall in their compliance. BPD and BPD-associated pulmonary hypertension (BPD-PH) together with systemic hypertension (sHTN) are chronic cardiopulmonary disorders which result in an increased mortality and long-term problems for these infants. Previous studies have predominantly focused on the pulmonary circulation (right ventricle and its function) and developing management strategies accordingly for BPD-PH. However, recent work has drawn attention to the importance of the left-sided cardiac function and its impact on BPD in a subset of infants arising from a unique pathophysiology termed postcapillary PH. BPD infants may have a mechanistic link arising from chronic inflammation, cytokines, oxidative stress, catecholamines, and renin-angiotensin system activation along with systemic arterial stiffness, all of which contribute to the development of BPD-sHTN. The focus for the treatment of BPD-PH has been improvement of the right heart function through pulmonary vasodilators. BPD-sHTN and a subset of postcapillary PH may benefit from afterload reducing agents such as angiotensin converting enzyme inhibitors. Preterm infants with BPD-PH are at risk of later cardiac and respiratory morbidities as young adults. This paper reviews the current knowledge of the pathophysiology, diagnosis, and treatment of BPD-PH and BPD-sHTN. Current knowledge gaps and emerging new therapies will also be discussed.
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Affiliation(s)
- Pramod Pharande
- Monash Newborn, Monash Children's Hospital, 246 Clayton Road, Clayton, Melbourne, VIC 3168, Australia
- Department of Pediatrics, Monash University, Melbourne, VIC 3800, Australia
| | - Arvind Sehgal
- Monash Newborn, Monash Children's Hospital, 246 Clayton Road, Clayton, Melbourne, VIC 3168, Australia
- Department of Pediatrics, Monash University, Melbourne, VIC 3800, Australia
| | - Samuel Menahem
- Department of Pediatrics, Monash University, Melbourne, VIC 3800, Australia
- Paediatric and Foetal Cardiac Units, Monash Medical Centre, Melbourne, VIC 3168, Australia
- Murdoch Children's Research Institute, University of Melbourne, Parkville, VIC 3052, Australia
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Carroll J, Rao R, Steinhorn RH. Targeted Therapies for Neonatal Pulmonary Hypertension: Beyond Nitric Oxide. Clin Perinatol 2024; 51:113-126. [PMID: 38325937 DOI: 10.1016/j.clp.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Pulmonary hypertension in the neonatal population can be acute or chronic and carries significant risk for morbidity and mortality. It can be idiopathic but more often is associated with comorbid pulmonary and heart disease. There are several pharmacotherapeutics aimed at pulmonary vasodilation. This review highlights the most common agents as well as those on the horizon for the treatment of pulmonary hypertension in the neonate.
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Affiliation(s)
- Jeanne Carroll
- Division of Neonatology, Department of Pediatrics, University of California, San Diego, Rady Children's Hospital-San Diego, 3030 Children's Way, San Diego, CA 92123, USA
| | - Rohit Rao
- Division of Cardiothoracic Critical Care, Department of Pediatrics, University of California, San Diego, Rady Children's Hospital-San Diego, 3030 Children's Way, San Diego, CA 92123, USA
| | - Robin H Steinhorn
- Department of Pediatrics, University of California, San Diego, Rady Children's Hospital-San Diego, 3020 Children's Way, San Diego, CA 92123, USA.
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Zhu F, Ibarra Rios D, Joye S, Baczynski M, Rios D, Giesinger RE, McNamara PJ, Jain A. Cardiopulmonary physiological effects of diuretic therapy in preterm infants with chronic pulmonary hypertension. J Perinatol 2023; 43:1288-1294. [PMID: 37550529 DOI: 10.1038/s41372-023-01742-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/10/2023] [Accepted: 07/27/2023] [Indexed: 08/09/2023]
Abstract
OBJECTIVE Using targeted neonatal echocardiography (TNE) to examine cardiopulmonary physiological impact of diuretics in preterm infants with chronic pulmonary hypertension (cPH). STUDY DESIGN Retrospective study comparing TNE indices pre- and ≤2 weeks (post) of initiating diuretic therapy in infants born <32 weeks gestational age with cPH. RESULTS Twenty-seven neonates with mean gestational age, birthweight and interval between pre-post diuretic TNE of 27.0 ± 2.8 weeks, 859 ± 294 grams, and 7.8 ± 3.0 days respectively were studied. Diuretics was associated with improvement in pulmonary vascular resistance [pulmonary artery acceleration time (PAAT); 34.27(9.76) vs. 40.24(11.10)ms, p = 0.01), right ventricular (RV) ejection time:PAAT ratio [5.92(1.66) vs. 4.83(1.14), p < 0.01)], RV fractional area change [41.6(9.8) vs. 46.4(6.5%), p = 0.03)] and left ventricular myocardial performance index [0.55(0.09) vs. 0.41(0.23), p < 0.01)]. Post-treatment, frequency of bidirectional/right-to-left inter-atrial shunts decreased significantly (24% vs. 4%, p = 0.05). CONCLUSION Primary diuretic treatment in neonates with cPH may result in improvement in PVR, RV and LV function and compliance.
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Affiliation(s)
- Faith Zhu
- Department of Paediatrics, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - Daniel Ibarra Rios
- Neonatology Department, Hospital Infantil de México Federico Gómez, Mexico City, Mexico
| | | | | | - Danielle Rios
- Department of Pediatrics, University of Iowa, Iowa City, IA, USA
| | | | | | - Amish Jain
- Department of Paediatrics, Mount Sinai Hospital, Toronto, ON, Canada.
- Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
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Dillon K, Lamba V, Philip RR, Weems MF, Talati AJ. Efficacy of Sildenafil in Infants with Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension. CHILDREN (BASEL, SWITZERLAND) 2023; 10:1397. [PMID: 37628395 PMCID: PMC10453183 DOI: 10.3390/children10081397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/30/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023]
Abstract
Background: Pulmonary hypertension (PH) is a common comorbidity in infants with bronchopulmonary dysplasia (BPD). Sildenafil is a widely recognized therapy for PH, but its efficacy in infants with BPD is questionable. We propose to assess the efficacy of sildenafil in BPD-associated PH as evaluated based on transthoracic echocardiography (TTE) changes and clinical measures. Methods: Data were retrospectively and prospectively collected. Inclusion criteria were gestational age (GA) < 32 weeks, birth weight (BW) < 1500 g with severe BPD, diagnosis of PH via TTE on sildenafil treatment. PH was evaluated via TTE, which was performed monthly after 36 weeks post-menstrual age (PMA) as a standard of care, and re-reviewed by a single pediatric cardiologist, who was blind to the initial reading. Results: In total, 19 patients were enrolled in the study, having a median GA of 24 3/7 weeks (IQR 23 5/7-25 5/7) and a median BW of 598 g (IQR 572-735). Sildenafil treatment was started at a median PMA of 40.4 weeks. The median respiratory severity score (RSS) at 28 d was 6.5, RSS and FiO2 showed improvement about 12 weeks after starting sildenafil treatment. Conclusions: Improvement in PH was noted via TTE, and patients had improvement in their RSS and FiO2 after prolonged therapy. However, TTE improvements did not correlate with clinical improvements.
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Affiliation(s)
- Kacie Dillon
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Vineet Lamba
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Ranjit R. Philip
- Division of Pediatric Cardiology, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA;
| | - Mark F. Weems
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Ajay J. Talati
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
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Schroeder L, Monno P, Strizek B, Dresbach T, Mueller A, Kipfmueller F. Intravenous sildenafil for treatment of early pulmonary hypertension in preterm infants. Sci Rep 2023; 13:8405. [PMID: 37225769 DOI: 10.1038/s41598-023-35387-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 05/17/2023] [Indexed: 05/26/2023] Open
Abstract
Data is lacking on the effect of continuous intravenous sildenafil treatment in preterm infants with early pulmonary hypertension (PH), especially in very low birth weight (VLBW) infants. Preterm infants (< 37 weeks of gestational age) with intravenous sildenafil treatment and diagnosis of PH between 01/12 and 12/21 were retrospectively screened for analysis. The primary clinical endpoint was defined as response to sildenafil according to the improvement of the oxygenation index (OI), the saturation oxygenation pressure index (SOPI) and PaO2/FiO2-ratio. Early-PH was defined as diagnosis < 28 day of life (DOL). 58 infants were finally included, with 47% classified as very low birth weight (VLBW) infants. The primary endpoint was reached in 57%. The likelihood to die during in-hospital treatment was more than three times higher (72 vs 21%, p < 0.001) in infants without response to sildenafil. The echocardiographic severity of PH and right-ventricular dysfunction (RVD) decreased significantly from baseline to 24 h (p = 0.045, and p = 0.008, respectively). Sildenafil treatment leads to significant improvement of the oxygenation impairment in 57% of the preterm infants, with similar response rates in VLBW infants. Intravenous sildenafil treatment is associated with a significant decrease of the PH-severity and RVD.
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Affiliation(s)
- Lukas Schroeder
- Department of Neonatology and Pediatric Intensive Care Medicine, University Children's Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
| | - Paulina Monno
- Department of Neonatology and Pediatric Intensive Care Medicine, University Children's Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Brigitte Strizek
- Department of Obstetrics and Prenatal Medicine, University Hospital Bonn, Bonn, Germany
| | - Till Dresbach
- Department of Neonatology and Pediatric Intensive Care Medicine, University Children's Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Andreas Mueller
- Department of Neonatology and Pediatric Intensive Care Medicine, University Children's Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Florian Kipfmueller
- Department of Neonatology and Pediatric Intensive Care Medicine, University Children's Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
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8
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Fike CD, Aschner JL. Pharmacotherapy for Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Past, Present, and Future. Pharmaceuticals (Basel) 2023; 16:503. [PMID: 37111262 PMCID: PMC10141152 DOI: 10.3390/ph16040503] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/07/2023] [Accepted: 03/09/2023] [Indexed: 03/31/2023] Open
Abstract
Approximately 8-42% of premature infants with chronic lung disease of prematurity, bronchopulmonary dysplasia (BPD), develop pulmonary hypertension (PH). Infants with BPD-PH carry alarmingly high mortality rates of up to 47%. Effective PH-targeted pharmacotherapies are desperately needed for these infants. Although many PH-targeted pharmacotherapies are commonly used to treat BPD-PH, all current use is off-label. Moreover, all current recommendations for the use of any PH-targeted therapy in infants with BPD-PH are based on expert opinion and consensus statements. Randomized Control Trials (RCTs) are needed to determine the efficacy of PH-targeted treatments in premature infants with or at risk of BPD-PH. Prior to performing efficacy RCTs, studies need to be conducted to obtain pharmacokinetic, pharmacodynamic, and safety data for any pharmacotherapy used in this understudied and fragile patient population. This review will discuss current and needed treatment strategies, identify knowledge deficits, and delineate both challenges to be overcome and approaches to be taken to develop effective PH-targeted pharmacotherapies that will improve outcomes for premature infants with or at risk of developing BPD-PH.
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Affiliation(s)
- Candice D. Fike
- Department of Pediatrics, University of Utah Health, Salt Lake City, UT 84108, USA
| | - Judy L. Aschner
- Department of Pediatrics, Joseph M. Sanzari Children’s Hospital at Hackensack University Medical Center, Hackensack, NJ 07601, USA
- Department of Pediatrics, Hackensack Meridian School of Medicine, Nutley, NJ 07110, USA
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9
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Giesinger RE, Stanford AH, Thomas B, Abman SH, McNamara PJ. Safety and Feasibility of Riociguat Therapy for the Treatment of Chronic Pulmonary Arterial Hypertension in Infancy. J Pediatr 2022; 255:224-229.e1. [PMID: 36462687 DOI: 10.1016/j.jpeds.2022.11.026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 10/26/2022] [Accepted: 11/18/2022] [Indexed: 12/03/2022]
Abstract
The effects of riociguat, an oral-soluble guanylate-cyclase stimulator, were studied in 10 infants with chronic pulmonary arterial hypertension. Respiratory status (n = 8/10), right heart dilation (n = 7/10), function (n = 9/10), and chronic pulmonary arterial hypertension (n = 8/10) improved. Median decrement in systolic (12 [4, 14]), diastolic (14 [7, 20]), and mean arterial (14 [10, 17]) pressures were noted; no critical hypotension or hypoxemia occurred.
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Affiliation(s)
| | - Amy H Stanford
- Department of Pediatrics, University of Iowa, Iowa City, IA
| | - Brady Thomas
- Department of Pediatrics, University of Iowa, Iowa City, IA
| | - Steven H Abman
- Department of Pediatrics, University of Colorado, Denver, CO
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Fetal growth restriction and neonatal-pediatric lung diseases: Vascular mechanistic links and therapeutic directions. Paediatr Respir Rev 2022; 44:19-30. [PMID: 36503648 DOI: 10.1016/j.prrv.2022.09.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/11/2022] [Accepted: 09/14/2022] [Indexed: 11/18/2022]
Abstract
Bronchopulmonary dysplasia (BPD) is the most common respiratory sequela of prematurity, and infants born with fetal growth restriction (FGR) are disproportionately represented in BPD statistics, as factors which affect somatic growth may also affect pulmonary growth. Effects of in-utero hypoxia underlying FGR on lung parenchymal architecture predisposing to BPD are well documented, but the pulmonary vascular constructs are not well appreciated. Disruption of angiogenesis during critical periods of lung growth impairs alveolarization, contributing to BPD pathogenesis. Pulmonary artery thickness/stiffness has been noted in FGR in the initial postnatal weeks, and also in well-grown infants with established BPD. The lack of waveform cushioning by the major arteries exposes the pulmonary resistance vessels to higher pulsatile stress, thereby accelerating microvascular disease. Reactive oxygen species, increased sympathetic activity and endothelial dysfunction are common mediators in FGR and BPD; each putative targets for prevention and/or therapeutics using interleukin (IL)-1 receptor antagonist (IL-1Ra), melatonin or inhibition of renin-angiotensin-aldosterone system. While BPD is the archetypal respiratory disease of infancy, effects of FGR on pulmonary function are long-term, extending well into childhood. This narrative links FGR in very/extremely preterm infants with BPD through the vascular affliction as a mechanistic and potentially, therapeutic pathway. Our objectives were to depict the burden of disease for FGR and BPD amongst preterm infants, portray vascular involvement in the placenta in FGR and BPD cohorts, provide high resolution vascular ultrasound information in both cohorts with a view to address therapeutic relevance, and lastly, link this information with paediatric age-group lung diseases.
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Li J, Zhao J, Yang XY, Shi J, Liu HT. Successful treatment of pulmonary hypertension in a neonate with bronchopulmonary dysplasia: A case report and literature review. World J Clin Cases 2022; 10:11898-11907. [PMID: 36405256 PMCID: PMC9669840 DOI: 10.12998/wjcc.v10.i32.11898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 09/03/2022] [Accepted: 10/11/2022] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Pulmonary hypertension (PH) is a severe complication of bronchopulmonary dysplasia (BPD) in premature neonates and is closely related to prognosis. However, there is no effective and safe treatment for PH due to BPD in infants. Successful treatment for cases of BPD-associated PH with Tadalafil combined with bosentan is rare. This case may make a significant contribution to the literature because PH is difficult to manage as a serious complication of BPD in preterm infants. Mortality is high, especially when it is complicated by heart failure.
CASE SUMMARY An extremely premature neonate with a gestational age of 26+5 wk and birth weight of 0.83 kg was diagnosed with BPD associated with PH; oral sildenafil did not improve the PH. The infant experienced sudden cardiac arrest and serious heart failure with severe PH. After a series of treatments, including cardiopulmonary resuscitation, mechanical ventilation, and inhaled nitric oxide (iNO), the respiratory and circulatory status improved but the pulmonary artery pressure remained high. Then oral sildenafil was replaced with oral tadalafil and bosentan; pulmonary artery pressure improved, and the infant recovered at our hospital. After 2 years of follow-up, she is in good condition, without any cardiovascular complications.
CONCLUSION INO can effectively improve the respiratory and circulatory status of infants with PH associated with premature BPD. B-type natriuretic peptide should be routinely measured during hospitalization to evaluate the risk and prognosis of BPD-associated PH in preterm infants. Tadalafil combined with bosentan for the treatment of PH associated with premature BPD was better than sildenafil in this case. Further studies are needed to explore the efficacy and safety of different vasodilators in the treatment of PH associated with premature BPD.
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Affiliation(s)
- Jiao Li
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jing Zhao
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiao-Yan Yang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jing Shi
- Neonatal Ward, West China Second University Hospital, Sichuan University, Chengdu 610066, Sichuan Province, China
| | - Hai-Ting Liu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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12
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Abstract
Inhaled nitric oxide (iNO) therapy had a transformational impact on the management of infants with persistent pulmonary hypertension of the newborn (PPHN). iNO remains the only approved pulmonary vasodilator for PPHN; yet 30% to 40% of patients do not respond or have incomplete response to iNO. Lung recruitment strategies with early surfactant administration and high-frequency ventilation can optimize the response to iNO in the presence of parenchymal lung diseases. Alternate pulmonary vasodilators are used commonly as rescue, life-saving measures, though there is a lack of high-quality evidence supporting their efficacy and safety. This article reviews the available evidence and future directions for research in PPHN.
