21 results on '"Eldredge LC"'
Search Results
2. Transpyloric feeding in severe BPD: a call for prospective trials.
- Author
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Baker CD, Liptzin DR, and Eldredge LC
- Subjects
- Humans, Infant, Newborn, Pylorus, Prospective Studies, Infant, Premature, Enteral Nutrition methods
- Published
- 2024
- Full Text
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3. Managing established bronchopulmonary dysplasia without using routine blood gas measurements.
- Author
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Kielt MJ, Eldredge LC, Shepherd EG, DiGeronimo RJ, Miller AN, Bapat R, El-Ferzli G, Welty SE, and Nelin LD
- Subjects
- Humans, Infant, Newborn, Female, Male, Infant, Premature, Retrospective Studies, Gestational Age, Bronchopulmonary Dysplasia blood, Bronchopulmonary Dysplasia diagnosis, Blood Gas Analysis, Intensive Care Units, Neonatal
- Abstract
Objective: Routine blood gas measurements are common in infants with severe bronchopulmonary dysplasia (sBPD) and are a noxious stimulus. We developed a guideline-driven approach to evaluate the care of infants with sBPD without routine blood gas sampling in the chronic phase of NICU care (after diagnosis at 36 weeks PMA)., Study Design: We examined blood gas utilization and outcomes in our sBPD inpatient care unit using data collected between 2014 and 2020., Results: 485 sBPD infants met inclusion criteria, and 303 (62%) never had a blood gas obtained after 36 weeks PMA. In infants who had blood gas measurements, the median number of total blood gases per patient was only 4 (IQR 1-10). We did not identify adverse effects on hospital outcomes in patients without routine blood gas measurements., Conclusions: We found that patients with established BPD could be managed without routine blood gas analyses after 36 weeks PMA., (© 2024. The Author(s).)
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- 2024
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4. Approaches to Interdisciplinary Care for Infants with Severe Bronchopulmonary Dysplasia: A Survey of the Bronchopulmonary Dysplasia Collaborative.
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Cristea AI, Tracy MC, Bauer SE, Guaman MC, Welty SE, Baker CD, Bhombal S, Collaco JM, Courtney SE, DiGeronimo RJ, Eldredge LC, Gibbs K, Hayden LP, Keszler M, Lai K, McGrath-Morrow SA, Moore PE, Rose R, Sindelar R, Truog WE, Nelin LD, and Abman S
- Subjects
- Humans, Infant, Newborn, Ambulatory Care, Infant, Extremely Premature, Surveys and Questionnaires, United States, Bronchopulmonary Dysplasia therapy, Patient Care Team organization & administration, Intensive Care Units, Neonatal
- Abstract
Objective: Bronchopulmonary dysplasia (BPD) remains the most common late morbidity for extremely premature infants. Care of infants with BPD requires a longitudinal approach from the neonatal intensive care unit to ambulatory care though interdisciplinary programs. Current approaches for the development of optimal programs vary among centers., Study Design: We conducted a survey of 18 academic centers that are members of the BPD Collaborative, a consortium of institutions with an established interdisciplinary BPD program. We aimed to characterize the approach, composition, and current practices of the interdisciplinary teams in inpatient and outpatient domains., Results: Variations exist among centers, including composition of the interdisciplinary team, whether the team is the primary or consult service, timing of the first team assessment of the patient, frequency and nature of rounds during the hospitalization, and the timing of ambulatory visits postdischarge., Conclusion: Further studies to assess long-term outcomes are needed to optimize interdisciplinary care of infants with severe BPD., Key Points: · Care of infants with BPD requires a longitudinal approach from the NICU to ambulatory care.. · Benefits of interdisciplinary care for children have been observed in other chronic conditions.. · Current approaches for the development of optimal interdisciplinary BPD programs vary among centers.., Competing Interests: None declared., (Thieme. All rights reserved.)
- Published
- 2024
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5. Long-term pulmonary outcomes in BPD throughout the life-course.
- Author
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Collaco JM, Eldredge LC, and McGrath-Morrow SA
- Abstract
Respiratory disease is one of the most common complications of preterm birth. Survivors of prematurity have increased risks of morbidities and mortalities independent of prematurity, and frequently require multiple medications, home respiratory support, and subspecialty care to maintain health. Although advances in neonatal and pulmonary care have improved overall survival, earlier gestational age, lower birth weight, chorioamnionitis and late onset sepsis continue to be major factors in the development of bronchopulmonary dysplasia. These early life events associated with prematurity can have respiratory consequences that persist into adulthood. Furthermore, after initial hospital discharge, air pollution, respiratory tract infections and socioeconomic status may modify lung growth trajectories and influence respiratory outcomes in later life. Given that the incidence of respiratory disease associated with prematurity remains stable or increased, there is a need for pediatric and adult providers to be familiar with the natural history, manifestations, and common complications of disease., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2024
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6. Exploring the Association of Male Sex With Adverse Outcomes in Severe Bronchopulmonary Dysplasia: A Retrospective, Multicenter Cohort Study.
