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Anesthesia-induced developmental neurotoxicity

Jennifer L Walters, Merle G Paule
Thousands of infants and children undergo complicated surgical procedures that require prolonged periods of anesthesia and/or sedation each year. A growing body of preclinical research suggests pediatric anesthetics are harmful to the developing brain; yet, the extent to which these effects generalize to the clinical setting remains unclear. As there will be a continuing need for surgical and other interventions requiring sedation and/or anesthesia during the neonatal period, it seems clear that research efforts should focus on determining the extent to which general anesthetics can affect the developing brain as well as determining strategies for preventing or ameliorating the adverse effects associated with exposure to such agents...
November 18, 2016: Neurotoxicology and Teratology
X Zhang, F Liu, W Slikker, C Wang, M G Paule
The association of general anesthesia with developmental neurotoxicity, while nearly impossible to study in pediatric populations, is clearly demonstrable in a variety of animal models from rodents to nonhuman primates. Nearly all general anesthetics tested have been shown to cause abnormal brain cell death in animals when administered during periods of rapid brain growth. The ability to repeatedly assess in the same subjects adverse effects induced by general anesthetics provides significant power to address the time course of important events associated with exposures...
October 23, 2016: Neurotoxicology and Teratology
Zeljko J Bosnjak, Sarah Logan, Yanan Liu, Xiaowen Bai
Mounting evidence has demonstrated that general anesthetics could induce developmental neurotoxicity, including acute widespread neuronal cell death, followed by long-term memory and learning abnormalities. Propofol is a commonly used intravenous anesthetic agent for the induction and maintenance of anesthesia and procedural and critical care sedation in children. Compared with other anesthetic drugs, little information is available on its potential contributions to neurotoxicity. Growing evidence from multiple experimental models showed a similar neurotoxic effect of propofol as observed in other anesthetic drugs, raising serious concerns regarding pediatric propofol anesthesia...
November 2016: Anesthesia and Analgesia
Catherine E Creeley
The fetal and neonatal periods are critical and sensitive periods for neurodevelopment, and involve rapid brain growth in addition to natural programmed cell death (i.e., apoptosis) and synaptic pruning. Apoptosis is an important process for neurodevelopment, preventing redundant, faulty, or unused neurons from cluttering the developing brain. However, animal studies have shown massive neuronal cell death by apoptosis can also be caused by exposure to several classes of drugs, namely gamma-aminobutyric acid (GABA) agonists and N-methyl-d-aspartate (NMDA) antagonists that are commonly used in pediatric anesthesia...
August 16, 2016: Brain Sciences
Vesna Jevtovic-Todorovic
Over a decade ago, alarming findings were reported that exposure of the very young and very old animals to clinically used general anesthetics could be detrimental to their brains. The evidence presented suggested that the exposure to commonly used gaseous and intravenous general anesthetics induces the biochemical and morphologic changes in the immature and aging neurons ultimately resulting in their demise. More alarming was the demonstration of significant cognitive and behavioral impairments noted long after the initial anesthesia exposure...
September 2016: Anesthesiology Clinics
Ayumi Konno, Akiko Nishimura, Shiro Nakamura, Ayako Mochizuki, Atsushi Yamada, Ryutaro Kamijo, Tomio Inoue, Takehiko Iijima
The neurotoxicity of anesthetics on the developing brain has drawn the attention of anesthesiologists. Several studies have shown that apoptosis is enhanced by exposure to anesthesia during brain development. Although apoptosis is a physiological developmental step occurring before the maturation of neural networks and the integration of brain function, pathological damage also involves apoptosis. Previous studies have shown that prolonged exposure to anesthetics causes apoptosis. Exactly when the apoptotic cascade starts in the brain remains uncertain...
April 26, 2016: International Journal of Developmental Neuroscience
Guorong Tao, Qingsheng Xue, Yan Luo, Guohui Li, Yimeng Xia, Buwei Yu
Demand is increasing for safer inhalational anesthetics for use in pediatric anesthesia. In this regard, researchers have debated whether isoflurane is more toxic to the developing brain than desflurane. In the present study, we compared the effects of postnatal exposure to isoflurane with those of desflurane on long-term cognitive performance and investigated the role of the Akt/GSK3β signaling pathway. Postnatal day 6 (P6) mice were exposed to either isoflurane or desflurane, after which the phosphorylation levels of Akt/GSK3β and learning and memory were assessed at P8 or P31...
