Developmental anaesthesia neurotoxicity in humans: finding the sweet spot?

A recent human epidemiological study in this issue of British Journal of Anaesthesia examined the association between anaesthesia exposure in pregnant women undergoing appendicectomy or cholecystectomy and the subsequent diagnosis of behavioural disorders in their offspring. When compared with unexposed children, prenatally exposed children had ∼30% greater likelihood of a diagnosis of disruptive or internalising behavioural disorders. Although these data are new and interesting, they should be interpreted with caution. Indeed, appendicitis and cholecystitis can produce acute and chronic systemic inflammation, and maternal immune activation can affect fetal neurodevelopment through inflammatory and epigenetic mechanisms. It is, therefore, possible that the findings are related to maternal and fetal inflammation than to anaesthesia exposure. As there is no causal evidence for the implication that anaesthesia and surgery induce such pathologies, it is unwise to consider alternative treatments when surgery is indicated in pregnant patients.

Pediatric anesthesia in Europe: Variations within uniformity.

Organization of healthcare strongly differs between European countries and results in country-specific requirements in postgraduate medical training. Within the European Union (EU), the European Board of Anaesthesiology has set recommendations of training for the Specialty of Anaesthesiology including standards for Postgraduate Medical Specialist training including a description for providing service in pediatric anesthesia. However, these standards are advisory and not mandatory. Here we aimed to review the current state and associated challenges of pediatric anesthesia training in Europe. We report an important country-specific variability both in training and regulations of practice of pediatric anesthesia in the EU and in the United Kingdom. The requirements for training in pediatric anesthesia varies between nothing specified (Belgium) or providing anesthesia with direct supervision to a minimum of 50 cases below 5 years of age (Germany) to 3-6 month clinical practice in a specialized pediatric hospital (France). Likewise, the regulations for providing anesthesia to children varies from no regulations at all (Belgium) to age specific requirements and centralization of all children below 4 years of age to specified centers (United Kingdom). Officially recognized pediatric anesthesia fellowship programs are not available in most countries of Europe. It remains unclear if and how country-specific differences in pediatric anesthesia training are associated with clinical outcomes in pediatric perioperative care. There is converging interest and support for the establishment of a European pediatric anesthesia curriculum.

Unanswered questions of anesthesia neurotoxicity in the developing brain.

PURPOSE OF REVIEW: This article reviews recent advances and controversies of developmental anesthesia neurotoxicity research with a special focus on the unanswered questions in the field both from clinical and preclinical perspectives. RECENT FINDINGS: Observational cohort studies of prenatal and early childhood exposure to anesthesia have reported mixed evidence of an association with impaired neurodevelopment. Meta-analyses of currently available studies of early childhood exposure to anesthesia suggest that, while limited to no change in general intelligence can be detected, more subtle deficits in specific neurodevelopmental domains including behavior and executive function may be seen. Several studies have evaluated intraoperative blood pressure values and neurocognitive outcomes and have not found an association. Although many animal studies have been performed, taking into consideration other peri-operative exposures such as pain and inflammation may help with translation of results from animal models to humans. SUMMARY: Advances have been made in the field of developmental anesthetic neurotoxicity over the past few years, including the recognition that anesthetic exposure is associated with deficits in certain cognitive domains but not others. Although the most important question of whether anesthetic agents actually cause long-term neurodevelopmental effects in children has still not been answered, results from recent studies will guide further studies necessary to inform clinical decision-making in children.

Clinical investigations on anesthesia-induced developmental neurotoxicity: The knowns, the unknowns and future prospects.

Pre-clinical experimental evidence, along with a plausible biological rational suggests that exposure of neonates and young children to anesthesia may harm brain development. However, the translational relevance of these observations remains unsolved. While a variety of lasting morpho-functional effects can be attributed to early life exposure to anesthetics in laboratory animals, we do not have a convincing human phenotype that reflects any causal effects of general anesthetic exposure on brain development and functional outcome. This review is aimed to provide a comprehensive description of the current state of clinical research alongside exploring future challenges in this field by focusing on the critical appraisal of methodological approaches applied in clinical research into developmental anesthesia neurotoxicity.

Opioids and autism spectrum disorder: liaisons dangereuses?

A recent laboratory study in the Journal examined the effects of repeated exposures of neonatal mice to fentanyl on autism-like behaviour via opioid receptor-mediated DNA hypermethylation of the Grin2B gene, which encodes the GluN2B subunit of the NMDA receptor. These experiments provide mechanisms and biological plausibility but do not directly demonstrate that opioid exposure in early life induces autism spectrum disorder in humans. Experimental modelling of human neuropsychiatric disorders is extremely challenging since most subjective psychiatric symptoms used to establish diagnosis in humans cannot be convincingly ascertained in laboratory rodents. While some human epidemiological data show associations between repeated exposures to opioids during early life, it remains undetermined whether opioid exposure is an independent risk factor for developing autism spectrum disorder in the young.

