Local Version of the Multi-center PREVENT Study Evaluating Cardio-respiratory Instability in Premature Infants

The broad long-term objective is to use comprehensive state-of-the high-fidelity monitoring
to investigate physiological biomarkers of autonomic neurorespiratory maturation with
integrated analysis of autonomic nervous system (ANS) responses in preterm infants, and to
evaluate their role in ventilatory instability, bronchopulmonary dysplasia (BPD), and
co-morbidities including neurodevelopment in the 1st year of life. Aim 1 will establish the
spectrum and developmental trajectory of ANS maturation/function using high-resolution
physiologic recordings of ventilatory, cardiovascular, and cerebrovascular measures during
typical daily activity (28, 32 and 36 wks gestational age (GA)(23-hour recordings); 3 and 12
mos corrected age (CA)(4-hour recordings)) and physiologic response testing (brief hyperoxic
and hypercarbic testing) to evaluate peripheral and central chemoreceptors responses and
maturation and to evaluate latent autonomic and respiratory instability (32 and 36 wks; 3 and
12 mos). Aim 1 tests the hypothesis that individual and integrated metrics of ANS function
will demonstrate maturational patterns that impart resilience or vulnerability to
environmental and exogenous challenges. Aim 2 will determine respiratory and
neurodevelopmental morbidity throughout the 1st year of life using clinically applicable
outcome measures and associate morbidity with ANS development and function using a
Respiratory Morbidity Severity Score, need for respiratory support, medications, or
hospitalization, Bayley Scales of Infant Development III (6, 12 mos), Neurological, Sensory,
Motor, Developmental Assessment (3, 6, 12 mos), and early measures of evoked-auditory
potentials (EAP) and General Movement Assessments (GMA)(28, 32, 36 wks; 3 months). Aim 2
tests the hypothesis that infants demonstrating delayed ANS maturation or vulnerability to
endogenous or exogenous challenges will require more respiratory interventions and will
demonstrate developmental delays in the 1st year of life. Aim 3 will determine endotypes of
autonomic neurorespiratory stability and maturation through trajectory analysis and
integrated physiological modeling. Aim 3 tests the hypothesis that trajectory analysis will
reveal 3 autonomic maturation patterns ("normal" maturation with ability to withstand
environmental perturbations; "normal" maturation without ability to withstand environmental
perturbations; delayed or disordered maturation with inability to maintain physiologic
stability in absence of environmental perturbations) that will be associated with severity of
respiratory morbidity and neuromotor impairment at 1 yr. In addition to lung-independent
mechanisms of respiratory dysfunction, this study aims to investigate lung-independent
mechanisms pulmonary hypertension (PH) in premature babies. Typically thought to be a
secondary effect of primary lung structural development and/or hypoxia, up to 40% of infants
with chronic respiratory dysfunction develop pulmonary hypertension (PH) and increased risk
for mortality. However, the investigators and others found that 10-30% of premature infants
who develop PH did not have clinical evidence of respiratory dysfunction, suggesting
pulmonary vascular mechanisms that are independent of clinically apparent respiratory
disease. Multiple molecular mechanisms are postulated by which hypoxia results in PH, but
preliminary data suggest a role for Fibroblast Growth Factor 2 (FGF2) and Granulocyte-Colony
Stimulating Factor (G-CSF) signaling in the development of pulmonary vascular remodeling in
PH. Thus, by serially using sensitive echocardiographic measures of Right
Ventricular-Pulmonary Circulation (RV-PC) coupling, the investigators can quantify hypoxic
exposure and RV-PC axis dysfunction and the investigators will couple these clinical
measurements with mechanistic studies of FGF2 signaling. The investigators hypothesize that
recurrent hypoxic exposure of dysmature pulmonary vasculature in premature newborns results
in RV-PC axis dysfunction and pulmonary hypertension that is mediated by FGF2 and G-CSF
independent of clinically apparent lung disease.

Inclusion Criteria:

- birth between 24 and 29 weeks of gestation

- less that 1 week of age

Exclusion Criteria:

- known congenital anomalies

- imminent death

- factors that preclude reliable follow-up