Long-Term Respiratory Morbidity in Preterm Infants: Is Noninvasive Support in the Delivery Room the Solution?
T
he adverse long-term pulmonary consequences of CPAP prevents 1 case of BPD). This NNT is higher than the extreme prematurity are increasingly recognized. Seminal NNT to prevent BPD for caffeine (10) and Vitamin A (12),22 work in animals suggests that lung injury likely starts durbut given the relative safety of CPAP, these data provide a ing the moments after birth.1,2 Therefore, much subsequent sound rationale for prioritizing non-invasive respiratory strategies in extremely premature infants. Such evidence led the clinical research has focused on optimizing the initial resuscitaAmerican Academy of Pediatrics Committee tion and stabilization of the extremely preSee related articles, p on Fetus and Newborn to publish a policy term infant. Two articles in this issue of The and p statement in January 2014 concluding that Journal provide insight into how delivery “the early use of CPAP with subsequent selective surfactant room (DR) practice may be improved and may influence the administration in extremely preterm infants results in lower short- and long-term outcomes of preterm infants.3,4 rates of BPD/death compared with treatment with prophylacIn survivors of prematurity, spirometry at school age tic or early surfactant therapy.”23 consistently demonstrates decreased lung function compared 5-10 with full-term controls. These deficits are more severe in In this issue of The Journal, Stevens et al report the Breathextremely preterm infants with bronchopulmonary dysplasia ing Outcomes Study, which evaluated parental reports of res(BPD). Worse, such effects persist throughout childhood and piratory outcomes over the first 18-22 months of life among likely into adulthood.11-13 In addition to the known impact participants in the National Institute of Child Health and Human Development Surfactant Positive Airway Pressure of prematurity on long-term respiratory morbidity, BPD is and Pulse Oximetry Trial (SUPPORT).3,17,24 The previously an independent predictor of neurodevelopmental outcomes 14 at 18 months. Similarly, duration of ventilation beyond reported SUPPORT compared DR CPAP with routine intubation and high to low oxygen saturation targeting in 60 days is correlated with developmental impairment at extremely preterm infants.17,24 The Breathing Outcomes 18 months.15 Thus, strategies to prevent lung disease of prematurity and its associated long-term sequelae are needed. Study showed no difference in the primary outcome of Although neonatologists have recognized the potential wheezing during the worst 2-week period or cough lasting impact of DR interventions on the outcomes of preterm infants more than 3 days (without a cold) by 18-22 months corrected for some time, such interventions have only recently been studage among any of the groups of SUPPORT. ied systematically in large randomized trials. Several trials have Because each individual trial of DR CPAP appears to show evaluated the use of continuous positive airway pressure only modest results and meta-analyses report large numbers (CPAP) in comparison with immediate intubation and surfacneeded to treat, it is reasonable to question why noninvasive tant administration.16-18 These individual studies show trends respiratory support in the DR has not thus far had more impact in limiting lung disease in preterm infants. We sugtoward decreased rates of death or BPD and reduced need for gest several potential explanations for the modest effect of a surfactant with the use of noninvasive support, but no signifinoninvasive DR strategy. First, the most effective methods cant differences. This is likely due to individual trials being unof performing noninvasive respiratory support to avoid intuderpowered to identify this treatment effect because three bation in the DR setting remain unclear. Although these trials pooled analyses including over 3000 infants demonstrate that were designed to compare CPAP vs routine intubation and strategies aimed at avoiding early mechanical ventilation in surfactant administration, many premature infants require preterm infants have a “small but significant beneficial impact” positive pressure ventilation (PPV) during their