Budesonide and hydrocortisone have differential effects on lung and brain in ventilated preterm lambs

Background: Both the addition of budesonide to surfactant and prophylactic hydrocortisone show promise for decreasing lung inflammation without increasing neurodevelopmental changes in preterm infants. Determining if combining these postnatal steroid therapies with antenatal steroids is safe is essential. Methods: Utilizing preterm sheep (n = 7–8/group) combining antenatal betamethasone (0.25 mg/kg) and brief injurious ventilation, lambs were randomized to endotracheal surfactant with budesonide (0.25 mg/kg) or saline and either hydrocortisone (1 mg/kg) or saline IV at 15 min. Lambs were then ventilated for 4 h to evaluate physiology and effects on the lungs, liver, and brain. Results: The addition of budesonide to surfactant, even after antenatal steroids, improved ventilation physiology, decreased lung inflammation, acute phase mRNA, and pro-inflammatory changes in the liver and the brain compared with mechanical ventilation with surfactant alone. Hydrocortisone had minimal effects on physiology, other than blood pressure, and decreased some of the anti-inflammatory effects seen with budesonide. Mechanical ventilation, with or without budesonide, activated GFAP+ astrocytes in the cortical tissue and white matter, and hydrocortisone further increased activation. Only hydrocortisone also activated Iba1+ microglial cells in the brain. Conclusions: Combining hydrocortisone with budesonide may decrease the anti-inflammatory effects of budesonide and hydrocortisone may induce astrocyte and microglial activation. Impact: Even after antenatal steroids, the addition of budesonide to surfactant improved ventilation physiology and markers of injury in the lung, liver, and brain. Hydrocortisone IV had minimal effects on physiology, other than blood pressure, and decreased some of the beneficial effects seen with budesonide in the lung and liver. Mechanical ventilation activated GFAP+ astrocytes in the cortical tissue and white matter, and hydrocortisone further increased this activation. Hydrocortisone also activated Iba1+ microglial cells, whereas neither mechanical ventilation or budesonide increased Iba1. The medications were given at same time, and clinical timing may differ in premature infants affecting the results.