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Yu Y, Yu J, Wu B, Wang Y, Li Y, Yang Y, Yu Y, Feng J. Enriched environment mitigates cognitive impairment in pre-adolescent mice following repeated neonatal sevoflurane exposure by reducing TTBK1 expression and Tau phosphorylation. Neuropharmacology 2025; 268:110327. [PMID: 39892471 DOI: 10.1016/j.neuropharm.2025.110327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/16/2025] [Accepted: 01/24/2025] [Indexed: 02/03/2025]
Abstract
Enriched environment (EE) is a living setting that provides visual, olfactory, tactile, and cognitive stimulation and has demonstrated potential treatment results in neurodevelopmental diseases. We aimed to elucidate whether the neurodevelopmental toxicity of sevoflurane is linked to TTBK1 and Tau phosphorylation, as well as to evaluate the neuroprotective mechanism of EE on mice following sevoflurane exposure. Female mice were anesthetized at postnatal day 6 (P6) or P60 with 3% sevoflurane for 2 h daily for three days. P6 mice received intraperitoneal injections of the TTBK1 inhibitor WHI-180 before anesthesia. The EE exposure was 2 h daily from P9 to P29. Cognitive function was assessed using the Morris water maze and novel object recognition tests. Hippocampal and cerebral cortical tissues were collected to measure levels of TTBK1, Tau-PS422, AT8, T22, and total Tau. Co-localization of TTBK1 and Tau-PS422 was identified via immunofluorescence. The dendritic spine count and shape classification were analyzed by Golgi staining. The results indicated elevated levels of TTBK1, phosphorylated Tau-PS422, and AT8 in neonatal mice compared to adults. Sevoflurane increased the levels of TTBK1 and Tau phosphorylation, causing cognitive impairment. Both TTBK1 inhibitor and EE reversed the sevoflurane-induced increase in TTBK1 and phosphorylated Tau levels, decrease in dendritic spine density and maturity, and cognitive impairment. In conclusion, the overexpression of TTBK1 and phosphorylated Tau in neonatal mice brain contributed to cognitive dysfunction after repeated sevoflurane anesthesia. EE played a cerebro-protective role by inhibiting the TTBK1/Tau pathway and promoting the development of dendritic spines after sevoflurane anesthesia.
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Affiliation(s)
- Yang Yu
- Department of Anesthesia, Tianjin Medical University General Hospital, PR China; Tianjin Institute of Anesthesiology, Tianjin, 300052, PR China
| | - Jiafeng Yu
- Department of Anesthesia, Tianjin Medical University General Hospital, PR China; Tianjin Institute of Anesthesiology, Tianjin, 300052, PR China
| | - Banglin Wu
- The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei, 444300, PR China
| | - Yuanlin Wang
- Department of Anesthesia, Tianjin Medical University General Hospital, PR China; Tianjin Institute of Anesthesiology, Tianjin, 300052, PR China
| | - Yun Li
- Department of Anesthesia, Tianjin Medical University General Hospital, PR China; Tianjin Institute of Anesthesiology, Tianjin, 300052, PR China
| | - Yongyan Yang
- Department of Anesthesia, Tianjin Medical University General Hospital, PR China; Tianjin Institute of Anesthesiology, Tianjin, 300052, PR China
| | - Yonghao Yu
- Department of Anesthesia, Tianjin Medical University General Hospital, PR China; Tianjin Institute of Anesthesiology, Tianjin, 300052, PR China.
| | - Jingyu Feng
- Department of Anesthesia, Tianjin Medical University General Hospital, PR China; Tianjin Institute of Anesthesiology, Tianjin, 300052, PR China.
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Borzage MT, Peterson BS. A Scoping Review of the Mechanisms Underlying Developmental Anesthetic Neurotoxicity. Anesth Analg 2025; 140:409-426. [PMID: 38536739 PMCID: PMC11427602 DOI: 10.1213/ane.0000000000006897] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2023] [Indexed: 09/28/2024]
Abstract
Although anesthesia makes painful or uncomfortable diagnostic and interventional health care procedures tolerable, it may also disrupt key cellular processes in neurons and glia, harm the developing brain, and thereby impair cognition and behavior in children. Many years of studies using in vitro, animal behavioral, retrospective database studies in humans, and several prospective clinical trials in humans have been invaluable in discerning the potential toxicity of anesthetics. The objective of this scoping review was to synthetize the evidence from preclinical studies for various mechanisms of toxicity across diverse experimental designs and relate their findings to those of recent clinical trials in real-world settings.
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Affiliation(s)
- Matthew Thomas Borzage
- From the Fetal and Neonatal Institute, Division of Neonatology, Children’s Hospital Los Angeles, Los Angeles, California
| | - Bradley S. Peterson
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California
- Institute for the Developing Mind, Children’s Hospital Los Angeles, Los Angeles, California
- Department of Psychiatry, Keck School of Medicine at the University of Southern California, Los Angeles, California
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3
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Ten Barge JA, Zwiers AJM, Vermeulen MJ, Keyzer-Dekker CMG, Simons SHP, Staals LM, van den Bosch GE. Current anesthesia practice for preterm infants undergoing surgery for necrotizing enterocolitis: A European survey. J Clin Anesth 2024; 97:111508. [PMID: 38843649 DOI: 10.1016/j.jclinane.2024.111508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/15/2024] [Accepted: 05/31/2024] [Indexed: 09/15/2024]
Abstract
STUDY OBJECTIVE Necrotizing enterocolitis (NEC) is a life-threatening intestinal illness mostly affecting preterm infants, which commonly requires surgery. Anesthetic care for these patients is challenging, due to their prematurity and critical illness with hemodynamic instability. Currently, there are no guidelines for anesthetic care for these vulnerable patients. Therefore, this study aimed to describe current anesthesia practices across Europe for infants undergoing surgery for NEC. DESIGN Cross-sectional survey study. PARTICIPANTS Anesthesiologists working in centers where surgery for NEC is performed across Europe. MEASUREMENTS A 46-item questionnaire assessing protocols for anesthesia practice, preoperative care, intraoperative care, postoperative care, and the respondent's opinion on the adequacy of anesthetic care for patients with NEC in their center. MAIN RESULTS Out of the 173 responding anesthesiologists from 31 countries, approximately a third had a written standard protocol for anesthetic care in infants. Three quarters of the respondents screened all patients with NEC preoperatively, and a third structurally performed preoperative multidisciplinary consultation. For induction of general anesthesia, most respondents opted for intravenous anesthesia (n = 73, 43%) or a combination of intravenous and inhalation anesthesia (n = 57, 33%). For intravenous induction, they mostly used propofol (n = 58, 44%), followed by midazolam (n = 43, 33%) and esketamine (n = 42, 32%). For maintenance of anesthesia, inhalation anesthetic agents were more commonly used (solely: n = 71, 41%; in combination: n = 37, 22%), almost exclusively with sevoflurane. Postoperative analgesics mainly included paracetamol and/or morphine. Sixty percent of the respondents (n = 104) considered their anesthetic care for patients with NEC adequate. Suggestions for further improvement mainly revolved around monitoring, protocols, and collaboration. CONCLUSIONS Anesthesia practice for infants undergoing surgery for NEC was highly variable. Most respondents considered the provided anesthetic care for patients with NEC adequate, but also recognized opportunities for further improvement, especially with regards to monitoring, protocols, and interdisciplinary collaboration.
