Inhaled nitric oxide (iNO) for preventing prematurity-related bronchopulmonary dysplasia (BPD): 7-year follow-up of the European Union Nitric Oxide (EUNO) trial

AbstractObjectivesMost studies of inhaled nitric oxide (iNO) for prevention of bronchopulmonary dysplasia (BPD) in premature infants have focused on short-term mortality and morbidity. Our aim was to determine the long-term effects of iNO.MethodsA 7-year follow-up was undertaken of infants entered into a multicenter, double-blind, randomized, placebo-controlled trial of iNO for prevention of BPD in premature infants born between 24 and 28 weeks plus six days of gestation. At 7 years, survival and hospital admissions since the 2-year follow-up, home oxygen therapy in the past year, therapies used in the previous month and growth assessments were determined. Questionnaires were used to compare general health, well-being, and quality of life.ResultsA total of 305 children were assessed. No deaths were reported. Rates of hospitalization for respiratory problems (6.6 vs. 10.5%, iNO and placebo group, respectively) and use of respiratory medications (6.6 vs. 9.2%) were similar. Two patients who received iNO and one who received placebo had received home oxygen therapy. There were no significant differences in any questionnaire-documented health outcomes.ConclusionsiNO for prevention of BPD in very premature infants with respiratory distress did not result in long-term benefits or adverse long-term sequelae. In the light of current evidence, routine use of iNO cannot be recommended for prevention of BPD in preterm infants.

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Oxigenoterapia Domiciliária de Longa Duração na Criança: Evidências e Questões em Aberto

Acta Médica Portuguesa ◽

10.20344/amp.5185 ◽

2014 ◽

Vol 27 (6) ◽

pp. 717 ◽

Cited By ~ 1

Author(s):

Lia Oliveira ◽

Joana Coelho ◽

Rosário Ferreira ◽

Teresa Nunes ◽

Ana Saianda ◽

...

Keyword(s):

Cystic Fibrosis ◽

Bronchopulmonary Dysplasia ◽

Bronchiolitis Obliterans ◽

Lung Diseases ◽

Oxygen Therapy ◽

Pediatric Population ◽

Home Oxygen Therapy ◽

Neonatal Lung

Introduction: Long-term home oxygen therapy is indicated for patients with chronic hypoxemia. We intend to describe pediatric population on long-term home oxygen therapy followed-up at Pediatric Respiratory Unit of a tertiary care hospital between 2003-2012 and to compare with previous 1991-2000 review; to verify conformity with international and national recommendations and need for specific pediatric national guidelines, non-existent in Portugal. Material and Methods: Retrospective, descriptive and comparative study based on clinical files review. Review the guidelines for oxygen therapy in pediatric population. Results: We studied 86 patients (59.3% males). The median age at the beginning of oxygen therapy was 0.0 (0.0-216.0) months, with a median duration of 15.0 (3.0-223.0) months. The most frequent diagnosis was bronchopulmonary dysplasia (53.5%), followed by bronchiolitis obliterans (14.0%), neurologic disorders (10.5%), cystic fibrosis (8.1%), miscellaneous syndromes (5.8%), sickle-cell disease (3.5%), other neonatal lung diseases (2.3%) and interstitial lung diseases (2.3%). Are maintained on follow-up 53 (61.6%) patients, 38 on oxygen therapy; 12 (13.9%) died. The median time of follow-up was 39.5 (1.0-246.0) months, minim on other neonatal lung diseases and maximum on cystic fibrosis. Comparing with previous review, this shows a relative increase in bronchiolitis obliterans and bronchopulmonary dysplasia patients, with increased duration in the latter, and inclusion of neurologic and hematologic patients. Discussion: Prescription of long-term oxygen therapy in pediatric age mainly occurs in specific diseases of infants and pre-school aged. Neurologic and hematologic patients represent new indications, similarly to international publications. Conclusion: The knowledge of national reality and pediatric orientations are needed for care plans and rational prescription. Keywords: Child; Long-Term Care; Respiratory Insufficiency; Oxygen Inhalation Therapy; Portugal.

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Ancestry and genetic associations with bronchopulmonary dysplasia in preterm infants

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00073.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. L858-L869 ◽

Cited By ~ 9

Author(s):

Dara G. Torgerson ◽

Philip L. Ballard ◽

Roberta L. Keller ◽

Sam S. Oh ◽

Scott Huntsman ◽

...

