Advances in perinatal care have dramatically improved survival of extremely preterm infants and the incidence of bronchopulmonary dysplasia (BPD) has not changed over the past few decades, which likely reflects the impact of increased survival of extremely preterm infants.1Stoll B.J. Hansen N.I. Bell E.F. Walsh M.C. Carlo W.A. Shankaran S. et al.Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012.JAMA. 2015; 314: 1039-1051Crossref PubMed Scopus (200) Google Scholar BPD remains the most common late morbidity of preterm birth, but many controversies persist regarding how to best define BPD, grade its severity, and prevent disease.2Poindexter B.B. Feng R. Schmidt B. Aschner J. Ballard R.A. Hamvas A. et al.Comparisons and limitations of current definitions of bronchopulmonary dysplasia for the prematurity and respiratory outcomes program.Ann Am Thorac Soc. 2015; 12: 1822-1830Crossref PubMed Scopus (39) Google Scholar Ongoing clinical care and research have largely focused on issues regarding the pathogenesis and prevention of BPD in preterm infants with the important goal of reducing the incidence of BPD at 36 weeks corrected age, with a focus on respiratory care related issues during the early neonatal intensive care unit (NICU) course.3McEvoy C.T. Jain L. Schmidt B. Abman S. Bancalari E. Aschner J.L. Bronchopulmonary dysplasia: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases.Ann Am Thorac Soc. 2014; 11: S146-53Crossref PubMed Scopus (56) Google Scholar However, some preterm infants develop particularly severe chronic respiratory disease and have related comorbidities that persist throughout their NICU course and post-discharge, as reflected by the prolonged need for high levels of respiratory support, including mechanical ventilation and high inspired oxygen concentrations. The management of infants with severe BPD (sBPD) has received less attention regarding clinical studies and interventions when compared with preventive strategies, yet these infants constitute a critical population who remain at high risk for extensive morbidities and late mortality (Figure 1). Based on consensus recommendations from a National Institutes of Health (NIH) workshop, BPD is commonly defined by the requirement for supplemental oxygen at 28 days in infants born at below 32 weeks gestation.4Jobe A.H. Bancalari E. Bronchopulmonary dysplasia.Am J Respir Crit Care Med. 2001; 163: 1723-1729Crossref PubMed Google Scholar Furthermore, BPD is divided into 3 severity grades (mild, moderate, or severe) based on respiratory support needs at 36 weeks postmenstrual age (PMA) (Table I). The incidence of sBPD is inversely correlated with gestational age and remains 16% for all infants born at <32 weeks (Table I).5Ehrenkranz R.A. Walsh M.C. Vohr B.R. Jobe A.H. Wright L.L. Fanaroff A.A. et al.Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia.Pediatrics. 2005; 116: 1353-1360Crossref PubMed Scopus (517) Google Scholar Unfortunately, high-quality evidence on which to base the care for infants and children with sBPD and consensus care guidelines are lacking. These knowledge gaps have contributed to marked variability in care within and between NICUs throughout the country. Current NIH definitions of BPD are almost exclusively focused on NICU-related issues, with limited discussion regarding long-term respiratory outcomes throughout infancy, childhood, and adulthood. In addition, the classification of sBPD is very broad and fails to differentiate between proposed phenotypes of infants with a persistent oxygen requirement and/or need forcontinuous positive airway pressure (CPAP) or high flow nasal cannula at 36 weeks postconceptual age who have relatively less severe respiratory disease (type 1 sBPD; Table I) from those with more extreme BPD (or type 2 sBPD), who remain ventilator-dependent and more often have severe complications, including pulmonary hypertension, poor growth, and neurodevelopmental problems. Understanding distinct antenatal, early postnatal, genetic, or epigenetic factors, or comorbidities that contribute to sBPD, especially the more severe phenotype (type 2 sBPD), are critical for enhancing late outcomes in this subgroup.Table IBPD definition with severityBPD severityDefinition(Modified from Jobe and Bancalari4Jobe A.H. Bancalari E. Bronchopulmonary dysplasia.Am J Respir Crit Care Med. 2001; 163: 1723-1729Crossref PubMed Google Scholar)Relative incidence (Data from Ehrenkranz et al5Ehrenkranz R.A. Walsh M.C. Vohr B.R. Jobe A.H. Wright L.L. Fanaroff A.A. et al.Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia.Pediatrics. 2005; 116: 1353-1360Crossref PubMed Scopus (517) Google Scholar)Postdischarge mortality(Data from Ehrenkranzet al5Ehrenkranz R.A. Walsh M.C. Vohr B.R. Jobe A.H. Wright L.L. Fanaroff A.A. et al.Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia.Pediatrics. 2005; 116: 1353-1360Crossref PubMed Scopus (517) Google Scholar)NoneO2 treatment <28 d and breathing room air at 36 wk PMA or discharge home, whichever comes first23.1%1.8%MildO2 treatment at least 28 d and breathing room air at 36 wk PMA or discharge home, whichever comes first30.3%1.5%ModerateO2 treatment at least 28 d and receiving <30% O2 at 36 wk PMA or discharge home, whichever comes first30.2%2.0%Severe (type 1)O2 treatment at least 28 d and receiving ≥30% O2 or nasal CPAP/HFNC at ≥36 wk PMA16.4%4.8%Severe (type 2)O2 treatment at least 28 d and receiving mechanical ventilation at ≥36 wk PMA.HFNC, high flow nasal cannula; O2, oxygen. Open table in a new tab HFNC, high flow nasal cannula; O2, oxygen. Clinical needs of infants with type 2 sBPD who require ongoing respiratory support beyond term corrected age are diverse and complex, and management strategies that optimize survival and long-term outcomes are controversial and uncertain. Several factors contribute to increased morbidity and mortality in this population. First, there are few evidence-based strategies to improve outcomes. Second, patients with chronic ventilator-dependent BPD have historically been cared for in acute care settings. Management strategies for chronic disease differ considerably from acute respiratory failure, especially regarding approaches to mechanical ventilation. When compared with approaches toward acute respiratory failure, neonatal and pediatric intensivists may have less experience with ventilator management of infants with severe chronic lung disease. Most importantly, poor communication between providers, subspecialists, nursing staff, and families during prolonged hospitalization may lead to inconsistent care and adverse outcomes. High staff turnover and infrequent communication among the doctors and bedside staff as well as between parents and the medical team may contribute to these inconsistencies. These infants have complex clinical courses with multiple morbidities, including frequent hospitalizations throughout childhood, and often with poor continuity of care. Interdisciplinary care teams have the potential to alleviate many of these issues and improve outcomes for these infants. Based on these concerns, a group of clinicians from interdisciplinary care programs for infants with sBPD at several major medical centers, including neonatologists, pulmonologists, critical care physicians, gastroenterologists, nurse specialists, and others, formed the “BPD Collaborative,” to address controversies and promote research to enhance the care of children with sBPD. In this review, we present an interdisciplinary approach to patients with sBPD and their families throughout the NICU and outpatient courses. Emphasis is placed on the rationale for developing the team approach to chronic care as well as highlighting key gaps in knowledge in our care for infants with sBPD, which would likely improve with multicenter investigations. Although marked improvements in care have led to milder respiratory courses for most preterm infants, sBPD remains a major problem. In the validation study from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, the incidence of sBPD was 16% in infants born at <32 weeks and weighing <1000 g (Table I).5Ehrenkranz R.A. Walsh M.C. Vohr B.R. Jobe A.H. Wright L.L. Fanaroff A.A. et al.Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia.Pediatrics. 