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MESH Headings
- Humans
- Enterocolitis, Necrotizing/surgery
- Europe
- Cross-Sectional Studies
- Infant, Newborn
- Infant, Premature
- Anesthesia, Intravenous/methods
- Anesthesia, Intravenous/statistics & numerical data
- Anesthesia/methods
- Health Care Surveys
- Surveys and Questionnaires/statistics & numerical data
- Anesthesiologists/statistics & numerical data
- Anesthesia, General/methods
- Practice Patterns, Physicians'/statistics & numerical data
- Practice Patterns, Physicians'/standards
- Preoperative Care/methods
- Preoperative Care/statistics & numerical data
- Preoperative Care/standards
- Anesthesia, Inhalation/methods
- Anesthesia, Inhalation/statistics & numerical data
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Affiliation(s)
- Judith A Ten Barge
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, the Netherlands.
| | - Alexandra J M Zwiers
- Department of Anesthesiology, Erasmus MC - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - Marijn J Vermeulen
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - Claudia M G Keyzer-Dekker
- Department of Pediatric Surgery, Erasmus MC - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - Sinno H P Simons
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - Lonneke M Staals
- Department of Anesthesiology, Erasmus MC - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - Gerbrich E van den Bosch
- Department of Neonatal and Pediatric Intensive Care, Division of Neonatology, Erasmus MC - Sophia Children's Hospital, Rotterdam, the Netherlands
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4
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Gao T, Huang Z. Novel insights into sevoflurane-induced developmental neurotoxicity mechanisms. Epigenomics 2024; 16:1231-1252. [PMID: 39316776 PMCID: PMC11485883 DOI: 10.1080/17501911.2024.2395250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 08/19/2024] [Indexed: 09/26/2024] Open
Abstract
Aim: This study explores Sevoflurane (Sevo)-induced neurotoxicity mechanisms in neonates through transcriptome sequencing and models.Methods: Seven-day-old mice were exposed to 3% Sevo, and hippocampal tissue was collected for analysis of differentially expressed lncRNAs and mRNAs compared with normal mice. MiR-152-3p was selected, and the interaction between H19, USP30, and miR-152-3p was explored in BV2 microglial cells and mouse hippocampal neurons.Results: Sevo disrupts mitochondrial autophagy via USP30 upregulation, exacerbating neurotoxicity and activating NLRP1 inflammasome-mediated inflammation.Conclusion: Sevo neurotoxicity is mediated through the H19/miR-152-3p/USP30 axis, implicating microglial regulation of neuronal pyroptosis.
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Affiliation(s)
- Tingting Gao
- Department of Anesthesia, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, P.R. China
| | - Zeqing Huang
- Department of Anesthesia, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, P.R. China
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Silber JH, Rosenbaum PR, Reiter JG, Jain S, Hill AS, Hashemi S, Brown S, Olfson M, Ing C. Exposure to Operative Anesthesia in Childhood and Subsequent Neurobehavioral Diagnoses: A Natural Experiment Using Appendectomy. Anesthesiology 2024; 141:489-499. [PMID: 38753986 PMCID: PMC11361557 DOI: 10.1097/aln.0000000000005075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2024]
Abstract
BACKGROUND Observational studies of anesthetic neurotoxicity may be biased because children requiring anesthesia commonly have medical conditions associated with neurobehavioral problems. This study takes advantage of a natural experiment associated with appendicitis to determine whether anesthesia and surgery in childhood were specifically associated with subsequent neurobehavioral outcomes. METHODS This study identified 134,388 healthy children with appendectomy and examined the incidence of subsequent externalizing or behavioral disorders (conduct, impulse control, oppositional defiant, attention-deficit hyperactivity disorder) or internalizing or mood or anxiety disorders (depression, anxiety, or bipolar disorder) when compared to 671,940 matched healthy controls as identified in Medicaid data between 2001 and 2018. For comparison, this study also examined 154,887 otherwise healthy children admitted to the hospital for pneumonia, cellulitis, and gastroenteritis, of which only 8% received anesthesia, and compared them to 774,435 matched healthy controls. In addition, this study examined the difference-in-differences between matched appendectomy patients and their controls and matched medical admission patients and their controls. RESULTS Compared to controls, children with appendectomy were more likely to have subsequent behavioral disorders (hazard ratio, 1.04; 95% CI, 1.01 to 1.06; P = 0.0010) and mood or anxiety disorders (hazard ratio, 1.15; 95% CI, 1.13 to 1.17; P < 0.0001). Relative to controls, children with medical admissions were also more likely to have subsequent behavioral (hazard ratio, 1.20; 95% CI, 1.18 to 1.22; P < 0.0001) and mood or anxiety (hazard ratio, 1.25; 95% CI, 1.23 to 1.27; P < 0.0001) disorders. Comparing the difference between matched appendectomy patients and their matched controls to the difference between matched medical patients and their matched controls, medical patients had more subsequent neurobehavioral problems than appendectomy patients. CONCLUSIONS Although there is an association between neurobehavioral diagnoses and appendectomy, this association is not specific to anesthesia exposure and is stronger in medical admissions. Medical admissions, generally without anesthesia exposure, displayed significantly higher rates of these disorders than appendectomy-exposed patients. EDITOR’S PERSPECTIVE
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Affiliation(s)
- Jeffrey H Silber
- Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and Center for Outcomes Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Paul R Rosenbaum
- Department of Statistics and Data Science, The Wharton School, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joseph G Reiter
- Center for Outcomes Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Siddharth Jain
- Center for Outcomes Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Alexander S Hill
- Center for Outcomes Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Sean Hashemi
- Center for Outcomes Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Sydney Brown
- Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan
| | - Mark Olfson
- Departments of Psychiatry and Epidemiology, Columbia University Vagelos College of Physicians and Surgeons and Mailman School of Public Health, New York, New York
| | - Caleb Ing
- Departments of Anesthesiology and Epidemiology, Columbia University Vagelos College of Physicians and Surgeons and Mailman School of Public Health, New York, New York
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Escobar N, Levy-Lambert D, Fisher J, DiMaggio C, Kazmi S, Tomita S. Early Findings of a Preterm Twin Cohort Study Examining the Effect of General Anesthesia on Developmental Outcomes. J Dev Behav Pediatr 2024; 45:e478-e482. [PMID: 38990148 DOI: 10.1097/dbp.0000000000001300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 05/13/2024] [Indexed: 07/12/2024]
Abstract
PURPOSE The premature infant brain may be particularly vulnerable to anesthesia effects, but there is conflicting evidence on the association between anesthesia exposure and developmental outcomes. Twin studies can control for confounding factors. A twin cohort of premature twins provides internal control of difficulty to measure confounders and delivers added power to a study examining the effects of anesthesia on neurodevelopmental outcomes. METHODS We conducted a retrospective cohort study of sets of premature twins and multiples born at an academic medical center, in which 1 member of the set was exposed to general anesthesia. The primary outcome was the composite scores using Bayley Scale of Infant and Toddler Development III performed at age 6 months to 18 months. Unpaired and paired analyses were performed with linear regression models, Wilcoxon signed rank test, and Mann-Whitney U test. RESULTS We identified 81 children born at less than 32 weeks gestation within 39 sets of twins and 1 set of triplets for a total of 18 paired observations. All of the exposed infants had a single exposure to general anesthesia. There was no significant association between anesthesia exposure and a diagnosis of developmental delay (OR = 0.8; 95% confidence interval, 0.2-3.2; p = 0.99). Regression models demonstrated no association between anesthesia exposure and cognitive (96.67 vs 97.50; p = 0.74), language (98.33 vs 98.61; p = 0.94), or motor (96.25 vs 96.44; p = 0.91) composite Bayley scores. There was no association between duration of anesthesia and the 3 composite Bayley scores ( p = 0.33; p = 0.40; p = 0.74). CONCLUSION Using a premature twin cohort with discordant exposure to anesthesia, our data did not demonstrate any association between anesthesia exposure and developmental delay in this vulnerable population of premature infants.