- Author
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Hammond JD 2nd, Kielt MJ, Conroy S, Lingappan K, Austin ED, Eldredge LC, Truog WE, Abman SH, Nelin LD, and Guaman MC
- Subjects
- Infant, Newborn, Infant, Humans, Male, Female, Retrospective Studies, Cohort Studies, Risk Factors, Intensive Care Units, Neonatal, Gestational Age, Bronchopulmonary Dysplasia diagnosis
- Abstract
Background: Bronchopulmonary dysplasia (BPD) is a significant contributor to morbidity and death in infants who are born premature. Male sex is an independent risk factor for the development of BPD. However, whether male sex is associated with adverse outcomes that occur after formal diagnosis of severe BPD prior to hospital discharge remains unclear., Research Question: Is male sex associated with a higher risk of adverse outcomes in infants with established severe BPD?, Study Design and Methods: A retrospective, multicenter cohort study of infants enrolled in the BPD Collaborative Registry from January 1, 2015, to June 29, 2022, was performed. Demographics, clinical characteristics, and outcomes were stratified by sex (ie, male vs female). Regression modeling was used to estimate the association of sex with the primary composite outcome of death or tracheostomy at hospital discharge., Results: We identified 1,156 infants with severe BPD, defined at 36 weeks postmenstrual age by the National Institutes of Health 2001 consensus definition. The cohort was predominantly male (59% male infants, 41% female infants). However, rates of mechanical ventilation at 36 weeks postmenstrual age (ie, type 2 severe BPD) did not differ by sex. Overall mortality rates within the cohort were low (male infants, 5.3%; female infants, 3.6%). The OR of death or tracheostomy for male-to-female infants was 1.0 (95% CI, 0.7-1.5)., Interpretation: Our results lead us to speculate that, although sex is an important variable that contributes to the development and pathogenesis of severe BPD, it does not appear to be associated with adverse outcomes in this cohort of infants with established disease. The surprising results raise important questions surrounding the temporal role of biological sex in the development of severe BPD and its progression during the neonatal ICU stay. As we explore the phenotypes and endotypes of BPD, it is imperative to consider how sex modulates the disease from birth through hospital discharge., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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7. Classifying multicenter approaches to invasive mechanical ventilation for infants with bronchopulmonary dysplasia using hierarchical clustering analysis.
- Author
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Kielt MJ, Hatch LD 3rd, Levin JC, Napolitano N, Abman SH, Baker CD, Eldredge LC, Collaco JM, McGrath-Morrow SA, Rose RS, Lai K, Keszler M, Sindelar R, Nelin LD, and McKinney RL
- Subjects
- Humans, Infant, Newborn, Prospective Studies, Positive-Pressure Respiration, Lung, Respiration, Artificial, Bronchopulmonary Dysplasia therapy, Bronchopulmonary Dysplasia epidemiology
- Abstract
Introduction: Evidence-based ventilation strategies for infants with severe bronchopulmonary dysplasia (BPD) remain unknown. Determining whether contemporary ventilation approaches cluster as specific BPD strategies may better characterize care and enhance the design of clinical trials. The objective of this study was to test the hypothesis that unsupervised, multifactorial clustering analysis of point prevalence ventilator setting data would classify a discrete number of physiology-based approaches to mechanical ventilation in a multicenter cohort of infants with severe BPD., Methods: We performed a secondary analysis of a multicenter point prevalence study of infants with severe BPD treated with invasive mechanical ventilation. We clustered the cohort by mean airway pressure (MAP), positive end expiratory pressure (PEEP), set respiratory rate, and inspiratory time (Ti) using Ward's hierarchical clustering analysis (HCA)., Results: Seventy-eight patients with severe BPD were included from 14 centers. HCA classified three discrete clusters as determined by an agglomerative coefficient of 0.97. Cluster stability was relatively strong as determined by Jaccard coefficient means of 0.79, 0.85, and 0.77 for clusters 1, 2, and 3, respectively. The median PEEP, MAP, rate, Ti, and PIP differed significantly between clusters for each comparison by Kruskall-Wallis testing (p < 0.0001)., Conclusions: In this study, unsupervised clustering analysis of ventilator setting data identified three discrete approaches to mechanical ventilation in a multicenter cohort of infants with severe BPD. Prospective trials are needed to determine whether these approaches to mechanical ventilation are associated with specific severe BPD clinical phenotypes and differentially modify respiratory outcomes., (© 2023 Wiley Periodicals LLC.)
