The American Heart Association recently released guidelines recommending the use of 21% oxygen during initial resuscitation of term newborn infants and use of blended supplemental oxygen to maintain target saturations in premature infants. The American Academy of Pediatrics recommends maintaining PaO2 between 50 and 80 mmHg in the management of sick neonates. These recommendations are based on studies using oxygen saturations in human infants and through translational studies in neonatal animal models without lung disease. Optimal oxygen concentration and target oxygen saturation range during resuscitation and ventilation of preterm and term neonates with lung injury/disease from a standpoint of tissue oxygen delivery and oxygen toxicity is not known. The overall goal of oxygen therapy is to provide adequate oxygen to meet tissue demand without risking oxygen toxicity. The overarching aim of this proposal is to determine the optimal concentration of inspired oxygen during resuscitation and ventilation of a newborn lamb with parenchymal lung disease/ lung injury. Two patterns of neonatal lung injury will be studied in this proposal. In ter lambs injury will be induced by aspiration of meconium during gasping respirations induced as a consequence of umbilical cord occlusion and asphyxia (""""""""asphyxia-MAS"""""""" group). Preterm lambs delivered at 126d gestation (term ~ 145d) have parenchymal lung injury as a consequence of surfactant deficiency and respiratory distress syndrome (""""""""preterm-RDS"""""""" group). Lambs will be resuscitated and ventilated with 21% oxygen, 100% oxygen or adjusted inspired oxygen concentration to maintain oxygen saturations between 85 to 89%, 90 to 94% or 95 to 99%. The first specific aim of this proposal is to determine the effect inspired oxygen concentration and saturations on oxygenation, lung oxygen uptake and oxygen delivery to the tissues. The second specific aim is to evaluate the effect of oxygen concentration and saturations on pulmonary, cerebral, coronary and ductal hemodynamics and assess delivery of oxygen to various vital organs. We intend to evaluate the risk of oxidant injury in the lung and brain associated with various levels of oxygen through our last specific aim.

Public Health Relevance

Oxygen supplementation during resuscitation and subsequent ventilation of newborn infants with lung disease is a delicate balance between providing adequate tissue oxygen delivery and formation of free radicals that overwhelm their deficient antioxidant defense system. The recently published SUPPORT trial report has heightened concern about lack of specific physiological knowledge regarding oxygen supplementation, delivery and toxicity in newborn infants. Data obtained from this grant will provide physiological data and aid in establishment of future guidelines for optimal oxygen delivery in preterm and term neonates with lung disease.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Special Emphasis Panel (ZRG1)
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Raju, Tonse N
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State University of New York at Buffalo
Schools of Medicine
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Lakshminrusimha, Satyan; Shankaran, Seetha; Laptook, Abbot et al. (2018) Pulmonary Hypertension Associated with Hypoxic-Ischemic Encephalopathy-Antecedent Characteristics and Comorbidities. J Pediatr 196:45-51.e3
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