Impact of Prolonged Perioperative Sedation on Infant Brain

ABSTRACT
Prolonged sedation treatment is currently considered standard practice in the safe and compassionate care of
critically ill neonates and infants despite leading to opioid tolerance and a high incidence (35-57%) of physical
dependence. A unique cohort of infants with congenital long-gap esophageal atresia (EA) undergoes complex
perioperative critical care necessitating extraordinarily prolonged sedation (on the scale of weeks). Although our
group recently reported decreased brain size and delayed brain growth in term-born infants following long-gap
EA repair with prolonged postoperative sedation, there is a fundamental gap in our knowledge of (i) underlying
mechanisms and (ii) long-term neurodevelopmental outcomes.
Guided by strong preliminary data, this proposal will address 3 key gaps in our knowledge: (1) timing of brain
findings (pre vs. during perioperative repair); (2) regional specificity (gray vs. white matter) of (mal)adaptations;
as well as (3) infant brain and clinical correlates to early neurodevelopmental outcomes at 1-year of age. The
study will employ structural MRI techniques to address these aims. Selected term-born and premature infants
with short-gap (brief pain/sedation treatment) and long-gap EA (prolonged sedation treatment) will be scanned
twice (AIM 1): before (as neonates), and after complex perioperative critical care (at 4(±1) months of age). Early
neurodevelopmental outcomes will be evaluated using standard approaches (AIM 2).
The findings will inform (I) mechanisms of brain (mal)adaptations associated with delayed vs. abnormal brain
development in infants exposed to prolonged sedation; (II) identify early diagnostic and prognostic indicators for
longitudinal neurocognitive correlates; and (III) inform future development of neonatal/infant therapies to mitigate
the neurological effects in vulnerable infants exposed to prolonged sedation. Our application aligns with the goals
of the National Institute of Child Health and Human Development (NICHD) and National Institute of Drug Abuse
(NIDA) to improve the lives of children throughout all stages of development. We established the feasibility
serving critical data collection, and we assembled an interdisciplinary team of experts for its successful
completion. This research is innovative in that it encompasses a selected group of term-born infants exposed
to prolonged sedation associated with dependence to drugs of sedation; novel in that it will investigate underlying
mechanisms and neurodevelopmental impact of complex thoracic non-cardiac critical care; and significant in
that it is expected to evolve pediatric critical care by developing novel adjunct therapies for age-specific pain and
sedation treatment in the United States and the world.

Grant Number: 5R21DA058072-02
NIH Institute/Center: NIH
Principal Investigator: DUSICA BAJIC