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

Mechanical ventilation from birth with normal tidal volumes (VT) 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 VT ventilation in preterm sheep. Lambs at 126 ± 1 day gestational age were ventilated from birth with either: 1) Normal VT [surfactant 200 mg/kg before ventilation, positive end expiratory pressure (PEEP) 5 cmH2O, VT 8 mL/kg] or 2) Injury VT (high pressure, 100% oxygen, no PEEP) for 15 min, then further randomized to surfactant + saline or surfactant + 0.25 mg/kg budesonide with Normal VT for 6 h. Lung function and lung, liver, and brain tissues were evaluated for indicators of injury. Injury VT + saline caused significant injury and systemic responses, and Injury VT + 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 VT + 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 VT and budesonide and the combination exposure. In lambs receiving Injury VT, 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 VT.

Surfactant and budesonide for respiratory distress syndrome: an observational study.

BACKGROUND: In preterm infants on moderately high ventilator support, the addition of budesonide to surfactant lowered bronchopulmonary dysplasia (BPD) rates by 20% without increased morbidity or mortality. The aim of this cohort comparison was to determine the safety and efficacy of the combination in infants with milder respiratory distress syndrome (RDS). METHODS: In August 2016 we began administering budesonide (0.25 mg/kg) mixed with surfactant (Survanta 4 mL/kg) to all infants ≤ 1250 g who failed CPAP and required intubation. Infants were compared to a historical cohort (2013-2016) who received surfactant alone. RESULTS: BPD or death did not change between the historical surfactant cohort (71%, n = 294) and the budesonide cohort (69%, n = 173). Budesonide was associated with a decrease in the need for continued mechanical ventilation, severe BPD type II or death (19-12%), grade III BPD or death (31-21%), and the median gestational age at discharge was 1 week earlier. Histologic chorioamnionitis was associated with decreased budesonide effects. Secondary morbidities (NEC, IVH, ROP, Sepsis) were similar. CONCLUSION: Overall BPD rates remained unchanged with the addition of budesonide. Budesonide was associated with decreased severity of BPD, decreased mechanical ventilation use, earlier discharge, and similar short-term outcomes.

Surfactant plus budesonide decreases lung and systemic inflammation in mechanically ventilated preterm sheep.

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.

Effects of budesonide and surfactant in preterm fetal sheep.

Mechanical ventilation causes lung injury and systemic inflammatory responses in preterm sheep and is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Budesonide added to surfactant decreased BPD by 20% in infants. We wanted to determine the effects of budesonide and surfactant on injury from high tidal volume (VT) ventilation in preterm lambs. Ewes at 125 ± 1 days gestational age had fetal surgery to expose fetal head and chest with placental circulation intact. Lambs were randomized to 1) mechanical ventilation with escalating VT to target 15 ml/kg by 15 min or 2) continuous positive airway pressure (CPAP) of 5 cmH2O. After the 15-min intervention, lambs were given surfactant 100 mg/kg with saline, budesonide 0.25 mg/kg, or budesonide 1 mg/kg. The fetuses were returned to the uterus for 24 h and then delivered and ventilated for 30 min to assess lung function. Budesonide levels were low in lung and plasma. CPAP groups had improved oxygenation, ventilation, and decreased injury markers compared with fetal VT lambs. Budesonide improved ventilation in CPAP lambs. Budesonide decreased lung weights and lung liquid and increased lung compliance and surfactant protein mRNA. Budesonide decreased proinflammatory and acute-phase responses in lung. Airway thickness increased in animals not receiving budesonide. Systemically, budesonide decreased monocyte chemoattractant protein-1 mRNA and preserved glycogen in liver. Results with 0.25 and 1 mg/kg budesonide were similar. We concluded that budesonide with surfactant matured the preterm lung and decreased the liver responses but did not improve lung function after high VT injury in fetal sheep.

Early Physiological and Adrenal Effects of Budesonide Mixed with Surfactant in Large Observational Preterm Cohort Study.