2016: BioMed Research International
Rany Makaryus, Hedok Lee, Tian Feng, June-Hee Park, Maiken Nedergaard, Zvi Jacob, Grigori Enikolopov, Helene Benveniste
BACKGROUND: A wealth of data shows neuronal demise after general anesthesia in the very young rodent brain. Herein, the authors apply proton magnetic resonance spectroscopy (1HMRS), testing the hypothesis that neurotoxic exposure during peak synaptogenesis can be tracked via changes in neuronal metabolites. METHODS: 1HMRS spectra were acquired in the brain (thalamus) of neonatal rat pups 24 and 48 h after sevoflurane exposure on postnatal day (PND) 7 and 15 and in unexposed, sham controls...
September 2015: Anesthesiology
Pavle M Joksovic, Nadia Lunardi, Vesna Jevtovic-Todorovic, Slobodan M Todorovic
Recent evidence supports the idea that common general anesthetics (GAs) such as isoflurane (Iso) and nitrous oxide (N2O; laughing gas) are neurotoxic and may harm the developing mammalian brain, including the thalamus; however, to date very little is known about how developmental exposure to GAs may affect synaptic transmission in the thalamus which, in turn, controls the function of thalamocortical circuitry. To address this issue we used in vitro patch-clamp recordings of evoked inhibitory postsynaptic currents (eIPSCs) from intact neurons of the nucleus reticularis thalami (nRT) in brain slices from rat pups (postnatal age P10-P18) exposed at age of P7 to clinically relevant GA combinations of Iso and N2O...
October 2015: Molecular Neurobiology
Li Li, Qiong Yu, Weimin Liang
The effect of anesthesia on the developing brain has attracted more attention and arguments. This review summarizes various studies on developmental neurotoxicity induced by anesthesia, particularly focuses on the function of the mitochondrial dysfunction. Experimental results present evidence that general anesthesia can cause mitochondrial dysfunction via complex pathways, including oxidative stress, electron transport chain dysfunction, mitochondrial dynamics, calcium homeostasis, and mitochondrion-dependent apoptotic pathway...
January 2015: Brain Research Bulletin
Guzel Sitdikova, Andrei Zakharov, Sona Janackova, Elena Gerasimova, Julia Lebedeva, Ana R Inacio, Dilyara Zaynutdinova, Marat Minlebaev, Gregory L Holmes, Roustem Khazipov
OBJECTIVE: Isoflurane and other volatile anesthetics are widely used in children to induce deep and reversible coma, but they may also exert neurotoxic actions. The effects of volatile anesthetics on the immature brain activity remain elusive, however. METHODS: The effects of isoflurane on spontaneous and sensory-evoked activity were explored using intracortical extracellular field potential and multiple unit recordings in the rat barrel cortex from birth to adulthood...
January 2014: Annals of Clinical and Translational Neurology
Mike Wang, John H Zhang, Richard L Applegate
We did a PubMed search and summarized studies on the potential adverse effect of anesthetics especially neurotoxicity in the developing brain, so named anesthesia-induced developmental neurotoxicity. Even though many experimental studies using animal models indicated some adverse effect of anesthetics, more evidence is needed before a recommendation can be made to change the way those anesthetics are used in the pediatric population. Two large clinical trials are underway and may provide insight to the potential human neurotoxic effect of anesthetics...
2014: Medical Gas Research
Vesna Jevtovic-Todorovic
There is a rapidly growing body of animal and clinical evidence suggesting that the exposure to anesthetics and sedatives during the critical stages of brain development results in long-lasting (perhaps permanent) impairment in cognitive development in a variety of mammalian species. With improved understanding of the mechanisms responsible for behavioral outcomes of anesthesia-induced developmental neurotoxicity, there is hope for development of protective strategies that will enable safe use of anesthesia in the youngest members of our society...
