Neurotoxicity, General Anesthesia, and the Developing Brain: What have We Learned from the Human Studies so Far? (original) (raw)
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Paediatric anaesthesia, 2015
A multitude of animal studies have shown that virtually all general anesthetics used in clinical practice possibly during a vulnerable period of brain development (i.e., brain growth spurt, peak of synaptogenesis) may lead to neurodegeneration (particularly apoptosis) and abnormal synaptic development with functional deficits in learning and behavior later in life. Initial studies were mainly performed in immature rodent pups, but more recent studies have included nonhumans primates (rhesus monkeys). Given the number of neonates, infants, and young children anesthetized annually worldwide, these findings could have significant public health implications. So far, relatively few human (cohort) studies focusing on this topic have been published with inconsistent results. While some studies have indicated an association between exposure to anesthesia and surgery, other studies have indicated no such association. Prospective studies are underway, but the result will not be available for ...
Anesthesia-induced Developmental Neurotoxicity in Pediatric Population
Anesthetics and sedatives may cause long-term negative neurocognitive consequences in children. Many clinical reports on this subject have had a profound impact on the field of clinical pediatric anesthesiology. Findings from animal models suggest that early exposure to anesthesia might cause neurocognitive impairment and apoptotic cell death in the brain. Even though the findings from the experimental animals cannot be directly translated to the use of anesthesia in pediatric population due to many variable factors, parents and government regulatory bodies have become sensitive and attentive to the potential adverse effects of anesthesia in children. Multiple epidemiological investigations in human have added to the growing body of evidence showing neurological impairment and cognitive decline after early anesthetic exposure.
General anesthesia and neurotoxicity on the developing brain
2018
With the evolution of surgical techniques and technology an increasing number of infants, neonates, and fetuses are exposed to general anesthesia. Despite the acknowledged safety of general anesthesia, a considerable amount of preclinical evidence shows that the developing brain is highly vulnerable to anesthetic drugs. Early-age anesthesia may impair the fine tuning of neurotransmitters and growth factors that orchestrate the replication, differentiation and organization of neural cells into functional networks. In order to translate these insights from animal models to human patients, large trials and observational studies have been published or are currently ongoing. The aim of this narrative review is to provide an update on the pathophysiologic mechanisms and published evidence of anesthesia-related neurotoxicity in pediatric patients.
A holistic view of anesthesia-related neurotoxicity in children
Ambulatory Anesthesia, 2015
Animal studies (including in nonhuman primates) have shown that most general anesthetics cause enhanced neuroapoptosis in the immature brain with subsequent long-term neurocognitive deficits later in life. Whether human neurons are equally affected is yet unknown, but a final answer to this issue is still pending. To date, most human studies within the field are of observational nature and the results are conflicting. Some studies indicate an association between exposure to anesthesia and surgery while others do not. Objective: This review summarizes results from preclinical and observational studies. Controversies and challenges regarding the interpretation of these results are presented. Crucial aspects of neurocognitive safety during pediatric anesthesia and surgery are highlighted. International initiatives aiming to improve the safe conductance of pediatric anesthesia are introduced. Conclusion: So far, anesthesia-related neurotoxicity in humans remains an area of concern but it cannot be completely excluded. Clinical practice should not be changed until there are definite proofs that anesthetic exposure causes neurocognitive impairment later in life. Withholding necessary and timely surgeries as a consequence of any such concerns could result in worse harm. Focus of current research should also be redirected to include other factors, than merely anesthetics and surgery, that influence the neurocognitive safety of children perioperatively.
CON: The Toxic Effects of Anesthetics in the Developing Brain: The Clinical Perspective
Anesthesia & Analgesia, 2008
Thi s quote by the statistician George E. P. Box seems to have relevance for the current preeminent controversy in pediatric anesthesiology, namely, developmental neuroapoptotic cell death after an anesthetic exposure in the immature brain. Worldwide, general anesthetics and sedatives are used in hundreds of thousands of neonates and infants every year during surgical operations, invasive procedures, and imaging studies. The possibility of anesthesiainduced neuronal cell loss, as suggested by animal models, during an otherwise uneventful procedure has sparked vigorous discussions among anesthesiologists about the safety of anesthesia in human newborns and infants. 2-6 These concerns were recently addressed at the March 29, 2007, public hearing of the Anesthesia and Life Support Drugs Advisory Committee of the Food and Drug Administration
The effects of anaesthesia on the developing brain: a summary of the clinical evidence
F1000Research, 2013
Introduction: There is data amassing in the literature regarding the potentially adverse effects of anaesthesia exposure on the developing human brain. The purpose of this article is to summarise current relevant data from clinical studies in this area. Methods: Articles from journals written in English were searched for using PubMed, Ovid and Medline. Keywords used included: brain (newborn, infant, child and neonate), neurodegeneration, apoptosis, toxicity, neurocognitive impairment (developmental impairment and learning disorders) and anaesthesia (intravenous, inhalational and sedation). Results: From the initial search, 23 articles were identified as potentially relevant, with publication dates spanning from 1978 to 2012. Twelve studies were deemed irrelevant to the research questions. The results of neurocognitive assessment from eight of the remaining eleven studies had showed some differences in the performances of children exposed to anaesthesia. The control population in th...
