CHRI sis at the NICU: The Medley with Midazolam

Approximately 1.5 million neonates undergo anesthesia for surgical procedures in the United States every year1. Midazolam is a commonly used anesthetic agent used in the Neonatal Intensive Care Unit (NICU). It is used to sedate neonates and facilitates complex procedures such as mechanical ventilation.2 The extensive use of midazolam has raised questions about whether it affects the cognitive development of infants. In 2014, the International Anesthesia Research Society released a statement saying, “Surgeries and procedures requiring anesthetic and sedative drugs that could reasonably be delayed should possibly be postponed because of the potential risk to the developing brain of infants, toddlers, and preschool children”. 3 Although some evidence shows that midazolam exposure could harm an infant’s cognitive development, little is known about what parts of the developing brain are directly affected by midazolam. Additionally, research has yet to uncover whether the effects of midazolam persist into adulthood. In order to examine the consequences of midazolam exposure, a holistic system biology approach should be implemented. Experimental data from four different levels ─ the molecular level, the physical trait level, the behavioral level, and “omics” level would help address these issues. Our objective is to investigate how prolonged exposure to midazolam affects cellular as well as behavioral functions. A rodent model was implemented to study the effects at infanthood, adolescence, and adulthood. Our molecular results revealed that midazolam could potentially cause disturbances in key brain protein levels. Additionally, midazolam could potentially contribute to social deficits as evidenced by behavioral results. Overall, the results all point to midazolam\u27s potential to delay proper neurodevelopment.https://digitalcommons.unmc.edu/surp2021/1028/thumbnail.jp

Crisis in the NICU and the Medley with Midazolam

Epidemiologic studies of human patients have revealed a correlation between childhood exposure to general anesthetic and sedative agents and subsequent cognitive deficits. This association is supported by data from animal models, which shows that developmental exposure to both anesthetics and sedatives causes lasting impairments in learning. This study focused on midazolam (MDZ), a common benzodiazepine regularly used as a sedative agent on neonates in the Neonatal Intensive Care Unit (NICU). However, a knowledge gap that remains is how long-term exposure to MDZ during very early stages of life impacts synaptic alterations and neurobiological mechanisms. Elucidation of these mechanisms is of high clinical importance and may develop neuroprotective therapeutic strategies for optimizing outcomes for uniquely vulnerable NICU populations. Using a preclinical rodent model system, we mimicked a dose-escalation regimen from postnatal day 3 (P3) pups until P21 to comprehensively characterize how early-life exposure to MDZ impacts neurodevelopment outcomes at different tiers ─ phenotypic, molecular, behavioral, and high throughput- “omics” levels. Our data demonstrated that repetitive exposure to MDZ at an early age stunts neurodevelopment during the early stages of life disrupts the blood-brain barrier, and alters the synaptic components and neurochemistry, which may be indicative of behavioral deficits at later development. Additionally, our bioinformatics analysis from purified synaptosome identified enrichment of proteins associated with actin-binding and protein depolymerization process. One potential hit identified was alpha adducin (ADD1), belonging to the family of cytoskeleton proteins, upregulated in the MDZ group and whose expression was further validated by western blot. Our study has provided a comprehensive characterization of MDZ effects on development at multiple tiers yielding novel insights on how long-term exposure to MDZ impacts development. Notably, the identification of ADD1 as a potential target and further characterization of its downstream mechanisms can give additional insights into its role as a potential therapeutic for treating neurodevelopmental alterations associated with long-term MDZ use in neonates.https://digitalcommons.unmc.edu/chri_forum/1056/thumbnail.jp