Birth asphyxia is a global issue accounting for about 23% of approximately 2.5 million neonatal deaths each year. These asphyxiated newly born infants require extensive resuscitation including chest compressions (CC) in the delivery room, and suffer from high mortality and neurologic morbidity. The optimal oxygen (O2) concentration during CC in an asphyxiated newborn is not known. The recommendation by the Neonatal Resuscitation Program (NRP) to provide 100% inspired O2 during CC is based on indirect evidence and expert opinion which has shown to cause oxidative injury. On the other hand, ventilation with 21% O2 could lead to inadequate oxygenation resulting in delayed pulmonary transition and elevated pulmonary vascular resistance (PVR) which may further extend the window of hypoxic-ischemic injury. An intermediate O2 concentration (inspired O2 of 50%) could balance these two competing processes and maintaining homeostasis after severe hypoxic-ischemic injury in cardiac arrest. In this proposal we plan to determine the optimal inspired O2 (21%, 50% or 100%) during CC using a randomized, masked study that optimizes oxygen delivery to the brain and heart leading to early return of spontaneous circulation with minimal oxidative stress in perinatal lambs with perinatal asphyxia-induced cardiac arrest. To accomplish this 21 term fetal lambs will be asphyxiated by umbilical cord occlusion resulting in cardiac arrest. Lambs will be randomized to 3 groups: Inspired oxygen of 21%, 50% and 100% during CC and rest of the resuscitation steps will follow the NRP guidelines. Blood gases and hemodynamic parameters will be continuously monitored. Lambs will be resuscitated for 20 minutes or till the ROSC is achieved, whichever is earlier. At the end of 20 minutes, lambs will be euthanized and tissues will be collected for oxidative stress markers. In this way, we can compare physiologic changes and the resultant oxidative stress markers to better understand what may be happening during the resuscitation of an asphyxiated human newborn. Relevance to current practice in neonatal resuscitation: Despite a lack of scientific evidence, supplemental oxygen has been used in neonatal resuscitation for more than 200 years. There is a growing demand to resolve the controversy on oxygen therapy during resuscitation of term asphyxiated infants in cardiac arrest. The studies proposed in this application are likely to provide physiologic and biochemical data to aid in determining the optimal inspired oxygen during CC and eventually refine neonatal resuscitation guidelines and may reduce the burden of birth complications.
Each year approximately one million neonates die to birth asphyxia and those who survive the extensive cardio-pulmonary resuscitation suffer severe neuro-developmental morbidity. Our proposal will be the first blinded randomized control study of neonatal resuscitation evaluating optimal inspired oxygen during chest compressions conducted in a perinatal lamb model of asphyxia induced by umbilical cord occlusion. These critical data are necessary to help guide clinical care of asphyxiated infants around the world that could significantly reduce the mortality and the burden of birth complications.