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Affiliation(s)
- Natalie Escobar
- Division of Pediatric Surgery, Department of Surgery, Hassenfeld Children's Hospital at NYU Langone, NYU Langone Grossman School of Medicine, New York, NY
| | - Dina Levy-Lambert
- Division of Pediatric Surgery, Department of Surgery, Hassenfeld Children's Hospital at NYU Langone, NYU Langone Grossman School of Medicine, New York, NY
| | - Jason Fisher
- Division of Pediatric Surgery, Department of Surgery, Hassenfeld Children's Hospital at NYU Langone, NYU Langone Grossman School of Medicine, New York, NY
| | - Charles DiMaggio
- Department of Surgery, NYU Langone Grossman School of Medicine, New York, NY
| | - Sadaf Kazmi
- Division of Neonatology, Department of Pediatrics, NYU Langone Grossman School of Medicine, New York, NY
| | - Sandra Tomita
- Division of Pediatric Surgery, Department of Surgery, Hassenfeld Children's Hospital at NYU Langone, NYU Langone Grossman School of Medicine, New York, NY
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7
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Xu J, Wen J, Mathena RP, Singh S, Boppana SH, Yoon OI, Choi J, Li Q, Zhang P, Mintz CD. Early Postnatal Exposure to Midazolam Causes Lasting Histological and Neurobehavioral Deficits via Activation of the mTOR Pathway. Int J Mol Sci 2024; 25:6743. [PMID: 38928447 PMCID: PMC11203812 DOI: 10.3390/ijms25126743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/11/2024] [Accepted: 06/16/2024] [Indexed: 06/28/2024] Open
Abstract
Exposure to general anesthetics can adversely affect brain development, but there is little study of sedative agents used in intensive care that act via similar pharmacologic mechanisms. Using quantitative immunohistochemistry and neurobehavioral testing and an established protocol for murine sedation, we tested the hypothesis that lengthy, repetitive exposure to midazolam, a commonly used sedative in pediatric intensive care, interferes with neuronal development and subsequent cognitive function via actions on the mechanistic target of rapamycin (mTOR) pathway. We found that mice in the midazolam sedation group exhibited a chronic, significant increase in the expression of mTOR activity pathway markers in comparison to controls. Furthermore, both neurobehavioral outcomes, deficits in Y-maze and fear-conditioning performance, and neuropathologic effects of midazolam sedation exposure, including disrupted dendritic arborization and synaptogenesis, were ameliorated via treatment with rapamycin, a pharmacologic mTOR pathway inhibitor. We conclude that prolonged, repetitive exposure to midazolam sedation interferes with the development of neural circuitry via a pathologic increase in mTOR pathway signaling during brain development that has lasting consequences for both brain structure and function.
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Affiliation(s)
- Jing Xu
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA; (J.X.); (J.W.); (R.P.M.); (S.S.); (S.H.B.); (J.C.); (Q.L.)
- Department of Anesthesiology, The First Affiliated Hospital of Xi’an Jiaotong University School of Medicine, Xi’an 710061, China
| | - Jieqiong Wen
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA; (J.X.); (J.W.); (R.P.M.); (S.S.); (S.H.B.); (J.C.); (Q.L.)
- Department of Anesthesiology, The Second Affiliated Hospital of Xi’an Jiaotong University School of Medicine, Xi’an 710000, China;
| | - Reilley Paige Mathena
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA; (J.X.); (J.W.); (R.P.M.); (S.S.); (S.H.B.); (J.C.); (Q.L.)
| | - Shreya Singh
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA; (J.X.); (J.W.); (R.P.M.); (S.S.); (S.H.B.); (J.C.); (Q.L.)
| | - Sri Harsha Boppana
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA; (J.X.); (J.W.); (R.P.M.); (S.S.); (S.H.B.); (J.C.); (Q.L.)
| | - Olivia Insun Yoon
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA; (J.X.); (J.W.); (R.P.M.); (S.S.); (S.H.B.); (J.C.); (Q.L.)
| | - Jun Choi
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA; (J.X.); (J.W.); (R.P.M.); (S.S.); (S.H.B.); (J.C.); (Q.L.)
| | - Qun Li
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA; (J.X.); (J.W.); (R.P.M.); (S.S.); (S.H.B.); (J.C.); (Q.L.)
| | - Pengbo Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Xi’an Jiaotong University School of Medicine, Xi’an 710000, China;
| | - Cyrus David Mintz
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA; (J.X.); (J.W.); (R.P.M.); (S.S.); (S.H.B.); (J.C.); (Q.L.)
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8
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Hang WX, Yang YC, Hu YH, Fang FQ, Wang L, Qian XH, Mcquillan PM, Xiong H, Leng JH, Hu ZY. General anesthetic agents induce neurotoxicity through oligodendrocytes in the developing brain. Zool Res 2024; 45:691-703. [PMID: 38766750 PMCID: PMC11188601 DOI: 10.24272/j.issn.2095-8137.2023.413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 04/01/2024] [Indexed: 05/22/2024] Open
Abstract
General anesthetic agents can impact brain function through interactions with neurons and their effects on glial cells. Oligodendrocytes perform essential roles in the central nervous system, including myelin sheath formation, axonal metabolism, and neuroplasticity regulation. They are particularly vulnerable to the effects of general anesthetic agents resulting in impaired proliferation, differentiation, and apoptosis. Neurologists are increasingly interested in the effects of general anesthetic agents on oligodendrocytes. These agents not only act on the surface receptors of oligodendrocytes to elicit neuroinflammation through modulation of signaling pathways, but also disrupt metabolic processes and alter the expression of genes involved in oligodendrocyte development and function. In this review, we summarize the effects of general anesthetic agents on oligodendrocytes. We anticipate that future research will continue to explore these effects and develop strategies to decrease the incidence of adverse reactions associated with the use of general anesthetic agents.
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Affiliation(s)
- Wen-Xin Hang
- Department of Anesthesiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Yan-Chang Yang
- Department of Anesthesiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Yu-Han Hu
- Department of Cell Biology, Yale University, New Haven, CT 06520, USA
| | - Fu-Quan Fang
- Department of Anesthesiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Lang Wang
- Department of Neurology of the First Affiliated Hospital, Interdisciplinary Institute of Neuroscience and Technology, School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310027, China
| | - Xing-Hua Qian
- Department of Anesthesiology, Jiaxing Maternity and Childcare Health Hospital, Jiaxing, Zhejiang 314009, China
| | - Patrick M Mcquillan
- Department of Anesthesiology, Penn State Hershey Medical Centre, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Hui Xiong
- Department of Anesthesiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Jian-Hang Leng
- Department of Central Laboratory, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang 310006, China. E-mail:
| | - Zhi-Yong Hu
- Department of Anesthesiology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China. E-mail:
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9
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Wang M, Feng N, Qin J, Wang S, Chen J, Qian S, Liu Y, Luo F. Abdominal surgery under ketamine anesthesia during second trimester impairs hippocampal learning and memory of offspring by regulating dendrite spine remodeling in rats. Neurotoxicology 2024; 101:82-92. [PMID: 38346645 DOI: 10.1016/j.neuro.2024.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 02/01/2024] [Accepted: 02/07/2024] [Indexed: 02/23/2024]
Abstract
Recent evidence showed that general anesthesia produces long-term neurotoxicity and cognitive dysfunction. However, it remains unclear whether maternal non-obstetric surgery under ketamine anesthesia during second trimester causes cognitive impairment in offspring. The present study assigned pregnant rats into three groups: 1) normal control group receiving no anesthesia and no surgery, 2) ketamine group receiving ketamine anesthesia for 2 h on the 14th day of gestation but no surgery, and 3) surgery group receiving abdominal surgery under ketamine anesthesia on the 14th day of gestation. On postnatal day 1, the offspring rats in Ketamine group and surgery group were assigned to receive intra-peritoneal injection of Senegenin (15 mg/kg), once per day for consecutive 14 days. The offspring's spatial perception, anxiety-like behavior, and learning and memory were evaluated. Then the offspring's hippocampal tissues were collected. The offspring of the surgery group were impaired in the spatial perception in the cliff avoidance test and the spatial learning and memory in the Morris water maze test. Accordingly, the activity of histone deacetylases increased, the protein levels of NEDD9, BDNF, p-TrkB, Syn and PSD-95 decreased, and the density of dendritic spines reduced in the hippocampus of the offspring of the surgery group, and such effects were not seen in the offspring of the ketamine group, neither in the offspring of control group. Senegenin alleviated the learning and memory impairment, and increased the protein levels of NEDD9, BDNF, p-TrkB, Syn and PSD-95 and the density of dendritic spines in the offspring of the surgery group. ketamine anesthesia plus surgery during second trimester impairs hippocampus-dependent learning and memory, and the deficits could be rescued by treatment with Senegenin.
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Affiliation(s)
- Mengdie Wang
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China
| | - Namin Feng
- Department of Anesthesiology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
| | - Jia Qin
- Rehabilitation Medical Center and Department of Anesthesiology, Zhejiang Provincial People's Hospital and Hangzhou Medical College Affiliated People's Hospital, Hangzhou, Zhejiang 310000, China
| | - Shengqiang Wang
- Department of Anesthesiology, Yichun People's Hospital, Yichun 336000, China
| | - Jiabao Chen
- Rehabilitation Medical Center and Department of Anesthesiology, Zhejiang Provincial People's Hospital and Hangzhou Medical College Affiliated People's Hospital, Hangzhou, Zhejiang 310000, China
| | - Shaojie Qian
- Rehabilitation Medical Center and Department of Anesthesiology, Zhejiang Provincial People's Hospital and Hangzhou Medical College Affiliated People's Hospital, Hangzhou, Zhejiang 310000, China
| | - Yulin Liu
- Department of Immunology, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Foquan Luo
- Rehabilitation Medical Center and Department of Anesthesiology, Zhejiang Provincial People's Hospital and Hangzhou Medical College Affiliated People's Hospital, Hangzhou, Zhejiang 310000, China.
