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Lucy Loft, Kristin N Ferguson, and David G Tingay from Australia review the EbNeo September 2023 Article of the Month: "Dargaville PA, Kamlin COF, Orsini F, Wang X, De Paoli AG, Kanmaz Kutman HG, et al. Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants. Follow-Up of the OPTIMIST-A Randomized Clinical Trial. JAMA 2023; 330:1054-63. PMID 37695601."

Read here!

Hear it discussed on the Incubator podcast!

Acta Commentary:

Acta Paediatrica - 2024 - Loft - EBNEO Commentary De%E2%80%90MIST%E2%80%90ifying the 2%E2%80%90year outcomes of non%E2%80%90invasive surfactant therapy.pdf

"Minimally invasive surfactant therapy (MIST), whereby surfactant is administered intra-tracheally during the continuation of non-invasive respiratory support, has been advocated as a method of addressing the dual respiratory challenges defining preterm birth; surfactant-deficiency and avoiding invasive respiratory support. The OPTIMIST-A trial, an international, blinded, randomised controlled trial, comparing MIST to a sham treatment in extremely preterm infants (25-28 weeks gestational age) receiving non-invasive support, found that although there was no difference in the primary composite outcome of death or bronchopulmonary dysplasia (BPD), rates of BPD and early intubation were lower in the MIST group.(1)

The authors of the OPTIMIST-A trial now report their secondary 2-year outcome data. There was no difference in the composite primary outcome of neurodevelopmental disability or death at 2-years corrected age, providing reassurance on the safety of the intervention. This is an important finding as both the parents and clinicians were blinded to their baby’s treatment, and sedation was not used during laryngoscopy.

There was, however, a statistically significant decrease in the measures of respiratory morbidity at 2-years corrected age in the MIST group. There is a biological plausibility to these findings, and they should be treated as important. Early surfactant likely blunts the early injury and inflammation events in the lung that lead to the cascade of escalating respiratory needs, BPD diagnosis and increased post-discharge risks (such as lower respiratory tract infection).(2) Interestingly, the authors found the rates of 2-year respiratory health were higher than BPD rates. The authors speculated that many infants without a diagnosis of BPD still had lung injury that manifested in early life with respiratory symptoms and vulnerability to respiratory infection. This highlights the limitations of BPD definitions in representing later functional respiratory status, which parents often rate as more important than a diagnosis of BPD.(3) Respiratory function was predominantly defined via parental reporting of hospital admissions and wheezing. Whilst pragmatic, the OPTIMIST-A study demonstrates the need for reproducible, objective and validated functional methods of defining early life respiratory health. This would benefit babies, their families, clinicians, and researchers, not only in understanding the expected respiratory trajectory, but also to guide the development of interventions both in the NICU and beyond to optimise long-term respiratory health.

Follow-up rates were high. The strength of this follow-up population size is however marred by the use of increasingly subjective follow-up techniques. Despite initially aiming for in-person health reviews and Bayley Scales of Infant and Toddler Development (Third Edition) assessment, this was impractical in some regions (in part due to the COVID-19 pandemic). Subsequently, an online parent-completed survey was developed utilising the validated Parent Report of Children’s Abilities (Revised) questionnaire for neurodevelopmental disability assessment.(4) This highlights a dilemma common to many international NICU trials involving multiple languages and health services; high follow-up rates with pragmatic follow-up measures versus standardised high-quality follow-up with high attrition rates and the risk of minimal meaningful outcome data. In the case of OPTIMIST-A, where no neurological risks were identified during the NICU admission, the balance of pragmatism appears appropriate.


Dargaville PA, Kamlin COF, Orsini F, Wang X, De Paoli AG, Kanmaz Kutman HG, et al. Effect of Minimally Invasive Surfactant Therapy Vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants with Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial. JAMA2021; 326; 2478-87.

Tingay DG, Wallace MJ, Bhatia R, Schmolzer GM, Zahra VA, Dolan MJ, et al. Surfactant before the first inflation at birth Improves spatial distribution of ventilation and reduces lung injury in preterm lambs. J Appl Physiol 2014; 116, 251-8.

Thivierge E, Luu TM, Bourque CJ, Barrington KJ, Pearce R, Jaworski M, et al. Pulmonary important outcomes after extremely preterm birth: Parental perspectives. Acta Paediatr 2023; 112, 970-6.

Johnson S, Bountziouka V, Brocklehurst P, Linsell L, Marlow N, et al. Standardisation of the Parent Report of Children’s Abilities-Revised (PARCA-R): a norm-referenced assessment of cognitive and language development at age 2 years. Lancet Child Adolesc Health 2019; 3: 705-712."

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