Respiratory Distress Syndrome and Neonatology: Forever Linked, Forever EvolvingThe evolution of neonatal practice is intimately linked to our treatment of one disease—respiratory distress syndrome (RDS).1Bancalari E.H. Jobe A.H. The respiratory course of extremely preterm infants: a dilemma for diagnosis and terminology.J Pediatr. 2012; 161: 585-588Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 2Curstedt T. Halliday H.L. Speer C.P. A unique story in neonatal research: the development of a porcine surfactant.Neonatology. 2015; 107: 321-329Crossref PubMed Scopus (44) Google Scholar, 3Halliday H.L. The fascinating story of surfactant.J Paediatr Child Health. 2017; 53: 327-332Crossref PubMed Scopus (11) Google Scholar The evolution of the threshold of viability has necessitated a continual reassessment of the application of well-studied and evidence-based treatments for this disease. Survival rates of extremely preterm neonates continue to improve, including for those born at 22-23 weeks of gestational age.4Ramaswamy V.V. Abiramalatha T. Bandyopadhyay T. Shaik N.B. Bandiya P. Nanda D. et al.ELBW and ELGAN outcomes in developing nations-Systematic review and meta-analysis.PLoS One. 2021; 16: e0255352Crossref PubMed Scopus (4) Google Scholar, 5Morgan A.S. Mendonca M. Thiele N. David A.L. Management and outcomes of extreme preterm birth.BMJ. 2022; 376: e055924PubMed Google Scholar, 6Backes C.H. Rivera B.K. Pavlek L. Beer L.J. Ball M.K. Zettler E.T. et al.Proactive neonatal treatment at 22 weeks of gestation: a systematic review and meta-analysis.Am J Obstet Gynecol. 2021; 224: 158-174Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 7Rysavy M.A. Mehler K. Oberthür A. Ågren J. Kusuda S. McNamara P.J. et al.An immature science: intensive care for infants born at </=23 weeks of gestation.J Pediatr. 2021; 233: 16-25.e11Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 8Ramaswamy V.V. Oommen V.I. Gupta A. Weerapperuma N. Zivanovic S. Roehr C.C. et al.Care practices and outcomes of extremely preterm neonates born at 22-24 weeks - a single centre experience.J Neonatal Perinatal Med. 2021; 14: 575-582Crossref PubMed Scopus (1) Google Scholar However, rates of respiratory morbidity and bronchopulmonary dysplasia (BPD) remain unacceptably high, especially among these most immature, highest risk neonates (<28 weeks of gestation, and in particular <25 weeks of gestation).9Siffel C. Kistler K.D. Lewis J.F.M. Sarda S.P. Global incidence of bronchopulmonary dysplasia among extremely preterm infants: a systematic literature review.J Matern Fetal Neonatal Med. 2021; 34: 1721-1731Crossref PubMed Scopus (41) Google Scholar Thus, choosing the best care options is one of the central challenges to be met.With continuous positive airway pressure (CPAP) and surfactant replacement therapy, present-day neonatologists are equipped with 2 powerful tools. This commentary seeks to explain how our treatment of RDS has evolved over time, and how lessons learned in more mature populations may both advance and hinder respiratory care when applied to this new population of extremely premature neonates. It addresses the question of whether and how RDS could be identified early and more precisely in the most immature preterm infants, allowing for a more fine-tuned approach to early respiratory support for this high-risk patient population. We ask whether our inability to diagnose RDS inadvertently causes harm by delaying exogenous surfactant therapy in those destined to fail CPAP/noninvasive ventilation (NIV), and whether less invasive surfactant administration (LISA) or minimally invasive surfactant administration (MIST) represents a pragmatic and beneficial approach in combining early surfactant and CPAP. Finally, we argue that it is time to distinguish high-risk very immature preterm infants (25-28 weeks of gestation) from the increasing number of highest risk, periviable preterm infants born at 22-24 weeks of gestation, to better adapt respiratory management meeting individual needs and risk profiles.BPD: The Reason Why Neonatologists Seek to Avoid Invasive Mechanical VentilationBPD remains among the most common morbidities after preterm birth, and rates are even increasing in the most immature preterm infants.10Thébaud B. Goss K.N. Laughon M. Whitsett J.A. Abman S.H. Steinhorn R.H. et al.Bronchopulmonary dysplasia.Nat Rev Dis Primers. 