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10
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Handlogten K. Pediatric regional anesthesiology: a narrative review and update on outcome-based advances. Int Anesthesiol Clin 2024; 62:69-78. [PMID: 38063039 DOI: 10.1097/aia.0000000000000421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Affiliation(s)
- Kathryn Handlogten
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota
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Alfouzan RK, Arun Gopinathan P, Ui Haq I, Iyer K, Nawab AA, Alhumaidan A. Bibliometric Evaluation of the 100 Top-Cited Articles on Anesthesiology. Cureus 2023; 15:e50959. [PMID: 38249230 PMCID: PMC10800154 DOI: 10.7759/cureus.50959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/22/2023] [Indexed: 01/23/2024] Open
Abstract
This review is a bibliometric analysis based on anesthesiology, which is a medical specialty that deals with a patient's complete preoperative, intraoperative, and postoperative care. The objective of the review attempts to analyze the bibliometric characteristics of the 100 most top-cited articles on anesthesiology. The meta-data of the study were collected from the Core Collection of Web of Science database. A title search option was employed, and "Anesthesia" and "Anesthesiology" were typed in two different search boxes separated with the Boolean operator ''OR''. Further, the data were sorted by highest citation order; later, "article" was selected from the filter of document type, and all other types of documents were excluded. Finally, downloaded the bibliographic details of the 100 top-cited articles. VOSviewer Software (version 1.6.10 by van Eck and Waltman) was used for bibliometric network analysis for co-authors and keywords. Pearson chi-square test was used for statistical analysis. The 100 top-cited articles were published between the years of 1971 and 2018. These articles gained a maximum of 1006 to a minimum of 276 citations with an average of 384.57 cites/article. Open accessed articles gained a slightly higher ratio of citations, while more than half of the articles were published in the two leading journals of "Anesthesiology" and "Anesthesia and Analgesia". There was no statistically significant difference in both citation analysis among open and closed access journals and Anesthesia vs Non-Anesthesia journals. Thirty-six articles were published in journals not specifically related to Anesthesia. Most of the top-cited articles were contributed by the United States, whereas Surgery and General Anesthesia were the two most occurred keywords. We conclude that all the top-cited articles in anesthesiology were contributed by authors who belonged to the developed nations and the United States outclassed the rest of the world. This bibliometric analysis would be valuable to practitioners, academics, researchers, and students to understand the dynamics of progress in the field of anesthesiology.
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Affiliation(s)
- Rakan Khalid Alfouzan
- Department of Anesthesiology, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, SAU
| | - Pillai Arun Gopinathan
- Department of Maxillofacial Surgery and Diagnostic Sciences, College of Dentistry, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, SAU
- Department of Maxillofacial Surgery and Diagnostic Sciences, King Abdullah International Medical Research Centre, Riyadh, SAU
| | - Ikram Ui Haq
- College of Dentistry, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, SAU
| | - Kiran Iyer
- Department of Preventive Dental Sciences, College of Dentistry, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, SAU
| | | | - Abdullah Alhumaidan
- Department of Medicine and Surgery, Imam Mohammad Ibn Saud Islamic University, Riyadh, SAU
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Traweek R, Phan V, Griesbach C, Hall C. General Surgery During Pregnancy and Gynecologic Emergencies. Surg Clin North Am 2023; 103:1217-1229. [PMID: 37838464 DOI: 10.1016/j.suc.2023.05.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2023]
Abstract
Nonobstetrical surgical emergencies can occur throughout pregnancy but are often difficult to diagnose due to the physiologic and anatomical changes that occur during pregnancy. Medical providers should have insight into these changes and be familiar with options for the diagnosis and management of common nonobstetrical surgical emergencies, such as appendicitis, cholecystitis, and small bowel obstruction. Surgeons should also be aware of obstetrical emergencies, such as ectopic pregnancy and severe vaginal bleeding, which may be life threatening to mother and the fetus. Intraoperatively, surgeons should be familiar with minimally invasive approaches for surgical diseases and special anesthetic considerations for pregnant patients.
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Affiliation(s)
- Raymond Traweek
- Baylor Scott & White Medical Center, 2401 South 31st Street, Temple, TX 76508, USA
| | - Vivy Phan
- Baylor Scott & White Medical Center, 2401 South 31st Street, Temple, TX 76508, USA
| | - Chad Griesbach
- Baylor Scott & White Medical Center, 2401 South 31st Street, Temple, TX 76508, USA
| | - Chad Hall
- Baylor Scott & White Medical Center, 2401 South 31st Street, Temple, TX 76508, USA.
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郭 志, 王 志, 曾 琳, 纪 雪. [Effects of propofol on myelin basic protein expression in zebrafish at different developmental stages]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2023; 43:1810-1814. [PMID: 37933659 PMCID: PMC10630208 DOI: 10.12122/j.issn.1673-4254.2023.10.21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Indexed: 11/08/2023]
Abstract
OBJECTIVE To observe the effect of propofol on the expression of myelin basic protein (MBP) in developing zebrafish and explore the possible mechanisms. METHODS A total of 180 zebrafish embryos at 6-48 h post-fertilization were randomly allocated into 3 equal groups and raised in fresh water (control group), water containing dimethyl sulfoxide (DMSO group) and water containing 30 μg/mL propofol (propofol group). On 3, 4, 5, 6, 7, 10 d post-fertilization, the juvenile fish were collected for detection of mRNA and protein expressions of MBP using RT-qPCR and Western blotting. TUNEL assay and immunofluorescence assay were used to detect apoptosis of the oligodendrocytes of the fish at 3 d post-fertilization; RT-qPCR and Western blotting were performed to detect the expressions of apoptosis-related factors caspase-8, caspase-9 and caspase-3. RESULTS Compared with the control group, the fish with propofol exposure showed significantly decreased mRNA and protein expression of MBP at 3-7 d post-fertilization (P<0.05) with increased apoptosis of the oligodendrocytes and upregulated expressions of caspase-8, caspase-9 and caspase-3 at both the mRNA and protein levels. CONCLUSION Propofol persistently inhibits MBP expression in developing zebrafish within a short term possibly by mediating apoptosis of the oligodendrocytes.
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Affiliation(s)
- 志华 郭
- />南方医科大学附属广东省人民医院(广东省医学科学院)麻醉科, 广东 广州 510080Department of Anesthesiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - 志鹏 王
- />南方医科大学附属广东省人民医院(广东省医学科学院)麻醉科, 广东 广州 510080Department of Anesthesiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - 琳玲 曾
- />南方医科大学附属广东省人民医院(广东省医学科学院)麻醉科, 广东 广州 510080Department of Anesthesiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
| | - 雪霞 纪
- />南方医科大学附属广东省人民医院(广东省医学科学院)麻醉科, 广东 广州 510080Department of Anesthesiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China
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Tomlinson C, Vlasova R, Al-Ali K, Young JT, Shi Y, Lubach GR, Alexander AL, Coe CL, Styner M, Fine J. Effects of anesthesia exposure on postnatal maturation of white matter in rhesus monkeys. Dev Psychobiol 2023; 65:e22396. [PMID: 37338252 PMCID: PMC11000522 DOI: 10.1002/dev.22396] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 09/21/2022] [Accepted: 03/24/2023] [Indexed: 06/21/2023]
Abstract
There is increasing concern about the potential effects of anesthesia exposure on the developing brain. The effects of relatively brief anesthesia exposures used repeatedly to acquire serial magnetic resonance imaging scans could be examined prospectively in rhesus macaques. We analyzed magnetic resonance diffusion tensor imaging (DTI) of 32 rhesus macaques (14 females, 18 males) aged 2 weeks to 36 months to assess postnatal white matter (WM) maturation. We investigated the longitudinal relationships between each DTI property and anesthesia exposure, taking age, sex, and weight of the monkeys into consideration. Quantification of anesthesia exposure was normalized to account for variation in exposures. Segmented linear regression with two knots provided the best model for quantifying WM DTI properties across brain development as well as the summative effect of anesthesia exposure. The resulting model revealed statistically significant age and anesthesia effects in most WM tracts. Our analysis indicated there were major effects on WM associated with low levels of anesthesia even when repeated as few as three times. Fractional anisotropy values were reduced across several WM tracts in the brain, indicating that anesthesia exposure may delay WM maturation, and highlight the potential clinical concerns with even a few exposures in young children.