- Published
- 2023
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8. Respiratory Outcomes for Ventilator-Dependent Children With Bronchopulmonary Dysplasia.
- Author
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Manimtim WM, Agarwal A, Alexiou S, Levin JC, Aoyama B, Austin ED, Bansal M, Bauer SE, Cristea AI, Fierro JL, Garey DM, Hayden LP, Kaslow JA, Miller AN, Moore PE, Nelin LD, Popova AP, Rice JL, Tracy MC, Baker CD, Dawson SK, Eldredge LC, Lai K, Rhein LM, Siddaiah R, Villafranco N, McGrath-Morrow SA, and Collaco JM
- Subjects
- Infant, Newborn, Infant, Humans, Child, Child, Preschool, Retrospective Studies, Respiration, Artificial, Ventilators, Mechanical, Tracheostomy, Bronchopulmonary Dysplasia therapy
- Abstract
Objectives: To describe outpatient respiratory outcomes and center-level variability among children with severe bronchopulmonary dysplasia (BPD) who require tracheostomy and long-term mechanical ventilation., Methods: Retrospective cohort of subjects with severe BPD, born between 2016 and 2021, who received tracheostomy and were discharged on home ventilator support from 12 tertiary care centers participating in the BPD Collaborative Outpatient Registry. Timing of key respiratory events including time to tracheostomy placement, initial hospital discharge, first outpatient clinic visit, liberation from the ventilator, and decannulation were assessed using Kaplan-Meier analysis. Differences between centers for the timing of events were assessed via log-rank tests., Results: There were 155 patients who met inclusion criteria. Median age at the time of the study was 32 months. The median age of tracheostomy placement was 5 months (48 weeks' postmenstrual age). The median ages of hospital discharge and first respiratory clinic visit were 10 months and 11 months of age, respectively. During the study period, 64% of the subjects were liberated from the ventilator at a median age of 27 months and 32% were decannulated at a median age of 49 months. The median ages for all key events differed significantly by center (P ≤ .001 for all events)., Conclusions: There is wide variability in the outpatient respiratory outcomes of ventilator-dependent infants and children with severe BPD. Further studies are needed to identify the factors that contribute to variability in practice among the different BPD outpatient centers, which may include inpatient practices., (Copyright © 2023 by the American Academy of Pediatrics.)
- Published
- 2023
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9. A multidisciplinary approach to severe bronchopulmonary dysplasia is associated with resolution of pulmonary hypertension.
- Author
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Yung D, Jackson EO, Blumenfeld A, Redding G, DiGeronimo R, McGuire JK, Riker M, Tressel W, Berkelhamer S, and Eldredge LC
- Abstract
Objective: To describe our multidisciplinary bronchopulmonary dysplasia (BPD) consult team's systematic approach to BPD associated pulmonary hypertension (PH), to report our center outcomes, and to evaluate clinical associations with outcomes., Study Design: Retrospective cohort of 60 patients with BPD-PH who were referred to the Seattle Children's Hospital BPD team from 2018 to 2020. Patients with critical congenital heart disease were excluded. Demographics, comorbidities, treatments, closure of hemodynamically relevant intracardiac shunts, and clinical outcomes including time to BPD-PH resolution were reviewed., Results: Median gestational age of the 60 patients was 25 weeks (IQR: 24-26). 20% were small for gestational age (SGA), 65% were male, and 25% received a tracheostomy. With aggressive cardiopulmonary management including respiratory support optimization, patent ductus arteriosus (PDA) and atrial septal defect (ASD) closure (40% PDA, 5% ASD, 3% both), and limited use of pulmonary vasodilators (8%), all infants demonstrated resolution of PH during the follow-up period, including three (5%) who later died from non-BPD-PH morbidities. Neither SGA status nor the timing of PH diagnosis (<36 vs. ≥36 weeks PMA) impacted the time to BPD-PH resolution in our cohort [median 72 days (IQR 30.5-166.5)]., Conclusion: Our multidisciplinary, systematic approach to BPD-PH management was associated with complete resolution of PH with lower mortality despite less sildenafil use than reported in comparable cohorts. Unique features of our approach included aggressive PDA and ASD device closure and rare initiation of sildenafil only after lack of BPD-PH improvement with respiratory support optimization and diagnostic confirmation by cardiac catheterization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SB declared a shared affiliation with the author AB to the handling editor at the time of review., (© 2023 Yung, Jackson, Blumenfeld, Redding, DiGeronimo, McGuire, Riker, Tressel, Berkelhamer and Eldredge.)
