Surfactant plus budesonide decreases lung and systemic responses to injurious ventilation in preterm sheep

Mechanical ventilation from birth with normal tidal volumes (V_T) causes lung injury and systemic responses in preterm sheep. The addition of budesonide to surfactant therapy decreases these injury markers. Budesonide and surfactant will decrease the injury from injurious V_T ventilation in preterm sheep. Lambs at 126 ± 1 day gestational age were ventilated from birth with either: 1) Normal V_T [surfactant 200 mg/kg before ventilation, positive end expiratory pressure (PEEP) 5 cmH₂O, V_T 8 mL/kg] or 2) Injury V_T (high pressure, 100% oxygen, no PEEP) for 15 min, then further randomized to surfactant + saline or surfactant + 0.25 mg/kg budesonide with Normal V_T for 6 h. Lung function and lung, liver, and brain tissues were evaluated for indicators of injury. Injury V_T + saline caused significant injury and systemic responses, and Injury V_T + budesonide improved lung physiology. Budesonide decreased lung inflammation and decreased pro-inflammatory cytokine mRNA in the lung, liver, and brain to levels similar to Normal V_T + saline. Budesonide was present in plasma within 15 min of treatment in both ventilation groups, and less than 5% of the budesonide remained in the lung at 6 h. mRNA sequencing of liver and periventricular white matter demonstrated multiple pathways altered by both Injury V_T and budesonide and the combination exposure. In lambs receiving Injury V_T, the addition of budesonide to surfactant improved lung physiology and decreased pro-inflammatory cytokine responses in the lung, liver, and brain to levels similar to lambs receiving Normal V_T.