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Affiliation(s)
- Chalmer Tomlinson
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Roza Vlasova
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Khalid Al-Ali
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jeffrey T Young
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Yundi Shi
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Gabriele R Lubach
- Harlow Center for Biological Psychology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Andrew L Alexander
- Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Christopher L Coe
- Harlow Center for Biological Psychology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Martin Styner
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
- Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jason Fine
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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15
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Feng J, Zhang X, Jiang M, Dai X, Li G, Liu Z. Effect of sevoflurane anesthesia to neonatal rat hippocampus by RNA-seq. Neurosci Lett 2023; 801:137141. [PMID: 36813076 DOI: 10.1016/j.neulet.2023.137141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/02/2023] [Accepted: 02/19/2023] [Indexed: 02/23/2023]
Abstract
BACKGROUND Sevoflurane is an inhalational anesthetic for the induction and maintenance of general anesthesia in pediatric surgery. However, few studies have paid attention to the multiple organ toxicity and the mechanism behind it. METHODS Inhalation anesthesia neonatal rat model were realized by exposing to 3.5% sevoflurane. RNA-seq was performed to find out how inhalation anesthesia affects the lung, cerebral cortex, hippocampus, and heart. Validation of RNA-seq results by QPCR after animal model establishment. Tunel assay detects cell apoptosis in each group. CCK-8, cell apoptosis assay and western blot assay validation of the role of siRNA-Bckdhb in the action of sevoflurane on rat hippocampal neuronal cells. RESULTS There are significant differences between different groups, especially the hippocampus and cerebral cortex. Bckdhb was significantly up-regulated in the hippocampus with sevoflurane-treated. Pathway analysis revealed several abundant pathways related to DEGs, e.g., protein digestion and absorption and PI3K-Akt signaling pathway. A series of cellular and animal experiments showed that siRNA-Bckdhb can inhibit the reduction of cellular activity caused by sevoflurane. CONCLUSION Bckdhb interference experiments indicated that sevoflurane induces hippocampal neuronal cells apoptosis by regulating Bckdhb expression. Our study provided new insights into the molecular mechanism of sevoflurane-induced brain damage in pediatrics.
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Affiliation(s)
- Jinhua Feng
- Department of Pharmacy, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, China
| | - Xuesong Zhang
- Department of Anesthesiology, Zhongshan Wusong Hospital, Fudan University, Shanghai, China
| | - Menglu Jiang
- Department of Anesthesiology, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, China
| | - Xu Dai
- Department of Anesthesiology, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, China
| | - Guowei Li
- Department of Anesthesiology, Wuxi Fifth People's Hospital Affiliated to Jiangnan University, Wuxi, China.
| | - Zhenqing Liu
- Department of Anesthesiology, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, China.
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Useinovic N, Jevtovic-Todorovic V. Controversies in Anesthesia-Induced Developmental Neurotoxicity. Best Pract Res Clin Anaesthesiol 2023. [DOI: 10.1016/j.bpa.2023.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
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Chen J, Xiao F, Chen L, Zhou Z, Wei Y, Zhong Y, Li L, Xie Y. Role of ferroptosis in hypoxic preconditioning to reduce propofol neurotoxicity. Front Pharmacol 2023; 14:1121280. [PMID: 36817119 PMCID: PMC9932196 DOI: 10.3389/fphar.2023.1121280] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 01/23/2023] [Indexed: 02/05/2023] Open
Abstract
Background: An increasing number of studies have reported that neurotoxicity of propofol may cause long-term learning and cognitive dysfunction. Hypoxic preconditioning has been shown to have neuroprotective effects, reducing the neurotoxicity of propofol. Ferroptosis is a new form of death that is different from apoptosis, necrosis, autophagy and pyroptosis. However, it is unclear whether hypoxic preconditioning reduces propofol neurotoxicity associated with ferroptosis. Thus, we aimed to evaluate the effect of propofol on primary hippocampal neurons in vitro to investigate the neuroprotective mechanism of hypoxic preconditioning and the role of ferroptosis in the reduction of propofol neurotoxicity by hypoxic preconditioning. Methods: Primary hippocampal neurons were cultured for 8 days in vitro and pretreated with or without propofol, hypoxic preconditioning, agonists or inhibitors of ferroptosis. Cell counting kit-8, Calcein AM, Reactive oxygen species (ROS), Superoxide dismutase (SOD), Ferrous iron (Fe2+), Malondialdehyde (MDA) and Mitochondrial membrane potential assay kit with JC-1 (JC-1) assays were used to measure cell viability, Reactive oxygen species level, Superoxide dismutase content, Fe2+ level, MDA content, and mitochondrial membrane potential. Cell apoptosis was evaluated using flow cytometry analyses, and ferroptosis-related proteins were determined by Western blot analysis. Results: Propofol had neurotoxic effects that led to decreased hippocampal neuronal viability, reduced mitochondrial membrane potential, decreased SOD content, increased ROS level, increased Fe2+ level, increased MDA content, increased neuronal apoptosis, altered expression of ferroptosis-related proteins and activation of ferroptosis. However, hypoxic preconditioning reversed these effects, inhibited ferroptosis caused by propofol and reduced the neurotoxicity of propofol. Conclusion: The neurotoxicity of propofol in developing rats may be related to ferroptosis. Propofol may induce neurotoxicity by activating ferroptosis, while hypoxic preconditioning may reduce the neurotoxicity of propofol by inhibiting ferroptosis.
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Affiliation(s)
- Jing Chen
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Fei Xiao
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lifei Chen
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhan Zhou
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yi Wei
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yu Zhong
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Li Li
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China,*Correspondence: Yubo Xie, ; Li Li,
| | - Yubo Xie
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China,Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, The First Affiliated Hospital of Guangxi Medical University, Nanning, China,*Correspondence: Yubo Xie, ; Li Li,
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Kiblawi R, Beck C, Keil O, Schukfeh N, Hofmann AD, Ure BM, Kuebler JF. Laparoscopic versus Open Inguinal Hernia Repair Is Feasible in Infants with Caudal Anesthesia and Spontaneous Respiration. Eur J Pediatr Surg 2023; 33:26-34. [PMID: 36220133 DOI: 10.1055/a-1958-7989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
INTRODUCTION Minimally invasive surgery (i.e., laparoscopy) and minimally invasive anesthesia (i.e., caudal anesthesia with spontaneous respiration) have separately shown benefits for inguinal hernia repair in infants, yet to what degree these techniques can be combined remains unknown. This study investigated whether laparoscopy impacts the feasibility of performing caudal anesthesia with spontaneous respiration in infants. METHODS Prospectively collected data of all infants less than 12 months old and over 3 kg weight who underwent laparoscopic indirect hernia repair (LAP) at our department from 2019 to 2021 were compared with a historical control-matched group of infants who underwent open repair (OPEN) from 2017 to 2021. We assessed the patients' characteristics, anesthesia, and surgical data as well as intra- and postoperative complications. RESULTS A total of 87 infants were included (LAP n = 29, OPEN n = 58). Caudal anesthesia with spontaneous respiration was feasible in 62.1% of cases (LAP n = 55.2%, OPEN n = 65.5%; nonsignificant). Neither group registered anesthetic intra- or postoperative complications. Sedatives were utilized in 97% of LAP patients versus 56.9% of OPEN patients (p < 0.00001). The airway was secured with a laryngeal mask in 89.7% of patients during LAP versus 41.4% during OPEN (p < 0.00001). No significant differences were found regarding the use frequency of opioids (48.3% LAP vs. 34.5% OPEN; nonsignificant) or neuromuscular blockers (6.9% LAP vs. 5.2% OPEN; nonsignificant). CONCLUSION This is the first comparative study on caudal anesthesia and spontaneous respiration in infants undergoing laparoscopic versus open inguinal hernia surgery. Laparoscopy increased the need for ventilatory support and sedatives but did not significantly impair the feasibility of caudal anesthesia and spontaneous respiration.
