A few years ago now a multicenter RCT among infants of 23 to 26 weeks gestation showed that LISA was possible in even these most immature infants., NINSAPP.
Kribs A, et al. Nonintubated Surfactant Application vs Conventional Therapy in Extremely Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2015;169(8):723-30. 211 infants were randomized if they were stabilized on CPAP at 10 to 120 minutes of age and were needing more than 30% oxygen. The original publication was a “negative trial’ in that the primary outcome (survival without BPD) was not very different between groups; although more frequent with LISA than with intubation for giving surfactant (67% compared to 59%) the risk difference of 8% could have been due to chance (95% compatibility limits 21% reduction to 5% increase of “death or BPD” with LISA).
One finding of the study was that almost all of the 23 and 24 week babies randomized to LISA were intubated later (14/15 at 23 weeks and 24/26 at 24 weeks), as well as 3/4 of the 25 week and 1/2 of the 26 week infants. The eventual median duration of mechanical ventilation was therefore only 2 days different between the groups. Of note the incidence of severe intracranial bleeding ‘grade 3 and 4 IVH’ was 22% among the controls, and of cystic PVL was 11%. Both of these frequencies are very high and were much higher than the LISA group, 10% for severe IVH and 4% for PVL. In recent years in the Canadian Neonatal Network the combined incidence of severe IVH and PVL has been between 17 and 19% for babies of 23 to 26 weeks GA, even allowing for some overlap in the NINSAPP babies some of whom might have had IVH and PVL, their frequency of serious brain injury was much higher among the controls than among our intubated babies. Did they by chance have a group of controls who had more brain injury than usual? Or was it truly the impact of LISA? Or was it because the routine was to perform intubation without pre-medication in the control group? (Which causes major hemodynamic fluctuations and is much more likely to need multiple intubation attempts).
It is hard to imagine how the occurrence of cystic PVL would be affected so dramatically by 2 fewer days of mechanical ventilation.
Long term follow-up of the infants has just been published (Mehler K, et al. Developmental outcome of extremely preterm infants is improved after less invasive surfactant application (LISA). Acta Paediatr. 2020.) 156 babies were evaluated at 2 years corrected age (86% of the survivors). Strangely these data are 5 years old now, as babies were recruited up to 2012, so the last follow up would have been in 2015.
The primary outcome of the follow-up study is vaguely defined as “neurodevelopment” and refer to the Bayley version 2, but do not mention a neurological exam.
Disability was defined if the mental development index (MDI) or psychomotor development index (PDI) was <85 but ≥70, severe disability was defined for MDIs or PDIs <70. Indices between 85 and 115 indicated normal development, indices >115 were defined as development above average. Developmental delay referred to any MDI or PDI <85.
This is the main table of the results which shows a very high frequency of what they call “severe disability” among infants of 25 and 26 weeks GA randomized to the intubation group. Firstly, I would like to re-iterate, a low score on a Bayley is not a disability. The Bayley Scales of Infant Development are a screening tool meant to identify children who require further evaluation, many of those with low scores at 24 months do not have impairments when evaluated later.
A systematic review of LISA was published in 2017, it included 6 trials Aldana-Aguirre JC, et al. Less invasive surfactant administration versus intubation for surfactant delivery in preterm infants with respiratory distress syndrome: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2017;102(1):F17-F23) and did not show an impact of LISA on intraventricular haemorrhage or PVL, but the other trials included very few infants at high risk, mostly specifically excluding infants below a certain GA.
Is it possible that LISA (or alternatively MIST, minimally invasive surfactant treatment) protects the brain? I would say that the data from NINSAPP are unconvincing; it was a well-performed study, but was too small, with an unusually high incidence of brain injury in the control group, and non-optimal intubation practices in those infants. Slightly delaying intubation in 23 and 24 week infants may have some benefits, and performing the procedure after the early perinatal hemodynamic changes. But it seems to me inherently unlikely that such a big difference in ultrasound brain inujry findings and in longer-term developmental scores would result from avoiding intubation overall of 25% of mostly 25 and 26 week infants and a median of 2 fewer days mechanical ventilation.
It would be good to be proved wrong (I think that happened once before😁). I am afraid to say it, more research is needed, to confirm or question these findings.
Also, and I know most of us are too busy and there are mutiple reasons why publications get delayed, but reporting dramatic differences in outcomes 5 years later does a disservice to our community, earlier reporting of these results could have helped to ensure that other trials get funded, and that other researchers include longer term neurological and developmental outcomes in their study designs.