Neurotoxicity caused by anesthetics in pediatric anesthesia
2016
In a review of the current literature assesses the recently discovered phenomenon and the toxicity of anesthetics in the developing child brain. The ways of diagnostics of morphological and functional abnormalities of brain activity in children. Provides indisputable data on the possibility of this type of interactions taking into account the mechanism of action of anesthetics. Comparative characteristics of strength toxic effects on children’s brain different types of inhalation and non-inhalation anesthetics. There is a comparison of the degree of toxic impact on the brain at single and repeated exposure of anesthesia. Emphasizes the lack of information and especially objective data visualization of degenerative changes in children’s brain due to ethical constraints and the impossibility of obtaining samples for biopsy. The conclusion about the appropriateness of expectant surgical tactics in the absence of urgent indications for surgical intervention to 4 years of a child’s life....
Neurodevelopmental implications of the general anesthesia in neonate and infants
Experimental Neurology, 2015
Each year, about six million children, including 1.5 million infants, in the United States undergo surgery with general anesthesia, often requiring repeated exposures. However, a crucial question remains of whether neonatal anesthetics are safe for the developing central nervous system (CNS). General anesthesia encompasses the administration of agents that induce analgesic, sedative, and muscle relaxant effects. Although the mechanisms of action of general anesthetics are still not completely understood, recent data have suggested that anesthetics primarily modulate two major neurotransmitter receptor groups, either by inhibiting N-methyl-D-aspartic acid (NMDA) receptors, or conversely by activating γ-aminobutyric acid (GABA) receptors. Both of these mechanisms result in the same effect of inhibiting excitatory activity of neurons. In developing brains, which are more sensitive to disruptions in activity-dependent plasticity, this transient inhibition may have longterm neurodevelopmental consequences. Accumulating reports from preclinical studies show that anesthetics in neonates cause cellular toxicity including apoptosis and neurodegeneration in the developing brain. Importantly, animal and clinical studies indicate that exposure to general anesthetics may affect CNS development, resulting in long-lasting cognitive and behavioral deficiencies, such as learning and memory deficits, as well as abnormalities in social memory and social activity. While the casual relationship between cellular toxicity and neurological impairments is still not clear, recent reports in animal experiments showed that anesthetics in neonates can affect neurogenesis, which could be a possible mechanism underlying the chronic effect of anesthetics. Understanding the cellular and molecular mechanisms of anesthetic effects will help to define the scope of the problem in humans and may lead to preventive and therapeutic strategies. Therefore, in this review, we summarize the current evidence on neonatal anesthetic effects in the developmental CNS and discuss how factors influencing these processes can be translated into new therapeutic strategies.
Long term neurotoxicity by general anesthetics in infants
Development of neurotoxicity in infants and children who had been exposed to general anesthetics has garnered attention in recent times and sparked vigorous debates. The effects range from learning disability, cognitive defects to development of neurodegenerative diseases like Alzheimer's disease in later life. Theories to explain these changes are calcium dysregulation leading to apoptosis, altered neurogenesis, accumulation of degenerative proteins like β amyloid and many others. A large volume of literature has accumulated in the form of animal and human studies which have implicated general anesthetic drugs like ketamine, propofol, volatile agents, and benzodiazepines in the development of neurodegenerative conditions in later life. These studies being retrospective are associated with a good deal of method-ological flaws. Hence a direct cause effect relationship is yet to be firmly established. In the present scenario, it would be prudent for the anaesthesiologists, to be aware of the possible existence of such an association. In the meantime, further research and evidence in this arena is demanded. Citation: Haldar R, Bajwa SJS. Long term neurotoxicity by general anesthetics in infants. Anaesth Pain & Intensive Care 2014:18(1):80-84