One size does not fit all: Respiratory phenotypes within the extremes of extreme prematurity

Background: All infants born 22-28 weeks' gestation are considered "extremely preterm" despite their substantial anatomical and physiological heterogeneity. This exploratory study aimed to chart the pulmonary response when a standardised lung protective ventilation strategy is applied at the extremes of extreme prematurity. Methods: 60 min of ventilation was provided from birth to lambs at 118-120d gestation (predominantly canalicular, PretermC; n=7), or 127-128d gestation (predominantly saccular, PretermS; n=8) or 139-140d gestation (Term,; n=9). Results from morphology and gene expression studies (lung tissue), SWATH-MS analysis (lung lavage), gas exchange and lung mechanics were compared between preterm and term lambs. Results: Changes in gas exchange and lung injury markers were more frequent and of a greater magnitude in PretermC lambs compared with PretermS lambs(selected results Figure1). We identified a PretermC-specific injurious phenotype containing inflammation, clotting and cell death proteins.  Conclusions: Our discovery of distinct physiological and biological responses in lambs at the extremes of extreme prematurity demonstrates that a "one size fits all" approach to respiratory support fails to appreciate the developmental differences in the preterm lung, especially the increased propensity for inflammation-initiated injury in the most preterm gestation.