Randomized Controlled Trial

. 2016 Jan:168:23-29.e4.

doi: 10.1016/j.jpeds.2015.09.031. Epub 2015 Oct 21.

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

Roberta A Ballard¹, Roberta L Keller², Dennis M Black³, Philip L Ballard², Jeffrey D Merrill⁴, Eric C Eichenwald⁵, William E Truog⁶, Mark C Mammel⁷, Robin H Steinhorn⁸, Elizabeth E Rogers², Rita M Ryan⁹, David J Durand⁴, Jeanette M Asselin⁴, Catherine M Bendel¹⁰, Ellen M Bendel-Stenzel¹¹, Sherry E Courtney¹², Ramasubbareddy Dhanireddy¹³, Mark L Hudak¹⁴, Frances R Koch⁹, Dennis E Mayock¹⁵, Victor J McKay¹⁶, T Michael O'Shea¹⁷, Nicolas F Porta¹⁸, Rajan Wadhawan¹⁹, Lisa Palermo³; TOLSURF Study Group

Collaborators, Affiliations

Collaborators

TOLSURF Study Group:
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, J Lucie, P Conway, M L Sacilowski, M Leadersdorff, P Orbank, K Wynn, M deUngria, J Khan, 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, J Helderman, K Warden, P Brown, J Griffin, L Conley, M Georgieff, B Davern, M Mills, S Ritter, C Wagner, D Fanning, J Roberson, A Lampland, P Meyers, A Brey, C Worwa, P Dixon, G Ebert, C Hejl, M Maxwell, K McCullough, M T El Abiad, A Talati, 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, J Hietpas, L Denton, L Wu, A Jobe, A Fanaroff, T Clemons, L Glantz, D Reboussin, K Van Meurs, M Allen, B Vohr, R Ballard, P Ballard, C Blaisdell, D Durand, D Black, E Eichenwald, R Keller, M Mammel, J Merrill, E Rogers, R Ryan, W Truog, J Asselin, N Newton

Affiliations

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

PMID: 26500107
PMCID: PMC4698022
DOI: 10.1016/j.jpeds.2015.09.031

Randomized Controlled Trial

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

Roberta A Ballard et al. J Pediatr. 2016 Jan.

. 2016 Jan:168:23-29.e4.

doi: 10.1016/j.jpeds.2015.09.031. Epub 2015 Oct 21.

Authors

Collaborators

TOLSURF Study Group:
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, J Lucie, P Conway, M L Sacilowski, M Leadersdorff, P Orbank, K Wynn, M deUngria, J Khan, 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, J Helderman, K Warden, P Brown, J Griffin, L Conley, M Georgieff, B Davern, M Mills, S Ritter, C Wagner, D Fanning, J Roberson, A Lampland, P Meyers, A Brey, C Worwa, P Dixon, G Ebert, C Hejl, M Maxwell, K McCullough, M T El Abiad, A Talati, 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, J Hietpas, L Denton, L Wu, A Jobe, A Fanaroff, T Clemons, L Glantz, D Reboussin, K Van Meurs, M Allen, B Vohr, R Ballard, P Ballard, C Blaisdell, D Durand, D Black, E Eichenwald, R Keller, M Mammel, J Merrill, E Rogers, R Ryan, W Truog, J Asselin, N Newton

Affiliations

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

PMID: 26500107
PMCID: PMC4698022
DOI: 10.1016/j.jpeds.2015.09.031

Abstract

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).

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**Figure 1. Consort Diagram for TOLSURF showing enrollment and completion of data for the two study groups**
* Withdrawn resulted in no further treatment with either iNO or Infasurf ** One infant in each group with no data, 36 weeks outcome unknown = Yes BPD

See this image and copyright information in PMC

References

1. Northway WH, Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med. 1967;276:357–68. - PubMed
1. Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics. 2005;116:1353–60. - PubMed
1. Hennessy EM, Bracewell MA, Wood N, Wolke D, Costeloe K, Gibson A, et al. Respiratory health in pre-school and school age children following extremely preterm birth. Archives of disease in childhood. 2008;93:1037–43. - PubMed
1. Natarajan G, Pappas A, Shankaran S, Kendrick DE, Das A, Higgins RD, et al. Outcomes of extremely low birth weight infants with bronchopulmonary dysplasia: impact of the physiologic definition. Early Hum Dev. 2012;8:509–15. - PMC - PubMed
1. Husain AN, Siddiqui NH, Stocker JT. Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Human pathology. 1998;29:710–7. - PubMed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical