Neurotoxicology and teratology
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The majority of commonly used anesthetic agents induce widespread neuronal degeneration in the developing mammalian brain. Downstream, the process appears to involve activation of the oxidative stress-associated mitochondrial apoptosis pathway. Targeting this pathway could result in prevention of anesthetic toxicity in the immature brain. ⋯ In recent work, low concentration CO exposures limited isoflurane-induced neuronal apoptosis in a dose-dependent manner in newborn mice and modulated oxidative stress within forebrain mitochondria. Because infants and children are routinely exposed to low levels of CO during low-flow general endotracheal anesthesia, such anti-oxidant and pro-survival cellular effects are clinically relevant. Here we provide an overview of anesthesia-related CO exposure, discuss the biological activity of low concentration CO, detail the effects of CO in the brain during development, and provide evidence for CO-mediated inhibition of anesthesia-induced neurotoxicity.
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Neurotoxicol Teratol · Mar 2017
ReviewDo anesthetics harm the developing human brain? An integrative analysis of animal and human studies.
Anesthetics that permit surgical procedures and stressful interventions have been found to cause structural brain abnormalities and functional impairment in immature animals, generating extensive concerns among clinicians, parents, and government regulators regarding the safe use of these drugs in young children. Critically important questions remain, such as the exact age at which the developing brain is most vulnerable to the effects of anesthetic exposure, whether a particular age exists beyond which anesthetics are devoid of long-term effects on the brain, and whether any specific exposure duration exists that does not lead to deleterious effects. Accordingly, the present analysis attempts to put the growing body of animal studies, which we identified to include >440 laboratory studies to date, into a translational context, by integrating the preclinical data on brain structure and function with clinical results attained from human neurocognitive studies, which currently exceed 30 studies. ⋯ Animal data did not clearly identify a specific age beyond which anesthetic exposure did not cause any structural or functional abnormalities. Several potential mitigating strategies were found, however, no general anesthetic was identified that consistently lacked neurodegenerative properties and could be recommended over other anesthetics. It therefore is imperative, to expand efforts to devise safer anesthetic techniques and mitigating strategies, even before long-term alterations in brain development are unequivocally confirmed to occur in millions of young children undergoing anesthesia every year.
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Neurotoxicol Teratol · Mar 2017
ReviewNeuroprotection and neurotoxicity in the developing brain: an update on the effects of dexmedetomidine and xenon.
Growing and consistent preclinical evidence, combined with early clinical epidemiological observations, suggest potentially neurotoxic effects of commonly used anesthetic agents in the developing brain. This has prompted the FDA to issue a safety warning for all sedatives and anesthetics approved for use in children under three years of age. ⋯ Although results from recent clinical trials and case reports have indicated the neuroprotective potential of xenon and dexmedetomidine, additional randomized clinical trials corroborating these studies are necessary. By reviewing both the existing preclinical and clinical evidence on the neuroprotective effects of dexmedetomidine and xenon, we hope to provide insight into the potential clinical efficacy of these agents in the management of pediatric surgical patients.
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Neurotoxicol Teratol · Mar 2017
ReviewA holistic approach to anesthesia-induced neurotoxicity and its implications for future mechanistic studies.
The year 2016 marked the 15th anniversary since anesthesia-induced developmental neurotoxicity and its resulting cognitive dysfunction were first described. Since that time, multiple scientific studies have supported these original findings and investigated possible mechanisms behind anesthesia-induced neurotoxicity. ⋯ Sections are divided into key stages in early neural development; apoptosis, neurogenesis, migration, differentiation, synaptogenesis, gliogenesis, myelination and blood brain barrier/cerebrovasculature. In addition, the authors combine the established literature in the field of anesthesia-induced neurotoxicity with literature from other related scientific fields to speculate on the potential role of non-neuronal cells and to generate new future hypotheses for understanding anesthetic toxicity and its application to the practice of pediatric anesthesia.
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The mechanism by which anesthetics might act on the developing brain in order to cause long term deficits remains incompletely understood. The hippocampus has been identified as a structure that is likely to be involved, as rodent models show numerous deficits in behavioral tasks of learning that are hippocampal-dependent. The hippocampus is an unusual structure in that it is the site of large amounts of neurogenesis postnatally, particularly in the first year of life in humans, and these newly generated neurons are critical to the function of this structure. ⋯ In this review, we examine the evidence for anesthetic effects on neurogenesis in the early postnatal period and ask whether neurogenesis should be studied further as a putative mechanism of injury. Multiple anesthetics are considered, and both in vivo and in vitro work is presented. While there is abundant evidence that anesthetics act to suppress neurogenesis at several different phases, evidence of a causal link between these effects and any change in learning behavior remains elusive.