Randomized Controlled Trial

. 2017 Apr:183:19-25.e2.

doi: 10.1016/j.jpeds.2016.12.059. Epub 2017 Jan 16.

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age

Roberta L Keller¹, Eric C Eichenwald², Anna Maria Hibbs³, Elizabeth E Rogers⁴, Katherine C Wai⁵, Dennis M Black⁶, Philip L Ballard⁴, Jeanette M Asselin⁷, William E Truog⁸, Jeffrey D Merrill⁷, Mark C Mammel⁹, Robin H Steinhorn¹⁰, Rita M Ryan¹¹, David J Durand⁷, Catherine M Bendel¹², Ellen M Bendel-Stenzel⁹, Sherry E Courtney¹³, Ramasubbareddy Dhanireddy¹⁴, Mark L Hudak¹⁵, Frances R Koch¹¹, Dennis E Mayock¹⁶, Victor J McKay¹⁷, Jennifer Helderman¹⁸, Nicolas F Porta¹⁹, Rajan Wadhawan²⁰, Lisa Palermo⁶, Roberta A Ballard⁴; TOLSURF Study Group

Affiliations

¹ Department of Pediatrics, University of California San Francisco, San Francisco, CA. Electronic address: kellerr@peds.ucsf.edu.
² Department of Pediatrics, University of Texas, Houston, TX.
³ Department of Pediatrics, Case Western Reserve University, Cleveland, OH.
⁴ Department of Pediatrics, University of California San Francisco, San Francisco, CA.
⁵ University of California San Francisco School of Medicine, San Francisco, CA.
⁶ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.
⁷ Department of Pediatrics, Benioff Children's Hospital Oakland, Oakland, CA.
⁸ Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO.
⁹ Department of Pediatrics, Children's Hospital and Clinics of Minnesota, St Paul and Minneapolis, MN.
¹⁰ Department of Pediatrics, Children's National Medical Center, Washington, DC.
¹¹ Department of Pediatrics, Medical University of South Carolina, Charleston, SC.
¹² Department of Pediatrics, University of Minnesota, Minneapolis, MN.
¹³ Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR.
¹⁴ Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN.
¹⁵ Department of Pediatrics, University of Florida College of Medicine, Jacksonville, FL.
¹⁶ Department of Pediatrics, University of Washington, Seattle, WA.
¹⁷ Department of Pediatrics, All Children's Hospital, St. Petersburg, FL.
¹⁸ Department of Pediatrics, Wake Forest School of Medicine/Forsyth Medical Center, Winston-Salem, NC.
¹⁹ Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL.
²⁰ Department of Pediatrics, Florida Hospital for Children, Orlando, FL.

PMID: 28100402
PMCID: PMC5367937
DOI: 10.1016/j.jpeds.2016.12.059

Randomized Controlled Trial

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age

Roberta L Keller et al. J Pediatr. 2017 Apr.

. 2017 Apr:183:19-25.e2.

doi: 10.1016/j.jpeds.2016.12.059. Epub 2017 Jan 16.

Authors

Affiliations

¹ Department of Pediatrics, University of California San Francisco, San Francisco, CA. Electronic address: kellerr@peds.ucsf.edu.
² Department of Pediatrics, University of Texas, Houston, TX.
³ Department of Pediatrics, Case Western Reserve University, Cleveland, OH.
⁴ Department of Pediatrics, University of California San Francisco, San Francisco, CA.
⁵ University of California San Francisco School of Medicine, San Francisco, CA.
⁶ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.
⁷ Department of Pediatrics, Benioff Children's Hospital Oakland, Oakland, CA.
⁸ Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO.
⁹ Department of Pediatrics, Children's Hospital and Clinics of Minnesota, St Paul and Minneapolis, MN.
¹⁰ Department of Pediatrics, Children's National Medical Center, Washington, DC.
¹¹ Department of Pediatrics, Medical University of South Carolina, Charleston, SC.
¹² Department of Pediatrics, University of Minnesota, Minneapolis, MN.
¹³ Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR.
¹⁴ Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN.
¹⁵ Department of Pediatrics, University of Florida College of Medicine, Jacksonville, FL.
¹⁶ Department of Pediatrics, University of Washington, Seattle, WA.
¹⁷ Department of Pediatrics, All Children's Hospital, St. Petersburg, FL.
¹⁸ Department of Pediatrics, Wake Forest School of Medicine/Forsyth Medical Center, Winston-Salem, NC.
¹⁹ Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL.
²⁰ Department of Pediatrics, Florida Hospital for Children, Orlando, FL.

PMID: 28100402
PMCID: PMC5367937
DOI: 10.1016/j.jpeds.2016.12.059

Abstract

Objective: To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control).

Study design: Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys).

Results: Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM.

Conclusion: Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity.

Trial registration: ClinicalTrials.gov: NCT01022580.

Keywords: bronchopulmonary dysplasia; prematurity; pulmonary morbidity; wheeze.

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Conflict of interest statement

The other authors declare no conflicts of interest.

Figures

**Figure 1**
(online only): Patient flow diagram. Deaths and study withdrawals prior to neonatal discharge detailed in Ballard *et al*, 2016 (13).

**Figure 2**
Proportion of infants with respiratory resource utilization at each survey time point, 3, 6, 9 and 12 months corrected age, in late surfactant and control groups: A, Total resource utilization, B, Respiratory medication exposure, C, Home respiratory support, D, Hospitalization for respiratory cause, and E, Diuretic, F, Bronchodilator, G, Inhaled corticosteroid and H, Systemic steroid exposure.

See this image and copyright information in PMC

Comment in

Is preventing BPD the target, or should we strive for something else?
Wright CJ. Wright CJ. J Pediatr. 2017 Apr;183:2. doi: 10.1016/j.jpeds.2017.02.016. J Pediatr. 2017. PMID: 28343533 No abstract available.
Reply.
Keller RL, Ballard RA. Keller RL, et al. J Pediatr. 2017 Oct;189:241-242. doi: 10.1016/j.jpeds.2017.05.064. Epub 2017 Jun 16. J Pediatr. 2017. PMID: 28625499 No abstract available.
Short-, medium-, and long-term assessment of pulmonary dysfunction in extremely low birth weight neonates.
Meyer S, Franz AR, Bay J, Gortner L. Meyer S, et al. J Pediatr. 2017 Oct;189:240-241. doi: 10.1016/j.jpeds.2017.05.062. Epub 2017 Jun 16. J Pediatr. 2017. PMID: 28625500 No abstract available.

References

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The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age

Affiliations

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age

Authors

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Abstract

Conflict of interest statement

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Medical