October 2013: Molecular Neurobiology
Deshui Yu, Bin Liu
Several animal studies have demonstrated that most routinely used general anesthetics induce widespread neuroapoptosis and long-term neurocognitive impairment in the immature brain. These findings have generated great interest among pediatric anesthesiologists and other practitioners regarding the safe use of general anesthetics in pediatric patients. Several human retrospective studies failed to confirm whether or not anesthesia exposure during the crucial phase of brain development induces long-term neurocognitive deficits in humans...
October 2013: Journal of Anesthesia
Rylon D Hofacer, Meng Deng, Christopher G Ward, Bernadin Joseph, Elizabeth A Hughes, Connie Jiang, Steve C Danzer, Andreas W Loepke
OBJECTIVE: Anesthetics have been linked to widespread neuronal cell death in neonatal animals. Epidemiological human studies have associated early childhood anesthesia with long-term neurobehavioral abnormalities, raising substantial concerns that anesthetics may cause similar cell death in young children. However, key aspects of the phenomenon remain unclear, such as why certain neurons die, whereas immediately adjacent neurons are seemingly unaffected, and why the immature brain is exquisitely vulnerable, whereas the mature brain seems resistant...
June 2013: Annals of Neurology
Cheng Wang, Fang Liu, Tucker A Patterson, Merle G Paule, William Slikker
Ketamine is used as a general anesthetic, and recent data suggest that anesthetics can cause neurodegeneration and/or neuroprotection. The precise mechanisms are not completely understood. This review is to examine the work on ketamine and to address how developmental biology may be utilized when combined with biochemical, pathological, and pharmacokinetic assessments to produce a bridging model that may decrease the uncertainty in extrapolating preclinical data to human conditions. Advantages of using preclinical models to study critical issues related to ketamine anesthesia have been described...
June 2013: CNS Neuroscience & Therapeutics
George K Istaphanous, Christopher G Ward, Xinyu Nan, Elizabeth A Hughes, John C McCann, John J McAuliffe, Steve C Danzer, Andreas W Loepke
BACKGROUND: Accumulating evidence indicates that isoflurane and other, similarly acting anesthetics exert neurotoxic effects in neonatal animals. However, neither the identity of dying cortical cells nor the extent of cortical cell loss has been sufficiently characterized. We conducted the present study to immunohistochemically identify the dying cells and to quantify the fraction of cells undergoing apoptotic death in neonatal mouse cortex, a substantially affected brain region. METHODS: Seven-day-old littermates (n = 36) were randomly assigned to a 6-hour exposure to either 1...
April 2013: Anesthesia and Analgesia
M E McCann, S G Soriano
Anaesthetic-induced developmental neurotoxicity (AIDN) has been clearly established in laboratory animal models. The possibility of neurotoxicity during uneventful anaesthetic procedures in human neonates or infants has led to serious questions about the safety of paediatric anaesthesia. However, the applicability of animal data to clinical anaesthesia practice remains uncertain. The spectre of cerebral injury due to cerebral hypoperfusion, metabolic derangements, coexisting disease, and surgery itself further muddles the picture...
December 2012: British Journal of Anaesthesia
Cheng Wang
Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of anesthetic procedures. A great deal of concern has recently arisen regarding the safety of anesthesia in infants and children. Because of obvious limitations, it is not possible to thoroughly explore the effects of anesthetic agents on neurons in vivo in human infants or children. However, the availability of some advanced pre-clinical research approaches and models, such as imaging technology both in vitro and in vivo, stem cells, and non-human primate experimental models, have provided potentially invaluable tools for examining the developmental effects of anesthetic agents...
2012: Frontiers in Neurology
Vesna Jevtovic-Todorovic, A Boscolo, V Sanchez, N Lunardi
Exposure to general anesthetics (GAs) and antiepileptics during critical stages of brain development causes significant neurotoxicity to immature neurons. Many animal, and emerging human studies have shown long-term functional sequelae manifested as behavioral deficits and cognitive impairments. Since GAs and antiepileptic drugs are a necessity, current research is focused on deciphering the mechanisms responsible for anesthesia-induced developmental neurotoxicity so that protective strategies can be devised...
2012: Frontiers in Neurology
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