2019; 5: 78Crossref PubMed Scopus (166) Google Scholar,11Sun S. Zivanovic S. Earnest A. Roehr C.C. Tan K. Respiratory management and bronchopulmonary dysplasia in extremely preterm infants: a comparison of practice between centres in Oxford and Melbourne.J Perinatol. 2022; 42: 53-57Crossref PubMed Scopus (1) Google Scholar In addition to predicting long-term pulmonary dysfunction,12Sillers L. Alexiou S. Jensen E.A. Lifelong pulmonary sequelae of bronchopulmonary dysplasia.Curr Opin Pediatr. 2020; 32: 252-260Crossref PubMed Scopus (19) Google Scholar BPD increases the risk of poor neurodevelopmental outcomes.13Cheong J.L.Y. Doyle L.W. An update on pulmonary and neurodevelopmental outcomes of bronchopulmonary dysplasia.Semin Perinatol. 2018; 42: 478-484Crossref PubMed Scopus (90) Google Scholar,14Katz T.A. Vliegenthart R.J.S. Aarnoudse-Moens C.S.H. Leemhuis A.G. Beuger S. Blok G.J. et al.Severity of bronchopulmonary dysplasia and neurodevelopmental outcome at 2 and 5 years corrected age.J Pediatr. 2021; 243: 40-46Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Thus, there is an urgent need to identify strategies that minimize the risk of developing BPD, particularly in high-risk patients. The pathogenesis of BPD is multifactorial, with the main contributing factors being mostly out of the clinicians' control, including preterm birth, structurally and biochemically immature lungs, intrauterine growth restriction, prenatal and postnatal inflammation, and neonatal infections.10Thébaud B. Goss K.N. Laughon M. Whitsett J.A. Abman S.H. Steinhorn R.H. et al.Bronchopulmonary dysplasia.Nat Rev Dis Primers. 2019; 5: 78Crossref PubMed Scopus (166) Google Scholar,15Groneck P. Gotze-Speer B. Oppermann M. Eiffert H. Speer C.P. Association of pulmonary inflammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: a sequential analysis of inflammatory mediators in respiratory fluids of high-risk preterm neonates.Pediatrics. 1994; 93: 712-718Crossref PubMed Google Scholar,16Speer C.P. Inflammation and bronchopulmonary dysplasia: a continuing story.Semin Fetal Neonatal Med. 2006; 11: 354-362Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar However, exposure to mechanical ventilation, one of the strongest risk factors for BPD, is within the clinicians’ control.17Van Marter L.J. Allred E.N. Pagano M. Sanocka U. Parad R. Moore M. et al.Do clinical markers of barotrauma and oxygen toxicity explain interhospital variation in rates of chronic lung disease? The Neonatology Committee for the Developmental Network.Pediatrics. 2000; 105: 1194-1201Crossref PubMed Scopus (441) Google Scholar, 18Oh W. Poindexter B.B. Perritt R. Lemons J.A. Bauer C.R. Ehrenkranz R.A. et al.Association between fluid intake and weight loss during the first ten days of life and risk of bronchopulmonary dysplasia in extremely low birth weight infants.J Pediatr. 2005; 147: 786-790Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 19Ambalavanan N. Van Meurs K.P. Perritt R. Carlo W.A. Ehrenkranz R.A. Stevenson D.K. et al.Predictors of death or bronchopulmonary dysplasia in preterm infants with respiratory failure.J Perinatol. 2008; 28: 420-426Crossref PubMed Scopus (80) Google Scholar, 20Ambalavanan N. Walsh M. Bobashev G. Das A. Levine B. Carlo W.A. et al.Intercenter differences in bronchopulmonary dysplasia or death among very low birth weight infants.Pediatrics. 