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13
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Mohammadi E, Noei Teymoordash S, Norouzi AR, Norouzi F, Norouzi HR. Comparison of the Effect of Nifedipine Alone and the Combination of Nifedipine and Sildenafil in Delaying Preterm Labor: A Randomized Clinical Trial. J Family Reprod Health 2021; 15:112-117. [PMID: 34721600 PMCID: PMC8520666 DOI: 10.18502/jfrh.v15i2.6452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Objective: Recently, sildenafil as a drug effective in relaxing smooth muscles can be used as an adjunct to delay the onset of uterine contractions and therefore the occurrence of preterm labor. The aim of this study was to evaluate the effect of nifedipine combination with sildenafil on preterm delivery compared with nifedipine alone. Materials and methods: This randomized double-blinded clinical trial was performed on pregnant women with a gestational age of 26-34 weeks with singleton pregnancy and symptoms of preterm delivery. The mothers were randomly assigned into two groups receiving nifedipine plus sildenafil or those receiving nifedipine alone. The time of delivery, maternal and neonatal complications were compared between the two groups. Results: Mothers who received the combination therapy experienced significantly lower preterm delivery within 72 hours of intervention compared to nifedipine alone (4.5% versus 27.3%, p = 0.002). The rate of delivery during the first 7 days after discharge was 7.6% and 31.8% in nifedipine plus sildenafil and nifedipine alone, respectively (P = 0.001). The prevalence of neonatal respiratory distress syndrome (RDS) as well as mean birth weight was higher in the nifedipine group alone. Treatment protocol with nifedipine and sildenafil compared with nifedipine alone was associated with a significant increase in preterm delivery delay (beta =-5.819, p = 0.001). Conclusion: The use of sildenafil in addition to nifedipine causes more delay in delivery in cases of preterm labor, followed by lower risk for RDS, reduces neonatal intensive care unit (NICU) admission, and preserves neonatal birth weight.
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Affiliation(s)
- Elham Mohammadi
- Department of Obstetrics and Gynecology, Shahid Akbarabadi Clinical Research Development Unit (ShACRDU), Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Somayyeh Noei Teymoordash
- Department of Obstetrics and Gynecology, Firoozgar Hospital, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Ali Reza Norouzi
- Pediatric Respiratory Diseases Research Center (PRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Norouzi
- Department of Midwifery, Arash Women's Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Reza Norouzi
- Department of Gastroenterology, Gastrointestinal and Liver Disease Research Center (GILDRC), Firoozgar Hospital, Iran University of Medical Sciences (IUMS), Tehran, Iran
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14
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He Z, Zhu S, Zhou K, Jin Y, He L, Xu W, Lao C, Liu G, Han S. Sildenafil for pulmonary hypertension in neonates: An updated systematic review and meta-analysis. Pediatr Pulmonol 2021; 56:2399-2412. [PMID: 33983650 DOI: 10.1002/ppul.25444] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 04/21/2021] [Accepted: 04/22/2021] [Indexed: 11/10/2022]
Abstract
OBJECTIVES To provide an updated review and meta-analysis on the efficacy and safety of sildenafil for treating persistent pulmonary hypertension in neonates (PPHN). METHODS PubMed/Medline, SCOPUS, Cochrane Central Register of Controlled Trials, and Web of Science were searched from the inception of publication to January 2021. The principal outcomes include oxygenation parameters, hemodynamic metrics and echocardiographic measurements, as well as adverse outcomes. RESULTS A total of eight studies were included with 216 term and premature neonates with PPHN. Compelling evidence showed the use of sildenafil could improve the prognosis of PPHN neonates, compared with baseline or placebo in neonates with PPHN, and a time-dependent pattern of the improvements can be observed. After 24 h of treatment, the Oxygenation index suggested a steady decrease (SD: -1.80, 95% confidence interval [CI]: -2.92, -0.67) and sildenafil exerted peak effects after 72 h of treatment (SD: -4.02, 95% CI: -5.45, -2.59). No clinically significant side effects were identified. Egger's test and funnel plots of the major outcomes were performed, and the publication bias was not significant. CONCLUSION Improvements were shown in oxygenation index, pulmonary arterial pressure, and adverse outcomes after using sildenafil for PPHN in neonates. However, future research with robust longitudinal or randomized controlled design is still needed.
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Affiliation(s)
- Zonglin He
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China.,Faculty of Medicine, International School, Jinan University, Guangzhou, China
| | - Sui Zhu
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Kai Zhou
- Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China.,Faculty of Medicine, International School, Jinan University, Guangzhou, China
| | - Ya Jin
- Department of Neonatology and Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Longkai He
- Department of Neonatology and Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Weipeng Xu
- Department of Neonatology and Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - CheokUn Lao
- Department of Neonatology and Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Guosheng Liu
- Department of Neonatology and Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Shasha Han
- Department of Neonatology and Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
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15
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Areola ED, Sabinari IW, Usman TO, Abayomi FI, Onyezia O, Onaolapo B, Adetokunbo PO, Adebanjo OO, Oladipupo FR, Olatunji LA. Sildenafil ameliorates leptin resistance and normalizes lipid handling in the hypothalamic and adipose tissues of testosterone-exposed pregnant rats. Heliyon 2021; 7:e07574. [PMID: 34337184 PMCID: PMC8313495 DOI: 10.1016/j.heliyon.2021.e07574] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/01/2021] [Accepted: 07/12/2021] [Indexed: 12/22/2022] Open
Abstract
Leptin and hypothalamic-adipose lipid handling are relevant in determining the shift of metabolic activities. There are scanty findings connecting glucose dysregulation as a result of hyperandrogenism during gestation to hypothalamic-adipose axis and leptin resistance. Sildenafil has recently gained attention in the prevention of intra-uterine growth restriction. The present study aimed at demonstrating the effect of sildenafil on leptin resistance and hypothalamic-adipose lipid handling in testosterone-exposed pregnant rats. Three groups of pregnant Wistar rats (n = 5/group) received olive oil (Ctr, S.C.) or testosterone propionate (Tes, 3.0 mg/kg; sc)or testosterone propionate (3.0 mg/kg; sc) and sildenafil (Tes + PDE5, 50 mg/kg; po)from gestational day 14-19. Blood samples, hypothalamus and adipose tissue were excised for biochemical analysis on day 20. Adipose and body weights, plasma leptin and adiponectin, adipose and hypothalamic leptin and triglyceride, adipose uric acid, hypothalamic Nrf2, catalase and nitric oxide were reduced following gestational testosterone exposure. Also, fasting insulin, plasma triglyceride, uric acid, leptin-adiponectin ratio, hypothalamic free fatty acid, total cholesterol, uric acid, aspartate transaminase and cyclic guanine monophosphate were elevated by testosterone exposure to pregnant animals. Sildenafil ameliorated leptin resistance and normalized hypothalamic-adipose lipid handling. Therefore, sildenafil protects against testosterone-induced leptin resistance and adverse hypothalamic-adipose lipid handling in pregnant rats.
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Affiliation(s)
- Emmanuel Damilare Areola
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Nigeria
| | - Isaiah Woru Sabinari
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Nigeria
| | - Taofeek Olumayowa Usman
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Nigeria.,Cardiovascular Unit, Department of Physiology, College of Health Sciences, Osun State University, Osogbo, Nigeria
| | - Faith Ifeoluwa Abayomi
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Nigeria
| | - Onyeka Onyezia
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Nigeria
| | - Bisola Onaolapo
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Nigeria
| | - Phebe Oluwaseun Adetokunbo
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Nigeria
| | - Olympus Oyewole Adebanjo
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Nigeria
| | - Funmilayo Rebecca Oladipupo
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Nigeria
| | - Lawrence Aderemi Olatunji
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Nigeria
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16
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Areola ED, Adewuyi IJ, Usman TO, Tamunoibuomi G, Arogundade LK, Olaoye B, Matt-Ojo DD, Jeje AO, Oyabambi AO, Afolayan EA, Olatunji LA. Sildenafil augments fetal weight and placental adiponectin in gestational testosterone-induced glucose intolerant rats. Toxicol Rep 2021; 8:1358-1368. [PMID: 34277360 PMCID: PMC8271103 DOI: 10.1016/j.toxrep.2021.06.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 06/04/2021] [Accepted: 06/14/2021] [Indexed: 02/07/2023] Open
Abstract
Testosterone induces intra-uterine growth restriction (IUGR) with maternal glucose dysregulation and oxidant release in various tissues. Adiponectin, which modulates the antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is expressed in the placenta and affects fetal growth. Sildenafil, a phosphodiesterase type 5 inhibitor (PDE5i), used mainly in erectile dysfunction has been widely studied as a plausible pharmacologic candidate in IUGR. Therefore, the present study sought to determine the effect of PDE5i on placental adiponectin/Nrf2 pathway in gestational testosterone-induced impaired glucose tolerance and fetal growth. Fifteen pregnant Wistar rats were allotted into three groups (n = 5/group) receiving vehicles (Ctr; distilled water and olive oil), testosterone propionate (Tes; 3.0 mg/kg; sc) or combination of testosterone propionate (3.0 mg/kg; sc) and sildenafil (50.0 mg/kg; po) from gestational day 14-19. On gestational day 20, plasma and placenta homogenates were obtained for biochemical analysis as well as fetal biometry. Pregnant rats exposed to testosterone had 4-fold increase in circulating testosterone compared with control (20.9 ± 2.8 vs 5.1 ± 1.7 ng/mL; p < 0.05) whereas placenta testosterone levels were similar in testosterone- and vehicle-treated rats. Exposure to gestational testosterone caused reduction in fetal and placental weights, placental Nrf2 and adiponectin. Moreover, impaired glucose tolerance, elevated plasma triglyceride-glucose (TyG) index, placental triglyceride, total cholesterol, lactate, malondialdehyde and alanine aminotransferase were observed in testosterone-exposed rats. Treatment with sildenafil improved glucose tolerance, plasma TyG index, fetal and placental weights and reversed placental adiponectin in testosterone-exposed pregnant rats without any effect on placental Nrf2. Therefore, in testosterone-exposed rats, sildenafil improves impaired glucose tolerance, poor fetal outcome which is accompanied by augmented placental adiponectin regardless of depressed Nrf2.
