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

Abstract

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.

Budesonide with surfactant decreases systemic responses in mechanically ventilated preterm lambs exposed to fetal intra-amniotic lipopolysaccharide

“…The animals in both treatment groups received similar fluid resuscitations in the first hour of ventilation, but the budesonide-treated lambs had stabilization of their blood pressures by 4 h. Due to the increased combination of the initial lung injury and the deterioration from the LPS exposure, we shortened the experiments to 4 h compared to previous 6-h experiments. 19 Previous animals ventilated 4 days after IA LPS did not have early blood pressure problems, whereas receiving a dose of IA LPS 5 days and 2 days prior to delivery had improved blood pressure control. 30,31 These findings are consistent with the lung inflammation that occurs after 2 days of IA LPS and the lung and systemic maturation that occurs with IA LPS by 5 days.…”

“…We have previously demonstrated changes in the mRNA patterns in the PVWM of the brain of preterm lambs receiving mechanical ventilation, and these changes were partially normalized by exposure to the combination of budesonide and surfactant. 19 The combination of surfactant and budesonide also had independent effects of hundreds of genes in the brains and could lead to long-term changes in brain function. 19 Similar to the PVWM, the current report demonstrates decreased pro-inflammatory cytokine mRNA in the hippocampal and cortical tissues.…”

“…Prior to surfactant treatment and with the intention of initiating lung injury, ventilation was initiated with a Fabian ventilator (Acutronic, Switzerland) with 100% oxygen, peak inspiratory pressure (PIP) of 40 cm H 2 O, using no positive end expiratory pressure (PEEP), a rate of 50 breaths/min, and an inspiratory time of 0.5 s. 19 Tidal volume/kg was monitored and the PIP was adjusted up to a maximum of 50 cm H 2 O to achieve a target tidal volume ( V T )/kg of 12 mL/kg by 15 min. 21 After 15 min of ventilation, the animals were treated with the assigned surfactant combination and ventilated using a gentler ventilation strategy for 3 h and 45 min.…”

“…23 Two days after IA LPS at 126 + 1 days GA, ewes were anesthetized with intravenous (IV) ketamine and midazolam (5-10 and 0.25-0.5 mg/kg, respectively) and given spinal anesthesia (lignocaine 60 mg) prior to laparotomy, hysterotomy, and euthanasia. 19,20 Immediately before delivery, the lamb was given ketamine 10 mg/kg intramuscular (IM), then a 4.5-mm endotracheal tube was secured in the trachea before gentle aspiration of fetal lung fluid. The lambs were then delivered, weighed, and placed under a radiant warmer.…”

“… 18 In preterm lambs, the combination of budesonide and surfactant decreases lung inflammation from injurious and non-injurious ventilation and decreases systemic inflammatory responses in the liver and brain. 19 , 20 Although the preterm lung can form budesonide esters for prolonged release, the majority of the budesonide is released into the systemic circulation by 6 h of ventilation. 21 The systemic budesonide, also found in the human studies, may be responsible for alterations in adrenal function found in pilot studies.…”