Mechanical ventilation with normal tidal volumes (VT) causes lung and systemic
inflammation in preterm sheep.
Mechanical ventilation is associated with
bronchopulmonary dysplasia (BPD) in preterm infants, and the addition of
budesonide to
surfactant decreases BPD in clinical trials.
Budesonide with
surfactant will decrease the
lung injury from
mechanical ventilation for 24 h in preterm sheep. Lambs at 126 ± 1 day gestational age were delivered and randomized to either: 1)
surfactant (200 mg/kg) or 2)
surfactant mixed with
budesonide (0.25 mg/kg) before
mechanical ventilation with VT of 7-8 ml/kg for 2, 6, or 24 h (n = 6 or 7/group). Lung physiology and
budesonide levels in the plasma and the lung were measured. Lung tissue, bronchoalveolar lavage fluid (BALF), liver, and brain tissues were evaluated for indicators of injury. High initial
budesonide plasma levels of 170 ng/ml decreased to 3 ng/ml at 24 h. Lung tissue
budesonide levels were less than 1% of initial dose by 24 h. Although physiological variables were generally similar,
budesonide-exposed lambs required lower mean airway pressures, had higher
hyperoxia responses, and had more stable blood pressures.
Budesonide decreased proinflammatory
mRNA in the lung, liver, and brain.
Budesonide also decreased total
protein and proinflammatory
cytokines in BALF, and decreased
inducible nitric oxide synthase activation at 24 h. In ventilated preterm lambs, most of the
budesonide left the lung within 24 h. The addition of
budesonide to
surfactant improved physiology, decreased markers of
lung injury, and decreased systemic responses in liver and brain.