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

ABSTRACT: 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.

SUBMITTER: Hillman NH

PROVIDER: S-EPMC6985873 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Hillman Noah H NH Kothe T Brett TB Schmidt Augusto F AF Kemp Matthew W MW Royse Emily E Fee Erin E Salomone Fabrizio F Clarke Michael W MW Musk Gabrielle C GC Jobe Alan H AH

American journal of physiology. Lung cellular and molecular physiology 20191016 1

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 pressu ...[more]

PMID: 31617728

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Project description:Preterm infants often require mechanical ventilation due to lung immaturity including reduced or abnormal surfactant. Since cyclic stretch with cycle-by-cycle variability is known to augment surfactant release by epithelial cells, we hypothesized that such in vivo mechanotransduction improves surfactant maturation and hence lung physiology in preterm subjects. We thus tested whether breath-by-breath variability in tidal volume (VT) in variable ventilation (VV) can be tuned for optimal performance in a preterm lamb model. Preterm lambs were ventilated for 3 h with conventional ventilation (CV) or two variants of VV that used a maximum VT of 1.5 (VV1) or 2.25 (VV2) times the mean VT. VT was adjusted during ventilation to a permissive pCO2 target range. Respiratory mechanics were monitored continuously using the forced oscillation technique, followed by postmortem bronchoalveolar lavage and tissue collection. Both VVs outperformed CV in blood gas parameters (pH, SaO2, cerebral O2 saturation). However, only VV2 lowered PaCO2 and had a higher specific respiratory compliance than CV. VV2 also increased surfactant protein (SP)-B release compared to VV1 and stimulated its production compared to CV. The production and release of proSP-C however, was increased with CV compared to both VVs. There was more SP-A in both VVs than CV in the lung, but VV2 downregulated SP-A in the lavage, whereas SP-D significantly increased in CV in both the lavage and lung. Compared to CV, the cytokines IL-1β, and TNFα decreased with both VVs with less inflammation during VV2. Additionally, VV2 lungs showed the most homogeneous alveolar structure and least inflammatory cell infiltration assessed by histology. CV lungs exhibited over-distension mixed with collapsed and interstitial edematous regions with occasional hemorrhage. Following VV1, some lambs had normal alveolar structure while others were similar to CV. The IgG serum proteins in the lavage, a marker of leakage, were the highest in CV. An overall combined index of performance that included physiological, biochemical and histological markers was the best in VV2 followed by VV1. Thus, VV2 outperformed VV1 by enhancing SP-B metabolism resulting in open alveolar airspaces, less leakage and inflammation and hence better respiratory mechanics.

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

Publications

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

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