2005; 116: 1353-1360Crossref PubMed Scopus (517) Google Scholar Reports using birth cohorts from Scandinavia found that the incidence of sBPD was 25% in infants born at <27 weeks gestation in Sweden, and 20% in infants born at <28 weeks in Norway.6EXPRESS GroupIncidence of and risk factors for neonatal morbidity after active perinatal care: extremely preterm infants study in Sweden (EXPRESS).Acta Paediatr. 2010; 99: 978-992Crossref PubMed Scopus (118) Google Scholar, 7Farstad T. Bratlid D. Medbo S. Markestad T. Norwegian Extreme Prematurity Study GroupBronchopulmonary dysplasia - prevalence, severity and predictive factors in a national cohort of extremely premature infants.Acta Paediatr. 2011; 100: 53-58Crossref PubMed Scopus (0) Google Scholar The Children's Hospital Neonatal Consortium reported a 16% incidence of sBPD of patients born at <32 weeks, of whom 91% survived to discharge, 66% were discharged on supplemental oxygen, 4% on mechanical ventilation, and 5% received tracheostomy.8Padula M.A. Grover T.R. Brozanski B. Zaniletti I. Nelin L.D. Asselin J.M. et al.Therapeutic interventions and short-term outcomes for infants with severe bronchopulmonary dysplasia born at <32 weeks' gestation.J Perinatol. 2013; 33: 877-881Crossref PubMed Scopus (8) Google Scholar The BPD Collaborative reported a point prevalence of sBPD of 36.5% with a range across centers of 11%-58%, and 41% of the patients with sBPD had type 2 sBPD with a range of 0%-68%.9Guaman MC Gien J Baker CD Zhang H Austin ED Collaco JM. Point prevalence, clinical characteristics, and treatment variation for infants with severe bronchopulmonary dysplasia.Am J Perinatol. 2015; 32: 960-967Crossref PubMed Scopus (14) Google Scholar Using an estimated incidence of sBPD of 16% for infants born at <32 weeks suggests that ~13 000 patients develop sBPD annually in the US alone.5Ehrenkranz R.A. Walsh M.C. Vohr B.R. Jobe A.H. Wright L.L. Fanaroff A.A. et al.Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia.Pediatrics. 2005; 116: 1353-1360Crossref PubMed Scopus (517) Google Scholar Epidemiologic data are limited, but estimates suggest that roughly 8000 children in the US receive mechanical ventilation at home.10Boroughs D. Dougherty J.A. Decreasing accidental mortality of ventilator-dependent children at home: a call to action.Home Healthc Nurse. 2012; 30 (quiz 12-3): 103-111Crossref PubMed Scopus (0) Google Scholar Based on 2011 data from the state of Pennsylvania's Ventilator Assisted Children's Home Program, 36% of ventilator-dependent children were diagnosed with chronic lung disease, 77% of these specifically with the diagnosis of sBPD.10Boroughs D. Dougherty J.A. Decreasing accidental mortality of ventilator-dependent children at home: a call to action.Home Healthc Nurse. 2012; 30 (quiz 12-3): 103-111Crossref PubMed Scopus (0) Google Scholar From these data, it can be extrapolated that ~2000 infants and children with sBPD are dependent on mechanical ventilation at home in the US. The exact pathogenic mechanisms underlying the development of sBPD in preterm infants and factors that favor the development of sBPD are uncertain. Similarly, factors that contribute to the receipt of prolonged mechanical ventilation within the subgroup with type 2 sBPD are uncertain. The incidence of sBPD is inversely related to gestational age at birth.6EXPRESS GroupIncidence of and risk factors for neonatal morbidity after active perinatal care: extremely preterm infants study in Sweden (EXPRESS).Acta Paediatr. 2010; 99: 978-992Crossref PubMed Scopus (118) Google Scholar, 11Laughon M.M. Langer J.C. Bose C.L. Smith P.B. Ambalavanan N. Kennedy K.A. et al.Prediction of bronchopulmonary dysplasia by postnatal age in extremely premature infants.Am J Respir Crit Care Med. 2011; 183: 1715-1722Crossref PubMed Scopus (106) Google Scholar, 12Natarajan G. Pappas A. Shankaran S. Kendrick D.E. Das A. Higgins R.D. et al.Outcomes of extremely low birth weight infants with bronchopulmonary dysplasia: impact of the physiologic definition.Early Hum Dev. 2012; 88: 509-515Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Male infants are more likely to develop sBPD and the need for mechanical ventilation. Patent ductus arteriosus, sepsis, and surgical necrotizing enterocolitis are strongly associated with the development of