Keyword(s):

Nitric Oxide ◽

High Risk ◽

Lung Disease ◽

Bronchopulmonary Dysplasia ◽

Premature Infants ◽

Genome Wide Association Study ◽

African Ancestry ◽

Inhaled Nitric Oxide ◽

Race Ethnicity ◽

Hispanic White

Bronchopulmonary dysplasia in premature infants is a common and often severe lung disease with long-term sequelae. A genetic component is suspected but not fully defined. We performed an ancestry and genome-wide association study to identify variants, genes, and pathways associated with survival without bronchopulmonary dysplasia in 387 high-risk infants treated with inhaled nitric oxide in the Trial of Late Surfactant study. Global African genetic ancestry was associated with increased survival without bronchopulmonary dysplasia among infants of maternal self-reported Hispanic white race/ethnicity [odds ratio (OR) = 4.5, P = 0.01]. Admixture mapping found suggestive outcome associations with local African ancestry at chromosome bands 18q21 and 10q22 among infants of maternal self-reported African-American race/ethnicity. For all infants, the top individual variant identified was within the intron of NBL1, which is expressed in midtrimester lung and is an antagonist of bone morphogenetic proteins ( rs372271081 , OR = 0.17, P = 7.4 × 10−7). The protective allele of this variant was significantly associated with lower nitric oxide metabolites in the urine of non-Hispanic white infants ( P = 0.006), supporting a role in the racial differential response to nitric oxide. Interrogating genes upregulated in bronchopulmonary dysplasia lungs indicated association with variants in CCL18, a cytokine associated with fibrosis and interstitial lung disease, and pathway analyses implicated variation in genes involved in immune/inflammatory processes in response to infection and mechanical ventilation. Our results suggest that genetic variation related to lung development, drug metabolism, and immune response contribute to individual and racial/ethnic differences in respiratory outcomes following inhaled nitric oxide treatment of high-risk premature infants.

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Effect of airway administration of budesonide for bronchopulmonary dysplasia in premature infants: A Systematic Review and Meta-Analysis

10.21203/rs.2.16768/v1 ◽

2019 ◽

Author(s):

kaixu wang ◽

Long Chen ◽

Fang Li

Keyword(s):

Bronchopulmonary Dysplasia ◽

Premature Infants ◽

Meta Analysis ◽

Cochrane Library ◽

Optimal Timing ◽

Composite Outcome ◽

Long Term Follow Up ◽

The Cochrane Library

Abstract Objective: Bronchopulmonary dysplasia (BPD) is one of the major challenges in preterm infants despite the therapeutic improvement. Airway administration of budesonide might be a safe and effective way. However, the optimal timing of airway administration is under determined. The meta-analysis was designed to evaluate the effectiveness and safety of early (≤1d after birth) and late (>1d after birth) airway administration of budesonide in decreasing the incidence of BPD and death as the primary outcome . Methods: PubMed, EMBASE, the Cochrane Library, China national knowledge internet (CNKI), China biology medicine disc (CBM), WANFANG data, and China Science and Technology Journal Database were searched for RCTs that compared airway administration of budesonide with controls. The meta-analysis was performed using Review Manager 5.3. Results: Airway administration of budesonide decreased the risk of BPD at 36 weeks PMA and the composite outcome of BPD or death (RR=0.64, 95%CI: 0.55~0.75 and RR=0.71, 95%CI: 0.57~0.89).Moreover, 37% and 36% reduction was observed in the incidence of BPD and the composite outcome of BPD or death in the early airway administration group (≤1d) (RR=0.63, 95%CI: 0.53~0.75 and RR=0.64, 95%CI: 0.47~0.87 ), while no difference was found in late airway administration group (>1d) (RR=0.74, 95%CI: 0.49~1.13 and RR=0.88, 95%CI: 0.64~1.21). Conclusion: early airway administration (≤1d) of budesonide reduced the incidence of BPD alone or composite outcome of death or BPD, and it is safe without increasing death as well as other short-term side effects. However, because of the small number of infants in late airway administration group and lacking of long-term follow-up, more randomized controlled trials are needed to testify for the outcomes. Keywords: Budesonide, bronchopulmonary dysplasia, premature infants, meta-analysis, airway administration.

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Impact of a protocol-driven unified service for neonates with bronchopulmonary dysplasia

ERJ Open Research ◽

10.1183/23120541.00183-2018 ◽

2019 ◽

Vol 5 (1) ◽

pp. 00183-2018

Author(s):

Natalie Batey ◽

Dushyant Batra ◽

Jon Dorling ◽

Jayesh Mahendra Bhatt

Keyword(s):

Bronchopulmonary Dysplasia ◽

Oxygen Therapy ◽

Hospital Readmissions ◽

Readmission Rates ◽

Hospital Readmission Rates ◽

Stay Time ◽

Overnight Oximetry ◽

Number Of Discharges

AimA new specialised service for preterm infants with bronchopulmonary dysplasia requiring long-term oxygen therapy (LTOT) was established in 2007, led by the paediatric respiratory team, transitioning from neonatal-led follow-up. The new service included the utilisation of a clear protocol. Our objective was to review whether this service initiation led to a reduction of time in LTOT and hospital readmissions.MethodsWe performed a retrospective cohort study of infants born at <32 weeks’ gestation requiring LTOT in a single tertiary neonatal service. Cases were identified from hospital records, BadgerNet and a local database for two cohorts, 2004–2006 and 2008–2010. Data collected for infants requiring LTOT included demographic details, length of neonatal stay, time in oxygen and hospital attendance rates.ResultsThe initiation of the service led to an increase in the number of discharges in LTOT: 13.1% of infants born alive before 32 weeks’ gestation in comparison to 3.5% (p<0.001). However, the length of time in LTOT reduced from 15 to 5 months (p=0.01). There was no difference in hospital readmission rates (p=0.365).ConclusionsIn our experience the increase in neonates requiring LTOT is likely to be due to enhanced provision of overnight oximetry studies prior to discharge. Structured monitoring and weaning led to a shorter duration of home oxygen therapy.

