Short-, medium-, and long-term assessment of pulmonary dysfunction in extremely low birth weight neonates

THE JOURNAL OF PEDIATRICS • www.jpeds.com Short-, medium-, and long-term assessment of pulmonary dysfunction in extremely low birth weight neonates To the Editor: Keller et al1 demonstrated in their randomized controlled trial, the Trial of Late Surfactant (TOLSURF) that treatment of extremely low gestational age neonates with late surfactant in combination with inhaled nitric oxide decreased the use of home oxygen while no difference in the rate of bronchopulmonary dysplasia (BPD) or death at 36 weeks of gestational age was seen. The results presented indicate that measures other than BPD may be more valuable in assessing pulmonary function in this cohort (eg, home oxygen use). However, no significant differences were seen in other important measures (eg, respiratory medications, hospitalization, etc).1 We would like to comment on their study from both a medical scientific and clinical point of view. First, with regard to the use of BPD2 and its scientific relevance and importance, we believe that for better comparison of important outcome measures such as BPD, a standardized definition of BPD is necessary. This definition should take into account new developments in the care of premature infants as well as different therapeutic approaches. A recent systematic review, however, demonstrated that a great variety of different definitions of BPD are in use in contemporaneous clinical trials as well as the need to harmonize the definition of BPD.3 To address this issue, in our current randomized controlled trial on the effect of early high-dose enteral vitamin A supplementation on BPD in extremely low birth weight infants,4 we use a definition that was adapted from the National Institute of Child Health and Human Development neonatal network consensus definition by Jobe and Bancalari.4 It incorporates important additional aspects that have evolved over time such as the use of high-flow nasal cannulas (≥2 L/minute, irrespective of oxygen supplementation) for positive pressure respiratory support and the application of different target ranges for arterial oxygen saturation among participating study centers.5,6 Second, given the imperfections of short-term outcome measures (ie, BPD), we agree with Keller et al1 that the additional use of medium-term, and even more importantly, long-term outcome measures are of utmost importance. Thus, in the NeoVitaA trial, pulmonary (dys)function will also be assessed at 12 and 24 months corrected age. This assessment will include the following data: Number of antibiotic treatments and number of hospital admissions for pulmonary reasons, concomitant use of drugs (oxygen, diuretics, methylxanthines, corticosteroids). Also, neurologic outcome will be assessed at 24 months corrected age (Bayley-III testing). This seems of particular relevance given the fact that pulmonary dysfunction (BPD) in premature infants has been associated with poorer neurologic outcome.7

LETTERS TO THE EDITOR

We hope that our further development of the definition of BPD will provide a basis for the development of a unified definition of BPD. We propose a consensus conference be held to generate a comprehensive and universally accepted definition (eg, similar to the definition of acute respiratory distress syndrome or sepsis). This will provide the medical community with a valuable research tool, which will allow for better comparison between different studies. However, we are well that controversies about the definition are manifold and not easy to resolve—even 50 years after its first introduction into clinical medicine.8 With regard to the prognosis and quality of life of extremely premature infants, other measures as proposed by Keller et al1 are also of great importance. In our opinion, future trials should assess both important short-term measures (eg, BPD) and medium- and long-term outcome variables, and assess their potential connectivity as it has been strongly suggested by Islam et al.9 S.M. is principal investigator of the NeoVitaA trial which is funded by the German Research council: Deutsche Forschungsgemeinschaft (DFG: ME 3827/1-1).

Sascha Meyer, MD, PhD Neonatal Intensive Care Unit University Children’s Hospital of Saarland Homburg, Germany Axel R. Franz, MD University Children’s Hospital Tübingen Tübingen, Germany Johannes Bay, MD Neonatal Intensive Care Unit University Children’s Hospital of Saarland Homburg, Germany Ludwig Gortner, MD Center for Pediatrics and Adolescent Medicine Medical University Vienna Vienna, Austria

References 1. Keller RL, Eichenwald EC, Hibbs AM, Rogers EE, Wai KC, Black DM, et al. The randomized, controlled trial of late surfactant: effects on respiratory outcomes at 1-year corrected age. J Pediatr 2017;183:19-25, e2. 2. Wright CJ. Is preventing BPD the target, or should we strive for something else? J Pediatr 2017;183:2. 3. Hines D, Modi N, Lee SK, Isayama T, Sjörs G, Gagliardi L, et al. Scoping review shows wide variation in the definitions of bronchopulmonary dysplasia in preterm infants and calls for a consensus. Acta Paediatr 2016;106:366-74. 4. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9. 5. Meyer S, Gortner L, NeoVitaA Trial Investigators. Early postnatal additional high-dose oral vitamin A supplementation versus placebo for 28 days 1

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THE JOURNAL OF PEDIATRICS • www.jpeds.com for preventing bronchopulmonary dysplasia or death in extremely low birth weight infants. Neonatology 2014;105:182-8. 6. Meyer S, Franz AR, Bay J, Gortner L, NeoVitaA Study Group. Developing a better and practical definition of bronchopulmonary dysplasia. Acta Paediatr 2017;106:842. 7. 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:

Volume ■■ results from the trial of indomethacin prophylaxis in preterms. JAMA 2003;289:1124-9. 8. Jobe AH, Bancalari EH. Controversies about the definition of bronchopulmonary dysplasia at 50 years. Acta Paediatr 2017;106:692-3. 9. Islam JY, Keller RL, Aschner JL, Hartert TV, Moore PE. Understanding the short- and long-term respiratory outcomes of prematurity and bronchopulmonary dysplasia. Am J Respir Crit Care Med 2015;192:13456.

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