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The ability to pharmacologically render patients insensible to noxious stimulation using general anesthetics and sedatives represents one of the greatest discoveries in medicine. Advanced physiological monitoring and meticulous administration of modern anesthetic drugs have facilitated surgical interventions to mitigate life-threatening conditions in very young children. Moreover, sedation during mechanical ventilation and painful procedures in intensive care units has shielded neonates from the deleterious effects of pain and suffering. Accordingly, every year, millions of young children worldwide are exposed to anesthetics and sedatives to ablate the stress response to noxious stimulation and to mitigate potential, stress-related morbidity during painful procedures and imaging studies.
However, recent findings in laboratory animals have demonstrated a widespread increase in apoptotic brain cell death, an inborn cell suicide program, immediately following exposure to all currently and commonly used sedatives and anesthetics. Moreover, several preclinical studies have also observed alterations in synaptic formation and subsequent impairment in neurocognitive function. These findings in newborn animals have led to significant concerns among pediatric anesthesiologists and parents. Given the potentially serious consequences of long-term neurological sequelae following uneventful pediatric surgery with anesthesia, our research aims to clarify the underlying mechanisms and the selectivity of anesthesia-induced neurotoxicity, which will be critical for assessing human relevance of this phenomenon, and if necessary, for aiding in the development of mitigating strategies.
Along those lines, our laboratory has previously demonstrated significant differences between anesthetic effects in young children during pediatric anesthesia and those in model species, revealing a progressive lactacidosis, hypoglycemia and lethality. Moreover, our group was able to establish that neuronal degeneration during an anesthetic exposure early in life may not be necessarily linked with subsequent neurocognitive dysfunction, which has now been confirmed by other groups. To compare the effects of the three most commonly used anesthetics, Desflurane, Isoflurane and Sevoflurane, in pediatric anesthesia, we have recently established their differential potencies and have found similar neurotoxic profiles among them.
To increase our understanding of anesthesia-induced neurotoxicity and to aid in the discovery of potentially mitigating therapies, we are currently characterizing the phenomenon’s selectivity as well as examining the underlying mechanisms. Moreover, our laboratory is working on the identification of minimally invasive biomarkers for neurotoxicity. We are also participating in several clinical research studies, including a multicenter study into the long-term neurocognitive effects of surgery with anesthesia early in life (PANDA study), as well as examining the effects of surgery with anesthesia early in life on subsequent brain morphology using noninvasive magnetic resonance imaging technology.
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A six-hour exposure to Desflurane, Isoflurane or Sevoflurane increases apoptotic cell death in neonatal mice, compared with fasted, unanesthetized littermates (no anesthesia). Representative, low-magnification photomicrographs of coronal brain sections, obtained with laser confocal microscopy, at bregma -2.46 mm, are shown, demonstrating the pattern of neuronal cell death. Brain sections from 7- to 8-day-old mouse pups were stained for the apoptotic cell death marker activated-caspase 3 (bright green) following a six-hour exposure to room air. (A) 7.4 percent Desflurane (B) 1.5 percent Isoflurane (C) 2.9 percent Sevoflurane (D) arrows mark clusters of dying neurons in neocortical layers II / III. Scale bar = 500 µm.
Neonatal Isoflurane exposure does not alter neuronal density in adulthood. Representative photomicrographs of neuronal marker NeuN expression in adulthood. Image of coronal brain section obtained with laser confocal microscope depicting part of left hemi-brain (top, scale bar=300 µm); boxes marking sampling areas for neuronal density count in retrosplenial cortex (arrow) and hippocampal CA3 region (arrowhead). High-power magnification depicting layers II / III of retrosplenial cortex (left column, scale bar=30 µm) and parts of hippocampal CA3 region (right column, scale bar=30 µm) in adult animals previously exposed as neonates to six hours of fasting without anesthesia (no anesthesia), Isoflurane (anesthesia), 1.5 percent Isoflurane with dextrose (anesthesia+D5), or 1.5 percent Isoflurane with normal saline (anesthesia+NS).
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