sBPD.11Laughon M.M. Langer J.C. Bose C.L. Smith P.B. Ambalavanan N. Kennedy K.A. et al.Prediction of bronchopulmonary dysplasia by postnatal age in extremely premature infants.Am J Respir Crit Care Med. 2011; 183: 1715-1722Crossref PubMed Scopus (106) Google Scholar A recent preclinical study suggests dose-related effects of antenatal endotoxin as a model for experimental chorioamnionitis that is sufficient to induce sBPD, and moderate oxygen treatment actually improved lung structure rather than worsening respiratory outcome, suggesting the complexity of pre- and postnatal events in driving BPD phenotypes.13Tang J.R. Seedorf G.J. Muehlethaler V. Walker D.L. Markham N.E. Balasubramaniam V. et al.Moderate postnatal hyperoxia accelerates lung growth and attenuates pulmonary hypertension in infant rats after exposure to intra-amniotic endotoxin.Am J Physiol Lung Cell Mol Physiol. 2010; 299: L735-48Crossref PubMed Scopus (28) Google Scholar The genetics and epigenetic, or gene/environmental factors, underlying the risk for sBPD remain to be determined, however, recent twin studies have demonstrated a genetic component to the development of BPD in general,14Bhandari V. Bizzarro M.J. Shetty A. Zhong X. Page G.P. Zhang H. et al.Familial and genetic susceptibility to major neonatal morbidities in preterm twins.Pediatrics. 2006; 117: 1901-1906Crossref PubMed Scopus (179) Google Scholar, 15Lavoie P.M. Pham C. Jang K.L. Heritability of bronchopulmonary dysplasia, defined according to the consensus statement of the national institutes of health.Pediatrics. 2008; 122: 479-485Crossref PubMed Scopus (107) Google Scholar and there are an increasing number of gene-targeted studies finding specific mutations in genes associated with lung development, immunity, and oxidative stress associated with BPD in preterm infants.16Rezvani M. Wilde J. Vitt P. Milaparambil B. Grychtol R. Krueger M. et al.Association of a FGFR-4 gene polymorphism with bronchopulmonary dysplasia and neonatal respiratory distress.Dis Markers. 2013; 35: 633-640Crossref PubMed Scopus (0) Google Scholar, 17Koroglu O.A. Onay H. Cakmak B. Bilgin B. Yalaz M. Tunc S. et al.Association of vitamin D receptor gene polymorphisms and bronchopulmonary dysplasia.Pediatr Res. 2014; 76: 171-176Crossref PubMed Scopus (9) Google Scholar, 18Sorensen G.L. Dahl M. Tan Q. Bendixen C. Holmskov U. Husby S. Surfactant protein-D-encoding gene variant polymorphisms are linked to respiratory outcome in premature infants.J Pediatr. 2014; 165: 683-689Abstract Full Text Full Text PDF PubMed Google Scholar, 19Wang X. Li W. Liu W. GSTM1 and GSTT1 gene polymorphisms as major risk factors for bronchopulmonary dysplasia in a Chinese Han population.Gene. 2014; 533: 48-51Crossref PubMed Scopus (0) Google Scholar, 20Winters A.H. Levan T.D. Vogel S.N. Chesko K.L. Pollin T.I. Viscardi R.M. Single nucleotide polymorphism in toll-like receptor 6 is associated with a decreased risk for ureaplasma respiratory tract colonization and bronchopulmonary dysplasia in preterm infants.Pediatr Infect Dis J. 2013; 32: 898-904PubMed Google Scholar, 21Ali S. Hirschfeld A.F. Mayer M.L. Fortuno E.S. Corbett N. Kaplan M. et al.Functional genetic variation in NFKBIA and susceptibility to childhood asthma, bronchiolitis, and bronchopulmonary dysplasia.J Immunol. 2013; 190: 3949-3958Crossref PubMed Scopus (0) Google Scholar However, specific genes that increase the risk for sBPD remain unknown. In particular, data are lacking that specifically address whether distinct genetic, epigenetic, or other etiologic mechanisms contribute to the development of sBPD in comparison with milder forms of BPD. In addition, there is a clear need to develop biomarkers and other predictors for the early identification of preterm newborns who are at risk for BPD and more specifically for sBPD. Although perhaps less common than in the past, infants with sBPD present persistent challenges, raise many questions regarding optimal strategies for enhancing outcomes, and may at times present significant ethical dilemmas. Furthermore, there is limited high quality evidence on which to base clinical management of the patient with sBPD. Evaluation of the patient with sBPD