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Affiliation(s)
- Emmanuel Damilare Areola
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Ifeoluwa Jesufemi Adewuyi
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Taofeek Olumayowa Usman
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
- Cardiovascular Unit, Department of Physiology, College of Health Sciences, Osun State University, Osogbo, Nigeria
| | - God’sgift Tamunoibuomi
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Lucy Kemi Arogundade
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Barakat Olaoye
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Deborah Damilayo Matt-Ojo
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Abdulrazaq Olatunji Jeje
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Adewumi Oluwafemi Oyabambi
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Enoch Abiodun Afolayan
- Department of Pathology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
| | - Lawrence Aderemi Olatunji
- HOPE Cardiometabolic Research Team and Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria
- Corresponding author at: Department of Physiology, University of Ilorin, P.M.B. 1515, Ilorin, 240003, Nigeria.
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17
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Baczynski M, Kelly E, McNamara PJ, Shah PS, Jain A. Short and long-term outcomes of chronic pulmonary hypertension in preterm infants managed using a standardized algorithm. Pediatr Pulmonol 2021; 56:1155-1164. [PMID: 33270376 DOI: 10.1002/ppul.25200] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 11/25/2020] [Accepted: 11/27/2020] [Indexed: 01/22/2023]
Abstract
BACKGROUND There is limited data on management strategies for chronic pulmonary hypertension (cPH) in chronic lung disease (CLD) of prematurity. Our objective was to evaluate clinical outcomes following a standardized policy, wherein only cPH with right-ventricular (RV) dilatation was treated and diuretics were employed as first-line therapy; cPH without RV-dilatation was managed expectantly. METHOD In this retrospective cohort study, all infants with CLD were categorized as "CLD-only" or "CLD-cPH," using echocardiography at ≥36 weeks postmenstrual age. Intergroup comparison was performed. Regression analysis examined the association between cPH and primary outcome of death or disability at 18-24 months. RESULTS Of 128 CLD infants, 48 (38%) had cPH, of which 29 (60%) received diuretics. Symptomatic improvement within 1-week was recorded in 90%. Although CLD-cPH had worse in-hospital respiratory course than CLD-only, all post-discharge respiratory and neurodevelopmental outcomes were similar. cPH was not associated with death or disability (adjusted odds ratio, 1.02; 95% confidence interval, 0.32-3.27). Disease progression treated with sildenafil occurred in 2 (4%) cases. There was no death from respiratory or RV failure. CONCLUSION Primary treatment of CLD-cPH with diuretics using RV-dilatation as therapeutic threshold, may result in symptomatic improvement, disease stabilization and post-discharge outcomes comparable to infants without cPH.
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Affiliation(s)
- Michelle Baczynski
- Department of Respiratory Therapy, Mount Sinai Hospital, Toronto, Canada
| | - Edmond Kelly
- Department of Pediatrics, Mount Sinai Hospital, Toronto, Canada
| | - Patrick J McNamara
- Division of Neonatology, University of Iowa Stead Family Children's Hospital, Iowa, USA
| | - Prakesh S Shah
- Department of Pediatrics, Mount Sinai Hospital, Toronto, Canada.,Lunnenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.,Department of Pediatrics, University of Toronto, Toronto, Canada
| | - Amish Jain
- Department of Pediatrics, Mount Sinai Hospital, Toronto, Canada.,Lunnenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.,Department of Pediatrics, University of Toronto, Toronto, Canada.,Department of Physiology, University of Toronto, Toronto, Canada
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18
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Children with Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension Treated with Pulmonary Vasodilators-The Pediatric Cardiologist Point of View. CHILDREN-BASEL 2021; 8:children8050326. [PMID: 33922327 PMCID: PMC8145230 DOI: 10.3390/children8050326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/13/2021] [Accepted: 04/19/2021] [Indexed: 11/17/2022]
Abstract
Pulmonary hypertension in children with bronchopulmonary dysplasia (BPD-PH) significantly worsens the prognosis. Pulmonary vasodilators are often used in BPD-PH but the short-term outcome of treatment is not well described. The aim of this study was to evaluate BPD-PH children diagnosed beyond 36 weeks postmenstrual age treated with pulmonary vasodilators (sildenafil, bosentan, or both) and to assess the short and long-term effect of oral pulmonary vasodilators treatment. Twenty patients were included in the study. Cardiology evaluation (WHO-FC, NTproBNP, oxygen saturation, pulmonary to systemic pressure ratio PAP/SAP) was performed at diagnosis and after treatment initiation. In the majority of patients improvement in all evaluated factors was observed. No side effects of vasodilators were observed. PH resolved in 10 patients after a mean of 21.4 months of treatment. Six patients died. The number of poor prognostic factors commonly used to assess patients with pulmonary arterial hypertension (PAH) decreased significantly during BPD-PH treatment. The influence of BPD-PH perinatal risk factors on prognosis was considered but was not confirmed. In conclusion, the treatment of BPD-PH with pulmonary vasodilators was well tolerated and led to a clinical improvement with the possibility of discontinuation without recurrence of PH. Prognostic factors used in pediatric PAH risk stratification also seem to be useful in assessing treatment efficacy and prognosis in patients with BPD-PH.
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19
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Li Z, Lv X, Liu Q, Dang D, Wu H. Update on the use of sildenafil in neonatal pulmonary hypertension: a narrative review of the history, current administration, and future directions. Transl Pediatr 2021; 10:998-1007. [PMID: 34012848 PMCID: PMC8107873 DOI: 10.21037/tp-20-277] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Pulmonary hypertension (PH) is a life-threatening syndrome in neonates and has multiple and varied etiologies. However, few clinical studies have systematically evaluated the treatment regimens for this population. Phosphodiesterase (PDE) inhibitors, such as milrinone, tadalafil, dipyridamole, and sildenafil, are the most important regulators of vascular relaxation in the normal pulmonary vascular transition after birth, and these agents are widely used in the treatment of PH. Sildenafil, a representative PDE-5 inhibitor, has an important role as a single mode of therapy. However, the lack of evidence from pharmacokinetic and clinical trials has limited the emergence of standardized treatment regimens for sildenafil. There are also differing opinions among researchers regarding the best route of sildenafil administration. Due to the interindividual variability in the neonatal population, it is worth selecting the most suitable route of sildenafil administration according to the specific conditions of the neonatal population. These may be evaluated using the oxygenation index (OI), pulmonary artery pressure, mean blood pressure, and the serological index. This article reviews the clinical data on the use of sildenafil, focusing on the current and promising alternative routes of administration, which may affect subsequent clinical research in term and preterm neonates.
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Affiliation(s)
- Zhenyu Li
- Department of Neonatology, The First Hospital of Jilin University, Changchun, China
| | - Xiaoming Lv
- Department of Neonatology, The First Hospital of Jilin University, Changchun, China
| | - Qinmei Liu
- Department of Neonatology, The First Hospital of Jilin University, Changchun, China
| | - Dan Dang
- Department of Neonatology, The First Hospital of Jilin University, Changchun, China
| | - Hui Wu
- Department of Neonatology, The First Hospital of Jilin University, Changchun, China
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20
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Du Y, Yuan L, Zhou JG, Huang XY, Lin SB, Yuan M, He Y, Mao WY, Ai DY, Chen C. Echocardiography evaluation of bronchopulmonary dysplasia-associated pulmonary hypertension: a retrospective observational cohort study. Transl Pediatr 2021; 10:73-82. [PMID: 33633939 PMCID: PMC7882291 DOI: 10.21037/tp-20-192] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Echocardiography 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. METHODS A 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. RESULTS Fifty-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). CONCLUSIONS Echocardiogram-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.
