TITLE OF WRITE-UP

De-MIST-ifying the two-year outcomes of non-invasive surfactant therapy

MANUSCRIPT CITATION

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.

REVIEWED BY

Lucy Loft MBBS
Neonatology, The Royal Women’s Hospital, Melbourne, Australia
Email: lucy.loft@thewomens.org.au

Kristin N Ferguson MBBS
Neonatal Research, Murdoch Children’s Research Institute, Melbourne, Australia
Neonatology, Mercy Hospital for Women, Melbourne, Australia
Email: kristinnarelle.ferguson@mercy.com.au

David G Tingay PhD
Neonatal Research, Murdoch Children’s Research Institute, Melbourne, Australia
Department of Paediatrics, The University of Melbourne, Melbourne, Australia
Email: david.tingay@mcri.edu.au

TYPE OF INVESTIGATION

Treatment

QUESTION

For preterm infants (25 to 28+6 weeks gestational age) with respiratory distress syndrome supported with continuous positive airway pressure (CPAP) or non-invasive positive pressure ventilation (NIPPV) (P), does minimally invasive surfactant therapy (MIST) (I) compared with sham treatment (C) improve survival without moderate to severe neurodevelopmental disability (NDD) (O) at 2 years corrected age (T)?

METHODS

Design: Follow up from a randomised controlled trial (OPTIMIST-A Trial; JAMA 2021; 326:2478-87).

Allocation: Infants were randomised 1:1 via a computer-generated code in permuted block sizes of 2, 4, or 6 and stratified by study centre and gestational age for the primary intervention. Multiple births were randomised independently.

Data collection: Follow up at 2 years corrected age of neurodevelopmental status, general and respiratory health was completed either face-to-face (Bayley Scales of Infant and Toddler Development, Third Edition [BSID-III]) or via a validated online questionnaire (Parent Report of Children’s Abilities-Revised [PARCA-R]). Where these assessments could not be performed, an abbreviated 6 question questionnaire was administered.

Blinding: Clinicians, parents and follow-up personnel were blinded to the original study allocation.

Follow up period: 2 years corrected age.

Setting: 33 tertiary level neonatal intensive care units in 11 countries.

Patients:

• Inclusion criteria: Preterm infants born 25+0 to 28+6 weeks gestational age receiving CPAP or NIPPV requiring FiO₂ greater than 0.30 at less than 6 hours of age.
• Exclusion criteria: Preterm infants receiving or clinically judged to be imminently needing invasive respiratory support, non-surfactant deficiency causes of respiratory failure or severe congenital anomalies.

Intervention

• Intervention – MIST: 200mg/kg surfactant administered into the trachea via a thin catheter under direct laryngoscopy (the Hobart method) with CPAP applied throughout (without sedation).
• Control: Sham intervention involving head repositioning but no instrumentation of the airway or administration of surfactant.

Outcomes

• Secondary outcome: Composite outcome, assessed at 2 years corrected age, of death or moderate-severe neurodevelopmental disability defined as:
  • Moderate to severe cognitive or language impairment
  • Cerebral palsy equivalent to Gross Motor Function Classification System (GMFCS) 2 or greater
  • Visual impairment
  • Hearing impairment

• Additional secondary outcomes (in addition to components of composite outcome) assessed in the first 2 years:
  • Overnight hospitalisation with any illness
  • Overnight hospitalisation with respiratory illness
  • Parent report of wheeze or breathing difficulty
  • Use of any bronchodilator therapy
  • Parent report of a physician diagnosis of asthma
  • Feeding via nasogastric or gastrostomy tube beyond 1-year corrected age

Analysis and sample size: 486 infants correctly randomised in the inception cohort. Projected sample size had been 606 infants based on detection of a 13% absolute risk reduction in the primary outcome of death or BPD with 90% power.

Patient follow up: 93% (400 infants) of the 431 infants who continued in the study and survived had follow up data available, with 88% (381 infants) having sufficient data for full assessment of NDD. 53 infants died before 2-year assessment.

MAIN RESULTS

No difference in death or NDD (or composite components of NDD) at 2 years corrected age. MIST group had less hospitalisations for respiratory disease (25.1% vs 38.2%; RR 0.66 [0.54-0.81]) and lower rates of parent-reported wheezing or breathing difficulties (40.6% vs 53.6%; RR 0.76 [0.63-0.90]).

CONCLUSION

The authors conclude that MIST compared with sham treatment did not reduce the incidence of NDD or death at 2 years corrected age. They did, however, find significantly improved respiratory health outcomes at 2 years corrected age in the MIST group.

COMMENTARY

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.

REFERENCES

1. 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.
2. 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.
3. 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.
4. 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.