can include a variety of studies discussed herein, which should be guided by clinical presentation. In the extreme preterm infant with type 2 sBPD with the usual NICU course, there is little need to exclude other potential causes of chronic lung disease. In the infant with an atypical presentation or NICU course, potential causes of chronic neonatal respiratory failure include surfactant protein deficiency, gastroesophageal reflux disease (GERD), cystic fibrosis, immune deficiency, anatomic heart disease, pulmonary infection, H-type tracheoesophageal fistula, primary ciliary dyskinesia, and other developmental lung diseases. Evaluations may include bronchoscopy, echocardiogram, esophageal pH and impedance probes, genetic testing, chest computed tomography scan, lung biopsy, and other studies. The NIH consensus statement that defined BPD severity4Jobe A.H. Bancalari E. Bronchopulmonary dysplasia.Am J Respir Crit Care Med. 2001; 163: 1723-1729Crossref PubMed Google Scholar did not address the wide range of disease severity within the group classified as sBPD. In 2003, the American Thoracic Society published a consensus statement pertaining to the care of children with BPD emphasizing the need for an interdisciplinary approach to address the multiorgan sequelae of premature birth.22Allen J. Zwerdling R. Ehrenkranz R. Gaultier C. Geggel R. Greenough A. et al.Statement on the care of the child with chronic lung disease of infancy and childhood.Am J Respir Crit Care Med. 2003; 168: 356-396Crossref PubMed Scopus (0) Google Scholar More specifically, infants with type 2 sBPD are at increased risk for adverse comorbidities including neurodevelopmental impairment, pulmonary hypertension (PH), GERD, feeding difficulties, airways disease, retinopathy of prematurity, and systemic hypertension. These comorbidities frequently complicate the course in sBPD, require the involvement of multiple subspecialists, and, when not integrated into the overall management plan, can further exacerbate gaps in communication and care. In centers that have adopted an interdisciplinary approach to care, survival for this subset of infants is over 75%-80% at discharge.9Guaman MC Gien J Baker CD Zhang H Austin ED Collaco JM. Point prevalence, clinical characteristics, and treatment variation for infants with severe bronchopulmonary dysplasia.Am J Perinatol. 2015; 32: 960-967Crossref PubMed Scopus (14) Google Scholar, 23Gien J Kinsella JP Grenolds A Thrasher J Abman SH Baker CD. Retrospective analysis of an interdisciplinary care program intervention on survival of infants with ventilator-dependent BPD.Am J Perinatol. 2016; (In Press)PubMed Google Scholar Because of the low incidence of type 2 sBPD at any single center, this population remains understudied, and many gaps in knowledge (Table II24Collaco J.M. Romer L.H. Stuart B.D. Coulson J.D. Everett A.D. Lawson E.E. et al.Frontiers in pulmonary hypertension in infants and children with bronchopulmonary dysplasia.Pediatr Pulmonol. 2012; 47: 1042-1053Crossref PubMed Scopus (28) Google Scholar) and controversies exist regarding optimal clinical strategies to improve outcomes in this subgroup of infants.Table IIIdentification of unique research needs to enhance our understanding of sBPD (Modified from Collaco et al24Collaco J.M. Romer L.H. Stuart B.D. Coulson J.D. Everett A.D. Lawson E.E. et al.Frontiers in pulmonary hypertension in infants and children with bronchopulmonary dysplasia.Pediatr Pulmonol. 2012; 47: 1042-1053Crossref PubMed Scopus (28) Google Scholar)Epidemiology1.To quantify the current incidence of sBPD among preterm infants2.To understand the natural history and outcomes of sBPD by large prospective studies in different areas of the world3.To understand the economic impact of sBPD on families and society4.To understand the impact of sBPD on quality of life in infants and their familiesRisk factors1.To identify prenatal and postnatal factors that increase risk of developing sBPD in preterm infants2.To identify risk factors that may exacerbate sBPD in preterm infants, including viral infections, lower respiratory tract disease, upper airway obstruction, intermittent hypoxia and hypercarbia, feeding