Emerging evidence has led to questions about the safety of anesthetic agents used in routine clinical practice, especially with regard to the use of general anesthesia in infancy. A wealth of data shows neuronal demise in response to general anesthesia in the very young brain of rodents and non-human primates. Thus far, parallel evidence in humans has been limited to retrospective studies correlating repetitive anesthesia exposures during early childhood. These studies have documented learning difficulties later in life as well as abnormal behavior and psychosocial issues. There is an urgent need to establish whether or not exposure to general anesthesia in the very young human brain interferes with normal brain development. We propose to implement a clinically relevant, non-invasive imaging technology - proton magnetic resonance spectroscopy (1HMRS) - that has the ability to track apoptosis, neurodegeneration, inflammation and metabolic status in the young brain, and use this approach in combination with traditional behavioral and histological techniques to provide a direct linkage between anesthesia exposure, brain defects and long-term behavioral effects. The proposed studies are based on our novel preliminary findings that very young rodents exposed to sevoflurane anesthesia on post-natal day 7 show 1) abnormalities in brain maturation determined by changes in the neuronal marker N-acetyl-aspartate (NAA), 2) inflammatory changes including reactive gliosis and changes in levels of choline metabolites, and 3) that these metabolite changes tracked non-invasively by 1HMRS are associated with increased apoptosis. Specifically, we propose an innovative hypothesis that metabolic profiling by 1HMRS can gauge anesthesia-induced neurotoxicity in the young brain over time. We further seek to establish whether repeated exposures to inhalational anesthetics (sevoflurane) at the time of peak synaptogenesis in the developing rodent brain result in severe cerebral metabolic defects including impediment of brain maturation reflected by age-dependent changes in the concentration of [NAA] and long-lasting reactive gliosis reflected by changes in choline and/or myo-inositol.
The specific aims are: 1) to evaluate metabolic profiles in the neonatal brain in 13, 20 and 90 day old rat pups with single or repetitive exposure to sevoflurane compared to non- exposed age-matched rat pups evaluated at the same time points, and 2) to evaluate whether cerebral metabolic defects impair cognitive functions and trigger neuronal loss and long-lasting activation of astrocytes and microglia after a single or repetitive exposure to sevoflurane at the time of peak synaptogenesis. Behavioral data in the neonatal rats exposed to single or repetitive sevoflurane anesthesia in Aim 1 will be collected at 30 to 80 days, to document the effect of neonatal sevoflurane exposure on complex brain function. The same rats will be evaluated for neuronal loss and reactive astro- and microgliosis at 3 months and compared to non-exposed rats. To our knowledge the proposed studies constitute the first attempt to develop a clinically relevant diagnostic test to assess anesthesia induced neurotoxicity in the young brain.

Public Health Relevance

Recent evidence has led to questions about the safety of routinely used anesthetic agents, particularly on infants and young children, and even more specifically when the young brain experiences repeated exposures to anesthesia. Research has been hampered by the lack of clinically relevant diagnostic tests for the assessment of anesthesia-induced toxicity in the developing brain. We propose to use minimally- invasive proton magnetic resonance spectroscopy (1HMRS) in concert with traditional behavioral and histological techniques to determine the possible linkage between anesthesia exposures, brain defects and long-term behavioral changes.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Raju, Tonse N
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State University New York Stony Brook
Schools of Medicine
Stony Brook
United States
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Benveniste, Helene; Dienel, Gerald; Jacob, Zvi et al. (2018) Trajectories of Brain Lactate and Re-visited Oxygen-Glucose Index Calculations Do Not Support Elevated Non-oxidative Metabolism of Glucose Across Childhood. Front Neurosci 12:631
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Benveniste, Helene; Makaryus, Rany (2016) Are We Moving Closer to Noninvasive Imaging and Monitoring of Neonatal Anesthesia-induced Neurotoxicity? Anesthesiology 125:22-4
Makaryus, Rany; Lee, Hedok; Feng, Tian et al. (2015) Brain maturation in neonatal rodents is impeded by sevoflurane anesthesia. Anesthesiology 123:557-68
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