initial stabifor the prevention death or BPD.19-21 Although these analyses lization after birth. Performing PPV in extremely low birth differ in significant details, they consistently report a significant weight infants is difficult: facemask leak, airway obstruction, reduction of death or BPD in infants treated with CPAP, with a and inability to accurately assess chest wall movement are number needed to treat (NNT, 25-35 infants treated with common problems, resulting in variable tidal volume delivery.25,26 Many extremely preterm infants are not well stabilized with noninvasive PPV after birth, and then require BPD Bronchopulmonary dysplasia BPM CPAP DR HR NNT PPV SUPPORT
Beats per minute Continuous positive airway pressure Delivery room Heart rate Number needed to treat Positive pressure ventilation Surfactant Positive Airway Pressure and Pulse Oximetry Trial
The University Pennsylvania and The Children’s Hospital of Philadelphia have been a participating site in the Neonatal Research Network since 2011. The authors were not involved in the Neonatal Research Network SUPPORT Trial as reported by Stevens et al. The author declares no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.04.018
1
THE JOURNAL OF PEDIATRICS
www.jpeds.com
tracheal intubation to achieve effective ventilation.27 Thus, in these trials, many infants assigned to CPAP were intubated within the first minutes of life for failed noninvasive resuscitation. For example, in SUPPORT, one-third of infants assigned to the CPAP arm were intubated in the DR for resuscitation.17 This co-intervention potentially diluted the observed treatment effect of a noninvasive strategy. Investigators have sought to improve the technical aspects of delivering noninvasive support (both CPAP and PPV) during DR resuscitation by studying alternate resuscitative devices,28 between device and infant,29,30 and respiratory function monitors in the DR.31 Although the Neonatal Resuscitation Program and the International Liaison Committee on Resuscitation have made considerable strides in standardization of neonatal resuscitation, recommendations remain cautious in some areas, including choice of apparatus.27,32 For instance, the Neonatal Resuscitation Program gives some guidance about the choice of T-piece vs self-inflating bag for administering PPV, but has not firmly advocated one modality. This is because until now, studies did not demonstrate clear superiority in any given method of administering noninvasive support. However, also in this issue of The Journal, Szyld et al report a large, international, cluster-randomized crossover study in newborns $26 weeks gestation requiring PPV after birth, comparing the safety and efficacy of the T-piece resuscitator with the self-inflating bag.4 Although no difference was observed between treatment arms with respect to the primary outcome of the proportion of infants with heart rate (HR) $100 beats per minute (BPM) at 2 minutes of life, infants randomized to the T-piece arm were intubated less frequently than infants in the self-inflating bag arm (17% vs 26%, P = .002). Provocatively, in a post hoc exploratory analysis of very low birth weight infants, subjects treated with the T-piece were significantly more likely to have a HR $100 BPM at 2 minutes of life, less likely to be intubated for ventilatory support, and less likely to develop BPD (25% vs 40%, P = .036). An additional problem of existing studies of DR interventions may be the choice of outcomes caught between two extremes, which we might label “proximate but largely surrogate” and “distant but clinically relevant.” Potentially useful outcomes of vital sign stability, such as HR $100 BPM at 2 minutes of life (the primary outcome in the Szyld trial), are often unavailable from cardiac or pulse oximeter monitors in the first minutes of life,33 and may be inaccurate when made by clinical assessment.34 Outcomes related to the need for further interventions (ie, need for intubation or increased supplemental oxygen) are prone to clinician preference, unless clearly defined by criteria. Further, it is unclear which of these short-term outcomes are associated with improvement in long-term respiratory outcomes. Despite its virtues, even the intermediate-term outcome of BPD has limitations. BPD is most frequently diagnosed by either an oxygen requirement or failure of an oxygen reduction test at 36 weeks corrected age.35-37 As we have argued above, the diagnosis of BPD clearly correlates with long-term respiratory and developmental outcomes. At the same time, many preterm infants without a diagnosis of BPD also experience 2