2011; 127: e106-e116Crossref PubMed Scopus (66) Google Scholar, 21Gagliardi L. Bellu R. Lista G. Zanini R. Network Neonatale Lombardo Study GroupDo differences in delivery room intubation explain different rates of bronchopulmonary dysplasia between hospitals?.Arch Dis Child Fetal Neonatal Ed. 2011; 96: F30-F35Crossref PubMed Scopus (34) Google Scholar, 22Laughon M. Bose C. Allred E.N. O'Shea T.M. Ehrenkranz R.A. Van Marter L.J. et al.Antecedents of chronic lung disease following three patterns of early respiratory disease in preterm infants.Arch Dis Child Fetal Neonatal Ed. 2011; 96: F114-F120Crossref PubMed Scopus (33) Google Scholar, 23May C. Patel S. Kennedy C. Pollina E. Rafferty G.F. Peacock J.L. et al.Prediction of bronchopulmonary dysplasia.Arch Dis Child Fetal Neonatal Ed. 2011; 96: F410-F416Crossref PubMed Scopus (29) Google Scholar, 24Jensen E.A. DeMauro S.B. Kornhauser M. Aghai Z.H. Greenspan J.S. Dysart K.C. Effects of multiple ventilation courses and duration of mechanical ventilation on respiratory outcomes in extremely low-birth-weight infants.JAMA Pediatr. 2015; 169: 1011-1017Crossref PubMed Scopus (90) Google Scholar Consistent with this finding, large randomized controlled trials (RCTs) have convincingly demonstrated that avoiding invasive mechanical ventilation (IMV) through the routine use of CPAP is safe and prevented BPD in very immature neonates at high risk of lung injury (25-30 weeks of gestation).25Fischer H.S. Bührer C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: a meta-analysis.Pediatrics. 2013; 132: e1351-e1360Crossref PubMed Scopus (189) Google Scholar, 26Schmölzer G.M. Kumar M. Pichler G. Aziz K. O'Reilly M. Cheung P.Y. Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis.BMJ. 2013; 347: f5980Crossref PubMed Scopus (328) Google Scholar, 27Wright C.J. Polin R.A. Kirpalani H. Continuous positive airway pressure to prevent neonatal lung injury: how did we get here, and how do we improve?.J Pediatr. 2016; 173: 17-24.e12Abstract Full Text Full Text PDF PubMed Scopus (22) Google ScholarCPAP and NIV: What Do The Guidelines Say?These data have largely convinced neonatologists that avoiding IMV is advantageous in very immature neonates. Thus, one might expect to find relatively consistent recommendations in national and international guidelines and expert consensus statements regarding the use of CPAP and NIV for initial respiratory support, as well as what constitutes CPAP failure and when to intervene and provide exogenous surfactant to treat RDS in this cohort.28Ramaswamy V.V. Abiramalatha T. Roehr C.C. Addressing the lack of clarity about administering surfactant in preterm infants with respiratory distress syndrome treated with noninvasive respiratory support.JAMA Pediatr. 2021; 173: 17-24Google ScholarUnfortunately, consensus in written guidelines regarding these issues does not exist.29Committee on Fetus and Newborn, American Academy of PediatricsRespiratory support in preterm infants at birth.Pediatrics. 2014; 33: 171-174Crossref Scopus (188) Google Scholar, 30Sweet D.G. Carnielli V. Greisen G. Hallman M. Ozek E. Te Pas A. et al.European Consensus Guidelines on the management of respiratory distress syndrome - 2019 update.Neonatology. 2019; 115: 432-450Crossref PubMed Scopus (497) Google Scholar, 31Ng E.H. Shah V. Guidelines for surfactant replacement therapy in neonates.Paediatr Child Health. 2021; 26: 35-49Crossref PubMed Scopus (21) Google Scholar Apparent inconsistencies in the recommendations of academic bodies and international societies in the US, Canada, and Europe reflect the different concepts, structures, and practices of neonatal medicine. And even though each set of guidelines proclaims to be firmly based on the available evidence, regional interpretation and clinical implementation result in a variability of practice that is based on practitioner preference. Although potentially frustrating, this variability highlights the gaps in and the urgent need for further improvement of the evidence base regarding the early respiratory management of preterm infants. Given today's cohort of extremely preterm, often periviable infants, the development of gestational age-specific optimal care seems inevitable.32Zivanovic S. Roehr C.C. One step further toward defining the optimal respiratory care package for neonates: interventions to successfully extubate preterm infants.JAMA Pediatr. 