Brain injury in the premature infant has become the leading known cause of cerebral palsy, and thus is a public health issue of major proportions. Cerebrovascular insults are the principal cause of brain injury and long-term neurodevelopmental morbidity in survivors of prematurity. These injuries result from immature hemodynamic control that predisposes to unstable systemic blood pressure (BP) and loss of cerebral autoregulation. In the preterm infant, this combination results in a pressure-passive cerebral circulation, the pivotal mechanism underlying both hemorrhagic and hypoxic ischemic brain injury. The lack of a continuous bedside technique that reliably identifies cerebral pressure-passivity has impeded the formulation of rational strategies to prevent these injuries. The overall aim of this study is to characterize the systemic and cerebral hemodynamic antecedents of germinal matrix-intraventricular hemorrhage (GM-IVH), the principal form of hemorrhagic injury in the preterm. We focus on GM-IVH because its onset is readily detectable by bedside ultrasound (US), allowing more accurate association with preceding hemodynamic patterns. In infants born before 32 weeks gestation, we will compare continuous BP changes with changes in the cerebral HbD signal (oxy- minus deoxyhemoglobin) measured by near-infrared spectroscopy (NIRS). We will perform 4-hourly cranial US studies (using a portable device) to identify the onset of GM-IVH. In specific aim 1 we will examine the relationship between time-locked cerebral and systemic hemodynamic changes, using frequency-domain coherence and transfer function analysis, to identify periods of pressure-passivity. Specifically, we will derive quantitative indices of cerebral pressure autoregulation (pressure passive index) and systemic blood pressure (mean, variability, hypo-/hypertensive indices) and its control (baroreceptor reflex). We will compare these quantitative indices between infants who develop GM-IVH and age-matched control infants without GM-IVH. In specific aim 2 we will seek to define the features of systemic BP that predispose to a pressure-passive cerebral circulation. In Specific Aim 3 we will aim to identify the baroreceptor dysfunction that leads to unstable patterns of systemic BP. Insights gained and techniques developed during the proposed research will facilitate the development of a much-needed cerebrovascular monitoring device, and ultimately to rational brain-oriented management of the critically-ill infant.