Vol. -, No. clinically important respiratory morbidity throughout childhood and beyond. Therefore, longer-term outcome measures may be more clinically relevant. In secondary analyses, Stevens et al report that infants who received CPAP instead of intubation and mechanical ventilation had less respiratory morbidity up to 18-22 months corrected age, including fewer episodes of wheezing without a cold, fewer diagnoses of respiratory illness by a doctor, fewer doctor or emergency room visits for breathing problems, and less impact of respiratory disease on the family.3 Although BPD predicted nearly all respiratory morbidities, there were still high rates of these outcomes even among infants without BPD. For example, 49% of children without BPD were diagnosed with asthma, reactive airway disease, BPD flare-up, bronchiolitis, bronchitis, or pneumonia, and 26% had to stay in the hospital overnight for wheezing or breathing problems during the first 18-22 months of life. Perhaps such outcomes are ultimately more important to the patient and family than the diagnosis of BPD. Are we improving respiratory outcomes with the use of noninvasive support in the DR? Can these benefits be boosted? In keeping with the prior literature, the studies by Stevens et al and Szyld et al in this issue of The Journal show further evidence of the benefits of noninvasive support in the DR. Together, these studies add to the existing literature suggesting that the trajectory of respiratory morbidity in some preterm infants may be modified by both the use and the quality of noninvasive DR respiratory support. Future research is critical to further decreasing the incidence of long-term respiratory morbidity after premature birth. Initial studies of sustained lung inflation, a novel method of recruiting the lung and establishing a functional residual capacity after birth, show early promise38,39; larger randomized trials are needed to determine the impact of this intervention on long-term respiratory morbidity. Studies such as the Sustained Aeration of the Infant Lung Trial will continue to advance our understanding of how to optimize noninvasive support,40 whereas studies such as the Prematurity and Respiratory Outcomes Program are poised to develop improved definitions of BPD that will better correlate with clinically important longer-term respiratory outcomes.41 However, it is unlikely that even optimally delivered noninvasive support in the DR will be the only solution to this problem. Ultimately, we are likely to find that properly delivered noninvasive respiratory support is just one critical element in a series of therapies that together will minimize the adverse long-term consequences of extreme prematurity. n Elizabeth E. Foglia, MD Haresh Kirpalani, BM, MSc Sara B. DeMauro, MD, MSCE The Children’s Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania Reprint requests: Sara B. DeMauro, MD, MSCE, The Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. E-mail: [email protected]
- 2014
References 1. Grossmann G, Nilsson R, Robertson B. Scanning electron microscopy of epithelial lesions induced by artificial ventilation of the immature neonatal lung: the prophylactic effect of surfactant replacement. Eur J Pediatr 1986;145:361-7. 2. Bohlin K, Bouhafs RK, Jarstrand C, Curstedt T, Blennow M, Robertson B. Spontaneous breathing or mechanical ventilation alters lung compliance and tissue association of exogenous surfactant in preterm newborn rabbits. Pediatr Res 2005;57:624-30. 3. Stevens TP, Finer NN, Carlo WA, Szilagyi PG, Phelps DL, Walsh MC, et al. Respiratory Outcomes of the Surfactant Positive Pressure and Oximetry Randomized Trial. J Pediatr 2014. in press. 4. Szyld E, Aguilar A, Musante GA, Vain N, Prudent L, Fabres J, et al. Comparison of devices for newborn ventilation in the delivery room. J Pediatr 2014. in press. 