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Affiliation(s)
- Rim Kiblawi
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Niedersachsen, Germany
| | - Christiane Beck
- Anaesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Niedersachsen, Germany
| | - Oliver Keil
- Clinic for Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Niedersachsen, Germany
| | - Nagoud Schukfeh
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Niedersachsen, Germany
| | | | - Benno Manfred Ure
- Department of Pediatric Surgery, Hannover Medical School, Hannover, Niedersachsen, Germany
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Pikwer A, Yang B, Granström M, Mattsson N, Sadr-Azodi O. General anesthesia in early childhood and possible association with autism: a population-based matched cohort study. Minerva Anestesiol 2023; 89:22-31. [PMID: 36282219 DOI: 10.23736/s0375-9393.22.16543-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND In experimental animal studies, exposure to general anesthesia in early childhood may results in changes in infant brain morphology and behavior, potentially leading to the development of autistic behaviors in the long-term. However, in clinical studies the role of exposure to general anesthesia in early childhood and the risk of autism is unknown. METHODS This is a population-based cohort study including all children aged 0-5 years of age exposed to general anesthesia between 2001 and 2014 and a corresponding matched population without such an exposure. Propensity score calculation was based on 49 variables (including age of parents, malformations, APGAR Score, and family income, among others). Quasi-Poisson regression was used to estimate risk ratios (RRs) with 95% confidence intervals (CIs) for the association between exposure to general anesthesia and autism or autism spectrum disorder. RESULTS In total, 401,750 children exposed to general anesthesia were compared with 1,187,796 unexposed individuals. Autism or autism spectrum disorder were more common in the children exposed to general anesthesia as compared to unexposed children (1.65% and 0.98%, respectively, P<0.01). There was a statistically significant higher risk of autism or autism spectrum disorder in children exposed to general anesthesia as compared to unexposed children also after propensity score adjustment (RR 1.62, 95% CI: 1.57-1.67). CONCLUSIONS Exposure to general anesthesia in early childhood was associated with an increased risk of autism or autism spectrum disorder. Future studies are needed to asses if general anesthesia may cause autism or if the association is due to other factors.
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Affiliation(s)
- Andreas Pikwer
- Center for Clinical Research Sörmland, Uppsala University, Uppsala, Sweden - .,Department of Anesthesia, Eskilstuna County Hospital, Eskilstuna, Sweden -
| | - Bei Yang
- Center for Clinical Research Sörmland, Uppsala University, Uppsala, Sweden
| | - Malin Granström
- Center for Clinical Research Sörmland, Uppsala University, Uppsala, Sweden.,Department of Anesthesia, Eskilstuna County Hospital, Eskilstuna, Sweden
| | - Niklas Mattsson
- Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden.,Department of Neurology, Skåne University Hospital, Lund, Sweden.,Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
| | - Omid Sadr-Azodi
- Center for Clinical Research Sörmland, Uppsala University, Uppsala, Sweden.,Unit of Surgery, Department of Clinical Sciences, Intervention and Technology, Karolinska Institute, Stockholm, Sweden.,Department of Surgery, Saint Goran Hospital, Stockholm, Sweden
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mTORC1-Dependent and GSDMD-Mediated Pyroptosis in Developmental Sevoflurane Neurotoxicity. Mol Neurobiol 2023; 60:116-132. [PMID: 36224321 DOI: 10.1007/s12035-022-03070-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 10/05/2022] [Indexed: 12/30/2022]
Abstract
Developmental sevoflurane exposure leads to neuronal cell death, and subsequent learning and memory cognitive defects. The underlyi\ng mechanism remains to be elucidated. Gasdermin D (GSDMD)-mediated pyroptosis is a form of inflammatory cell death and participates in a variety of neurodegenerative diseases. Several studies illustrated that dysregulation of mTOR activity is involved in pyroptotic cell death. The current study was designed to interrogate the role of GSDMD-mediated pyroptosis and mTOR activity in developmental sevoflurane exposure. We found that inhibition of GSDMD pore formation with Disulfiram (DSF) or Necrosulfonamide (NSA) significantly attenuated sevoflurane neurotoxicity in vitro. In addition, treatment with DSF or NSA also mitigated damage-associated molecular patterns (DAMPs) release and subsequent plasma membrane rupture (PMR) induced by sevoflurane challenge. Further investigation showed that the overactivation of mTOR signaling is involved in sevoflurane induced pyroptosis both in vivo and in vitro. Intriguingly, we found that the DAMPs release and subsequent PMR triggered by developmental sevoflurane priming were compromised by knocking down the expression of mTORC1 component Raptor, but not mTORC2 component Rictor. Moreover, sevoflurane induced pyroptosis could also be restored by suppressing mTOR activity or knocking down the expressions of Ras-related small GTPases RagA or RagC. Finally, administration of DSF or NSA dramatically improved the spatial and emotional cognitive disorders without alternation of locomotor activity. Taken together, these results indicate that mTORC1-dependent and GSDMD-mediated pyroptosis contributes to the developmental sevoflurane neurotoxicity. Characterizing these processes may provide experimental evidence for the possible prevention of developmental sevoflurane neurotoxicity.
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Feng J, Lin H, Zhao Y, Yang Y, Zhuang X, Yu Y, Yu Y. Tandem mass tag-based quantitative proteomic analysis of effects of multiple sevoflurane exposures on the cerebral cortex of neonatal and adult mice. Front Neurol 2022; 13:1056947. [PMID: 36582614 PMCID: PMC9792844 DOI: 10.3389/fneur.2022.1056947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
Introduction Sevoflurane is the most commonly used general anesthetic in pediatric surgery, but it has the potential to be neurotoxic. Previous research found that long-term or multiple sevoflurane exposures could cause cognitive deficits in newborn mice but not adult mice, whereas short-term or single inhalations had little effect on cognitive function at both ages. The mechanisms behind these effects, however, are unclear. Methods In the current study, 6- and 60-day-old C57bl mice in the sevoflurane groups were given 3% sevoflurane plus 60% oxygen for three consecutive days, each lasting 2 hours, while those in the control group only got 60% oxygen. The cortex tissues were harvested on the 8th or 62nd day. The tandem mass tags (TMT)pro-based quantitative proteomics combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, Golgi staining, and western blotting analysis were applied to analyze the influences of multiple sevoflurane anesthesia on the cerebral cortex in mice with various ages. The Morris water maze (MWM) test was performed from postnatal day (P)30 to P36 or P84 to P90 after control or multiple sevoflurane treatment. Sevoflurane anesthesia affected spatial learning and memory and diminished dendritic spines primarily in newborn mice, whereas mature animals exhibited no significant alterations. Results A total of 6247 proteins were measured using the combined quantitative proteomics methods of TMTpro-labeled and LC-MS/MS, 443 of which were associated to the age-dependent neurotoxic mechanism of repeated sevoflurane anesthesia. Furthermore, western blotting research revealed that sevoflurane-induced brain damage in newborn mice may be mediated by increasing the levels of protein expression of CHGB, PTEN, MAP2c, or decreasing the level of SOD2 protein expression. Conclusion Our findings would help to further the mechanistic study of age-dependent anesthetic neurotoxicity and contribute to seek for effective protection in the developing brain under general anesthesia.