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- 2023
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10. Summary for Clinicians: Clinical Practice Guidelines for Outpatient Respiratory Management of Infants, Children, and Adolescents with Post-Prematurity Respiratory Disease.
- Author
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Eldredge LC, Levin JC, Tracy MC, Cristea AI, Baker CD, Ruminjo JK, and Thomson CC
- Subjects
- Adolescent, Child, Humans, Infant, Ambulatory Care, Respiratory Tract Diseases therapy
- Published
- 2022
- Full Text
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11. Preventable ATII Proliferation after Hyperoxia: The "Tempo" of Folate Metabolism in the Neonatal Lung.
- Author
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Eldredge LC
- Subjects
- Alveolar Epithelial Cells metabolism, Cell Proliferation, Folic Acid metabolism, Humans, Infant, Newborn, Bronchopulmonary Dysplasia metabolism, Hyperoxia metabolism
- Published
- 2022
- Full Text
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12. Ventilatory Strategies in Infants with Established Severe Bronchopulmonary Dysplasia: A Multicenter Point Prevalence Study.
- Author
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McKinney RL, Napolitano N, Levin JJ, Kielt MJ, Abman SH, Guaman MC, Rose RS, Courtney SE, Matlock D, Agarwal A, Leeman KT, Sanlorenzo LA, Sindelar R, Collaco JM, Baker CD, Hannan KE, Douglass M, Eldredge LC, Lai K, McGrath-Morrow SA, Tracy MC, Truog W, Lewis T, Murillo AL, and Keszler M
- Subjects
- Humans, Infant, Infant, Newborn, Prevalence, Ventilators, Mechanical, Bronchopulmonary Dysplasia epidemiology, Bronchopulmonary Dysplasia therapy
- Abstract
We performed a point prevalence study on infants with severe bronchopulmonary dysplasia (BPD), collecting data on type and settings of ventilatory support; 187 infants, 51% of whom were on invasive positive-pressure ventilation (IPPV), from 15 centers were included. We found a significant center-specific variation in ventilator modes., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2022
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13. Outpatient Respiratory Management of Infants, Children, and Adolescents with Post-Prematurity Respiratory Disease: An Official American Thoracic Society Clinical Practice Guideline.
- Author
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Cristea AI, Ren CL, Amin R, Eldredge LC, Levin JC, Majmudar PP, May AE, Rose RS, Tracy MC, Watters KF, Allen J, Austin ED, Cataletto ME, Collaco JM, Fleck RJ, Gelfand A, Hayes D Jr, Jones MH, Kun SS, Mandell EW, McGrath-Morrow SA, Panitch HB, Popatia R, Rhein LM, Teper A, Woods JC, Iyer N, and Baker CD
- Subjects
- Adolescent, Aftercare, Child, Chronic Disease, Humans, Infant, Infant, Newborn, Infant, Premature, Infant, Premature, Diseases therapy, Respiratory Tract Diseases therapy
- Abstract
Background: Premature birth affects millions of neonates each year, placing them at risk for respiratory disease due to prematurity. Bronchopulmonary dysplasia is the most common chronic lung disease of infancy, but recent data suggest that even premature infants who do not meet the strict definition of bronchopulmonary dysplasia can develop adverse pulmonary outcomes later in life. This post-prematurity respiratory disease (PPRD) manifests as chronic respiratory symptoms, including cough, recurrent wheezing, exercise limitation, and reduced pulmonary function. This document provides an evidence-based clinical practice guideline on the outpatient management of infants, children, and adolescents with PPRD. Methods: A multidisciplinary panel of experts posed questions regarding the outpatient management of PPRD. We conducted a systematic review of the relevant literature. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of the clinical recommendations. Results: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations were developed for or against three common medical therapies and four diagnostic evaluations in the context of the outpatient management of PPRD. Conclusions: The panel developed recommendations for the outpatient management of patients with PPRD on the basis of limited evidence and expert opinion. Important areas for future research were identified.
- Published
- 2021
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14. Acute Kidney Injury and Bronchopulmonary Dysplasia in Premature Neonates Born Less than 32 Weeks' Gestation.