5. Rosenfeld M, Allen J, Arets BH, Aurora P, Beydon N, Calogero C, et al. An official American thoracic society workshop report: optimal lung function tests for monitoring cystic fibrosis, bronchopulmonary dysplasia, and recurrent wheezing in children less than 6 years of age. Ann Am Thorac Soc 2013;10:S1-11. 6. Kotecha SJ, Edwards MO, Watkins WJ, Henderson AJ, Paranjothy S, Dunstan FD, et al. Effect of preterm birth on later FEV1: a systematic review and meta-analysis. Thorax 2013;68:760-6. 7. Hacking DF, Gibson AM, Robertson C, Doyle LW. Respiratory function at age 8-9 years after extremely low birthweight or preterm birth in Victoria in 1997. Pediatr Pulmonol 2013;48:449-55. 8. Lum S, Kirkby J, Welsh L, Marlow N, Hennessy E, Stocks J. Nature and severity of lung function abnormalities in extremely pre-term children at 11 years of age. Eur Respir J 2011;37:1199-207. 9. Vom Hove M, Prenzel F, Uhlig HH, Robel-Tillig E. Pulmonary outcome in former preterm, very low birth weight children with bronchopulmonary dysplasia: a case-control follow-up at school age. J Pediatr 2014;164:40-5.e4. 10. Doyle LW. Respiratory function at age 8-9 years in extremely low birthweight/very preterm children born in Victoria in 1991-1992. Pediatr Pulmonol 2006;41:570-6. 11. Halvorsen T, Skadberg BT, Eide GE, Roksund OD, Carlsen KH, Bakke P. Pulmonary outcome in adolescents of extreme preterm birth: a regional cohort study. Acta Paediatr 2004;93:1294-300. 12. Bates ML, Farrell ET, Eldridge MW. Abnormal ventilatory responses in adults born prematurely. N Engl J Med 2014;370:584-5. 13. Fawke J, Lum S, Kirkby J, Hennessy E, Marlow N, Rowell V, et al. Lung function and respiratory symptoms at 11 years in children born extremely preterm: the EPICure study. Am J Respir Crit Care Med 2010;182:237-45. 14. Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003;289:1124-9. 15. Walsh MC, Morris BH, Wrage LA, Vohr BR, Poole WK, Tyson JE, et al. Extremely low birthweight neonates with protracted ventilation: mortality and 18-month neurodevelopmental outcomes. J Pediatr 2005;146: 798-804. 16. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 2008; 358:700-8. 17. Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, Laptook AR, et al. Early CPAP vs surfactant in extremely preterm infants. N Engl J Med 2010;362:1970-9. 18. Dunn MS, 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:e1069-76. 19. Fischer HS, Buhrer C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: a meta-analysis. Pediatrics 2013;132: e1351-60.
EDITORIAL 20. Wright CJ, Kirpalani H. Targeting inflammation to prevent bronchopulmonary dysplasia: can new insights be translated into therapies? Pediatrics 2011;128:111-26. 21. Schmolzer GM, Kumar M, Pichler G, Aziz K, O’Reilly M, Cheung PY. Noninvasive vs invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. BMJ 2013;347:f5980. 22. Schmidt B, Roberts R, Millar D, Kirpalani H. Evidence-based neonatal drug therapy for prevention of bronchopulmonary dysplasia in verylow-birth-weight infants. Neonatology 2008;93:284-7. 23. Committee on Fetus and Newborn Policy Statement. Respiratory support in preterm infants at birth. Pediatrics 2014;133:171-4. 24. Carlo WA, Finer NN, Walsh MC, Rich W, Gantz MG, Laptook AR, et al. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med 2010;362:1959-69. 25. Schilleman K, Siew ML, Lopriore E, Morley CJ, Walther FJ, Te Pas AB. Auditing resuscitation of preterm infants at birth by recording video and physiological parameters. Resuscitation 2012;83:1135-9. 26. Schm€ olzer GM, Dawson JA, Kamlin CO, O’Donnell CP, Morley CJ, Davis PG. Airway obstruction and gas leak during mask ventilation of preterm infants in the delivery room. Arch Dis Child Fetal Neonatal Ed 2011;96:F254-7. 27. Kattwinkel J, Perlman JM, Aziz K, Colby C, Fairchild K, Gallagher J, et al. Neonatal resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Pediatrics 2010;126:e1400-13. 28. Hawkes CP, Ryan CA, Dempsey EM. Comparison of the T-piece resuscitator with other neonatal manual ventilation devices: a qualitative review. Resuscitation 2012;83:797-802. 29. McCarthy LK, Twomey AR, Molloy EJ, Murphy JF, O’Donnell CP. A randomized trial of nasal prong or face mask for respiratory support for preterm newborns. Pediatrics 2013;132:e389-95. 