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      Systematic Review of Inhaled Bronchodilator and Corticosteroid Therapies in Infants with Bronchopulmonary Dysplasia: Implications and Future Directions

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          Abstract

          Background

          There is much debate surrounding the use of inhaled bronchodilators and corticosteroids for infants with bronchopulmonary dysplasia (BPD).

          Objective

          The objective of this systematic review was to identify strengths and knowledge gaps in the literature regarding inhaled therapies in BPD and guide future research to improve long-termoutcomes.

          Methods

          The databases of Academic Search Complete, CINAHL, PUBMED/MEDLINE, and Scopus were searched for studies that evaluated both acute and long-term clinical outcomes related to the delivery and therapeutic efficacy of inhaled beta-agonists, anticholinergics and corticosteroids in infants with developing and/or established BPD.

          Results

          Of 181 articles, 22 met inclusion criteria for review. Five evaluated beta-agonist therapies ( n = 84, weighted gestational age (GA) of 27.1(26–30) weeks, weighted birth weight (BW) of 974(843–1310) grams, weighted post menstrual age (PMA) of 34.8(28–39) weeks, and weighted age of 53(15–86) days old at the time of evaluation). Fourteen evaluated inhaled corticosteroids ( n = 2383, GA 26.2(26–29) weeks, weighted BW of 853(760–1114) grams, weighted PMA of 27.0(26–31) weeks, and weighted age of 6(0–45) days old at time of evaluation). Three evaluated combination therapies ( n = 198, weighted GA of 27.8(27–29) weeks, weighted BW of 1057(898–1247) grams, weighted PMA of 30.7(29–45) weeks, and age 20(10–111) days old at time of evaluation).

          Conclusion

          Whether inhaled bronchodilators and inhaled corticosteroids improve long-term outcomes in BPD remains unclear. Literature regarding these therapies mostly addresses evolving BPD. There appears to be heterogeneity in treatment responses, and may be related to varying modes of administration. Further research is needed to evaluate inhaled therapies in infants with severe BPD. Such investigations should focus on appropriate definitions of disease and subject selection, timing of therapies, and new drugs, devices and delivery methods as compared to traditional methods across all modalities of respiratory support, in addition to the assessment of long-term outcomes of initial responders.

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          Most cited references64

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          Early Inhaled Budesonide for the Prevention of Bronchopulmonary Dysplasia.

          Systemic glucocorticoids reduce the incidence of bronchopulmonary dysplasia among extremely preterm infants, but they may compromise brain development. The effects of inhaled glucocorticoids on outcomes in these infants are unclear.
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            Influence of nebulizer type, position, and bias flow on aerosol drug delivery in simulated pediatric and adult lung models during mechanical ventilation.

            The effectiveness of aerosol drug delivery during mechanical ventilation is influenced by the patient, ventilator, and nebulizer variables. The impact of nebulizer type, position on the ventilator circuit, and bias flow on aerosol drug delivery has not been established for different age populations. To determine the influence of nebulizer position and bias flow with a jet nebulizer and a vibrating-mesh nebulizer on aerosol drug delivery in simulated and mechanically ventilated pediatric and adult patients. Albuterol sulfate (2.5 mg) was nebulized with a jet nebulizer and a vibrating-mesh nebulizer, using simulated pediatric and adult lung models. The 2 nebulizer positions were: (1) jet nebulizer placed 15 cm from the Y-piece adapter, and vibrating-mesh nebulizer attached directly to the Y-piece; and (2) jet nebulizer placed prior to the heated humidifier with 15 cm of large-bore tubing, and vibrating-mesh nebulizer positioned at an inlet to the humidifier. A ventilator with a heated humidifier and ventilator circuit was utilized in both lung models. The adult ventilator settings were V(T) 500 mL, PEEP 5 cm H2O, respiratory rate 20 breaths/min, peak inspiratory flow 60 L/min, and descending ramp flow waveform. The pediatric ventilator settings were V(T) 100 mL, PEEP 5 cm H2O, respiratory rate 20 breaths/min, inspiratory time 1 s. We tested bias flows of 2 and 5 L/min. The adult and pediatric lung models used 8-mm and 5-mm inner-diameter endotracheal tubes, respectively. Each experiment was run 3 times (n = 3). The albuterol sulfate was eluted from the filter and analyzed via spectrophotometry (276 nm). Nebulizer placement prior to the humidifier increased drug delivery with both the jet nebulizer and the vibrating-mesh nebulizer, with a greater increase with the vibrating-mesh nebulizer. Higher bias flow reduced drug delivery. Drug delivery with the vibrating-mesh nebulizer was 2-4-fold greater than with the jet nebulizer at all positions (P < .05) in both lung models. During simulated mechanical ventilation in pediatric and adult models, bias flow and nebulizer type and position impact aerosol drug delivery.
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              Statement on the care of the child with chronic lung disease of infancy and childhood.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                3 February 2016
                2016
                : 11
                : 2
                : e0148188
                Affiliations
                [1 ]Center for Perinatal Research, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
                [2 ]Division of Neonatology, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
                [3 ]The Ohio State University College of Medicine, Columbus, Ohio, United States of America
                Technion - Israel Institute of Technology, ISRAEL
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: BJC. Performed the experiments: BJC JLS. Analyzed the data: BJC SRJ JLS. Contributed reagents/materials/analysis tools: BJC SRJ JLS. Wrote the paper: BJC SRJ JLS.

                Article
                PONE-D-15-42148
                10.1371/journal.pone.0148188
                4740433
                26840339
                4e285ab9-a1ef-4076-8e64-3d9842d7ae0c
                © 2016 Clouse et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 23 September 2015
                : 14 January 2016
                Page count
                Figures: 2, Tables: 3, Pages: 18
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                People and Places
                Population Groupings
                Age Groups
                Infants
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Receptor Antagonist Therapy
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Respiration
                Breathing
                Medicine and Health Sciences
                Physiology
                Physiological Processes
                Respiration
                Breathing
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Bronchodilators
                Physical Sciences
                Materials Science
                Materials by Structure
                Mixtures
                Aerosols
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Steroid Therapy
                Corticosteroid Therapy
                Research and Analysis Methods
                Database and Informatics Methods
                Database Searching
                Medicine and Health Sciences
                Pulmonology
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Uncategorized
                Uncategorized

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