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Journal ArticleDOI

Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar

TL;DR: mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes, however, definitive clinical data remain elusive.
Abstract: Although previously considered entirely reversible, general anaesthesia is now being viewed as a potentially significant risk to cognitive performance at both extremes of age. A large body of preclinical as well as some retrospective clinical evidence suggest that exposure to general anaesthesia could be detrimental to cognitive development in young subjects, and might also contribute to accelerated cognitive decline in the elderly. A group of experts in anaesthetic neuropharmacology and neurotoxicity convened in Salzburg, Austria for the BJA Salzburg Seminar on Anaesthetic Neurotoxicity and Neuroplasticity. This focused workshop was sponsored by the British Journal of Anaesthesia to review and critically assess currently available evidence from animal and human studies, and to consider the direction of future research. It was concluded that mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes. However, definitive clinical data remain elusive. Since general anaesthesia often cannot be avoided regardless of patient age, it is important to understand the complex mechanisms and effects involved in anaesthesia-induced neurotoxicity, and to develop strategies for avoiding or limiting potential brain injury through evidence-based approaches.
Citations
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Journal ArticleDOI
TL;DR: This trial found no evidence that just under an hour of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at two years of age compared to RA.

839 citations

Journal ArticleDOI
TL;DR: An overview of the PK and PD of propofol is provided in order to refresh readers’ knowledge of its clinical applications, while discussing the main avenues of research where significant recent advances have been made.
Abstract: Propofol is an intravenous hypnotic drug that is used for induction and maintenance of sedation and general anaesthesia. It exerts its effects through potentiation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) at the GABAA receptor, and has gained widespread use due to its favourable drug effect profile. The main adverse effects are disturbances in cardiopulmonary physiology. Due to its narrow therapeutic margin, propofol should only be administered by practitioners trained and experienced in providing general anaesthesia. Many pharmacokinetic (PK) and pharmacodynamic (PD) models for propofol exist. Some are used to inform drug dosing guidelines, and some are also implemented in so-called target-controlled infusion devices, to calculate the infusion rates required for user-defined target plasma or effect-site concentrations. Most of the models were designed for use in a specific and well-defined patient category. However, models applicable in a more general population have recently been developed and published. The most recent example is the general purpose propofol model developed by Eleveld and colleagues. Retrospective predictive performance evaluations show that this model performs as well as, or even better than, PK models developed for specific populations, such as adults, children or the obese; however, prospective evaluation of the model is still required. Propofol undergoes extensive PK and PD interactions with both other hypnotic drugs and opioids. PD interactions are the most clinically significant, and, with other hypnotics, tend to be additive, whereas interactions with opioids tend to be highly synergistic. Response surface modelling provides a tool to gain understanding and explore these complex interactions. Visual displays illustrating the effect of these interactions in real time can aid clinicians in optimal drug dosing while minimizing adverse effects. In this review, we provide an overview of the PK and PD of propofol in order to refresh readers’ knowledge of its clinical applications, while discussing the main avenues of research where significant recent advances have been made.

277 citations

Journal ArticleDOI
TL;DR: The FDA collaboration SmartTots recommends undertaking large-scale clinical studies and avoiding nonurgent surgical procedures requiring anesthesia in children younger than 3 years of age.
Abstract: Some anesthetics and sedatives have been shown to cause neurotoxic effects in laboratory animals. The FDA collaboration SmartTots recommends undertaking large-scale clinical studies and avoiding nonurgent surgical procedures requiring anesthesia in children younger than 3 years of age.

274 citations

Journal ArticleDOI
TL;DR: Findings in children anesthetized with modern techniques largely confirm those found in an older birth cohort and provide additional evidence that children with multiple exposures are more likely to develop adverse outcomes related to learning and attention.
Abstract: Background Exposure of young animals to general anesthesia (GA) causes neurodegeneration and lasting behavioral abnormalities; whether these findings translate to children remains unclear. This study used a population-based birth cohort to test the hypothesis that multiple, but not single, exposures to procedures requiring GA prior to age 3 years are associated with adverse neurodevelopmental outcomes.