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Affiliation(s)
- Jingyu Feng
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China,Tianjin Institute of Anesthesiology, Tianjin, China
| | - Hua Lin
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China,Tianjin Institute of Anesthesiology, Tianjin, China
| | - Yue Zhao
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China,Tianjin Institute of Anesthesiology, Tianjin, China
| | - Yongyan Yang
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China,Tianjin Institute of Anesthesiology, Tianjin, China
| | - Xiaoli Zhuang
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China,Tianjin Institute of Anesthesiology, Tianjin, China
| | - Yang Yu
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China,Tianjin Institute of Anesthesiology, Tianjin, China,*Correspondence: Yang Yu
| | - Yonghao Yu
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China,Tianjin Institute of Anesthesiology, Tianjin, China,Yonghao Yu
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Bleeser T, Hubble TR, Van de Velde M, Deprest J, Rex S, Devroe S. Introduction and history of anaesthesia-induced neurotoxicity and overview of animal models. Best Pract Res Clin Anaesthesiol 2022. [DOI: 10.1016/j.bpa.2022.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
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Xiao A, Feng Y, Yu S, Xu C, Chen J, Wang T, Xiao W. General anesthesia in children and long-term neurodevelopmental deficits: A systematic review. Front Mol Neurosci 2022; 15:972025. [PMID: 36238262 PMCID: PMC9551616 DOI: 10.3389/fnmol.2022.972025] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundMillions of children experienced surgery procedures requiring general anesthesia (GA). Any potential neurodevelopmental risks of pediatric anesthesia can be a serious public health issue. Various animal studies have provided evidence that commonly used GA induced a variety of morphofunctional alterations in the developing brain of juvenile animals.MethodsWe conducted a systematic review to provide a brief overview of preclinical studies and summarize the existing clinical studies. Comprehensive literature searches of PubMed, EMBASE, CINAHL, OVID Medline, Web of Science, and the Cochrane Library were conducted using the relevant search terms “general anesthesia,” “neurocognitive outcome,” and “children.” We included studies investigating children who were exposed to single or multiple GA before 18, with long-term neurodevelopment outcomes evaluated after the exposure(s).ResultsSeventy-two clinical studies originating from 18 different countries published from 2000 to 2022 are included in this review, most of which are retrospective studies (n = 58). Two-thirds of studies (n = 48) provide evidence of negative neurocognitive effects after GA exposure in children. Neurodevelopmental outcomes are categorized into six domains: academics/achievement, cognition, development/behavior, diagnosis, brain studies, and others. Most studies focusing on children <7 years detected adverse neurocognitive effects following GA exposure, but not all studies consistently supported the prevailing view that younger children were at greater risk than senior ones. More times and longer duration of exposures to GA, and major surgeries may indicate a higher risk of negative outcomes.ConclusionBased on current studies, it is necessary to endeavor to limit the duration and numbers of anesthesia and the dose of anesthetic agents. For future studies, we require cohort studies with rich sources of data and appropriate outcome measures, and carefully designed and adequately powered clinical trials testing plausible interventions in relevant patient populations.
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Affiliation(s)
- Aoyi Xiao
- Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yingying Feng
- Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Shan Yu
- Department of Anesthesiology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Chunli Xu
- Department of Anesthesiology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Jianghai Chen
- Department of Hand Surgery, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Tingting Wang
- Department of Anesthesiology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- Tingting Wang
| | - Weimin Xiao
- Department of Anesthesiology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Weimin Xiao
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24
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Wong-Kee-You AMB, Loveridge-Easther C, Mueller C, Simon N, Good WV. The impact of early exposure to general anesthesia on visual and neurocognitive development. Surv Ophthalmol 2022; 68:539-555. [PMID: 35970232 DOI: 10.1016/j.survophthal.2022.08.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 08/03/2022] [Accepted: 08/08/2022] [Indexed: 11/19/2022]
Abstract
Every year millions of children are exposed to general anesthesia while undergoing surgical and diagnostic procedures. In the field of ophthalmology, 44,000 children are exposed to general anesthesia annually for strabismus surgery alone. While it is clear that general anesthesia is necessary for sedation and pain minimization during surgical procedures, the possibility of neurotoxic impairments from its exposure is of concern. In animals there is strong evidence linking early anesthesia exposure to abnormal neural development. but in humans the effects of anesthesia are debated. In humans many aspects of vision develop within the first year of life, making the visual system vulnerable to early adverse experiences and potentially vulnerable to early exposure to general anesthesia. We attempt to address whether the visual system is affected by early postnatal exposure to general anesthesia. We first summarize key mechanisms that could account for the neurotoxic effects of general anesthesia on the developing brain and review existing literature on the effects of early anesthesia exposure on the visual system in both animals and humans and on neurocognitive development in humans. Finally, we conclude by proposing future directions for research that could address unanswered questions regarding the impact of general anesthesia on visual development.
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Affiliation(s)
| | - Cam Loveridge-Easther
- Smith-Kettlewell Eye Research Institute, San Francisco, CA, USA; University of Auckland, Auckland, New Zealand
| | - Claudia Mueller
- Sutter Health, San Francisco, CA, USA; Stanford Children's Health, Palo Alto, CA, USA
| | | | - William V Good
- Smith-Kettlewell Eye Research Institute, San Francisco, CA, USA.
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25
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Yu Y, Yang M, Zhuang X, Pan J, Zhao Y, Yu Y. Effects of toxic apolipoprotein E fragments on Tau phosphorylation and cognitive impairment in neonatal mice under sevoflurane anesthesia. Brain Behav 2022; 12:e2702. [PMID: 35810473 PMCID: PMC9392520 DOI: 10.1002/brb3.2702] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/18/2022] [Accepted: 06/24/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Anesthesia induces Tau phosphorylation and cognitive impairment in young, but not adult, mice. Apolipoprotein E (ApoE) may play a protective role in neuronal activity and injury repair, whereas its toxic fragments are reported to induce neurodegeneration and neurocognitive impairment in patients with Alzheimer's disease (AD). Therefore, we set out to test the hypothesis that the difference in ApoE fragments, but not the full-length ApoE, contributes to the difference in Tau phosphorylation and neurocognitive functions following sevoflurane anesthesia in young mice. METHODS Sevoflurane was administered to wild-type (WT), ApoE-knockout (ApoE-KO), ApoE3-targeted replacement (ApoE3 expresses both full-length and fragmented ApoE), and ApoE2-targeted replacement (ApoE2 only expresses full-length ApoE) mice. The mRNA and protein levels of ApoE, phosphorylated Tau (pTau), and cognitive function were tested in the mice. RESULTS Sevoflurane anesthesia enhanced ApoE mRNA, total ApoE, full-length ApoE, ApoE fragments, Tau phosphorylation (AT8 and PHF1), and cognitive impairment in young mice, but not in adult mice. ApoE2, but not ApoE3 or ApoE-KO, mice showed reduced sevoflurane-induced pTau elevation and cognitive impairment. CONCLUSION These data suggest that elevated ApoE fragments rather than full-length ApoE might be one of the underlying mechanisms of age-dependent Tau phosphorylation and cognitive impairment in young mice following sevoflurane anesthesia.
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Affiliation(s)
- Yang Yu
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Anesthesiology, Tianjin, China
| | - Man Yang
- Department of Anesthesiology, Sichuan University West China Hospital, Chengdu, China
| | - Xiaoli Zhuang
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Anesthesiology, Tianjin, China
| | - Jiacheng Pan
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Anesthesiology, Tianjin, China
| | - Yue Zhao
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Anesthesiology, Tianjin, China
| | - Yonghao Yu
- Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Anesthesiology, Tianjin, China
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26
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Robinson EJ, Lyne TC, Blaise BJ. Safety of general anaesthetics on the developing brain: are we there yet? BJA OPEN 2022; 2:100012. [PMID: 37588272 PMCID: PMC10430845 DOI: 10.1016/j.bjao.2022.100012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 04/11/2022] [Indexed: 08/18/2023]
Abstract
Thirty years ago, neurotoxicity induced by general anaesthetics in the developing brain of rodents was observed. In both laboratory-based and clinical studies, many conflicting results have been published over the years, with initial data confirming both histopathological and neurodevelopmental deleterious effects after exposure to general anaesthetics. In more recent years, animal studies using non-human primates and new human cohorts have identified some specific deleterious effects on neurocognition. A clearer pattern of neurotoxicity seems connected to exposure to repeated general anaesthesia. The biochemistry involved in this neurotoxicity has been explored, showing differential effects of anaesthetic drugs between the developing and developed brains. In this narrative review, we start with a comprehensive description of the initial concerning results that led to recommend that any non-essential surgery should be postponed after the age of 3 yr and that research into this subject should be stepped up. We then focus on the neurophysiology of the developing brain under general anaesthesia, explore the biochemistry of the observed neurotoxicity, before summarising the main scientific and clinical reports investigating this issue. We finally discuss the GAS trial, the importance of its results, and some potential limitations that should not undermine their clinical relevance. We finally suggest some key points that could be shared with parents, and a potential research path to investigate the biochemical effects of general anaesthesia, opening up perspectives to understand the neurocognitive effects of repetitive exposures, especially in at-risk children.