2017; 171: 120-121Crossref PubMed Scopus (5) Google ScholarThe Benefit of Early and Liberal CPAP: Applicable to the Very Tiny Baby?When analyzing the question whether routine use of CPAP in extremely premature infants compared with routine intubation and prophylactic surfactant prevents BPD assessed at 36 weeks’ postmenstrual age, it is necessary to exclusively consider patients at the highest risk of BPD development and to enroll adequate numbers. Ideally the control group would be managed with the current standard of care. By the late 1990s and early 2000s, the then best available evidence supported the practice of routine intubation and prophylactic or early surfactant for infants at high risk of RDS, but this approach had not been compared with CPAP alone.33Horbar J.D. Rogowski J. Plsek P.E. Delmore P. Edwards W.H. Hocker J. et al.Collaborative quality improvement for neonatal intensive care. NIC/Q Project Investigators of the Vermont Oxford Network.Pediatrics. 2001; 107: 14-22Crossref PubMed Scopus (307) Google Scholar, 34Horbar J.D. Carpenter J.H. Buzas J. Soll R.F. Suresh G. Bracken M.B. et al.Timing of initial surfactant treatment for infants 23 to 29 weeks' gestation: is routine practice evidence based?.Pediatrics. 2004; 113: 1593-1602Crossref PubMed Scopus (67) Google Scholar, 35Carlo W.A. Gentle ventilation: the new evidence from the SUPPORT, COIN, VON, CURPAP, Colombian Network, and Neocosur Network trials.Early Hum Dev. 2012; 88: S81-S83Crossref PubMed Scopus (46) Google Scholar, 36Rojas-Reyes M.X. Morley C.J. Soll R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants.Cochrane Database Syst Rev. 2012; 3: CD000510PubMed Google Scholar Importantly, the studies supporting prophylactic or early surfactant enrolled very few infants born at 25-28 weeks of gestation, and rates of antenatal corticosteroid exposure were much lower than seen in current practice.35Carlo W.A. Gentle ventilation: the new evidence from the SUPPORT, COIN, VON, CURPAP, Colombian Network, and Neocosur Network trials.Early Hum Dev. 2012; 88: S81-S83Crossref PubMed Scopus (46) Google Scholar,36Rojas-Reyes M.X. Morley C.J. Soll R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants.Cochrane Database Syst Rev. 2012; 3: CD000510PubMed Google Scholar Thus, changes in obstetrical practice (increased antenatal corticosteroids) and the evolving neonatal intensive care unit patient population (increasing survival of extremely premature neonates) created a knowledge gap.Two RCTs performed in the late 2000s—Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) and the Vermont Oxford Network Delivery Room Management Trial (VON-DRM)—demonstrated that, compared with prophylactic surfactant, the routine use of early CPAP in very high-risk neonates with high rates of antenatal corticosteroid exposure, prevents BPD and death with a number needed to treat of 17.7.27Wright C.J. Polin R.A. Kirpalani H. Continuous positive airway pressure to prevent neonatal lung injury: how did we get here, and how do we improve?.J Pediatr. 2016; 173: 17-24.e12Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar,37Finer N.N. Carlo W.A. Walsh M.C. Rich W. Gantz M.G. et al.SUPPORT 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 (824) Google Scholar,38Dunn 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-e1076Crossref PubMed Scopus (338) Google Scholar More inclusive meta-analyses cite a number needed to treat of 25 and 35.25Fischer H.S. Bührer C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: a meta-analysis.Pediatrics. 2013; 132: e1351-e1360Crossref PubMed Scopus (189) Google Scholar,26Schmölzer G.M. Kumar M. Pichler G. Aziz K. O'Reilly M. Cheung P.Y. Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis.BMJ. 2013; 347: f5980Crossref PubMed Scopus (328) Google Scholar This treatment effect is encouraging for what is essentially a de-escalation of therapeutic invasiveness (ie, no intubation and no administration of exogenous surfactant) and supports the broad implementation of this approach in infants at high risk of developing BPD. Aiming to minimize the exposure to IMV, these data supported the adoption of rather liberal criteria of CPAP or NIV failure—comprising a higher fraction of inspired oxygen (FiO2) as well as CPAP levels—in the Canadian and US guidelines.29Committee on Fetus and Newborn, American Academy of PediatricsRespiratory support in preterm infants at birth.Pediatrics. 2014; 33: 171-174Crossref Scopus (188) Google Scholar,31Ng E.H. Shah V. Guidelines for surfactant replacement therapy in neonates.Paediatr Child Health. 2021; 26: 35-49Crossref PubMed Scopus (21) Google Scholar However, it is reasonable to ask why the treatment effect (number needed to treat of 17.7-35.0) is not larger, given the known risks of exposure to IMV.High Incidence of CPAP Failure: Does It Blunt the Treatment Effect in the Extremely Premature Infant?One conceivable explanation of this lack of treatment effect is that CPAP and NIV do not sufficiently decrease exposure to IMV when broadly applied to a high-risk population. Stoll et al reported outcomes of preterm infants born at less than 28 weeks of gestation at Neonatal Research Network centers.39Stoll 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 (1496) Google Scholar In 2012, and despite the increased use of CPAP for initial respiratory support, more than 85% of those who survived more than 12 hours were exposed to IMV. Consistent with these data, rates of CPAP failure in the first week approached 50% in SUPPORT and VON-DRN trials37Finer N.N. Carlo W.A. Walsh M.C. Rich W. Gantz M.G. et al.SUPPORT 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 (824) Google Scholar,38Dunn 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-e1076Crossref PubMed Scopus (338) Google Scholar and are similarly high in observational studies.40Ammari A. Suri M. Milisavljevic V. Sahni R. Bateman D. Sanocka U. et al.Variables associated with the early failure of nasal CPAP in very low birth weight infants.J Pediatr. 2005; 147: 341-347Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar, 41Fuchs H. Lindner W. Leiprecht A. Mendler M.R. Hummler H.D. Predictors of early nasal CPAP failure and effects of various intubation criteria on the rate of mechanical ventilation in preterm infants of <29 weeks gestational age.Arch Dis Child Fetal Neonatal Ed. 2011; 96: F343-F347Crossref PubMed Scopus (66) Google Scholar, 42Dargaville P.A. Aiyappan A. De Paoli A.G. Dalton R.G. Kuschel C.A. Kamlin C.O. et al.Continuous positive airway pressure failure in preterm infants: incidence, predictors and consequences.Neonatology. 2013; 104: 8-14Crossref PubMed Scopus (109) Google ScholarAlthough the benefits of CPAP and NIV are clear, the NIV approach, when broadly applied, apparently fails to adequately support more than one-half of the target population. It is, thus, important to ask whether this broad application mixes 2 distinct patient populations, each needing a different approach. Although the routine or liberal use of CPAP may adequately support one subset of high-risk neonates and effectively decrease the burden of BPD, the same approach may be associated with high rates of failure in another subset of high-risk infants. The first population—those most likely to need only NIV support—should demonstrate a greater treatment effect with a targeted application. The second population—those who ultimately will not sustain on NIV support—may suffer significant harm from the delay of an adequate treatment.Surfactant Deficiency: Primary Driver of NIV Failure in the Extremely Premature InfantIt is necessary to identify the primary cause of NIV failure to target appropriate therapy. Data from RCTs and observational studies depict that approximately 50% of infants initially supported with CPAP require IMV within the first week of life, with a majority failing within the first 8 hours.37Finer N.N. Carlo W.A. Walsh M.C. Rich W. Gantz M.G. et al.SUPPORT 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 (824) Google Scholar,38Dunn 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-e1076Crossref PubMed Scopus (338) Google Scholar,42Dargaville P.A. Aiyappan A. De Paoli A.G. Dalton R.G. Kuschel C.A. Kamlin C.O. et al.Continuous positive airway pressure failure in preterm infants: incidence, predictors and consequences.Neonatology. 