Treatment of prematurity remains an unsolved problem and a top public health priority. There are nearly 500,000 premature births each year and more infants die of preterm-related problems than from any other single cause. Although many of these babies recover with conventional management, the mortality and morbidity of extremely low gestational age newborns (ELGANs, defined as <28 weeks estimated gestational age) is extremely high, with less than 50% surviving without disability. Many of these complications are caused, in part, by our attempts to ventilate the immature lungs and reverse fetal circulation. Although incremental progress has been made in treating premature infants with surfactant and less invasive ventilation strategies, effective treatment options remain an unsolved problem. A major paradigm shift in the post-natal treatment of prematurity would be to simulate the intrauterine environment with a specially designed extracorporeal gas exchange system which maintains fetal circulation and allows growth and development without air breathing; we call this technology the Artificial Placenta (AP). Our long term goal is the clinical application of the AP to improve survival and reduce morbidity in ELGANs. We have developed fetal lamb models which correspond to various stages of prematurity in humans. We initially developed the AP in fetal lambs of 130 day gestation (corresponding to 29 weeks human gestation; saccular stage of lung development) with recovery to air breathing. More recent preliminary data demonstrate the feasibility of providing complete extracorporeal support for one week in a 110 day sheep model (equivalent to a 22 week gestation human fetus; canalicular stage of lung development) with hemodynamic stability, excellent gas exchange, normally developing alveolarization, stable cerebral perfusion and maintenance of fetal circulation, all without mechanical ventilation. The goal of this research proposal is to evaluate and refine this system of intrauterine simulation to support fetal lambs from extreme prematurity, at the canalicular stage of lung development, to viable extra-uterine neonatal physiology. To accomplish this goal, the specific aims of this proposal are: 1. to evaluate fetal circulation, hemodynamics, and lung development under variable conditions of airway management and controlled fetal/newborn circulation in the 118 day lamb model. 2. To evaluate brain and systemic bleeding and embolism during AP without heparin and assess cerebral perfusion, function, development, and white matter injury. 3. To maintain the simulated intrauterine environment using the artificial placenta until lung development and circulation can support air breathing, including addressing potential problems with long-term support (infection, nutrition, gastrointestinal function, and metabolic issues).
Effective treatment of extremely premature infants remains an unsolved problem and a top public health priority. We propose developing a mechanical artificial placenta that would allow a premature infant to grow and thrive while avoiding the many complications associated with conventional treatment. Development of an artificial placenta would revolutionize the care of premature infants.