191 citations

Journal ArticleDOI
TL;DR: With increased understanding of the cognitive and self-regulatory vulnerabilities experienced by children and adolescents with CHD, it may be possible to identify risks early and provide individualized supports to promote optimal neurodevelopment.
Abstract: Children and adolescents with critical cyanotic congenital heart disease (CHD) are at risk for deficits in aspects of executive function (EF). The primary aim of this investigation was to compare EF outcomes in three groups of children/adolescents with severe CHD and controls (ages 10-19 years). Participants included 463 children/adolescents with CHD [dextro-transposition of the great arteries (TGA), n=139; tetralogy of Fallot (TOF), n=68; and, single-ventricle anatomy requiring Fontan procedure (SVF), n=145] and 111 controls, who underwent laboratory and informant-based evaluation of EF skills. Rates of EF impairment on D-KEFS measures were nearly twice as high for CHD groups (75-81%) than controls (43%). Distinct EF profiles were documented between CHD groups on D-KEFS tasks. Deficits in flexibility/problem-solving and verbally mediated EF skills were documented in all three CHD groups; visuo-spatially mediated EF abilities were impaired in TOF and SVF groups, but preserved in TGA. Parent, teacher, and self-report ratings on the BRIEF highlighted unique patterns of metacognitive and self-regulatory concerns across informants. CHD poses a serious threat to EF development. Greater severity of CHD is associated with worse EF outcomes. With increased understanding of the cognitive and self-regulatory vulnerabilities experienced by children and adolescents with CHD, it may be possible to identify risks early and provide individualized supports to promote optimal neurodevelopment.

171 citations


Cites background from "Anaesthetic neurotoxicity and neuro..."

  • ...On the other hand, children with single-ventricle conditions nearly always require more than one surgery, which not only exposes them to higher levels of general anesthetics (Jevtovic-Todorovic et al., 2013) and additional opportunities for surgical complications, but also necessitates that they endure a period of chronic hypoxemia while awaiting completion of staged palliation (Fenton, Lessman, Glogowski, Fogg, & Duncan, 2007)....

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  • ...…with single-ventricle conditions nearly always require more than one surgery, which not only exposes them to higher levels of general anesthetics (Jevtovic-Todorovic et al., 2013) and additional opportunities for surgical complications, but also necessitates that they endure a period of chronic…...

    [...]

References
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Journal ArticleDOI
14 Dec 2007-Cell
TL;DR: It is shown that C1q, the initiating protein in the classical complement cascade, is expressed by postnatal neurons in response to immature astrocytes and is localized to synapses throughout the postnatal CNS and retina, supporting a model in which unwanted synapses are tagged by complement for elimination and suggesting that complement-mediated synapse elimination may become aberrantly reactivated in neurodegenerative disease.

2,501 citations

Journal ArticleDOI
TL;DR: The brain in all species appears to grow through a sigmoid trajectory when its weight is plotted against its age, but the timing of the brain growth spurt is different in relation to birth in different species, so this must be one of the major factors to be taken into account when any attempt is made to extrapolate results obtained in one species to any other.

2,428 citations

Journal ArticleDOI
TL;DR: This work proposes that GABA becomes inhibitory by the delayed expression of a chloride exporter, leading to a negative shift in the reversal potential for choride ions, and provides a solution to the problem of how to excite developing neurons to promote growth and synapse formation.
Abstract: In the immature brain, GABA (gamma-aminobutyric acid) is excitatory, and GABA-releasing synapses are formed before glutamatergic contacts in a wide range of species and structures. GABA becomes inhibitory by the delayed expression of a chloride exporter, leading to a negative shift in the reversal potential for choride ions. I propose that this mechanism provides a solution to the problem of how to excite developing neurons to promote growth and synapse formation while avoiding the potentially toxic effects of a mismatch between GABA-mediated inhibition and glutamatergic excitation. As key elements of this cascade are activity dependent, the formation of inhibition adds an element of nurture to the construction of cortical networks.

2,275 citations

Journal ArticleDOI
TL;DR: The findings of this international multicentre study have implications for studies of the causes of cognitive decline and, in clinical practice, for the information given to patients before surgery.

2,075 citations

Journal ArticleDOI
04 May 2007-Science
TL;DR: Reducing endogenous tau levels prevented behavioral deficits in transgenic mice expressing human amyloid precursor protein, without altering their high Aβ levels, and protected both transgenic and nontransgenic mice against excitotoxicity.
Abstract: Many potential treatments for Alzheimer9s disease target amyloid-β peptides (Aβ), which are widely presumed to cause the disease. The microtubule-associated protein tau is also involved in the disease, but it is unclear whether treatments aimed at tau could block Aβ-induced cognitive impairments. Here, we found that reducing endogenous tau levels prevented behavioral deficits in transgenic mice expressing human amyloid precursor protein, without altering their high Aβ levels. Tau reduction also protected both transgenic and nontransgenic mice against excitotoxicity. Thus, tau reduction can block Aβ- and excitotoxin-induced neuronal dysfunction and may represent an effective strategy for treating Alzheimer9s disease and related conditions.

1,790 citations

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