30. Kamlin CO, Schilleman K, Dawson JA, Lopriore E, Donath SM, Schmolzer GM, et al. Mask vs nasal tube for stabilization of preterm infants at birth: a randomized controlled trial. Pediatrics 2013;132:e381-8. 31. Schmolzer GM, Morley CJ, Wong C, Dawson JA, Kamlin CO, Donath SM, et al. Respiratory function monitor guidance of mask ventilation in the delivery room: a feasibility study. J Pediatr 2012;160: 377-81.e2. 32. The International Liaison Committee on Resuscitation (ILCOR) consensus on science with treatment recommendations for pediatric and neonatal patients: neonatal resuscitation. Pediatrics 2006;117: e978-88. 33. Katheria A, Rich W, Finer N. Electrocardiogram provides a continuous heart rate faster than oximetry during neonatal resuscitation. Pediatrics 2012;130:e1177-81. 34. Kamlin CO, O’Donnell CP, Everest NJ, Davis PG, Morley CJ. Accuracy of clinical assessment of infant heart rate in the delivery room. Resuscitation 2006;71:319-21. 35. Walsh MC, Wilson-Costello D, Zadell A, Newman N, Fanaroff A. Safety, reliability, and validity of a physiologic definition of bronchopulmonary dysplasia. J Perinatol 2003;23:451-6. 36. Walsh MC, Yao Q, Gettner P, Hale E, Collins M, Hensman A, et al. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics 2004;114:1305-11. 37. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9. 38. Lista G, Fontana P, Castoldi F, Cavigioli F, Dani C. Does sustained lung inflation at birth improve outcome of preterm infants at risk for respiratory distress syndrome? Neonatology 2011;99:45-50. 39. Te Pas AB, Walther FJ. A randomized, controlled trial of delivery-room respiratory management in very preterm infants. Pediatrics 2007;120: 322-9. 40. Kirpalani H. Susatined Aeration of the Infant Lung (SAIL) Trial. Clinicaltrials.gov number: NCT02139800. 41. Prematurity and Respiratory Outcomes Program (PROP). Clinincaltrials. gov number: NCT01435187.
3
T
he adverse long-term pulmonary consequences of CPAP prevents 1 case of BPD). This NNT is higher than the extreme prematurity are increasingly recognized. Seminal NNT to prevent BPD for caffeine (10) and Vitamin A (12),22 work in animals suggests that lung injury likely starts durbut given the relative safety of CPAP, these data provide a ing the moments after birth.1,2 Therefore, much subsequent sound rationale for prioritizing non-invasive respiratory strategies in extremely premature infants. Such evidence led the clinical research has focused on optimizing the initial resuscitaAmerican Academy of Pediatrics Committee tion and stabilization of the extremely preSee related articles, p on Fetus and Newborn to publish a policy term infant. Two articles in this issue of The and p statement in January 2014 concluding that Journal provide insight into how delivery “the early use of CPAP with subsequent selective surfactant room (DR) practice may be improved and may influence the administration in extremely preterm infants results in lower short- and long-term outcomes of preterm infants.3,4 rates of BPD/death compared with treatment with prophylacIn survivors of prematurity, spirometry at school age tic or early surfactant therapy.”23 consistently demonstrates decreased lung function compared 5-10 with full-term controls. These deficits are more severe in In this issue of The Journal, Stevens et al report the Breathextremely preterm infants with bronchopulmonary dysplasia ing Outcomes Study, which evaluated parental reports of res(BPD). Worse, such effects persist throughout childhood and piratory outcomes over the first 18-22 months of life among likely into adulthood.11-13 In addition to the known impact participants in the National Institute of Child Health and Human Development Surfactant Positive Airway Pressure of prematurity on long-term respiratory morbidity, BPD is and Pulse Oximetry Trial (SUPPORT).3,17,24 The previously an independent predictor of neurodevelopmental outcomes 14 at 18 months. Similarly, duration of ventilation beyond reported SUPPORT compared DR CPAP with routine intubation and high to low oxygen saturation targeting in 60 days is correlated with developmental impairment at extremely preterm infants.17,24 The Breathing Outcomes 18 months.15 Thus, strategies to prevent lung disease of prematurity and its associated long-term sequelae are needed. Study showed no difference in the