Perils of paediatric anaesthesia and novel molecular approaches: An evidence-based review (original) (raw)
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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...
2014
The practices of anaesthesiology and intensive therapy are difficult to imagine without sedation or general anaesthesia , regardless of whether the patient is a newborn, baby, child or adult. The relevant concerns for children are distinct from those for adults, primarily due to the effects of anatomical, physiological and pharmacokinetic-phar-macodynamic (PK/PD) differences, which become increasingly important in the brains of children as they develop. The process of central nervous system maturation in humans lasts for years, but its greatest activity (myelination and synaptogenesis) occurs during the fetal period and the first two years of life. Many experimental studies have demonstrated that exposure to anaesthetic drugs during this period can induce neurodegenerative changes in the central nervous systems of animals. The extrapolation of these results directly to humans must be performed with great caution, but anaesthesiologists around the world must begin to debate the safet...
Logistical and ethical reasons make conducting clinical research in paediatric practice difficult, and therefore safe and efficacious advances are dependent on good preclinical research. For example, notable advances have been made in preclinical studies of pain processing that correlate well with patient data. Other areas of paediatric anaesthetic research remain in their infancy including mechanisms of anaesthesia and anaesthetic neuroprotection and neurotoxicity. Animal data have identified the potential 'double-edged' sword of administering anaesthetic agents in the young; although these agents can be neuroprotective in certain circumstances, they can be neurotoxic in others. The potential for this toxicity must be balanced against the importance of providing adequate anaesthesia for which there can be no compromise. We review the current state of preclinical research in paediatric anaesthesia and identify areas which require further exploration in order to provide the foundations for well-conducted clinical trials.
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
Current Anesthesiology Reports, 2013
A multitude of animal studies have shown that virtually all general anesthetics used in clinical practice exert detrimental effects on the developing brain, notably enhanced neuroapoptosis. Some studies have also indicated that animals exposed to general anesthesia may experience long term neurobehavioral deficits later in life. The neurotoxic effects seem to be dose-dependent and have been suspected to occur at certain early developmental stages. Initially, the animal studies comprised primarily rodents but recently they have been confirmed in non-human primates. Recently, a number of (mainly retrospective) human cohort studies have been published with inconsistent results. While some studies have indicated an association between anesthesia and surgery and adverse neurobehavioral outcome, other studies have indicated no association. The cohort studies have many constraints and shortcomings. While prospective studies are underway, they will not provide any answers for several more years. The aim of this review is to provide the reader with a summary of recent human cohort studies and discuss their limitations and weaknesses. Although disturbing, the animal data lacks verification in humans. To date there are no data to support any change in clinical pediatric anesthetic practice. Any such change will be premature and potentially dangerous until we have evidence as to if and how general anesthesia impairs neurocognition and behaviour in infants and young children.
Anesthetic Neurotoxicity to the Fragile Young Brain: Where Do We Stand?
Journal of Pregnancy and Child Health, 2015
Anesthetics behavioural changes Is Anesthesia Safe to Young Brains? Advances in neonatal and pediatric surgery and intensive care demanded for increasing general anesthesia requirements in small infants, as well as the need for prolonged infusions for sedation. General anesthesia results from a complex pharmacological interaction of different drugs, many with still incompletely known mechanisms [1]. Consequently, their immediate and long-term effects are not completely understood. Traditionally, anesthetic drugs' effects were thought to dissipate as early as the end of their administration, without prospective effects on children development [2]. Since fifties, a concern about anesthetic consequences in the developing brain started to rise due to studies that have showed that vinyl ether, cyclopropane or ethyl chloride administration to young children could cause long-term personality changes [3]. During the past three decades, strong evidence from animal studies have questioned the anesthetic safety profile on central nervous system development, and inflamed debate surrounds the negative effects of anesthesia in the developing brain. In fact, animal studies to date reveal very robust and consistent data concerning anesthesia-induced neurotoxicity in immature mammals and rodents. Considering the universal and serious possible impact of this issue in pediatric health care, the Food and Drug Administration (FDA) established a partnership with the International Anesthesia Research Society (IARS), called SmartTots (Strategies for Mitigating Anesthesia-Related Neurotoxicity in Tots), to specifically address and make recommendations on this matter.
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.
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.
GENERAL ANESTHESIA: IS IT SAFE FOR NEWBORNS, INFANTS AND YOUNG CHILDREN
The exposure of neonates, infants and small children to general anesthesia is becoming a common occurrence.Accumulating preclinical data indicate that exposure to commonly used general anesthetic agents during key periods of brain developmentin this population (between late gestation and 3 to 4 years of age), can lead to apoptotic neurodegeneration, syn-apse loss, and cognitive and neurobehavioral deficits that persist as the organism matures. New work suggests that infants and small children undergoing some types of surgery could have better recovery if they receive regional anesthesia rather than general anesthesia. In response to this concerns, the Food and drug administration (FDA) and the International Research Society in anesthesia (IARS) started an initiative called Smart Tots (Strategies for Mitigating Anesthesia-related neuro Toxicity in Tots)which examine the effects of anesthesia on brain development.Also another two major prospective studies are ongoing in children: PANDA (Pediatric Anesthesia Neurodevelopment assessment Study) project is a large, multi-center study based at the Morgan Stanley Children's Hospital of New York at Columbia University, and another one is GAS study which is a multisite randomized controlled trial comparing neurodevelopment outcomes in infant receiving general anesthesia compared to spinal and other regional anesthetics to the stress response to surgery. The findings from these studies will help researches to design the safest anesthetic regimens and to develop the new and safer anesthetic drugs for use in pe-diatric medicine.