Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide

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• 作者：Roberta A. Ballard ; MD¹ ; ^{ballardr@peds.ucsf.edu" class="auth_mail" title="E-mail the corresponding author} ; Roberta L. Keller ; MD¹ ; Dennis M. Black ; PhD² ; Philip L. Ballard ; MD ; PhD¹ ; Jeffrey D. Merrill ; MD³ ; Eric C. Eichenwald ; MD⁴ ; William E. Truog ; MD⁵ ; Mark C. Mammel ; MD⁶ ; Robin H. Steinhorn ; MD⁷ ; Elizabeth E. Rogers ; MD¹ ; Rita M. Ryan ; MD⁸ ; David J. Durand ; MD³ ; Jeanette M. Asselin ; MS ; RRT-NPS³ ; Catherine M. Bendel ; MD⁹ ; Ellen M. Bendel-Stenzel ; MD¹⁰ ; Sherry E. Courtney ; MD¹¹ ; Ramasubbareddy Dhanireddy ; MD¹² ; Mark L. Hudak ; MD¹³ ; Frances R. Koch ; MD⁸ ; Dennis E. Mayock ; MD¹⁴ ; Victor J. McKay ; MD¹⁵ ; T. Michael O'Shea ; MD¹⁶ ; Nicolas F. Porta ; MD¹⁷ ; Rajan Wadhawan ; MD¹⁸ ; Lisa Palermo ; MS² ; for the TOLSURF Study Group^&lowast ; S. Hamilton Strong ; J. Immamura-Ching ; M. Orfanos-Villalobos ; C. Williams ; D. Horton ; L. Pacello ; A. Willard ; C. Gauldin ; A. Holmes ; P. Johnson ; K. Meinert ; A.M. Reynolds ; MD ; J. Lucie ; P. Conway ; M.l. Sacilowski ; M. Leadersdorff ; P. Orbank ; K. Wynn ; M. deUngria ; MD ; J. Khan ; MD ; K. Hamann ; M. Schau ; B. Hopkins ; J. Jenson ; C. Garcia ; J. Shariff ; R. McGovern ; J. Adelman ; A. Combs ; M. Tjersland ; S. Walker ; E. Howland ; J. Longoria ; H. Meo ; G. McDavid ; K. Burson ; R. Hinojosa ; C. Johnson ; K. Miller ; S. Rogers ; S. Wright ; K. Barnette ; A. Kellum ; M. Burke ; C. Hayes ; S. Chadwick ; D. Howard ; C. Kennedy ; R. Prince ; B. Stefanescu ; MD ; J. Helderman ; MD ; K. Warden ; P. Brown ; J. Griffin ; L. Conley ; M. Georgieff ; MD ; B. Davern ; M. Mills ; S. Ritter ; C. Wagner ; MD ; D. Fanning ; J. Roberson ; A. Lampland ; MD ; P. Meyers ; A. Brey ; C. Worwa ; P. Dixon ; G. Ebert ; C. Hejl ; M. Maxwell ; K. McCullough ; MT ; M.T. El Abiad ; MD ; A. Talati ; MD ; S. Dempsey ; K. Gammage ; G. Gower ; K. James ; P. LeNoue ; S. Bell ; D. Bruton ; M. Beaulieu ; R. Williams ; R. Barron-Nelson ; S. Taylor ; N.C. Sikes ; G. Lowe ; B. Proffitt ; C. Chapin ; H. Horneman ; K. Hamann ; S. Kelley ; E. Vittinghoff ; PhD ; J. Hietpas ; L. Denton ; L. Wu ; A. Jobe ; MD ; A. Fanaroff ; MD ; T. Clemons ; L. Glantz ; D. Reboussin ; K. Van Meurs ; MD ; M. Allen ; MD ; B. Vohr ; MD ; R. Ballard ; MD (Steering Committee) ; P. Ballard ; MD ; PhD (Steering Committee) ; C. Blaisdell ; MD (Steering Committee) ; D. Durand ; MD (Steering Committee) ; D. Black ; PhD (Steering Committee) ; E. Eichenwald ; MD (Steering Committee) ; R. Keller ; MD (Steering Committee) ; M. Mammel ; MD (Steering Committee) ; J. Merrill ; MD (Steering Committee) ; E. Rogers ; MD (Steering Committee) ; R. Ryan ; MD (Steering Committee) ; W. Truog ; MD (Steering Committee) ; J. Asselin (Steering Committee) ; N. Newton (Steering Committee)
• 关键词：AE ; Adverse event ; BPD ; Bronchopulmonary dysplasia ; DSMB ; Data Safety Monitoring Board ; ELGAN ; Extremely low gestational age newborn ; FiO2 ; Fraction of inspired oxygen ; GA ; Gestational age ; iNO ; Inhaled nitric oxide ; IVH ; Intraventricular hemorrhage ; NCPAP ; Nasal continuous positive airway pressure ; NIH ; National Institutes of Health ; NO CLD ; Inhaled Nitric Oxide to Prevent Chronic Lung Disease ; PMA ; Postmenstrual age ; SAE ; Serious adverse event ; SP-B ; Surfactant protein B ; TA ; Tracheal aspirate
• 刊名：The Journal of Pediatrics
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：168
• 期：Complete
• 页码：23-29.e4
• 全文大小：439 K

文摘

To assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD).

Study design

Extremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction.

Results

A total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or comorbidities of prematurity. Survival without BPD did not differ between the treated and control groups at 36 weeks PMA (31.3% vs 31.7%; relative benefit, 0.98; 95% CI, 0.75-1.28; P = .89) or 40 weeks PMA (58.7% vs 54.1%; relative benefit, 1.08; 95% CI, 0.92-1.27; P = .33). There were no between-group differences in serious adverse events, comorbidities of prematurity, or severity of lung disease to 36 weeks.

Conclusion

Late treatment with up to 5 doses of surfactant in ventilated premature infants receiving inhaled nitric oxide was well tolerated, but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing.

Trial registration

ClinicalTrials.gov: NCT01022580.