Moderate tidal volumes and oxygen exposure during initiation of ventilation in preterm fetal sheep

Abstract

Background Preterm infants often receive mechanical ventilation and oxygen at birth. Exposure to large tidal volumes (VT) at birth causes lung inflammation and oxygen may amplify the injury. We hypothesized that normal VT ventilation at birth causes lung injury that is exacerbated by 95% oxygen. Methods The head and chest of anesthetized preterm fetal sheep (129±1d gestation) were surgically exteriorized while maintaining the placental circulation. Fetuses were randomized to four groups with either: 1) VT ventilation to 6 mL/kg or 2) CPAP of 5 cm H2O, and either: a) 95%O2/5%CO2 or b) 95%N2/5%CO2. Age-matched fetuses were controls. After a 15-minute intervention, the fetal lamb was returned to the uterus for 1 h 45 min. Results In ventilated lambs, VT was 6.2±0.4 mL/kg at 15 min. Ventilation increased pro-inflammatory cytokines compared to control and CPAP only lambs, with recruitment of primarily monocytes to bronchioalveolar lavage fluid. Early response protein 1 was activated around the bronchioles in VT ventilated animals. The 15-min oxygen exposure did not change inflammatory mediators or other markers of lung and oxidative stress. Conclusions A VT of 6–7 mL/kg at birth increased early markers of injury and lung inflammation. Brief exposure to 95% oxygen did not alter lung inflammation.

Sustained inflation at birth did not protect preterm fetal sheep from lung injury

“…The initiation of ventilation at birth, even with V T similar to those achieved in spontaneously breathing sheep, is injurious, and this injury is likely due to shear force injury to the epithelium and from repetitive opening of distal airspaces in the fluid-filled, surfactant-deficient lung (10,13). We used a preterm fetal sheep model to test the hypothesis that a SI to recruit FRC would decrease lung injury from subsequent ventilation at birth.…”

“…18S primers (Applied Biosystems) were used for the internal loading control. Tissues from age-matched unventilated controls (UVC) from previous experiments were used as additional controls (13,32), and results are reported as fold increase over mean for the unventilated animals.…”

“…cDNA was produced from 1 mg mRNA using the Verso cDNA kit (Thermoscientific). We used custom Taqman gene primers (Applied Biosystems) for ovine sequences for IL-1␤, IL-6, IL-8, monocyte chemotactic protein-1 (MCP-1), early growth response protein 1 (Egr-1), nuclear receptor family 77 (Nur77), cysteine rich 61 (Cyr61), and connective tissue growth factor (CTGF) (13,14). Quantitative RT-PCR was performed with 5 ng cDNA using Taqman Master mix in a 20-l reaction on a 7300 RT-PCR machine and software (Applied Biosystems).…”

“…However, even ventilation at birth with a V T similar to spontaneous breathing lambs causes an inflammation in the lungs of preterm sheep (13). MV at birth leads to the release of stored acute-phase proteins in lung fluid and activation of mRNA for inflammatory mediators within the lung parenchyma (13,14). The combination of surfactant deficiency and increased lung fluid in the airways leads to increased sheer force injury to the airways during the initiation of ventilation at birth in preterm lambs (10).…”

“…However, even ventilation at birth with a V T similar to spontaneous breathing lambs causes an inflammation in the lungs of preterm sheep (13). MV at birth leads to the release of stored acute-phase proteins in lung fluid and activation of mRNA for inflammatory mediators within the lung parenchyma (13,14).…”