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Ancestry and Genetic Associations with Bronchopulmonary Dysplasia in Preterm Infants

10.1101/263814 ◽

2018 ◽

Cited By ~ 1

Author(s):

Dara G. Torgerson ◽

Philip L. Ballard ◽

Roberta L. Keller ◽

Sam S. Oh ◽

Scott Huntsman ◽

...

Keyword(s):

Nitric Oxide ◽

High Risk ◽

Lung Disease ◽

Bronchopulmonary Dysplasia ◽

Premature Infants ◽

Genome Wide Association Study ◽

African Ancestry ◽

Inhaled Nitric Oxide ◽

Race Ethnicity ◽

Hispanic White

ABSTRACTBronchopulmonary dysplasia in premature infants is a common and often severe lung disease with long term sequelae. A genetic component is suspected but not fully defined. We performed an ancestry and genome-wide association study to identify variants, genes and pathways associated with survival without bronchopulmonary dysplasia in 387 high-risk infants treated with inhaled nitric oxide in the Trial of Late Surfactant study. Global African genetic ancestry was associated with increased survival without bronchopulmonary dysplasia among infants of maternal self-reported Hispanic White race/ethnicity (OR=4.5, p=0.01). Admixture mapping found suggestive outcome associations with local African ancestry at 18q21 and 10q22 among infants of maternal self-reported African American race/ethnicity. For all infants, the top individual variant identified was within the intron of NBL1, which is expressed in mid-trimester lung and is an antagonist of bone morphogenetic proteins (rs372271081, OR=0.17, p=7.4 × 10−7). The protective allele of this variant was significantly associated with lower nitric oxide metabolites in the urine of non-Hispanic white infants (p= 0.006), supporting a role in the racial differential response to nitric oxide. Interrogating genes upregulated in bronchopulmonary dysplasia lungs indicated association with variants in CCL18, a cytokine associated with fibrosis and interstitial lung disease, and pathway analyses implicated variation in genes involved in immune/inflammatory processes in response to infection and mechanical ventilation. Our results suggest that genetic variation related to lung development, drug metabolism, and immune response contribute to individual and racial/ethnic differences in respiratory outcomes following inhaled nitric oxide treatment of high-risk premature infants.

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Pharmacotherapy for the Prevention of Bronchopulmonary Dysplasia: Can Anything Compete with Caffeine and Corticosteroids?

Neonatal Network The Journal of Neonatal Nursing ◽

10.1891/0730-0832.38.4.242 ◽

2019 ◽

Vol 38 (4) ◽

pp. 242-249 ◽

Cited By ~ 1

Author(s):

Christopher McPherson

Keyword(s):

Nitric Oxide ◽

Clinical Practice ◽

Bronchopulmonary Dysplasia ◽

Diuretic Therapy ◽

Inhaled Nitric Oxide ◽

Multiple Risk Factors ◽

Systemic Corticosteroids ◽

Optimal Dosing ◽

Nitric Oxide Therapy

Bronchopulmonary dysplasia (BPD) is a morbidity of prematurity with implications for respiratory and neurologic health into adulthood. Multiple risk factors contribute to the development of BPD leading to examination of various prevention strategies. The roles of systemic corticosteroids and caffeine have been addressed by the American Academy of Pediatrics. The place in therapy of other agents commonly utilized in clinical practice remains unclear. Inhaled nitric oxide has been the subject of numerous large, randomized controlled trials in preterm infants. Despite sound rationale, these trials have largely failed to document benefit, suggesting a limited role for inhaled nitric oxide therapy in the preterm population. In contrast, intramuscular vitamin A has been documented to reduce the incidence of BPD in randomized trials. However, the invasiveness and the sporadic availability of this therapy have led to decreased utilization. All macrolide antibiotics do not appear to have a similar impact on the incidence of BPD; however, azithromycin administered to infants colonized with Ureaplasma may have impact. Questions remain about the optimal dosing approach and long-term safety of this intervention. Finally, diuretic therapy is widely used in clinical practice despite significant toxicities and limited data supporting a role in BPD prevention. Taken together, available data suggest that caffeine and selective use of corticosteroids remain the mainstays of pharmacologic BPD prevention.

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