- Author
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Starr MC, Boohaker L, Eldredge LC, Menon S, Griffin R, Mayock DE, Li L, Askenazi D, and Hingorani S
- Subjects
- Acute Kidney Injury mortality, Female, Gestational Age, Humans, Incidence, Infant, Newborn, Infant, Premature, Logistic Models, Male, Odds Ratio, Retrospective Studies, Acute Kidney Injury complications, Bronchopulmonary Dysplasia etiology, Infant, Premature, Diseases mortality
- Abstract
Objective: This study aimed to evaluate the association between acute kidney injury (AKI) and bronchopulmonary dysplasia (BPD) in infants born <32 weeks of gestational age (GA)., Study Design: Present study is a secondary analysis of premature infants born at <32 weeks of GA in the Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) retrospective cohort ( n = 546). We stratified by gestational age and used logistic regression to determine association between AKI and moderate or severe BPD/mortality., Results: Moderate or severe BPD occurred in 214 of 546 (39%) infants, while death occurred in 32 of 546 (6%); the composite of moderate or severe BPD/death occurred in 246 of 546 (45%). For infants born ≤29 weeks of gestation, the adjusted odds ratio (OR) of AKI and the primary outcome was 1.15 (95% confidence interval [CI] = 0.47-2.86; p = 0.76). Infants born between 29 and 32 weeks of gestation with AKI had four-fold higher odds of moderate or severe BPD/death that remained after controlling for multiple factors (adjusted OR = 4.21, 95% CI: 2.07-8.61; p < 0.001)., Conclusion: Neonates born between 29 and 32 weeks who develop AKI had a higher likelihood of moderate or severe BPD/death than those without AKI. Further studies are needed to validate our findings and evaluate mechanisms of multiorgan injury., Competing Interests: All authors report no real or perceived conflicts of interest that could affect the study design, collection, analysis, and interpretation of data, the writing of the report, or the decision to submit the manuscript for publication. This study was supported by the NIH U01NS077953 (L.B., R.G., L.L., and D.A.) and T32DK007662 (MS). For full disclosure, we provide the additional list of authors' other commitments and funding sources that are not directly related to this study. D.A. reports serving on the speaker board for Baxter and for the Acute Kidney Injury Foundation; he also reported receiving grant funding for studies not related to this work, grant R01 DK103608 from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, and grant R01 FD005092 from the National Institutes of Health/US Food and Drug Administration. S.G. reports receiving grant funding for studies not related to this work, grant R01 DK103608 from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. No other disclosures were reported., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)
- Published
- 2020
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15. Acute Kidney Injury is Associated with Poor Lung Outcomes in Infants Born ≥32 Weeks of Gestational Age.
- Author
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Starr MC, Boohaker L, Eldredge LC, Menon S, Griffin R, Mayock D, Askenazi D, and Hingorani S
- Subjects
- Acute Kidney Injury mortality, Chronic Disease, Female, Humans, Infant, Newborn, Infant, Premature, Intensive Care Units, Neonatal, Logistic Models, Male, Respiration, Artificial, Retrospective Studies, Risk Factors, Acute Kidney Injury complications, Infant, Premature, Diseases mortality, Lung Diseases etiology
- Abstract
Objective: This study aimed to evaluate the association between acute kidney injury (AKI) and lung outcomes in infants born ≥32 weeks of gestational age (GA)., Study Design: Secondary analysis of infants ≥32 weeks of GA in the assessment of worldwide acute kidney injury epidemiology in neonates (AWAKEN) retrospective cohort ( n = 1,348). We used logistic regression to assess association between AKI and a composite outcome of chronic lung disease (CLD) or death at 28 days of age and linear regression to evaluate association between AKI and duration of respiratory support., Results: CLD occurred in 82/1,348 (6.1%) infants, while death occurred in 22/1,348 (1.6%); the composite of CLD/death occurred in 104/1,348 (7.7%). Infants with AKI had an almost five-fold increased odds of CLD/death, which remained after controlling for GA, maternal polyhydramnios, multiple gestations, 5-minute Apgar's score, intubation, and hypoxic-ischemic encephalopathy (adjusted odds ratio [OR] = 4.9, 95% confidence interval [CI]: 3.2-7.4; p < 0.0001). Infants with AKI required longer duration of respiratory support (count ratio = 1.59, 95% CI: 1.14-2.23, p = 0.003) and oxygen (count ratio = 1.43, 95% CI: 1.22-1.68, p < 0.0001) compared with those without AKI., Conclusion: AKI is associated with CLD/death and longer duration of respiratory support in infants born at ≥32 weeks of GA. Further prospective studies are needed to elucidate the pathophysiologic relationship., Competing Interests: All authors report no real or perceived conflicts of interest that could affect the study design; collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the manuscript for publication. This study was supported by the NIH U01NS077953 (L.B., R.G., D.A.) and T32DK007662 (M.C.S.). For full disclosure, we provide the additional list of authors' other commitments and funding sources that are not directly related to this study. D.A. reported serving on the speaker board for Baxter and for the Acute Kidney Injury Foundation; he also reported receiving grant funding for studies not related to this work: grant R01 DK103608 from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases and grant R01 FD005092 from the National Institutes of Health/U.S. Food and Drug Administration. No other disclosures were reported., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)
- Published
- 2020
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16. Infants with evolving bronchopulmonary dysplasia demonstrate monocyte-specific expression of IL-1 in tracheal aspirates.
