For preterm infants with respiratory distress syndrome supported with continuous positive airway pressure (CPAP), does administration of surfactant via a thin catheter improve survival without moderate to severe neurodevelopmental disability (NDD) at 2 years of age compared with sham treatment?
In this follow-up of a randomized clinical trial of 486 infants at 25 to 28 weeks’ gestation, the composite outcome of death or NDD at 2 years of age occurred in 36.3% receiving minimally invasive surfactant therapy compared with 36.1% receiving sham treatment.
In preterm infants supported with CPAP, minimally invasive surfactant therapy did not lead to a reduction in the composite outcome of death or neurodevelopmental disability at 2 years of age.
The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified.
To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years’ corrected age.
Design, Setting, and Participants
Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years’ corrected age was completed on December 9, 2022.
Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment.
Main Outcomes and Measures
The key secondary outcome of death or moderate to severe NDD was assessed at 2 years’ corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years.
Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, −7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]).
Conclusions and Relevance
In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life.
anzctr.org.au Identifier: ACTRN12611000916943
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Accepted for Publication: July 27, 2023.
Published Online: September 11, 2023. doi:10.1001/jama.2023.15694
Corresponding Author: Peter A. Dargaville, MD, Department of Paediatrics, Royal Hobart Hospital, 48 Liverpool St, Hobart, TAS 7000, Australia (firstname.lastname@example.org).
Author Contributions: Dr Dargaville and Ms Orsini had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The trial coordinating center and data management and statistics center were led by Drs Dargaville and Carlin, respectively.
Concept and design: Dargaville, Kamlin, Orsini, Soll, Carlin, Davis.
Acquisition, analysis, or interpretation of data: Dargaville, Kamlin, Orsini, Wang, De Paoli, Kanmaz Kutman, Cetinkaya, Kornhauser-Cerar, Derrick, Özkan, Hulzebos, Schmölzer, Aiyappan, Lemyre, Kuo, Rajadurai, O’Shea, Biniwale, Ramanathan, Kushnir, Bader, Thomas, Chakraborty, Buksh, Bhatia, Sullivan, Shinwell, Dyson, Barker, Kugelman, Donovan, Goss, Tauscher, Murthy, Ali, Clark, Johnson, Cheong, Carlin, Davis.
Drafting of the manuscript: Dargaville, Orsini, Wang, Kanmaz Kutman, Cetinkaya, Carlin.
Critical review of the manuscript for important intellectual content: Dargaville, Kamlin, Orsini, De Paoli, Kanmaz Kutman, Cetinkaya, Kornhauser-Cerar, Derrick, Özkan, Hulzebos, Schmölzer, Aiyappan, Lemyre, Kuo, Rajadurai, O’Shea, Biniwale, Ramanathan, Kushnir, Bader, Thomas, Chakraborty, Buksh, Bhatia, Sullivan, Shinwell, Dyson, Barker, Kugelman, Donovan, Goss, Tauscher, Murthy, Ali, Clark, Soll, Johnson, Cheong, Carlin, Davis.
Statistical analysis: Orsini, Wang, Carlin.
Obtained funding: Dargaville, Kamlin.
Administrative, technical, or material support: Dargaville, De Paoli, Kanmaz Kutman, Derrick, Hulzebos, Buksh, Donovan, Johnson, Davis.
Supervision: Dargaville, Orsini, Rajadurai, Biniwale, Ramanathan, Kushnir, Chakraborty, Clark, Carlin.
Other–site investigator: Özkan, Schmölzer, Aiyappan, Kuo, Thomas, Sullivan, Dyson, Barker, Kugelman, Goss, Tauscher, Murthy.
Conflict of Interest Disclosures: Dr Dargaville reported receiving personal fees from AbbVie (advisory board consultancy 2014) and Chiesi Farmaceutici (advisory board consultancies 2016, 2021) and provision of surfactant at reduced cost and support for conference travel from Chiesi Farmaceutici during the conduct of the study; in addition, Dr Dargaville has a patent for a catheter design (USD752215S) issued. Dr Hulzebos reported receiving grants from Chiesi Farmaceutici during the conduct of the study. Dr Kushnir reported receiving grants from the University of Sydney outside the submitted work. Dr Goss reported serving as chief investigator for OPTI-SURF, an observational study on UK neonatal surfactant use in respiratory distress syndrome funded by Chiesi UK outside the submitted work. Dr Clark reported receiving personal fees from Chiesi Farmaceutici outside the submitted work. No other disclosures were reported.
Funding/Support: This study was funded by grants from the Royal Hobart Hospital Research Foundation (#11-382; #21-202) and the Australian National Health and Medical Research Council (#1049114). Exogenous surfactant was provided at reduced cost by Chiesi Farmaceutici.
Role of the Funder/Sponsor: The funders and the trial sponsor (University of Tasmania) had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. These organizations did not have the right to veto publication or to control decisions regarding to which journal the manuscript was submitted.
Group Information: The OPTIMIST-A Trial Investigators appear in Supplement 4.
Data Sharing Statement: See Supplement 5.
Additional Contributions: We thank the families of infants in this study for their willingness to participate and are grateful for the assistance of staff at all sites in the conduct of the trial (Supplement 4). We thank the members of the data and safety monitoring committee for their voluntary contribution to the trial: Brian A. Darlow, MD, University of Otago, committee chair; Michael Dunn, MD, University of Toronto; and Amy Salter, PhD, The University of Adelaide. We thank the staff at the data management center at Murdoch Children’s Research Institute: Ross Dunn, BAS; Luke Stevens, BSc (salaried data managers) and the staff at the trial coordinating center at the Menzies Institute for Medical Research, University of Tasmania: Karen Butterley, RN; Nicky Stephens, MPhil; Lizzy Reid, MSc (salaried trial coordinators).
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