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Affiliation(s)
- Yang Du
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China
| | - Lin Yuan
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China
| | - Jian-Guo Zhou
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China
| | - Xiang-Yuan Huang
- Department of Clinical Epidemiology, Children's Hospital of Fudan University, Shanghai, China
| | - Sam Bill Lin
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China
| | - Meng Yuan
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China
| | - Yue He
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China
| | - Wei-Ying Mao
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China
| | - Dan-Yang Ai
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China
| | - Chao Chen
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China
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21
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Nees SN, Rosenzweig EB, Cohen JL, Valencia Villeda GA, Krishnan US. Targeted Therapy for Pulmonary Hypertension in Premature Infants. CHILDREN-BASEL 2020; 7:children7080097. [PMID: 32824244 PMCID: PMC7464771 DOI: 10.3390/children7080097] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 08/13/2020] [Accepted: 08/13/2020] [Indexed: 11/16/2022]
Abstract
Pulmonary hypertension (PH) is common in premature infants with bronchopulmonary dysplasia (BPD) and is associated with significant mortality. Despite expert consensus suggesting the use of targeted therapies such as phosphodiesterase inhibitors, endothelin receptor antagonists, and prostanoids, there is little data on safety and outcomes in infants with BPD-associated PH (BPD-PH) treated with these medications. We sought to describe the pharmacologic management of BPD-PH and to report outcomes at our institution. Premature infants with BPD-PH born between 2005 and 2016 were included. Follow-up data were obtained through January 2020. A total of 101 patients (61 male, 40 female) were included. Of these, 99 (98.0%) patients were treated with sildenafil, 13 (12.9%) with bosentan, 35 (34.7%) with inhaled iloprost, 12 (11.9%) with intravenous epoprostenol, and nine (8.9%) with subcutaneous treprostinil. A total of 33 (32.7%) patients died during the study period and 10 (9.9%) were secondary to severe to pulmonary hypertension. Of the surviving patients, 57 (83.8%) had follow-up data at a median of 5.1 (range 0.38-12.65) years and 44 (77.2%) were weaned off PH medications at a median 2.0 (range 0-8) years. Mortality for BPD-PH remains high mostly due to co-morbid conditions. However, for those patients that survive to discharge, PH therapies can frequently be discontinued in the first few years of life.
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Affiliation(s)
- Shannon N. Nees
- Division of Pediatric Cardiology, Columbia University Irving Medical Center, New York, NY 10032, USA; (S.N.N.); (E.B.R.)
| | - Erika B. Rosenzweig
- Division of Pediatric Cardiology, Columbia University Irving Medical Center, New York, NY 10032, USA; (S.N.N.); (E.B.R.)
| | - Jennifer L. Cohen
- Division of Pediatric Cardiology, Mount Sinai Medical Center, New York, NY 10029, USA;
| | | | - Usha S. Krishnan
- Division of Pediatric Cardiology, Columbia University Irving Medical Center, New York, NY 10032, USA; (S.N.N.); (E.B.R.)
- Correspondence:
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22
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Baczynski M, Bell EF, Finan E, McNamara PJ, Jain A. Survey of practices in relation to chronic pulmonary hypertension in neonates in the Canadian Neonatal Network and the National Institute of Child Health and Human Development Neonatal Research Network. Pulm Circ 2020; 10:2045894020937126. [PMID: 32728420 PMCID: PMC7366415 DOI: 10.1177/2045894020937126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 06/03/2020] [Indexed: 11/17/2022] Open
Abstract
Current knowledge gaps pertaining to diagnosis and management of neonatal chronic
pulmonary hypertension (cPH) may result in significant variability in clinical practice.
The objective of the study is to understand cPH management practices in neonatal intensive
care units affiliated with the Canadian Neonatal Network (CNN) and National Institute of
Child Health and Human Development Neonatal Research Network (NRN). A 32-question survey
seeking practice details for cPH evaluation, diagnostic criteria, conservative measures,
pharmacotherapeutics, and follow-up was e-mailed to a designated physician at each center.
Responses were described as frequency (percentage) and compared between CNN and NRN, where
appropriate. Overall response rate was 67% (CNN 20/28 (71%), NRN 9/15 (60%)). While 8
(28%) centers had standardized management protocols, 17 (59%) routinely evaluate high-risk
patients; moderate-severe chronic lung disease being the commonest indication. While
interventricular septal flattening on echocardiography was the commonest listed diagnostic
criterion, several adjunctive indices were also identified. Asymptomatic neonates with cPH
were managed expectantly (routine care) in 50% of sites, and using various conservative
measures in others. Pulmonary vasodilators were prescribed for symptomatic cases, with 60%
of sites using them early (86% reporting any use). Seventy-five percent of sites use
inhaled nitric oxide and sildenafil citrate as first- and second-line agents,
respectively. Use of standard protocols, cardiac catheterization, and conservative
measures for asymptomatic cases was more common in NRN units
(p < 0.05). While there is relative homogeneity in patient
identification and diagnostic criteria used for neonatal cPH, significant interunit
inconsistencies still exists in routine evaluation, use of additional investigations,
management of asymptomatic cases, frequency and type of conservative measures, and choice
of pulmonary vasodilators.
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Affiliation(s)
| | - Edward F Bell
- Division of Neonatology, University of Iowa Stead Family Children's Hospital, Iowa City, IA, USA
| | - Emer Finan
- Department of Pediatrics, Mount Sinai Hospital, Toronto, Canada.,Lunnenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.,Department of Paediatrics, University of Toronto, Toronto, Canada
| | - Patrick J McNamara
- Division of Neonatology, University of Iowa Stead Family Children's Hospital, Iowa City, IA, USA.,Physiology, University of Toronto, Toronto, Canada
| | - Amish Jain
- Department of Pediatrics, Mount Sinai Hospital, Toronto, Canada.,Lunnenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.,Department of Paediatrics, University of Toronto, Toronto, Canada
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23
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Beghetti M, Gorenflo M, Ivy DD, Moledina S, Bonnet D. Treatment of pediatric pulmonary arterial hypertension: A focus on the NO-sGC-cGMP pathway. Pediatr Pulmonol 2019; 54:1516-1526. [PMID: 31313530 PMCID: PMC6771736 DOI: 10.1002/ppul.24442] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 05/28/2019] [Indexed: 11/20/2022]
Abstract
OBJECTIVE While pulmonary arterial hypertension (PAH) is rare in infants and children, it results in substantial morbidity and mortality. In recent years, prognosis has improved, coinciding with the introduction of new PAH-targeted therapies, although much of their use in children is off-label. Evidence to guide the treatment of children with PAH is less extensive than for adults. The goal of this review is to discuss the treatment recommendations for children with PAH, as well as the evidence supporting the use of prostanoids, endothelin receptor antagonists (ERAs), and phosphodiesterase type 5 inhibitors (PDE5i) in this setting. DATA SOURCES Nonsystematic PubMed literature search and authors' expertise. STUDY SELECTION Articles were selected concentrating on the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway in PAH. The methodology of an ongoing study evaluating the sGC stimulator riociguat in children with PAH is also described. RESULTS Despite recent medical advances, improved therapeutic strategies for pediatric PAH are needed. The efficacy and tolerability of riociguat in adults with PAH have been well trialed. CONCLUSION The pooling of data across trials, supplemented by registry data, will help to confirm the safety and tolerability of prostanoids, ERAs, and PDE5i in children. Ongoing studies will clarify the place of sGC stimulators in the treatment strategy for pediatric PAH.