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Eldredge LC, Creasy RS, Presnell S, Debley JS, Juul SE, Mayock DE, and Ziegler SF
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- Bronchoalveolar Lavage Fluid chemistry, Bronchoalveolar Lavage Fluid immunology, Bronchopulmonary Dysplasia immunology, Bronchopulmonary Dysplasia pathology, Female, GPI-Linked Proteins deficiency, GPI-Linked Proteins genetics, GPI-Linked Proteins immunology, Gene Expression Regulation, Gestational Age, Humans, Infant, Infant, Newborn, Infant, Premature, Interleukin 1 Receptor Antagonist Protein immunology, Interleukin-1alpha immunology, Interleukin-1beta immunology, Lipopolysaccharide Receptors genetics, Lipopolysaccharide Receptors immunology, Male, Monocytes pathology, Pilot Projects, Prospective Studies, RNA, Messenger immunology, Receptors, IgG deficiency, Receptors, IgG genetics, Receptors, IgG immunology, Sequence Analysis, RNA, Signal Transduction, Trachea immunology, Trachea pathology, Bronchopulmonary Dysplasia genetics, Interleukin 1 Receptor Antagonist Protein genetics, Interleukin-1alpha genetics, Interleukin-1beta genetics, Monocytes immunology, RNA, Messenger genetics
- Abstract
Bronchopulmonary dysplasia (BPD) remains a devastating consequence of prematurity. Repeated inflammatory insults worsen lung injury, but there are no predictors for BPD-related respiratory outcomes or targeted therapies. We sought to understand inflammatory mechanisms in evolving BPD through molecular characterization of monocytes in tracheal aspirates from infants at risk for developing BPD. We performed flow cytometry targeting myeloid cell populations on prospectively collected tracheal aspirates from intubated patients born before 29 wk of gestation and <30 days old. We identified CD14
+ CD16+ (double-positive) and CD14+ CD16- (single-positive) monocytes and characterized their gene expression profiles by RNA sequencing and quantitative PCR. We further analyzed differential gene expression between time points to evaluate changes in monocyte function over the first weeks of life. Expression of IL-1A, IL-1B, and IL-1 receptor antagonist mRNA was increased in monocytes collected at day of life ( DOL ) 7 , DOL 14 , and DOL 28 compared with those collected at DOL 3 . This study suggests that early changes in monocyte-specific IL-1 cytokine pathways may be associated with evolving BPD.- Published
- 2019
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17. Imbalance of Ly-6C hi and Ly-6C lo Monocytes/Macrophages Worsens Hyperoxia-Induced Lung Injury and Is Rescued by IFN-γ.
- Author
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Eldredge LC, Creasy RS, Tanaka S, Lai JF, and Ziegler SF
- Subjects
- Animals, Gene Expression Regulation, Enzymologic drug effects, Gene Expression Regulation, Enzymologic immunology, Hyperoxia pathology, Interferon-gamma pharmacology, Lung Injury pathology, Macrophages pathology, Matrix Metalloproteinase 9 immunology, Mice, Monocytes pathology, Antigens, Ly immunology, Hyperoxia immunology, Interferon-gamma immunology, Lung Injury immunology, Macrophages immunology, Monocytes immunology
- Abstract
Inflammation in response to oxygen exposure is a major contributing factor in neonatal lung injury leading to bronchopulmonary dysplasia. Although increased levels of proinflammatory cytokines are seen in airway samples and blood from bronchopulmonary dysplasia patients, the innate immune responses in this common neonatal lung condition have not been well characterized. We previously reported that depletion of murine CD11b-expressing mononuclear phagocytes at birth led to severe acute hyperoxia-induced lung injury (HILI) and significant mortality. In this study, we further define the mononuclear phagocyte populations that are present in the neonatal lung and characterize their responses to hyperoxia exposure. We used myeloid depleter mice (CD11b-DTR and CCR2-DTR) to contrast the effects of depleting different monocyte/macrophage subpopulations on the innate immune response to hyperoxia. Using RNA sequencing and subsequent data analysis, we identified an IFN-γ-mediated role for interstitial monocytes/macrophages in acute HILI, in which decreased IFN-γ expression led to increased disease severity and increased Mmp9 mRNA expression. Importantly, intranasal administration of rIFN-γ largely rescued CD11b-DTR
+ mice from severe HILI and decreased Mmp9 mRNA expression in Ly-6Clo and Ly-6Chi interstitial monocyte/macrophages. We conclude that the proinflammatory effects of hyperoxia exposure are, at least in part, because of the modulation of effectors downstream of IFN-γ by pulmonary monocytes/macrophages., (Copyright © 2019 by The American Association of Immunologists, Inc.)- Published
- 2019
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18. CD11b(+) Mononuclear Cells Mitigate Hyperoxia-Induced Lung Injury in Neonatal Mice.
