In the 2010 guidelines for newborn resuscitation, the International Liaison Committee on Resuscitation (ILCOR) identified gaps in knowledge, for both preterm and term infants. The gaps are the optimal maneuvers to inflate and ventilate the lungs at birth. The initiation of ventilation at birth is unique because the fetal lung must transition rapidly from fluid filled airspaces to a gas exchange, and ventilation with positive pressure at birth causes airway epithelial injury which progresses to diffuse lung inflammation. Although the lung injury is initiated with ventilation at birth, it takes time for markers of injury to develop.To overcome the confounding effects of continued ventilation, we developed a fetal sheep model of newborn resuscitation that maintains placental circulation, thus allowing us to isolate and evaluate resuscitation maneuvers designed to reduce lung injury during the transition to air breathing at birth. These maneuvers are difficult to evaluate in the clinical setting because of th necessities to resuscitate without focusing on single components of the procedure, the great variability in the clinical status of infants, and the need to continue support beyond the specific intervention. Clinicians routinely introduce new treatments, such as a sustained inflation, into newborn care without knowledge of benefits or potential for injury. The goal of this grant is to identify the safe and useful recruitment maneuvers for newborn resuscitation in preterm and near-term lambs, evaluations that cannot be easily assessed clinically. We will measure early response gene expression that activates inflammatory pathways and the location of expression of the inflammation within the lungs of preterm and term lambs. We also will test whether the severity of lung injury is dependent on gestational age (GA), and whether different acute phase injury pathways are activated during initiation of ventilation of very preterm, moderately preterm and term lungs. We will also validate protective strategies and potential therapeutic pathways in preterm newborn lambs ventilated for 4 and 24 hours. By combining a reproducible lamb model of resuscitation with advanced molecular techniques, we will determine: 1) which lung gas volume recruitment maneuvers will minimize injury, 2) how lung injury from resuscitation maneuvers differs based on the developmental stage of the lungs, and 3) if an optimum initiation of ventilation will result in decreased amplification of lung injury with continued ventilation. These innovative studies will define the molecular and physiologic responses to recruitment maneuvers in preterm and near-term lambs, resulting in new insights into how injurious pathways progress to acute and chronic lung disease. The results also will allow us to identify potential treatment targets and biomarkers for the field. These studies will provide a scientific basis for ILCOR recommendations for clinical practices that are very difficult to verify by clinical trials.

Public Health Relevance

Although approximately 10% of all newborns and the majority of very low birth weight preterm infants need some assistance to breathe at birth, the optimal maneuvers to inflate and ventilate the lungs have not been defined. It is easy to injure the preterm lung at birth and mechanical ventilation contributes to the long term disability in very preterm infants. These studies will determine beneficial lung recruitment maneuvers for both term and preterm infants, and advance our knowledge on inflammatory pathways activated by ventilation at birth.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Raju, Tonse N
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Kothe, T Brett; Royse, Emily; Kemp, Matthew W et al. (2018) Epidermal growth factor receptor inhibition with Gefitinib does not alter lung responses to mechanical ventilation in fetal, preterm lambs. PLoS One 13:e0200713
Deptula, Nicole; Royse, Emily; Kemp, Matthew W et al. (2016) Brief mechanical ventilation causes differential epithelial repair along the airways of fetal, preterm lambs. Am J Physiol Lung Cell Mol Physiol 311:L412-20
Tingay, David G; Polglase, Graeme R; Bhatia, Risha et al. (2015) Pressure-limited sustained inflation vs. gradual tidal inflations for resuscitation in preterm lambs. J Appl Physiol (1985) 118:890-7
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Hillman, Noah H; Kemp, Matthew W; Miura, Yuichiro et al. (2014) Sustained inflation at birth did not alter lung injury from mechanical ventilation in surfactant-treated fetal lambs. PLoS One 9:e113473
Hillman, Noah H; Gisslen, Tate; Polglase, Graeme R et al. (2014) Ventilation-induced increases in EGFR ligand mRNA are not altered by intra-amniotic LPS or ureaplasma in preterm lambs. PLoS One 9:e96087
Polglase, Graeme R; Tingay, David G; Bhatia, Risha et al. (2014) Pressure- versus volume-limited sustained inflations at resuscitation of premature newborn lambs. BMC Pediatr 14:43
Hillman, Noah H; Kemp, Matthew W; Noble, Peter B et al. (2013) Sustained inflation at birth did not protect preterm fetal sheep from lung injury. Am J Physiol Lung Cell Mol Physiol 305:L446-53
Jobe, Alan H (2012) Effects of chorioamnionitis on the fetal lung. Clin Perinatol 39:441-57
Hillman, Noah H; Moss, Timothy J; Nitsos, Ilias et al. (2012) Moderate tidal volumes and oxygen exposure during initiation of ventilation in preterm fetal sheep. Pediatr Res 72:593-9

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