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Affiliation(s)
- Maurice Beghetti
- Pediatric Cardiology Unit and Centre Universitaire de Cardiologie et Chirurgie Cardiaque PédiatriqueChildren's University HospitalGenevaSwitzerland
| | - Matthias Gorenflo
- Department of Pediatrics II, Pediatric Cardiology and Congenital Heart Defects, Center for PediatricsUniversity Hospital HeidelbergGermany
| | - D. Dunbar Ivy
- Children's Hospital Colorado, Heart InstituteUniversity of Colorado School of MedicineDenverColorado
| | - Shahin Moledina
- Cardiology DepartmentGreat Ormond Street Hospital for Children NHS Foundation TrustLondonUK
| | - Damien Bonnet
- M3C‐Paediatric Cardiology, Necker Enfants Malades, AP‐HPUniversité Paris DescartesParisFrance
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Ferreira RDDS, Negrini R, Bernardo WM, Simões R, Piato S. The effects of sildenafil in maternal and fetal outcomes in pregnancy: A systematic review and meta-analysis. PLoS One 2019; 14:e0219732. [PMID: 31339910 PMCID: PMC6655684 DOI: 10.1371/journal.pone.0219732] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 07/02/2019] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND The number of studies associating the use of sildenafil in gestation is increasing. This drug inhibits phosphodiesterase type 5 (PDE5), an enzyme responsible for degradation of nitric oxide, and its efficacy is greater in the placental territory, as the maternal side of the placenta have more PDE5 than other sites. For this reason, promising results have been observed related to the prevention of preeclampsia and intrauterine growth restriction and to improvement of maternal-fetal morbidity in cases of placental insufficiency. OBJECTIVE To evaluate the benefits of using sildenafil in pregnancy. SEARCHED STRATEGY MEDLINE, ClinicalTrials.gov, Embase, LILACS and Cochrane databases were searched through September 2018. There was no restriction in language or year of publication. This study was registered in PROSPERO (CRD42017060288). SELECTION CRITERIA Randomized clinical trials which used sildenafil for treatment or prevention of obstetric diseases compared with placebo were selected. DATA COLLECTION AND ANALYSIS The results were obtained using the inverse variance method for continuous variables and Man-Whitney for categorical variables. MAIN RESULTS Among a population of 598 pregnant women from the seven clinical trials included, 139 had pre-eclampsia, 275 had intrauterine growth restriction, and 184 had oligohydramnios. A significant increase of 222.58 grams [27.75 to 417.41] was observed in the fetal weight at birth of patients taking sildenafil. The other outcomes did not show any statistical significance. This may be due to the small number of patients used in each study and the great heterogeneity between the groups. CONCLUSIONS Sildenafil could be associated with increasing fetal weight at birth in placental insufficiency despite the limitations of this meta-analysis, even though more studies in this field are needed to introduce this drug into obstetric clinical practice.
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Affiliation(s)
- Raquel Domingues da Silva Ferreira
- Department of Obstetrics & Gynaecology, Irmandade Santa Casa de Misericórdia de São Paulo, São Paulo, Brazil, São Paulo
- Department of Obstetrics & Gynaecology, Hospital Israelita Albert Einstein, São Paulo, Brazil, São Paulo
| | - Romulo Negrini
- Department of Obstetrics & Gynaecology, Irmandade Santa Casa de Misericórdia de São Paulo, São Paulo, Brazil, São Paulo
- Department of Obstetrics & Gynaecology, Hospital Israelita Albert Einstein, São Paulo, Brazil, São Paulo
| | | | - Ricardo Simões
- Medicine Department, Universidade de São Paulo, São Paulo, Brazil, São Paulo
| | - Sebastião Piato
- Department of Obstetrics & Gynaecology, Irmandade Santa Casa de Misericórdia de São Paulo, São Paulo, Brazil, São Paulo
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Abstract
Introduction: Bronchopulmonary dysplasia (BPD) is a common long-term adverse complication of very premature delivery. Affected infants can suffer chronic respiratory morbidities including lung function abnormalities and reduced exercise capacity even as young adults. Many studies have investigated possible preventative strategies; however, it is equally important to identify optimum management strategies for infants with evolving or established BPD. Areas covered: Respiratory support modalities and established and novel pharmacological treatments. Expert opinion: Respiratory support modalities including proportional assist ventilation and neurally adjusted ventilatory assist are associated with short term improvements in oxygenation indices. Such modalities need to be investigated in appropriate RCTs. Many pharmacological treatments are routinely used with a limited evidence base, for example diuretics. Stem cell therapies in small case series are associated with promising results. More research is required before it is possible to determine if such therapies should be investigated in large RCTs with long-term outcomes.
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Affiliation(s)
- Emma Williams
- a Department of Women and Children's Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London , UK.,b The Asthma UK Centre for Allergic Mechanisms in Asthma, King's College London , UK
| | - Anne Greenough
- a Department of Women and Children's Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London , UK.,c NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London , London , UK
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van der Graaf M, Rojer LA, Helbing WA, Reiss IKM, Etnel JRG, Bartelds B. EXPRESS: Sildenafil for bronchopulmonary dysplasia and pulmonary hypertension: a meta-analysis. Pulm Circ 2019; 9:2045894019837875. [PMID: 30803328 PMCID: PMC6681505 DOI: 10.1177/2045894019837875] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Accepted: 02/19/2019] [Indexed: 01/28/2023] Open
Abstract
Bronchopulmonary dysplasia (BPD) is the most common complication in preterm infants and often complicated by pulmonary hypertension (PH), leading to substantial morbidity and mortality. Sildenafil is often used to treat PH and improve symptoms in this condition, even though evidence of safety and effectiveness is scarce. The aim of this study was to perform a systematic review and meta-analysis about the effectiveness and safety of chronic use of sildenafil in preterm infants with BPD-associated PH. Data sources were PubMed, EMBASE, and Medline. Studies reporting the effectiveness of sildenafil therapy in BPD-associated PH in newborns and infants were included. All-cause mortality, improvement in PH, improvement in respiratory scores, and adverse events were extracted. Five studies were included, yielding a total of 101 patients with 94.2 patient-years of total follow-up. The pooled mortality rate was 29.7%/year (95% confidence interval [CI] = 6.8–52.7). Estimated pulmonary arterial pressure improved > 20% in 69.3% (95% CI = 56.8–81.8) of patients within 1–6 months. Respiratory scores improved in 15.0% (95% CI = 0.0–30.4) of patients within 2–7 days. There were no serious adverse events during sildenafil therapy. This systematic review shows that in the treatment of BPD-associated PH in preterm infants, sildenafil may be associated with improvement in PAP and respiratory scores. However, there is no clear evidence of its effect on mortality rates. Considering BPD as a complex disease with variable expression patterns, these results support the need for a prospective registry and standardized approach.
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Affiliation(s)
- Marisa van der Graaf
- Department of Pediatrics, Division of
Cardiology, Erasmus University Medical Centre - Sophia Children’s Hospital,
Rotterdam, The Netherlands
| | - Leonne Arindah Rojer
- Department of Pediatrics, Division of
Cardiology, Erasmus University Medical Centre - Sophia Children’s Hospital,
Rotterdam, The Netherlands
| | - Willem Arnold Helbing
- Department of Pediatrics, Division of
Cardiology, Erasmus University Medical Centre - Sophia Children’s Hospital,
Rotterdam, The Netherlands
- Department of Pediatrics, Division of
Cardiology, Radboud University Medical Centre - Amalia Children’s Hospital,
Nijmegen, The Netherlands
| | - Irwin Karl Marcel Reiss
- Department of Pediatrics, Division of
Cardiology, Erasmus University Medical Centre - Sophia Children’s Hospital,
Rotterdam, The Netherlands
| | | | - Beatrijs Bartelds
- Department of Pediatrics, Division of
Cardiology, Erasmus University Medical Centre - Sophia Children’s Hospital,
Rotterdam, The Netherlands
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Thompson EJ, Perez K, Hornik CP, Smith PB, Clark RH, Laughon M. Sildenafil Exposure in the Neonatal Intensive Care Unit. Am J Perinatol 2019; 36:262-267. [PMID: 30081404 PMCID: PMC6996478 DOI: 10.1055/s-0038-1667378] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
OBJECTIVE Pulmonary hypertension causes substantial morbidity and mortality in infants. Although Food and Drug Administration approved to treat pulmonary arterial hypertension in adults, sildenafil is not approved for infants. We sought to describe sildenafil exposure and associated diagnoses and outcomes in infants. STUDY DESIGN Retrospective cohort of neonates discharged from more than 300 neonatal intensive care units from 2001 to 2016. RESULTS Sildenafil was administered to 1,336/1,161,808 infants (0.11%; 1.1 per 1,000 infants); 0/35,977 received sildenafil in 2001 versus 151/90,544 (0.17%; 1.7 per 1,000 infants) in 2016. Among infants <32 weeks' gestational age (GA) with enough data to determine respiratory outcome, 666/704 (95%) had bronchopulmonary dysplasia (BPD). Among infants ≥32 weeks GA, 248/455 (55%) had BPD and 76/552 (14%) were diagnosed with meconium aspiration. Overall, 209/921 (23%) died prior to discharge. CONCLUSION The use of sildenafil has increased since 2001. Exposed infants were commonly diagnosed with BPD. Further studies evaluating dosing, safety, and efficacy of sildenafil are needed.