primary outcome of Although neonatologists have recognized the potential wheezing during the worst 2-week period or cough lasting impact of DR interventions on the outcomes of preterm infants more than 3 days (without a cold) by 18-22 months corrected for some time, such interventions have only recently been studage among any of the groups of SUPPORT. ied systematically in large randomized trials. Several trials have Because each individual trial of DR CPAP appears to show evaluated the use of continuous positive airway pressure only modest results and meta-analyses report large numbers (CPAP) in comparison with immediate intubation and surfacneeded to treat, it is reasonable to question why noninvasive tant administration.16-18 These individual studies show trends respiratory support in the DR has not thus far had more impact in limiting lung disease in preterm infants. We sugtoward decreased rates of death or BPD and reduced need for gest several potential explanations for the modest effect of a surfactant with the use of noninvasive support, but no signifinoninvasive DR strategy. First, the most effective methods cant differences. This is likely due to individual trials being unof performing noninvasive respiratory support to avoid intuderpowered to identify this treatment effect because three bation in the DR setting remain unclear. Although these trials pooled analyses including over 3000 infants demonstrate that were designed to compare CPAP vs routine intubation and strategies aimed at avoiding early mechanical ventilation in surfactant administration, many premature infants require preterm infants have a “small but significant beneficial impact” positive pressure ventilation (PPV) during their initial stabifor the prevention death or BPD.19-21 Although these analyses lization after birth. Performing PPV in extremely low birth differ in significant details, they consistently report a significant weight infants is difficult: facemask leak, airway obstruction, reduction of death or BPD in infants treated with CPAP, with a and inability to accurately assess chest wall movement are number needed to treat (NNT, 25-35 infants treated with common problems, resulting in variable tidal volume delivery.25,26 Many extremely preterm infants are not well stabilized with noninvasive PPV after birth, and then require BPD Bronchopulmonary dysplasia BPM CPAP DR HR NNT PPV SUPPORT
Beats per minute Continuous positive airway pressure Delivery room Heart rate Number needed to treat Positive pressure ventilation Surfactant Positive Airway Pressure and Pulse Oximetry Trial
The University Pennsylvania and The Children’s Hospital of Philadelphia have been a participating site in the Neonatal Research Network since 2011. The authors were not involved in the Neonatal Research Network SUPPORT Trial as reported by Stevens et al. The author declares no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2014.04.018
1
THE JOURNAL OF PEDIATRICS
www.jpeds.com
tracheal intubation to achieve effective ventilation.27 Thus, in these trials, many infants assigned to CPAP were intubated within the first minutes of life for failed noninvasive resuscitation. For example, in SUPPORT, one-third of infants assigned to the CPAP arm were intubated in the DR for resuscitation.17 This co-intervention potentially diluted the observed treatment effect of a noninvasive strategy. Investigators have sought to improve the technical aspects of delivering noninvasive support (both CPAP and PPV) during DR resuscitation by studying alternate resuscitative devices,28 between device and infant,29,30 and respiratory function monitors in the DR.31 Although the Neonatal Resuscitation Program and the International Liaison Committee on Resuscitation have made considerable strides in standardization of neonatal resuscitation, recommendations remain cautious in some areas, including choice of apparatus.27,32 For instance, the Neonatal Resuscitation Program gives some guidance about the choice of T-piece vs self-inflating bag for administering PPV, but has not firmly advocated one modality. This is because until now, studies did not demonstrate clear superiority in any given method of administering noninvasive support. However, also in this issue of The Journal, Szyld