- Author
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Eldredge LC, Treuting PM, Manicone AM, Ziegler SF, Parks WC, and McGuire JK
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- Animals, Animals, Newborn, Bronchopulmonary Dysplasia etiology, Bronchopulmonary Dysplasia immunology, Bronchopulmonary Dysplasia metabolism, Bronchopulmonary Dysplasia pathology, CD11b Antigen genetics, Disease Models, Animal, Heparin-binding EGF-like Growth Factor genetics, Heparin-binding EGF-like Growth Factor metabolism, Inflammation Mediators metabolism, Lung immunology, Lung pathology, Lung Injury etiology, Lung Injury immunology, Lung Injury metabolism, Lung Injury pathology, Macrophage Activation, Macrophages immunology, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Pulmonary Edema etiology, Pulmonary Edema immunology, Pulmonary Edema metabolism, Pulmonary Edema prevention & control, Severity of Illness Index, Time Factors, Bronchopulmonary Dysplasia prevention & control, CD11b Antigen metabolism, Hyperoxia complications, Lung metabolism, Lung Injury prevention & control, Macrophages metabolism
- Abstract
Bronchopulmonary dysplasia (BPD) is a common consequence of life-saving interventions for infants born with immature lungs. Resident tissue myeloid cells regulate lung pathology, but their role in BPD is poorly understood. To determine the role of lung interstitial myeloid cells in neonatal responses to lung injury, we exposed newborn mice to hyperoxia, a neonatal mouse lung injury model with features of human BPD. In newborn mice raised in normoxia, we identified a CD45(+) F4/80(+) CD11b(+), Ly6G(lo-int) CD71(+) population of cells in lungs of neonatal mice present in significantly greater percentages than in adult mice. In response to hyperoxia, surface marker and gene expression in whole lung macrophages/monocytes was biased to an alternatively activated phenotype. Partial depletion of these CD11b(+) mononuclear cells using CD11b-diphtheria toxin (DT) receptor transgenic mice resulted in 60% mortality by 40 hours of hyperoxia exposure with more severe lung injury, perivascular edema, and alveolar hemorrhage compared with DT-treated CD11b-DT receptor-negative controls, which displayed no mortality. These results identify an antiinflammatory population of CD11b(+) mononuclear cells that are protective in hyperoxia-induced neonatal lung injury in mice, and suggest that enhancing their beneficial functions may be a treatment strategy in infants at risk for BPD.
- Published
- 2016
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19. Remarkable progress toward new treatments for cystic fibrosis.
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Eldredge LC and Ramsey BW
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- Aminophenols therapeutic use, Aminopyridines therapeutic use, Animals, Benzodioxoles therapeutic use, Clinical Trials, Phase III as Topic, Cystic Fibrosis genetics, Cystic Fibrosis physiopathology, Cystic Fibrosis Transmembrane Conductance Regulator drug effects, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Cystic Fibrosis Transmembrane Conductance Regulator physiology, Disease Models, Animal, Forced Expiratory Volume physiology, Humans, Mutation genetics, Quinolones therapeutic use, Cystic Fibrosis therapy
- Published
- 2014
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20. Egr3 dependent sympathetic target tissue innervation in the absence of neuron death.