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Affiliation(s)
| | - Krystle Perez
- Department of Pediatrics, University of Washington, Seattle, Washington
| | - Christoph P. Hornik
- Department of Pediatrics, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
| | - P. Brian Smith
- Department of Pediatrics, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
| | - Reese H. Clark
- Pediatrix-Obstetrix Center for Research and Education, Sunrise, Florida
| | - Matthew Laughon
- Department of Pediatrics, University of Washington, Seattle, Washington
- Division of Neonatal-Perinatal Medicine, UNC Hospital, Chapel Hill, North Carolina
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Qasim A, Dasgupta S, Aly AM, Jain SK. Sildenafil Use in the Treatment of Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension: A Case Series. AJP Rep 2018; 8:e219-e222. [PMID: 30345157 PMCID: PMC6188884 DOI: 10.1055/s-0038-1673343] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 04/18/2018] [Indexed: 11/02/2022] Open
Abstract
Objective This article studies the role of sildenafil in reducing myocardial stress (measured by serial N-terminal pro b-type natriuretic peptide [NTproBNP] levels) secondary to bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH). Study Design This is a case series of three extremely low birth weight infants with severe BPD at 36 weeks' postmenstrual age. All infants had very elevated NTproBNP (> 2,000 ng/dL) levels and echocardiographic evidence of BPD-PH. Sildenafil was started and infants were followed up every 2 weeks clinically along with NTproBNP levels and echocardiograms. Results After 4 weeks of sildenafil treatment, NTproBNP levels decreased significantly in all infants, echocardiograms showed significant improvement in one infant, and respiratory severity score improved significantly in one infant. All infants tolerated sildenafil. Conclusion Sildenafil reduced NTproBNP levels in all infants with BPD-PH but the echocardiographic findings and respiratory scores did not improve consistently. We speculate that this may be due to a delay in diagnosis and initiation of therapy after irreversible pulmonary changes have set in.
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Affiliation(s)
- Amna Qasim
- Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas
| | - Soham Dasgupta
- Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas
| | - Ashraf M Aly
- Division of Pediatric Cardiology, University of Texas Medical Branch, Galveston, Texas
| | - Sunil K Jain
- Division of Neonatology, University of Texas Medical Branch, Galveston, Texas
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Aboudi D, Swaminathan N, Brumberg H, Shi Q, Friedman D, Parvez B, Krishnan U. Sildenafil and Retinopathy of Prematurity in Preterm Infants with Bronchopulmonary Dysplasia. J Pediatr 2018; 199:16-21. [PMID: 29753546 DOI: 10.1016/j.jpeds.2018.04.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 03/30/2018] [Accepted: 04/03/2018] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To assess whether sildenafil is associated with worsening retinopathy of prematurity (ROP) in very low birth weight (VLBW) infants (≤1500 g) with bronchopulmonary dysplasia (BPD). STUDY DESIGN This retrospective case-control study included VLBW infants admitted to the neonatal intensive care unit between January 1, 2006, and December 31, 2012. Each infant treated with sildenafil was assigned 3 unexposed controls matched for gestational age, birth weight, and BPD diagnosis. Severe ROP was defined as stage ≥3 ROP. Worsening ROP was defined as increased stage of ROP within 8 weeks + 4 days after initiation of sildenafil or matched postmenstrual age. RESULTS Twenty-three exposed infants and 69 matched controls met the inclusion criteria for the study (mean birth weight, 715 ± 210 g; mean gestational age, 25 ± 1 weeks). The mean postmenstrual age at sildenafil treatment was 42 ± 8 weeks. Exposed infants had more days of respiratory support (mean, 208 ± 101 days vs 102 ± 33 days; P < .001). Exposed infants had a higher prevalence of severe ROP (26% [6 of 23] vs 7% [5 of 69]; OR, 6.4; 95% CI, 1.2-32.9; P = .026). Five exposed infants and 2 unexposed infants had severe ROP before starting sildenafil and were excluded from the analysis for worsening ROP. The rate of worsening ROP did not differ significantly between exposed infants and unexposed infants ((41% [7 of 17] vs 24% [12 of 51]; OR, 8.4; 95% CI, 0.9-78.6; P = .061). CONCLUSION Although sildenafil treatment was not statistically significantly associated with worsening of ROP, the raw difference in ROP rate is concerning. Larger studies are warranted to confirm this finding.
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Affiliation(s)
- David Aboudi
- Department of Pediatrics, New York Medical College, Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, NY; Department of Epidemiology and Community Health, New York Medical College, Valhalla, NY
| | - Nithya Swaminathan
- Department of Pediatrics, Columbia University Medical Center, New York, NY; Department of Pediatrics, Le Bonheur Hospital, University of Tennessee Health Science Center, Memphis, TN
| | - Heather Brumberg
- Department of Pediatrics, New York Medical College, Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, NY
| | - Qiuhu Shi
- Department of Epidemiology and Community Health, New York Medical College, Valhalla, NY
| | - Deborah Friedman
- Department of Pediatrics, New York Medical College, Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, NY
| | - Boriana Parvez
- Department of Pediatrics, New York Medical College, Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, NY
| | - Usha Krishnan
- Department of Pediatrics, New York Medical College, Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, NY; Department of Pediatrics, Columbia University Medical Center, New York, NY.
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Hwang JS, Rehan VK. Recent Advances in Bronchopulmonary Dysplasia: Pathophysiology, Prevention, and Treatment. Lung 2018; 196:129-138. [PMID: 29374791 DOI: 10.1007/s00408-018-0084-z] [Citation(s) in RCA: 127] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 01/04/2018] [Indexed: 12/16/2022]
Abstract
Bronchopulmonary dysplasia (BPD) is potentially one of the most devastating conditions in premature infants with longstanding consequences involving multiple organ systems including adverse effects on pulmonary function and neurodevelopmental outcome. Here we review recent studies in the field to summarize the progress made in understanding in the pathophysiology, prognosis, prevention, and treatment of BPD in the last decade. The work reviewed includes the progress in understanding its pathobiology, genomic studies, ventilatory strategies, outcomes, and therapeutic interventions. We expect that this review will help guide clinicians to treat premature infants at risk for BPD better and lead researchers to initiate further studies in the field.
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Affiliation(s)
- Jung S Hwang
- Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, 1124 West Carson Street, Torrance, CA, 90502, USA
| | - Virender K Rehan
- Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, 1124 West Carson Street, Torrance, CA, 90502, USA.
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Pulmonary hypertension associated with bronchopulmonary dysplasia in preterm infants. J Reprod Immunol 2017; 124:21-29. [PMID: 29035757 DOI: 10.1016/j.jri.2017.09.013] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 09/11/2017] [Accepted: 09/29/2017] [Indexed: 12/12/2022]
Abstract
Bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension (BPD-PH) are chronic inflammatory cardiopulmonary diseases with devastating short- and long-term consequences for infants born prematurely. The immature lungs of preterm infants are ill-prepared to achieve sufficient gas exchange, thus usually necessitating immediate commencement of respiratory support and oxygen supplementation. These therapies are life-saving, but they exacerbate the tissue damage that is inevitably inflicted on a preterm lung forced to perform gas exchange. Together, air-breathing and necessary therapeutic interventions disrupt normal lung development by aggravating pulmonary inflammation and vascular remodelling, thus frequently precipitating BPD and PH via an incompletely understood pathogenic cascade. BPD and BPD-PH share common risk factors, such as low gestational age at birth, fetal growth restriction and perinatal maternal inflammation; however, these risk factors are not unique to BPD or BPD-PH. Occurring in 17-24% of BPD patients, BPD-PH substantially worsens the morbidity and mortality attributable to BPD alone, thus darkening their outlook; for example, BPD-PH entails a mortality of up to 50%. The absence of a safe and effective therapy for BPD and BPD-PH renders neonatal cardiopulmonary disease an area of urgent unmet medical need. Besides the need to develop new therapeutic strategies, a major challenge for clinicians is the lack of a reliable method for identifying babies at risk of developing BPD and BPD-PH. In addition to discussing current knowledge on pathophysiology, diagnosis and treatment of BPD-PH, we highlight emerging biomarkers that could enable clinicians to predict disease-risk and also optimise treatment of BPD-PH in our tiniest patients.
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Perez M, Lee KJ, Cardona HJ, Taylor JM, Robbins ME, Waypa GB, Berkelhamer SK, Farrow KN. Aberrant cGMP signaling persists during recovery in mice with oxygen-induced pulmonary hypertension. PLoS One 2017; 12:e0180957. [PMID: 28792962 PMCID: PMC5549891 DOI: 10.1371/journal.pone.0180957] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 06/23/2017] [Indexed: 12/25/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD), a common complication of preterm birth, is associated with pulmonary hypertension (PH) in 25% of infants with moderate to severe BPD. Neonatal mice exposed to hyperoxia for 14d develop lung disease similar to BPD, with evidence of associated PH. The cyclic guanosine monophosphate (cGMP) signaling pathway has not been well studied in BPD-associated PH. In addition, there is little data about the natural history of hyperoxia-induced PH in mice or the utility of phosphodiesterase-5 (PDE5) inhibition in established disease. C57BL/6 mice were placed in room air or 75% O2 within 24h of birth for 14d, followed by recovery in room air for an additional 7 days (21d). Additional pups were treated with either vehicle or sildenafil for 7d during room air recovery. Mean alveolar area, pulmonary artery (PA) medial wall thickness (MWT), RVH, and vessel density were evaluated at 21d. PA protein from 21d animals was analyzed for soluble guanylate cyclase (sGC) activity, PDE5 activity, and cGMP levels. Neonatal hyperoxia exposure results in persistent alveolar simplification, RVH, decreased vessel density, increased MWT, and disrupted cGMP signaling despite a period of room air recovery. Delayed treatment with sildenafil during room air recovery is associated with improved RVH and decreased PA PDE5 activity, but does not have significant effects on alveolar simplification, PA remodeling, or vessel density. These data are consistent with clinical studies suggesting inconsistent effects of sildenafil treatment in infants with BPD-associated PH.
