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


METHODS
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.


CONCLUSIONS
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.


BACKGROUND
ClinicalTrials.gov: NCT01022580.
Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, CA. Electronic address: ballardr@peds.ucsf.edu.
Roberta A
RA
Ballard
Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, CA.
Roberta L
RL
Keller
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.
Dennis M
DM
Black
Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, CA.
Philip L
PL
Ballard
Department of Pediatrics, UCSF Benioff Children's Hospital Oakland, Oakland, CA.
Jeffrey D
JD
Merrill
Department of Pediatrics, The University of Texas Health Science Center Houston, Houston, TX.
Eric C
EC
Eichenwald
Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO.
William E
WE
Truog
Department of Pediatrics, Children's Hospitals and Clinics of Minnesota, St Paul, MN.
Mark C
MC
Mammel
Department of Pediatrics, UC Davis Children's Hospital, Sacramento, CA.
Robin H
RH
Steinhorn
Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, CA.
Elizabeth E
EE
Rogers
Department of Pediatrics, Medical University of South Carolina, Charleston, SC.
Rita M
RM
Ryan
Department of Pediatrics, UCSF Benioff Children's Hospital Oakland, Oakland, CA.
David J
DJ
Durand
Department of Pediatrics, UCSF Benioff Children's Hospital Oakland, Oakland, CA.
Jeanette M
JM
Asselin
Department of Pediatrics, University of Minnesota Amplatz Children's Hospital, Minneapolis, MN.
Catherine M
CM
Bendel
Department of Pediatrics, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN.
Ellen M
EM
Bendel-Stenzel
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR.
Sherry E
SE
Courtney
Department of Pediatrics, The University of Tennessee Health Science Center, Memphis, TN.
Ramasubbareddy
R
Dhanireddy
Department of Pediatrics, University of Florida College of Medicine-Jacksonville, Jacksonville, FL.
Mark L
ML
Hudak
Department of Pediatrics, Medical University of South Carolina, Charleston, SC.
Frances R
FR
Koch
Department of Pediatrics, University of Washington, Seattle, WA.
Dennis E
DE
Mayock
Department of Pediatrics, All Children's Hospital, St Petersburg, FL.
Victor J
VJ
McKay
Department of Pediatrics, Wake Forest School of Medicine and Forsyth Medical Center, Winston-Salem, NC.
T Michael
TM
O'Shea
Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL.
Nicolas F
NF
Porta
Department of Pediatrics, Florida Hospital for Children, Orlando, FL.
Rajan
R
Wadhawan
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.
Lisa
L
Palermo
D000280:Administration, Inhalation; D001997:Bronchopulmonary Dysplasia / Q000453:epidemiology / Q000209:etiology*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000401:mortality / Q000628:therapy; D019102:Infant, Very Low Birth Weight; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000009:adverse effects; D011663:Pulmonary Surfactants / Q000009:adverse effects / Q000627:therapeutic use*; D012121:Respiration, Artificial / Q000009:adverse effects* / Q000401:mortality; D015996:Survival Rate; D014481:United States
D011663:Pulmonary Surfactants; D009569:Nitric Oxide