BACKGROUND: The combination of surfactant and budesonide has been shown to decrease BPD rates and severity. Budesonide may be released systemically from lungs, and the effects on the immature adrenal glands are not known. OBJECTIVE: The aim of this study was to determine if adrenal suppression rates are higher in preterm infants receiving budesonide with surfactant compared to surfactant alone. METHODS: A retrospective chart review of 608 infants ≤1,250 g received intubation for surfactant therapy from 2013 through 2020. In August 2016, budesonide was added to surfactant for these infants. Indicators of adrenal suppression, including mean blood pressures, plasma electrolyte levels, hydrocortisone use, and the use of vasoactive medications, were analyzed for the first 14 days after birth. Respiratory variables, biochemical signs of adrenal insufficiency, and neonatal morbidities were analyzed. RESULTS: There was no difference in hydrocortisone administration in the first 14 days between infants receiving budesonide with surfactant (n = 314) or surfactant alone (n = 294) (23% vs. 19%, p = 0.38). Budesonide exposed infants received hydrocortisone 3 days later than surfactant only infants (median DOL 5 vs. 2, p < 0.001). Infants receiving budesonide had higher blood pressures, required less dopamine (19% vs. 39%, p < 0.001) and dobutamine (2% vs. 6%, p = 0.02). Budesonide exposed infants were discharged home after a shorter NICU stay (85 days vs. 94 days, p = 0.02) and at a younger gestational age (39 vs. 40 weeks, p = 0.001). CONCLUSIONS: The use of surfactant and budesonide does not alter the rate of hydrocortisone use, but does delay the timing of treatment initiation and decreases the use of vasoactive medications.

Budesonide mixed with surfactant did not affect neurodevelopmental outcomes at 6 or 18 months corrected age in observational cohorts.

BACKGROUND: The addition of budesonide to surfactant in very-low-birth-weight infants with less severe RDS decreased bronchopulmonary dysplasia (BPD) severity. Long-term neurodevelopmental follow-up was needed to monitor for systemic effects of budesonide. METHODS: Infants ≤1250 g who received intratracheal budesonide (0.25 mg/kg) with surfactant (n = 173) were compared to a historical cohort who received surfactant alone (n = 294). Peabody Developmental Motor Scales II at 4-6 months corrected age and Bayley Scales of Infant & Toddler Development III at 18-22 months corrected age were compared. RESULTS: There were no differences in muscle tone or motor skills by Peabody exam. There were no differences in the cognitive, language, or motor domains between cohorts on Bayley III. CONCLUSIONS: In a cohort of infants treated with budesonide mixed with surfactant, there were no differences in developmental outcomes at 4-6 months or 18-22 months corrected age.

Epidermal growth factor receptor inhibition with Gefitinib does not alter lung responses to mechanical ventilation in fetal, preterm lambs.

BACKGROUND: Epidermal growth factor receptor (EGFR) is important for airway branching and lung maturation. Mechanical ventilation of preterm lambs causes increases in EGFR and EGFR ligand mRNA in the lung. Abnormal EGFR signaling may contribute to the development of bronchopulmonary dysplasia. HYPOTHESIS: Inhibition of EGFR signaling will decrease airway epithelial cell proliferation and lung inflammation caused by mechanical ventilation in preterm, fetal sheep. METHODS: Following exposure of the fetal head and chest at 123±1 day gestational age and with placental circulation intact, fetal lambs (n = 4-6/group) were randomized to either: 1) Gefitinib 15 mg IV and 1 mg intra-tracheal or 2) saline IV and IT. Lambs were further assigned to 15 minutes of either: a) Injurious mechanical ventilation (MV) or b) Continuous positive airway pressure (CPAP) 5 cmH2O. After the 15 minute intervention, the animals were returned to the uterus and delivered after i) 6 or ii) 24 hours in utero. RESULTS: MV caused lung injury and inflammation, increased lung mRNA for cytokines and EGFR ligands, caused airway epithelial cell proliferation, and decreased airway epithelial phosphorylated ERK1/2. Responses to MV were unchanged by Gefitinib. Gefitinib altered expression of EGFR mRNA in the lung and liver of both CPAP and MV animals. Gefitinib decreased the liver SAA3 mRNA response to MV at 6 hours. There were no differences in markers of lung injury or inflammation between CPAP animals receiving Gefitinib or saline. CONCLUSION: Inhibition of the EGFR pathway did not alter acute lung inflammation or injury from mechanical ventilation in preterm sheep.