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Affiliation(s)
- Marta Perez
- Department of Pediatrics, Northwestern University, Chicago, IL, United States of America
- * E-mail:
| | - Keng Jin Lee
- Department of Pediatrics, Northwestern University, Chicago, IL, United States of America
| | - Herminio J. Cardona
- Department of Pediatrics, Northwestern University, Chicago, IL, United States of America
| | - Joann M. Taylor
- Department of Pediatrics, Northwestern University, Chicago, IL, United States of America
| | - Mary E. Robbins
- Department of Pediatrics, Northwestern University, Chicago, IL, United States of America
| | - Gregory B. Waypa
- Department of Pediatrics, Northwestern University, Chicago, IL, United States of America
| | - Sara K. Berkelhamer
- Department of Pediatrics, University at Buffalo, Buffalo, NY, United States of America
| | - Kathryn N. Farrow
- Department of Pediatrics, Northwestern University, Chicago, IL, United States of America
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34
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Ling R, Greenough A. Advances in emerging treatment options to prevent bronchopulmonary dysplasia. Expert Opin Orphan Drugs 2017. [DOI: 10.1080/21678707.2017.1281736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Davidson LM, Berkelhamer SK. Bronchopulmonary Dysplasia: Chronic Lung Disease of Infancy and Long-Term Pulmonary Outcomes. J Clin Med 2017; 6:E4. [PMID: 28067830 PMCID: PMC5294957 DOI: 10.3390/jcm6010004] [Citation(s) in RCA: 267] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 12/28/2016] [Accepted: 12/28/2016] [Indexed: 12/16/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD) is a chronic lung disease most commonly seen in premature infants who required mechanical ventilation and oxygen therapy for acute respiratory distress. While advances in neonatal care have resulted in improved survival rates of premature infants, limited progress has been made in reducing rates of BPD. Lack of progress may in part be attributed to the limited therapeutic options available for prevention and treatment of BPD. Several lung-protective strategies have been shown to reduce risks, including use of non-invasive support, as well as early extubation and volume ventilation when intubation is required. These approaches, along with optimal nutrition and medical therapy, decrease risk of BPD; however, impacts on long-term outcomes are poorly defined. Characterization of late outcomes remain a challenge as rapid advances in medical management result in current adult BPD survivors representing outdated neonatal care. While pulmonary disease improves with growth, long-term follow-up studies raise concerns for persistent pulmonary dysfunction; asthma-like symptoms and exercise intolerance in young adults after BPD. Abnormal ventilatory responses and pulmonary hypertension can further complicate disease. These pulmonary morbidities, combined with environmental and infectious exposures, may result in significant long-term pulmonary sequalae and represent a growing burden on health systems. Additional longitudinal studies are needed to determine outcomes beyond the second decade, and define risk factors and optimal treatment for late sequalae of disease.
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Affiliation(s)
- Lauren M Davidson
- Department of Pediatrics, University at Buffalo SUNY, Buffalo, NY 14228, USA.
| | - Sara K Berkelhamer
- Department of Pediatrics, University at Buffalo SUNY, Buffalo, NY 14228, USA.
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Ambalavanan N, Aschner JL. Management of hypoxemic respiratory failure and pulmonary hypertension in preterm infants. J Perinatol 2016; 36 Suppl 2:S20-7. [PMID: 27225961 DOI: 10.1038/jp.2016.45] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 02/10/2016] [Accepted: 02/16/2016] [Indexed: 01/26/2023]
Abstract
While diagnoses of hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH) in preterm infants may be based on criteria similar to those in term infants, management approaches often differ. In preterm infants, HRF can be classified as 'early' or 'late' based on an arbitrary threshold of 28 postnatal days. Among preterm infants with late HRF, the pulmonary vascular abnormalities associated with bronchopulmonary dysplasia (BPD) represent a therapeutic challenge for clinicians. Surfactant, inhaled nitric oxide (iNO), sildenafil, prostacyclin and endothelin receptor blockers have been used to manage infants with both early and late HRF. However, evidence is lacking for most therapies currently in use. Chronic oral sildenafil therapy for BPD-associated PH has demonstrated some preliminary efficacy. A favorable response to iNO has been documented in some preterm infants with early PH following premature prolonged rupture of membranes and oligohydramnios. Management is complicated by a lack of clear demarcation between interventions designed to manage respiratory distress syndrome, prevent BPD and treat HRF. Heterogeneity in clinical phenotype, pathobiology and genomic underpinnings of BPD pose challenges for evidence-based management recommendations. Greater insight into the spectrum of disease phenotypes represented by BPD can optimize existing therapies and promote development of new treatments. In addition, better understanding of an individual's phenotype, genotype and biomarkers may suggest targeted personalized interventions. Initiatives such as the Prematurity and Respiratory Outcomes Program provide a framework to address these challenges using genetic, environmental, physiological and clinical data as well as large repositories of patient samples.
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Affiliation(s)
- N Ambalavanan
- Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - J L Aschner
- Department of Pediatrics, and Obstetrics, Gynecology and Women's Health, Albert Einstein College of Medicine; Children's Hospital at Montefiore, Bronx, NY, USA
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Signal Mechanisms of Vascular Remodeling in the Development of Pulmonary Arterial Hypertension. J Cardiovasc Pharmacol 2016; 67:182-90. [DOI: 10.1097/fjc.0000000000000328] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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König K. More safety data: what about efficacy of sildenafil? J Perinatol 2016; 36:79. [PMID: 26814802 DOI: 10.1038/jp.2015.201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- K König
- Children's Hospital Lucerne, Lucerne, Switzerland
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Jeung MS, Kong YH, Sung SI, Song J. Survival of the Infants with Bronchopulmonary Dysplasia and Congenital Heart Disease. NEONATAL MEDICINE 2016. [DOI: 10.5385/nm.2016.23.4.190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Affiliation(s)
- Min Sub Jeung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Hwa Kong
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se In Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jinyoung Song
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Kraemer U, Cochius-den Otter S, Snoek KG, Tibboel D. Pharmacodynamic considerations in the treatment of pulmonary hypertension in infants: challenges and future perspectives. Expert Opin Drug Metab Toxicol 2015; 12:1-19. [DOI: 10.1517/17425255.2016.1116520] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Ribeiro JD, Fischer GB. Chronic obstructive pulmonary diseases in children. J Pediatr (Rio J) 2015; 91:S11-25. [PMID: 26354868 DOI: 10.1016/j.jped.2015.06.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 06/15/2015] [Accepted: 06/16/2015] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES To verify and describe the main events related to the diagnosis and management of chronic obstructive pulmonary diseases in children (COPDC) and adolescents, considering the interrelated physiopathology, genetic, and environmental characteristics. SOURCES Relevant literature from PubMed was selected and reviewed. SUMMARY OF THE FINDINGS COPDC have an environmental and/or genetic origin and its manifestation has manifold genotypes, phenotypes, and endotypes. Although COPDC has no cure, it can be clinically controlled. Chronic cough is the main symptom and bronchiectasis can be present in several COPDC patients. The management of COPDC is more effective if based on guidelines and when treatment regimen adherence is promoted. Oral and inhaled corticosteroids, bronchodilators, inhaled antibiotics, and treatment of pulmonary exacerbation (PE) are the bases of COPDC management, and should be individualized for each patient. CONCLUSIONS Correct diagnosis and knowledge of risk factors and comorbidities are essential in COPDC management. Procedures and drugs used should be based on specific guidelines for each COPDC case. Treatment adherence is critical to obtain the benefits of management. COPDC clinical control must be evaluated by the decrease in PEs, improved quality of life, reduction of pulmonary function loss, and lung structural damage. For most cases of COPDC, monitoring by interdisciplinary teams in specialized reference centers with surveillance strategies and continuous care leads to better outcomes, which must be evaluated by decreasing pulmonary function damage and deterioration, better prognosis, better quality life, and increased life expectancy.
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Affiliation(s)
- Jose Dirceu Ribeiro
- Department of Pediatrics, Faculdade de Ciências Médicas (FCM), Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil.
| | - Gilberto Bueno Fischer
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil
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Ribeiro JD, Fischer GB. Chronic obstructive pulmonary diseases in children. JORNAL DE PEDIATRIA (VERSÃO EM PORTUGUÊS) 2015. [DOI: 10.1016/j.jpedp.2015.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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