Isoelectric Electroencephalography in Infants and Toddlers during Anesthesia for Surgery: An International Observational Study.

BACKGROUND: Intraoperative isoelectric electroencephalography (EEG) has been associated with hypotension and postoperative delirium in adults. This international prospective observational study sought to determine the prevalence of isoelectric EEG in young children during anesthesia. The authors hypothesized that the prevalence of isoelectric events would be common worldwide and associated with certain anesthetic practices and intraoperative hypotension. METHODS: Fifteen hospitals enrolled patients age 36 months or younger for surgery using sevoflurane or propofol anesthetic. Frontal four-channel EEG was recorded for isoelectric events. Demographics, anesthetic, emergence behavior, and Pediatric Quality of Life variables were analyzed for association with isoelectric events. RESULTS: Isoelectric events occurred in 32% (206 of 648) of patients, varied significantly among sites (9 to 88%), and were most prevalent during pre-incision (117 of 628; 19%) and surgical maintenance (117 of 643; 18%). Isoelectric events were more likely with infants younger than 3 months (odds ratio, 4.4; 95% CI, 2.57 to 7.4; P < 0.001), endotracheal tube use (odds ratio, 1.78; 95% CI, 1.16 to 2.73; P = 0.008), and propofol bolus for airway placement after sevoflurane induction (odds ratio, 2.92; 95% CI, 1.78 to 4.8; P < 0.001), and less likely with use of muscle relaxant for intubation (odds ratio, 0.67; 95% CI, 0.46 to 0.99; P = 0.046]. Expired sevoflurane was higher in patients with isoelectric events during preincision (mean difference, 0.2%; 95% CI, 0.1 to 0.4; P = 0.005) and surgical maintenance (mean difference, 0.2%; 95% CI, 0.1 to 0.3; P = 0.002). Isoelectric events were associated with moderate (8 of 12, 67%) and severe hypotension (11 of 18, 61%) during preincision (odds ratio, 4.6; 95% CI, 1.30 to 16.1; P = 0.018) (odds ratio, 3.54; 95% CI, 1.27 to 9.9; P = 0.015) and surgical maintenance (odds ratio, 3.64; 95% CI, 1.71 to 7.8; P = 0.001) (odds ratio, 7.1; 95% CI, 1.78 to 28.1; P = 0.005), and lower Pediatric Quality of Life scores at baseline in patients 0 to 12 months (median of differences, -3.5; 95% CI, -6.2 to -0.7; P = 0.008) and 25 to 36 months (median of differences, -6.3; 95% CI, -10.4 to -2.1; P = 0.003) and 30-day follow-up in 0 to 12 months (median of differences, -2.8; 95% CI, -4.9 to 0; P = 0.036). Isoelectric events were not associated with emergence behavior or anesthetic (sevoflurane vs. propofol). CONCLUSIONS: Isoelectric events were common worldwide in young children during anesthesia and associated with age, specific anesthetic practices, and intraoperative hypotension.

Downregulation of the schizophrenia risk-gene Dgcr2 alters early microcircuit development in the mouse medial prefrontal cortex.

Alterations in the generation, migration and integration of different subtypes of neurons in the medial prefrontal cortex (mPFC) microcircuit could play an important role in vulnerability to schizophrenia. Using in vivo cell-type specific manipulation of pyramidal neurons (PNs) progenitors, we aim to investigate the role of the schizophrenia risk-gene DiGeorge Critical Region 2 (Dgcr2) on cortical circuit formation in the mPFC of developing mice. This report describes how Dgcr2 knock down in upper-layer PNs impacts the functional maturation of PNs and interneurons (INs) in the mPFC. First, we demonstrate that Dgcr2 knock-down disrupts laminar positioning, dendritic morphology and excitatory activity of upper-layer PNs. Interestingly, inhibitory activity is also modified in Dgcr2 knock-down PNs, suggesting a broader microcircuit alteration involving interneurons. Further analyses show that the histological maturation of parvalbumin (PV) INs is not dramatically impaired, thus implying that other INs subtypes might be at play in the reported microcircuit alteration. Overall, this study unravels how local functional deficits of the early postnatal development of the mPFC can be induced by Dgcr2 knock-down in PNs.

Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward.

Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins.