Systemic inflammation exacerbates developmental neurotoxicity induced by sevoflurane in neonatal rats

Useinovic, Nemanja; Maksimovic, Stefan; Liechty, Cole; Cabrera, Omar H.; Quillinan, Nidia; Jevtović-Todorović, Vesna

doi:10.1016/j.bja.2022.05.008

Cited by 20 publications

(9 citation statements)

References 38 publications

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“…Sevoflurane animals did not experience moderate (SpO 2 <95%) or severe (SpO 2 <90%) hypoxemia following 6 h of anesthesia. As expected based on our previous reports, 35,36 pups receiving 6-h sevoflurane had decreased heart rate and respiration compared with control pups that received only carrier gases. Thirty minutes after cessation of anesthesia, pups anesthetized with sevoflurane had recovered mobility and responded vigorously to tail and toe pinch.…”

Section: Methodssupporting

confidence: 89%

Neonatal sevoflurane exposure induces long-term changes in dendritic morphology in juvenile rats and mice

Useinovic

Near

Cabrera

et al. 2023

Exp Biol Med (Maywood)

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General anesthetics are potent neurotoxins when given during early development, causing apoptotic deletion of substantial number of neurons and persistent neurocognitive and behavioral deficits in animals and humans. The period of intense synaptogenesis coincides with the peak of susceptibility to deleterious effects of anesthetics, a phenomenon particularly pronounced in vulnerable brain regions such as subiculum. With steadily accumulating evidence confirming that clinical doses and durations of anesthetics may permanently alter the physiological trajectory of brain development, we set out to investigate the long-term consequences on dendritic morphology of subicular pyramidal neurons and expression on genes regulating the complex neural processes such as neuronal connectivity, learning, and memory. Using a well-established model of anesthetic neurotoxicity in rats and mice neonatally exposed to sevoflurane, a volatile general anesthetic commonly used in pediatric anesthesia, we report that a single 6 h of continuous anesthesia administered at postnatal day (PND) 7 resulted in lasting dysregulation in subicular mRNA levels of cAMP responsive element modulator ( Crem), cAMP responsive element-binding protein 1 ( Creb1), and Protein phosphatase 3 catalytic subunit alpha, a subunit of calcineurin ( Ppp3ca) (calcineurin) when examined during juvenile period at PND28. Given the critical role of these genes in synaptic development and neuronal plasticity, we deployed a set of histological measurements to investigate the implications of anesthesia-induced dysregulation of gene expression on morphology and complexity of surviving subicular pyramidal neurons. Our results indicate that neonatal exposure to sevoflurane induced lasting rearrangement of subicular dendrites, resulting in higher orders of complexity and increased branching with no significant effects on the soma of pyramidal neurons. Correspondingly, changes in dendritic complexity were paralleled by the increased spine density on apical dendrites, further highlighting the scope of anesthesia-induced dysregulation of synaptic development. We conclude that neonatal sevoflurane induced persistent genetic and morphological dysregulation in juvenile rodents, which could indicate heightened susceptibility toward cognitive and behavioral disorders we are beginning to recognize as sequelae of early-in-life anesthesia.

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Section: Methodssupporting

confidence: 89%

Neonatal sevoflurane exposure induces long-term changes in dendritic morphology in juvenile rats and mice

Useinovic

Near

Cabrera

et al. 2023

Exp Biol Med (Maywood)

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“…[2] There are conflicting results in the literature about anesthesia-induced neurotoxicity. [4] Especially in clinical trials, it is impossible to ignore the effects and the cause of the surgery. Each day millions of children are exposed to anesthesia drugs for surgery or interventions so it is important to understand the real effects of anesthetics on central nervous system.…”

Section: Discussionmentioning

confidence: 99%

“…Retrospective clinical trials have conflicting results; while some trials found anesthesia related awareness or behavioral abnormalities, the others didn't show such effect. [3,4] Even though there are conflicting results in clinical research about anesthesia-induced neurotoxicity is a big concern for pediatric anesthetists. Besides children, experimental studies also showed that anesthesia could be related with postoperative delirium and neurocognitive dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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The bibliometric analysis of most cited 100 papers in anesthesia-induced neurotoxicity

Ocmen,

Erdost,

Hanci

2023

Medicine

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Anesthesia-induced neurotoxicity is a major concern for anesthetists for more than 20 years. Many experimental and clinical studies have been conducted on this topic since late 1990s. However, bibliometric analysis of these papers has not been reported. In this study, we aimed to analyze the 100 most cited articles on anesthesia-induced neurotoxicity. It was planned as cross-sectional study. On January 30, 2023, we searched the “Web of Science (WOS)” database for anesthesia-induced neurotoxicity and most cited 100 papers about this topic were obtained. Data such as authors’ names, year of publication, name of the journal, type of paper, and citation numbers were analyzed. The most cited 100 papers were read by the investigators, and the anesthetic, animal type in experimental studies, any protective agent and the method for detecting neurotoxicity used in the studies were also noted. There were 75 articles and 22 reviews in the 100 most cited articles. We found that most of the papers in most cited 100 list were published between 2010 to 1024. Most of the papers (11%) were from Harvard University and almost half of the papers (49%) were published in Anesthesiology. A great number of studies were performed in newborns or early childhood (85.5%) and inhalational anesthetics (54.7%) were the most studied anesthetic type. Most of the most cited 100 papers were published in Q1 journals (P = .012) and the continent of the most journals in this list was America (P = .014). The median total and annual citation numbers of funded papers were statistically significantly higher (P < .001 and P < .001 respectively). Anesthesia-induced neurotoxicity is very important, especially for pediatric anesthetists. This study is the first to conduct a bibliometric analysis of the most cited 100 publications on this field. Although there was a gap in the publications about this topic during COVID-19 pandemic, we believe that there will be many more publications on anesthesia-induced neurotoxicity since the mechanism, outcome and possible protection are still unknown.

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“…Although some observations suggest that ketamine administration may have neuroprotective effects following inflammatory pain in newborn rats [21][22][23], other preclinical data demonstrates additive neurotoxic effects of general anesthesia and noxious stimuli [24]. Likewise, the limited amount of laboratory data on the interaction between systemic inflammation and exposure to general anesthesia in terms of neonatal brain toxicity also provides us with contradicting results [25,26 ]. The lack of experimental models and data addressing the effects of neonatal surgery on brain development is primarily related to the fact that surgery in neonatal rodents, weighing just a few grams, is technically highly challenging if not impossible [27].…”

Section: Beyond Drugs: What Is the Contribution Of Surgery And Other ...mentioning

confidence: 99%

Unanswered questions of anesthesia neurotoxicity in the developing brain

Ing

Vutskits

2023

Current Opinion in Anaesthesiology

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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.

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Systemic inflammation exacerbates developmental neurotoxicity induced by sevoflurane in neonatal rats

Cited by 20 publications

References 38 publications

Neonatal sevoflurane exposure induces long-term changes in dendritic morphology in juvenile rats and mice

Neonatal sevoflurane exposure induces long-term changes in dendritic morphology in juvenile rats and mice

The bibliometric analysis of most cited 100 papers in anesthesia-induced neurotoxicity

Unanswered questions of anesthesia neurotoxicity in the developing brain

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