et al report a large, international, cluster-randomized crossover study in newborns $26 weeks gestation requiring PPV after birth, comparing the safety and efficacy of the T-piece resuscitator with the self-inflating bag.4 Although no difference was observed between treatment arms with respect to the primary outcome of the proportion of infants with heart rate (HR) $100 beats per minute (BPM) at 2 minutes of life, infants randomized to the T-piece arm were intubated less frequently than infants in the self-inflating bag arm (17% vs 26%, P = .002). Provocatively, in a post hoc exploratory analysis of very low birth weight infants, subjects treated with the T-piece were significantly more likely to have a HR $100 BPM at 2 minutes of life, less likely to be intubated for ventilatory support, and less likely to develop BPD (25% vs 40%, P = .036). An additional problem of existing studies of DR interventions may be the choice of outcomes caught between two extremes, which we might label “proximate but largely surrogate” and “distant but clinically relevant.” Potentially useful outcomes of vital sign stability, such as HR $100 BPM at 2 minutes of life (the primary outcome in the Szyld trial), are often unavailable from cardiac or pulse oximeter monitors in the first minutes of life,33 and may be inaccurate when made by clinical assessment.34 Outcomes related to the need for further interventions (ie, need for intubation or increased supplemental oxygen) are prone to clinician preference, unless clearly defined by criteria. Further, it is unclear which of these short-term outcomes are associated with improvement in long-term respiratory outcomes. Despite its virtues, even the intermediate-term outcome of BPD has limitations. BPD is most frequently diagnosed by either an oxygen requirement or failure of an oxygen reduction test at 36 weeks corrected age.35-37 As we have argued above, the diagnosis of BPD clearly correlates with long-term respiratory and developmental outcomes. At the same time, many preterm infants without a diagnosis of BPD also experience 2
Vol. -, No. clinically important respiratory morbidity throughout childhood and beyond. Therefore, longer-term outcome measures may be more clinically relevant. In secondary analyses, Stevens et al report that infants who received CPAP instead of intubation and mechanical ventilation had less respiratory morbidity up to 18-22 months corrected age, including fewer episodes of wheezing without a cold, fewer diagnoses of respiratory illness by a doctor, fewer doctor or emergency room visits for breathing problems, and less impact of respiratory disease on the family.3 Although BPD predicted nearly all respiratory morbidities, there were still high rates of these outcomes even among infants without BPD. For example, 49% of children without BPD were diagnosed with asthma, reactive airway disease, BPD flare-up, bronchiolitis, bronchitis, or pneumonia, and 26% had to stay in the hospital overnight for wheezing or breathing problems during the first 18-22 months of life. Perhaps such outcomes are ultimately more important to the patient and family than the diagnosis of BPD. Are we improving respiratory outcomes with the use of noninvasive support in the DR? Can these benefits be boosted? In keeping with the prior literature, the studies by Stevens et al and Szyld et al in this issue of The Journal show further evidence of the benefits of noninvasive support in the DR. Together, these studies add to the existing literature suggesting that the trajectory of respiratory morbidity in some preterm infants may be modified by both the use and the quality of noninvasive DR respiratory support. Future research is critical to further decreasing the incidence of long-term respiratory morbidity after premature birth. Initial studies of sustained lung inflation, a novel method of recruiting the lung and establishing a functional residual capacity after birth, show early promise38,39; larger randomized trials are needed to determine the impact of this intervention on long-term respiratory morbidity. Studies such as the Sustained Aeration of the Infant Lung Trial will continue to advance our understanding of how to optimize noninvasive support,40 whereas studies such as the Prematurity and Respiratory Outcomes Program are poised to develop improved definitions of BPD that will better correlate with clinically important longer-term respiratory outcomes.41 However, it is unlikely that even optimally delivered noninvasive support in the DR will be the only solution to this problem. Ultimately, we are likely to find that properly delivered noninvasive respiratory support is just one critical element in a series of therapies that together will minimize the adverse long-term consequences of extreme prematurity. n Elizabeth E. Foglia, MD Haresh Kirpalani, BM, MSc Sara B. DeMauro, MD, MSCE The Children’s Hospital of Philadelphia University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania Reprint requests: Sara B. DeMauro, MD, MSCE, The Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. E-mail: [email protected]
- 2014
References 1. Grossmann G, Nilsson R, Robertson B. Scanning electron microscopy of epithelial lesions induced by artificial ventilation of the immature neonatal lung: the prophylactic effect of surfactant replacement. Eur J Pediatr 1986;145:361-7. 2. Bohlin K, Bouhafs RK, Jarstrand C, Curstedt T, Blennow M, Robertson B. Spontaneous breathing or mechanical ventilation alters lung compliance and tissue association of exogenous surfactant in preterm newborn rabbits. Pediatr Res 2005;57:624-30. 3. Stevens TP, Finer NN, Carlo WA, Szilagyi PG, Phelps DL, Walsh MC, et al. Respiratory Outcomes of the Surfactant Positive Pressure and Oximetry Randomized Trial. J Pediatr 2014. in press. 4. Szyld E, Aguilar A, Musante GA, Vain N, Prudent L, Fabres J, et al. Comparison of devices for newborn ventilation in the delivery room. J Pediatr 2014. in press. 5. Rosenfeld M, Allen J, Arets BH, Aurora P, Beydon N, Calogero C, et al. An official American thoracic society workshop report: optimal lung function tests for monitoring cystic fibrosis, bronchopulmonary dysplasia, and recurrent wheezing in children less than 6 years of age. Ann Am Thorac Soc 2013;10:S1-11. 6. Kotecha SJ, Edwards MO, Watkins WJ, Henderson AJ, Paranjothy S, Dunstan FD, et al. Effect of preterm birth on later FEV1: a systematic review and meta-analysis. Thorax 2013;68:760-6. 7. Hacking DF, Gibson AM, Robertson C, Doyle LW. Respiratory function at age 8-9 years after extremely low birthweight or preterm birth in Victoria in 1997. Pediatr Pulmonol 2013;48:449-55. 8. Lum S, Kirkby J, Welsh L, Marlow N, Hennessy E, Stocks J. Nature and severity of lung function abnormalities in extremely pre-term children at 11 years of age. Eur Respir J 2011;37:1199-207. 9. Vom Hove M, Prenzel F, Uhlig HH, Robel-Tillig E. Pulmonary outcome in former preterm, very low birth weight children with bronchopulmonary dysplasia: a case-control follow-up at school age. J Pediatr 2014;164:40-5.e4. 10. Doyle LW. Respiratory function at age 8-9 years in extremely low birthweight/very preterm children born in Victoria in 1991-1992. Pediatr Pulmonol 2006;41:570-6. 11. Halvorsen T, Skadberg BT, Eide GE, Roksund OD, Carlsen KH, Bakke P. Pulmonary outcome in adolescents of extreme preterm birth: a regional cohort study. Acta Paediatr 2004;93:1294-300. 12. Bates ML, Farrell ET, Eldridge MW. Abnormal ventilatory responses in adults born prematurely. N Engl J Med 2014;370:584-5. 13. Fawke J, Lum S, Kirkby J, Hennessy E, Marlow N, Rowell V, et al. Lung function and respiratory symptoms at 11 years in children born extremely preterm: the EPICure study. Am J Respir Crit Care Med 2010;182:237-45. 14. Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003;289:1124-9. 15. Walsh MC, Morris BH, Wrage LA, Vohr BR, Poole WK, Tyson JE, et al. Extremely low birthweight neonates with protracted ventilation: mortality and 18-month neurodevelopmental outcomes. J Pediatr 2005;146: 798-804. 16. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med 2008; 358:700-8. 17. Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, Laptook AR, et al. Early CPAP vs surfactant in extremely preterm infants. N Engl J Med 2010;362:1970-9. 18. Dunn MS, 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:e1069-76. 19. Fischer HS, Buhrer C. Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: a meta-analysis. Pediatrics 2013;132: e1351-60.
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