Differential short-term regional effects of early high dose erythropoietin on white matter in preterm lambs after mechanical ventilation

Key points id=tjp6825-list-0001 list-type=bulleted Erythropoietin is a neuroprotectant undergoing clinical trial for brain injury in term and preterm infants. This is the first experimental study to assess the acute effects of erythropoietin on the cerebral white matter in preterm ventilated lambs. Administration of erythropoietin within minutes of injurious ventilation onset Inadvertently injurious ventilation of preterm neonates in the delivery room can cause cerebral white matter (WM) inflammation and injury. We investigated the impact of an early high dose of recombinant human erythropoietin (EPO) on ventilation-induced WM changes in preterm lambs. Injurious ventilation, targeting a V-T of 15mlkg(-1) with no positive end-expiratory pressure, was initiated for 15min in preterm lambs (0.85 gestation). Conventional ventilation was continued for a further 105min. Lambs received either 5000IUkg(-1) of EPO (EPREX (R); Vent+EPO; n=6) or vehicle (Vent; n=8) via an umbilical vein at 42min. Markers of WM injury and inflammation were assessed using quantitative real-time PCR (qPCR) and immunohistochemistry and compared to a group of unventilated controls (UVC; n=4). In Vent+EPO lambs compared to Vent lambs: (i) interleukin (IL)-1 and IL-6 mRNA levels in the periventricular WM and IL-8 mRNA levels in the subcortical WM were higher (P<0.05 for all); (ii) the density of microglia within the aggregations was not different in the periventricular WM and was lower in the subcortical WM (P=0.001); (iii) the density of astrocytes was lower in the subcortical WM (P=0.002); (iv) occludin and claudin-1 mRNA levels were higher in the periventricular WM (P<0.02 for all) and (vi) the number of blood vessels with protein extravasation was lower (P<0.05). Recombinant human EPO had variable regional effects within the WM when administered during injurious ventilation. The adverse short-term outcomes discourage the use of early high dose EPO administration in preterm ventilated babies.