- Author
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Li L, Eldredge LC, Quach DH, Honasoge A, Gruner K, and Tourtellotte WG
- Subjects
- Animals, Atrophy genetics, Atrophy metabolism, Cell Death genetics, Early Growth Response Protein 3 deficiency, Early Growth Response Protein 3 genetics, Gene Deletion, Gene Expression Regulation, Mice, Mice, Inbred C57BL, Nerve Growth Factor metabolism, Nerve Growth Factors metabolism, Neurons pathology, bcl-2-Associated X Protein deficiency, bcl-2-Associated X Protein genetics, Early Growth Response Protein 3 metabolism, Neurons cytology, Sympathetic Nervous System cytology, Sympathetic Nervous System physiology
- Abstract
Nerve Growth Factor (NGF) is a target tissue derived neurotrophin required for normal sympathetic neuron survival and target tissue innervation. NGF signaling regulates gene expression in sympathetic neurons, which in turn mediates critical aspects of neuron survival, axon extension and terminal axon branching during sympathetic nervous system (SNS) development. Egr3 is a transcription factor regulated by NGF signaling in sympathetic neurons that is essential for normal SNS development. Germline Egr3-deficient mice have physiologic dysautonomia characterized by apoptotic sympathetic neuron death and abnormal innervation to many target tissues. The extent to which sympathetic innervation abnormalities in the absence of Egr3 is caused by altered innervation or by neuron death during development is unknown. Using Bax-deficient mice to abrogate apoptotic sympathetic neuron death in vivo, we show that Egr3 has an essential role in target tissue innervation in the absence of neuron death. Sympathetic target tissue innervation is abnormal in many target tissues in the absence of neuron death, and like NGF, Egr3 also appears to effect target tissue innervation heterogeneously. In some tissues, such as heart, spleen, bowel, kidney, pineal gland and the eye, Egr3 is essential for normal innervation, whereas in other tissues such as lung, stomach, pancreas and liver, Egr3 appears to have little role in innervation. Moreover, in salivary glands and heart, two tissues where Egr3 has an essential role in sympathetic innervation, NGF and NT-3 are expressed normally in the absence of Egr3 indicating that abnormal target tissue innervation is not due to deregulation of these neurotrophins in target tissues. Taken together, these results clearly demonstrate a role for Egr3 in mediating sympathetic target tissue innervation that is independent of neuron survival or neurotrophin deregulation.
- Published
- 2011
- Full Text
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21. Abnormal sympathetic nervous system development and physiological dysautonomia in Egr3-deficient mice.
- Author
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Eldredge LC, Gao XM, Quach DH, Li L, Han X, Lomasney J, and Tourtellotte WG
- Subjects
- Animals, Animals, Newborn, Apoptosis drug effects, Arylalkylamine N-Acetyltransferase metabolism, Axons drug effects, Axons metabolism, Blepharoptosis pathology, Blepharoptosis physiopathology, Cell Movement drug effects, Early Growth Response Protein 3 genetics, Early Growth Response Protein 3 metabolism, Ganglia, Spinal drug effects, Ganglia, Spinal pathology, Gene Expression Regulation, Developmental drug effects, Heart innervation, Mice, Nerve Growth Factor pharmacology, Neurons drug effects, Neurons pathology, Pineal Gland drug effects, Pineal Gland enzymology, Pineal Gland innervation, Signal Transduction drug effects, Sympathetic Nervous System cytology, Sympathetic Nervous System drug effects, Autonomic Nervous System Diseases congenital, Early Growth Response Protein 3 deficiency, Sympathetic Nervous System embryology, Sympathetic Nervous System physiopathology
- Abstract
Sympathetic nervous system development depends upon many factors that mediate neuron migration, differentiation and survival. Target tissue-derived nerve growth factor (NGF) signaling-induced gene expression is required for survival, differentiation and target tissue innervation of post-migratory sympathetic neurons. However, the transcriptional regulatory mechanisms mediated by NGF signaling are very poorly defined. Here, we identify Egr3, a member of the early growth response (Egr) family of transcriptional regulators, as having an important role in sympathetic nervous system development. Egr3 is regulated by NGF signaling and it is expressed in sympathetic neurons during development when they depend upon NGF for survival and target tissue innervation. Egr3-deficient mice have severe sympathetic target tissue innervation abnormalities and profound physiological dysautonomia. Unlike NGF, which is essential for sympathetic neuron survival and for axon branching within target tissues, Egr3 is required for normal terminal axon extension and branching, but not for neuron survival. The results indicate that Egr3 is a novel NGF signaling effector that regulates sympathetic neuron gene expression required for normal target tissue innervation and function. Egr3-deficient mice have a phenotype that is remarkably similar to humans with sympathetic nervous system disease, raising the possibility that it may have a role in some forms of human dysautonomia, most of which have no known cause.
- Published
- 2008
- Full Text
- View/download PDF
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