2013; 104: 8-14Crossref PubMed Scopus (109) Google Scholar, 43Morley C.J. Davis P.G. Doyle L.W. Brion L.P. Hascoet J.M. Carlin J.B. COIN Trial InvestigatorsNasal CPAP or intubation at birth for very preterm infants.N Engl J Med. 2008; 358: 700-708Crossref PubMed Scopus (984) Google Scholar, 44Sandri F. Plavka R. Ancora G. Simeoni U. Stranak Z. Martinelli S. et al.Prophylactic or early selective surfactant combined with nCPAP in very preterm infants.Pediatrics. 2010; 125: e1402-e1409Crossref PubMed Scopus (251) Google Scholar Failure is foreshown by increasing oxygen requirement, and the most immature neonates are at highest risk of not sustaining on CPAP or NIV alone.41Fuchs H. Lindner W. Leiprecht A. Mendler M.R. Hummler H.D. Predictors of early nasal CPAP failure and effects of various intubation criteria on the rate of mechanical ventilation in preterm infants of <29 weeks gestational age.Arch Dis Child Fetal Neonatal Ed. 2011; 96: F343-F347Crossref PubMed Scopus (66) Google Scholar, 42Dargaville P.A. Aiyappan A. De Paoli A.G. Dalton R.G. Kuschel C.A. Kamlin C.O. et al.Continuous positive airway pressure failure in preterm infants: incidence, predictors and consequences.Neonatology. 2013; 104: 8-14Crossref PubMed Scopus (109) Google Scholar, 43Morley C.J. Davis P.G. Doyle L.W. Brion L.P. Hascoet J.M. Carlin J.B. COIN Trial InvestigatorsNasal CPAP or intubation at birth for very preterm infants.N Engl J Med. 2008; 358: 700-708Crossref PubMed Scopus (984) Google Scholar, 44Sandri F. Plavka R. Ancora G. Simeoni U. Stranak Z. Martinelli S. et al.Prophylactic or early selective surfactant combined with nCPAP in very preterm infants.Pediatrics. 2010; 125: e1402-e1409Crossref PubMed Scopus (251) Google Scholar, 45Roberts C.T. Owen L.S. Frøisland D.H. Doyle L.W. Davis P.G. Manley B.J. Predictors and outcomes of early intubation in infants born at 28-36 weeks of gestation receiving noninvasive respiratory support.J Pediatr. 2020; 216: 109-116Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Multiple contributing factors, ultimately leading to ineffective gas exchange and the requirement of maximal respiratory support, have been identified. These factors include surfactant deficiency, unique anatomic and physiologic features in the extremely premature infant causing an inability to effectively deliver distending pressure and maintain sufficient functional residual capacity, and an impaired respiratory drive. Surfactant deficiency as a major feature of pulmonary immaturity increases with decreasing gestational age. It is, therefore, not surprising that the best estimates place surfactant deficiency, synonymously referred to as RDS, as the key driver of CPAP failure in 80% of cases of extremely premature infants.46Dargaville P.A. Gerber A. Johansson S. De Paoli A.G. Kamlin C.O. Orsini F. et al.Incidence and outcome of CPAP failure in preterm infants.Pediatrics. 2016; 138: e2013985Crossref Scopus (119) Google ScholarThe initial trials evaluating exogenous surfactant for RDS convincingly demonstrated that earlier administration of treatment is related to greater treatment effect in terms of air leak and pneumothorax, chronic lung disease and mortality.47Bahadue F.L. Soll R. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome.Cochrane Database Syst Rev. 2012; 11: CD001456PubMed Google Scholar Strategies referred to as prophylactic surfactant use or early rescue surfactant decreased air leak and improved survival of infants at highest risk of developing RDS.36Rojas-Reyes M.X. Morley C.J. Soll R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants.Cochrane Database Syst Rev. 2012; 3: CD000510PubMed Google Scholar,48Morley C.J. Systematic review of prophylactic vs rescue surfactant.Arch Dis Child Fetal Neonatal Ed. 1997; 77: F70-F74Crossref PubMed Scopus (69) Google Scholar,49Soll R.F. Morley C.J. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants.Cochrane Database Syst Rev. 2001; 14: CD000510Google Scholar However, it is necessary to highlight that infants enrolled in these early studies of surfactant replacement therapy were relatively mature, had lower antenatal corticosteroid exposure rates, and were already intubated owing to RDS. Nonetheless, it is reasonable to assume that the well-proven lung-protective properties of exogenous surfactant therapy should extend to extremely premature neonates with RDS, whether supported by IMV or CPAP or NIV. The desire to capture the beneficial effects of early surfactant treatment and to avoid the potential harm of treatment delay drove the adoption of very inclusive surfactant treatment criteria (an FiO2 of ≥0.3) in the European Consensus Guidelines (in addition to critical assessment of clinical symptoms, such as increased work of breathing and sternal retractions).30Sweet D.G. Carnielli V. Greisen G. Hallman M. Ozek E. Te Pas A. et al.European Consensus Guidelines on the management of respiratory distress syndrome - 2019 update.Neonatology. 2019; 115: 432-450Crossref PubMed Scopus (497) Google Scholar In summary, the current recommendations reflect the dilemma still present for neonatologists: RDS and its severity can only be determined clinically by the judgment of progressive dyspnea and FiO2 requirement. In line with this finding, signs of increased work of breathing, apnea, or respiratory acidosis together with an increased oxygen need despite presumed optimized CPAP or positive end-expiratory pressure are used as pointers toward respiratory failure.50Setty S.G. Batra M. Hedstrom A.B. The Silverman Andersen respiratory severity score can be simplified and still predicts increased neonatal respiratory support.Acta Paediatr. 2020; 109: 1273-1275Crossref PubMed Scopus (2) Google Scholar In an even more immature preterm infant population, these limitations in our diagnostic repertoire and their impact on therapeutic decisions must not be underestimated. One cannot help but argue that these clinical signs are merely confirming CPAP failure, rather than providing useful information toward its prevention.FiO2 as a Determinant of CPAP Failure: The Need to Improve Our Predictive CapacityFiO2 requirement is a consistent and objective marker heavily relied upon when determining CPAP failure in the extremely premature neonate. Although lower FiO2 thresholds result in earlier treatment, higher thresholds will maximize the number of infants managed successfully with CPAP alone. The impact of FiO2 criteria on intubation rates was demonstrated by Fuchs et al.41Fuchs H. Lindner W. Leiprecht A. Mendler M.R. Hummler H.D. Predictors of early nasal CPAP failure and effects of various intubation criteria on the rate of mechanical ventilation in preterm infants of <29 weeks gestational age.Arch Dis Child Fetal Neonatal Ed. 2011; 96: F343-F347Crossref PubMed Scopus (66) Google Scholar By lowering the intubation criteria from FiO2 0.6 to 0.35, rates of intubation increased by 16%. Dargaville et al demonstrated that FiO2 levels in the first 2 hours of life had the “strongest predictive effect on CPAP failure” in neonates born at 25-28 weeks of gestation.42Dargaville P.A. Aiyappan A. De Paoli A.G. Dalton R.G. Kuschel C.A. Kamlin C.O. et al.Continuous positive airway pressure failure in preterm infants: incidence, predictors and consequences.Neonatology. 2013; 104: 8-14Crossref PubMed Scopus (109) Google Scholar However, the need to improve this predictive capacity is clearly demonstrated by the poor positive predictive value of FiO2 in the given study. Applying the reported sensitivity of approximately 85% and specificity of approximately 50% of an early life (<2 hours of life) FiO2 requirement of 0.3 to the patients born at 25-28 weeks of gestation in this dataset, we calculated a positive predictive value of 59% and a negative predictive value of 82%. Thus, FiO2 might function as a relatively good s