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For preterm infants with respiratory distress syndrome supported with continuous positive airway pressure (CPAP), does selective administration of surfactant via a thin catheter at a low oxygenation threshold improve survival without bronchopulmonary dysplasia compared with continuation of CPAP?
In this randomized clinical trial including 485 infants with a gestational age of 25 to 28 weeks and respiratory distress syndrome, minimally invasive surfactant therapy delivered via a thin catheter at a fraction of inspired oxygen threshold of 0.30 or greater within 6 hours of birth compared with sham (control) treatment resulted in attainment of the composite outcome of death or bronchopulmonary dysplasia in 43.6% vs 49.6%, respectively, of infants in the 2 groups. This difference was not statistically significant.
Among preterm infants with respiratory distress syndrome, surfactant administration via a thin catheter did not result in a statistically significant reduction in the likelihood of the composite outcome of death or bronchopulmonary dysplasia.
The benefits of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome are uncertain.
To examine the effect of selective application of MIST at a low fraction of inspired oxygen threshold on survival without bronchopulmonary dysplasia (BPD).
Design, Setting, and Participants
Randomized clinical trial including 485 preterm infants with a gestational age of 25 to 28 weeks who were supported with continuous positive airway pressure (CPAP) and required a fraction of inspired oxygen of 0.30 or greater within 6 hours of birth. The trial was conducted at 33 tertiary-level neonatal intensive care units around the world, with blinding of the clinicians and outcome assessors. Enrollment took place between December 16, 2011, and March 26, 2020; follow-up was completed on December 2, 2020.
Infants were randomized to the MIST group (n = 241) and received exogenous surfactant (200 mg/kg of poractant alfa) via a thin catheter or to the control group (n = 244) and received a sham (control) treatment; CPAP was continued thereafter in both groups unless specified intubation criteria were met.
Main Outcomes and Measures
The primary outcome was the composite of death or physiological BPD assessed at 36 weeks’ postmenstrual age. The components of the primary outcome (death prior to 36 weeks’ postmenstrual age and BPD at 36 weeks’ postmenstrual age) also were considered separately.
Among the 485 infants randomized (median gestational age, 27.3 weeks; 241 [49.7%] female), all completed follow-up. Death or BPD occurred in 105 infants (43.6%) in the MIST group and 121 (49.6%) in the control group (risk difference [RD], −6.3% [95% CI, −14.2% to 1.6%]; relative risk [RR], 0.87 [95% CI, 0.74 to 1.03]; P = .10). Incidence of death before 36 weeks’ postmenstrual age did not differ significantly between groups (24 [10.0%] in MIST vs 19 [7.8%] in control; RD, 2.1% [95% CI, −3.6% to 7.8%]; RR, 1.27 [95% CI, 0.63 to 2.57]; P = .51), but incidence of BPD in survivors to 36 weeks’ postmenstrual age was lower in the MIST group (81/217 [37.3%] vs 102/225 [45.3%] in the control group; RD, −7.8% [95% CI, −14.9% to −0.7%]; RR, 0.83 [95% CI, 0.70 to 0.98]; P = .03). Serious adverse events occurred in 10.3% of infants in the MIST group and 11.1% in the control group.
Conclusions and Relevance
Among preterm infants with respiratory distress syndrome supported with CPAP, minimally invasive surfactant therapy compared with sham (control) treatment did not significantly reduce the incidence of the composite outcome of death or bronchopulmonary dysplasia at 36 weeks’ postmenstrual age. However, given the statistical uncertainty reflected in the 95% CI, a clinically important effect cannot be excluded.
anzctr.org.au Identifier: ACTRN12611000916943
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Corresponding Author: Peter A. Dargaville, MD, Department of Paediatrics, Royal Hobart Hospital, 48 Liverpool St, Hobart, TAS 7000, Australia (email@example.com).
Accepted for Publication: November 18, 2021.
Published Online: December 13, 2021. doi:10.1001/jama.2021.21892
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.
Concept and design: Dargaville, Kamlin, Rajadurai, 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, Tauscher, Murthy, Ali, Yossuck, Clark, Carlin, Davis.
Drafting of the manuscript: Dargaville, Orsini, Soll, Carlin.
Critical revision of the manuscript for important intellectual content: 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, Tauscher, Murthy, Ali, Yossuck, Clark, Carlin, Davis.
Statistical analysis: Kamlin, Orsini, Wang, Carlin.
Obtained funding: Dargaville, Kamlin, Rajadurai, Carlin, Davis.
Administrative, technical, or material support: Dargaville, Kamlin, De Paoli, Murthy.
Supervision: Dargaville, Kamlin, Orsini, Carlin.
Conflict of Interest Disclosures: Dr Dargaville reported receiving support for attending meetings or travel from Chiesi Farmaceutici; serving as a consultant on advisory boards established by Chiesi Farmaceutici and AbbVie; and holding (without royalty claims) a design patent for a catheter for surfactant instillation. Dr Hulzebos reported receiving grants from Chiesi Farmaceutici. Dr Biniwale reported receiving grants from Chiesi Farmaceutici, Vyaire Medical, and Medtronic. Dr Clark reported receiving grants from Chiesi Farmaceutici and having a patent for a potential therapy for neonatal respiratory distress syndrome. No other disclosures were reported.
Funding/Support: This study was funded by grant 11-382 from the Royal Hobart Hospital Research Foundation and by grant 1049114 from the Australian National Health and Medical Research Council. Chiesi Farmaceutici provided the exogenous surfactant at reduced cost.
Role of the Funder/Sponsor: The funders/sponsors 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.
Collaborator Information: A list of the OPTIMIST-A Trial Investigators appears 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. We thank the members of the data and safety monitoring committee for their voluntary contribution to the trial: Brian A. Darlow, MD (committee chair; University of Otago), Michael Dunn, MD (University of Toronto), and Amy Salter, PhD (University of Adelaide). We thank the staff at the data management center at Murdoch Children’s Research Institute, including Ross Dunn, BAppSci, and Luke Stevens, BSc (Hons) (salaried data managers), and the staff at the trial coordinating center at the Menzies Institute for Medical Research, University of Tasmania, including Karen Butterley, RN, Nicky Stephens, MPhil, and Lizzy Reid, MSc (salaried trial coordinators).
Additional Information: The trial coordinating center and data management and statistics center were led by Drs Dargaville and Carlin, respectively.
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