problems with aspiration, and gastroesophageal reflux3.To understand the role of pulmonary vascular disease in determining the severity of BPDPathophysiology1.To further identify clinical, epidemiologic and biomarker features to better phenotype subtypes of sBPD2.To identify genetic and epigenetic factors that influence the development and severity of sBPDDiagnosis1.To determine the best non-invasive studies for diagnosis and following infants with sBPDManagement1.To develop guidelines for treatment and preventative strategies for preterm infants at risk for the development of sBPD2.To determine the optimal prescription of existing medications in preterm infants with sBPD3.To determine optimal ventilatory strategies in the neonatal intensive care unit and home settings4.To identify newer therapeutic agents for the treatment of sBPD Open table in a new tab The strategy for respiratory support in the acute phases of extreme prematurity is to avoid unnecessary intubation and mechanical ventilation to prevent secondary ventilator-associated lung injury. Persistent need for mechanical ventilator support at postnatal day 7 is associated with high risk for BPD,11Laughon M.M. Langer J.C. Bose C.L. Smith P.B. Ambalavanan N. Kennedy K.A. et al.Prediction of bronchopulmonary dysplasia by postnatal age in extremely premature infants.Am J Respir Crit Care Med. 2011; 183: 1715-1722Crossref PubMed Scopus (106) Google Scholar however, the link between BPD risk and sustained ventilator support at this time point may simply reflect the critical impacts of adverse antenatal and early postnatal events on lung structure and not merely be due to ventilator-associated lung injury alone. Recent multicenter trials no longer support intubation solely for the purpose of treatment with exogenous surfactant.25Support Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research NetworkEarly CPAP versus surfactant in extremely preterm infants.N Engl J Med. 2010; 362: 1970-1979Crossref PubMed Scopus (511) Google Scholar, 26Morley C.J. Davis P.G. Doyle L.W. Brion L.P. Hascoet J.M. Carlin J.B. Nasal CPAP or intubation at birth for very preterm infants.N Engl J Med. 2008; 358: 700-708Crossref PubMed Scopus (666) Google Scholar, 27Dunn M.S. Kaempf J. de Klerk A. de Klerk R. Reilly M. Howard D. et al.Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates.Pediatrics. 2011; 128: e1069-76Crossref PubMed Scopus (190) Google Scholar Unfortunately, a significant proportion of infants cannot be stabilized and supported on nasal CPAP during their entire hospital course. Several recent trials have shown that infants randomized to immediate nasal CPAP were intubated secondary to apnea or respiratory failure in at least 50% of cases.25Support Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research NetworkEarly CPAP versus surfactant in extremely preterm infants.N Engl J Med. 2010; 362: 1970-1979Crossref PubMed Scopus (511) Google Scholar, 26Morley C.J. Davis P.G. Doyle L.W. Brion L.P. Hascoet J.M. Carlin J.B. Nasal CPAP or intubation at birth for very preterm infants.N Engl J Med. 2008; 358: 700-708Crossref PubMed Scopus (666) Google Scholar, 27Dunn M.S. Kaempf J. de Klerk A. de Klerk R. Reilly M. Howard D. et al.Randomized trial comparing 3 approaches to the initial respiratory management of preterm neonates.Pediatrics. 2011; 128: e1069-76Crossref PubMed Scopus (190) Google Scholar Hence, the proportion of infants exposed to intubation and mechanical ventilation remains high along with a continued high incidence of chronic respiratory failure and the subsequent development of sBPD. In extremely low birth weight infants in the first week of life, attempts at extubation to and stabilization on nasal CPAP are still warranted, based on the potential impact of prolonged ventilator support on sBPD and adverse neurodevelopmental outcomes.28Walsh M.C. Morris B.H. Wrage L.A. Vohr B.R. Poole W.K. Tyson J.E. et al.Extremely low birthweight neonates with protracted ventilation: mortality and 18-month neurodevelopmental outcomes.J Pediatr. 2005; 146: 798-804Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar However, at some point during the respiratory course of premature infants with evolving BPD, lung structure and function may become sufficiently abnormal that attempts at extubation to nasal CPAP are neither feasible nor desirable. Some indicators include sustained respiratory distress with retractions, recurrent cyanotic or bradycardic episodes, intolerance of respiratory and physical therapies or handling, poor growth, and the apparent use of or need for repeated steroid courses without sustained benefit. At this point, the goals of care need to be redirected toward optimizing management on mechanical ventilation to support adequate gas exchange, reduce the work of breathing, and optimize growth and healing of the injured lungs. Resolution of the lung disease and improvement in lung function depends on emphasizing nutritional strategies that enhance somatic and lung growth. Determining the specific type and level of respiratory support for infants with sBPD is challenging, as an optimal ventilator strategy required by these infants is frequently dramatically different than the strategy utilized in the first few weeks of life (Table III).29Abman S.H. Nelin L.D. Management of the infant with severe bronchopulmonary dysplasia.in: Bancalari E. The newborn lung: neonatology questions and controversies. Elsevier Saunders, Philadelphia (PA)2012: 407-425Crossref Scopus (1) Google Scholar The strategy must reflect the transition from lung mechanics in the first few days of life, which are dominated by low compliance, relative homogeneity, and normal airway resistance, to the mechanics that are seen in sBPD, dominated by high airway resistance, air trapping, and heterogeneous aeration (Figure 2).29Abman S.H. Nelin L.D. Management of the infant with severe bronchopulmonary dysplasia.in: Bancalari E. The newborn lung: neonatology questions and controversies. Elsevier Saunders, Philadelphia (PA)2012: 407-425Crossref Scopus (1) Google Scholar In the first week of life, lung mechanics suggest that a ventilator strategy aimed at the relatively uniform respiratory system with short time constants is reasonable and would include a fast rate, low tidal volume (Vt), short inspiratory time (Ti) strategy (Figure 2).29Abman S.H. Nelin L.D. Management of the infant with severe bronchopulmonary dysplasia.in: Bancalari E. The newborn lung: neonatology questions and controversies. Elsevier Saunders, Philadelphia (PA)2012: 407-425Crossref Scopus (1) Google Scholar, 30Jarriel W.S. Richardson P. Knapp R.D. Hansen T.N. A nonlinear regression analysis of nonlinear, passive-deflation flow-volume plots.Pediatr Pulmonol. 1993; 15: 175-182Crossref PubMed Scopus (7) Google Scholar, 31Castile R.G. Nelin L.D. Lung function, structure and the physiologic basis for mechanical ventilation of infants with established BPD.in: Abman S.H. Bronchopulmonary dysplasia. Informa Healthcare, New York (NY)2010: 328-346Google Scholar In sBPD, the lung is characterized by different combinations of lung regions with different levels of airway resistance and altered distal lung compliance, which leads to highly diverse time constants (Figure 2). Thus, to enhance gas exchange, reduce the risk for atelectasis, decrease dead space ventilation, and perhaps lower pulmonary vascular resistance, the ventilator support strategy needs to change dramatically from a fast-rate, low Vt strategy during the early course to a slow-rate, high Vt and prolonged Ti strategy for chronic disease (Table III).Table IIIComparison of ventilator strategies and goals during progression of early disease to established sBPD (modified from Abman and Nelin29Abman S.H. Nelin L.D. Management of the infant with severe bronchopulmonary dysplasia.in: Bancalari E. The newborn lung: neonatology questions and controversies. Elsevier Saunders, Philadelphia (PA)2012: 407-425Crossref Scopus (1) Google Scholar)Early (prevention)Strategies to prevent acute lung injuryLow tidal volumes (3-5 mL/kg)Short inspiratory times (0.2-0.3 seconds)Increased PEEP for lung recruitment without overdistensionStrategies for gas exchangeAdjust FiO2 to target SpO2 (range: 91%-95%)Permissive hypercapniaLate (established BPD)Strategies for gas exchangeMarked regional heterogeneityLarger tidal volumes (10-12 mL/kg)L
