OPTImal vasoPRESsor in persistent pulmonary hypertension of the newborn (OPTIPRES)

PROJECT SUMMARY Perinatal asphyxia is the leading cause of mortality in term newborns globally. Persistent pulmonary hypertension of the newborn (PPHN) is reported in about a quarter of the neonates with perinatal asphyxia is often secondary to meconium aspiration syndrome (MAS) and is a significant contributor to mortality. Majority of critically ill newborn infants with asphyxia and PPHN undergo therapeutic hypothermia and have systemic hypotension requiring vasopressors. However, commonly used vasopressors in newborns have variable effects on systemic and pulmonary vascular beds. Non-selective increase vascular tone in both systemic and pulmonary circulations in response to vasopressor agents may exacerbate PPHN. However, persistently low systemic blood pressure can lead to prolongation of a right-to-left shunt and worsen hypoxemia. The ideal vasopressor that is selective to systemic circulation and increases the ratio of systemic to pulmonary vascular resistance (SVR/PVR ratio) and enhances vital organ perfusion is not known. Additionally, the vascular and cellular mechanisms of vasopressor-induced changes in systemic and pulmonary circulations, in the setting of increased pulmonary vasoconstriction from PPHN and exposure to supplemental oxygen therapy remain unknown. In this K08, I will perform a randomized trial comparing the effect of use of dopamine, norepinephrine, epinephrine and vasopressin on SVR/PVR ratio, ventricular function, and cardiac output in a perinatal term ovine model of meconium aspiration, PPHN, therapeutic hypothermia and systemic hypotension. I hypothesize that use of norepinephrine and vasopressin will selectively increase SVR resulting in higher SVR/PVR ratio compared to dopamine and epinephrine that will non-selectively increase SVR and PVR without affecting the SVR/PVR ratio. Furthermore, I will perform in-vitro vascular reactivity testing with the vasopressor agents on systemic and pulmonary arteries from control and PPHN lambs ventilated with 30% and 100% O2 respectively and investigate vasopressor receptor expression. My training goals include acquiring hands-on experience in performing bedside targeted neonatal echocardiography, attaining practical experience in testing in-vitro vascular reactivity in response to vasopressors, interpreting vasopressor receptor expression in PPHN and hyperoxia, and enhancing my knowledge of biostatistics while developing professional and leadership skills necessary for executing development, that are in line with my research aims in this K08. These four key training goals along with preliminary data generated from this K08 will prepare me in applying for an R01 to investigate optimal blood pressure management in PPHN including dose-escalation of vasopressors.