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Affiliation(s)
- Emily J. Robinson
- School of Population Health and Environmental Sciences, King's College London, London, UK
| | - Tom C. Lyne
- Center for the Developing Brain, School of Biomedical Engineering and Imaging Sciences, King's College London, St. Thomas' Hospital, London, UK
| | - Benjamin J. Blaise
- Center for the Developing Brain, School of Biomedical Engineering and Imaging Sciences, King's College London, St. Thomas' Hospital, London, UK
- Department of Paediatric Anaesthetics, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK
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27
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Reighard C, Junaid S, Jackson WM, Arif A, Waddington H, Whitehouse AJO, Ing C. Anesthetic Exposure During Childhood and Neurodevelopmental Outcomes: A Systematic Review and Meta-analysis. JAMA Netw Open 2022; 5:e2217427. [PMID: 35708687 PMCID: PMC9204549 DOI: 10.1001/jamanetworkopen.2022.17427] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/29/2022] [Indexed: 01/05/2023] Open
Abstract
Importance Clinical studies of neurodevelopmental outcomes after anesthetic exposure have evaluated a range of outcomes with mixed results. Objective To examine via meta-analyses the associations between exposure to general anesthesia and domain-specific neurodevelopmental outcomes in children. Data Sources PubMed/MEDLINE, Embase, CINAHL, Web of Science and the Cochrane Library were searched from inception to August 31, 2021. Study Selection Inclusion criteria were exposures to procedures requiring general anesthesia at younger than 18 years and evaluation of long-term neurodevelopmental function after exposure. Studies lacking unexposed controls or focused on children with major underlying comorbidities were excluded. Data Extraction and Synthesis Extracted variables included effect size; hazard, risk, or odds ratio; number of exposures; procedure type; major comorbidities; age of exposure and assessment; presence of unexposed controls; and study design. Studies were independently reviewed by 2 coders, and review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were pooled using a random-effects model. Main Outcomes and Measures The main outcomes were standardized mean differences (SMD) for scores in the neurodevelopmental domains of academics, behavioral problems, cognition, executive function, general development, language, motor function, nonverbal reasoning, social cognition, and hazard and risk of neurodevelopmental disorder diagnoses. Results A total of 31 studies contributed data for meta-analysis. For each of the assessed neurodevelopmental domains, the numbers of children evaluated ranged from 571 to 63 315 exposed and 802 to 311 610 unexposed. Children with any exposure (single or multiple) had significantly worse behavioral problems scores, indicating more behavioral problems (SMD, -0.10; 95% CI, -0.18 to -0.02; P = .02), and worse scores in academics (SMD, -0.07; 95% CI -0.12 to -0.01; P = .02), cognition (SMD, -0.03; 95% CI, -0.05 to 0.00; P = .03), executive function (SMD, -0.20; 95% CI, -0.32 to -0.09; P < .001), general development (SMD, -0.08; 95% CI, -0.13 to -0.02; P = .01), language (SMD, -0.08; 95% CI, -0.14 to -0.02; P = .01), motor function (SMD, -0.11; 95% CI, -0.21 to -0.02; P = .02), and nonverbal reasoning (SMD, -0.15; 95% CI, -0.27 to -0.02; P = .02). Higher incidences of neurodevelopmental disorder diagnoses were also reported (hazard ratio, 1.19; 95% CI, 1.09 to 1.30; P < .001; risk ratio, 1.81; 95% CI, 1.25 to 2.61; P = .002). Conclusions and Relevance These findings support the hypothesis that associations between anesthetic exposure during childhood and subsequent neurodevelopmental deficits differ based on neurodevelopmental domain.
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Affiliation(s)
- Charles Reighard
- Department of Anesthesiology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
| | - Shaqif Junaid
- Department of Anesthesiology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
| | - William M. Jackson
- Department of Anesthesiology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
| | - Ayesha Arif
- Department of Anesthesiology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York
| | - Hannah Waddington
- Faculty of Education, Victoria University of Wellington, Wellington, New Zealand
| | | | - Caleb Ing
- Department of Anesthesiology and Epidemiology, Columbia University Vagelos College of Physicians and Surgeons and Mailman School of Public Health, New York, New York
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28
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Yin X, Jiang P, Li J. Dexmedetomidine Combined with Low-Dose Propofol Declines Learning and Memory Impairment and Neural Cell Injury in Developing Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2022; 2022:9543459. [PMID: 35685722 PMCID: PMC9173978 DOI: 10.1155/2022/9543459] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/13/2022] [Accepted: 05/19/2022] [Indexed: 11/30/2022]
Abstract
Background General anesthesia in early childhood may affect all aspects of neurodevelopment, resulting in learning and behavior defects. Therefore, there is an urgent need to find safe anesthetics or put forward more comprehensive anesthesia schemes to solve the negative effects caused by existing anesthetics. The objective of this study is to explore the impact of dexmedetomidine (Dex) incorporated with low-dose propofol (PRO) on learning and memory ability and neural cells in developing rats. Methods Eighty SD rats were randomly divided into 4 groups including the Sham group, Lipid group, L-PRO group, and Dex + L-PRO group. After treatment, the spatial learning and memory ability of rats in each group were assessed by the water maze test and the passive avoidance test. The damage of hippocampal tissues was assessed by Nissl staining; the apoptosis, the levels of inflammatory factors, and the level of oxidative stress were measured by Tunel staining, ELISA, and biochemical assays, respectively. Besides, qRT-PCR and Western Blot determined the expression of apoptosis-related proteins, neurotrophic factors, and MAPK signaling pathway-related proteins in the hippocampus. Results Compared with the L-PRO group, the Dex + L-PRO group had better spatial learning and memory ability. Administration of Dex and L-PRO greatly alleviated neural cell damage in the hippocampus and decreased the levels of IL-6, IL-1β, and TNF-α. Besides, it significantly decreased the content of ROS and malondialdehyde (MDA), glutathione (GSH), when up-regulating the levels of IL-10, antioxidant superoxide dismutase (SOD) and BDNF, receptor tyrosine kinase B (TrkB), and neurotrophin-3 (NT-3) related to hearing function and significantly lower activity of MAPK signaling pathway. Conclusion Dex combined with low-dose PRO can significantly inhibit inflammation, oxidative stress response, neuronal apoptosis, MAPK signaling pathway activity and promote the secretion of neurokines in hippocampus to reduce neural cell damage and avoid the learning and memory impairment caused by anesthetics in developing rats.
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Affiliation(s)
- Xiaoxu Yin
- Department of Anesthesiology, Huizhou Central People's Hospital, Huizhou, Guangdong 516001, China
| | - Peng Jiang
- Department of Anesthesiology, Huizhou Central People's Hospital, Huizhou, Guangdong 516001, China
| | - Jing Li
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi 710038, China
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29
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Donoso F, Beckman A, Malinovschi A, Engstrand Lilja H. Predictors of histopathological esophagitis in infants and adolescents with esophageal atresia within a national follow-up programme. PLoS One 2022; 17:e0266995. [PMID: 35427378 PMCID: PMC9012387 DOI: 10.1371/journal.pone.0266995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 03/25/2022] [Indexed: 11/18/2022] Open
Abstract
PURPOSE Esophageal atresia (EA) is a congenital anomaly of the foregut. Although the survival has improved over the years there is a significant gastrointestinal morbidity affecting physical function and health-related quality of life. The aims of the study were to identify and evaluate predictors of histopathological esophagitis in infants and adolescents with EA. METHODS Single centre, cross-sectional study including one and 15-year-old patients operated for EA that participated in the national follow-up programme between 2012 and 2020 according to a pre-established protocol including upper endoscopy with oesophageal biopsies and 24h-pH-test. Data was collected from patients' medical records and pH-analysis software. Regression models were used to identify predictors of histopathological oesophagitis. Possible predictors were abnormal reflux index, endoscopic esophagitis, hiatal hernia, symptoms of gastroesophageal reflux (GER) and age. RESULTS 65 patients were included, 47 children and 18 adolescents. All children were treated with PPI during their first year of life. Symptoms of GER were reported by 13 (31.7%) of the infant's caregivers, 34 of the children (72.3%) had abnormal reflux index and 32 (68.1%) had histopathological esophagitis. The corresponding numbers for adolescents were 8 (50%), 15 (83.3%) and 10 (55.6%). We found no significant associations between histopathological esophagitis and endoscopic esophagitis, symptoms of GER, hiatus hernia or age group. Abnormal reflux index was an independent predictor of histopathological esophagitis. Seven patients with normal reflux index had histopathological esophagitis, all grade I. CONCLUSIONS We found a high prevalence of histopathological esophagitis despite PPI treatment in accordance with recommendations. No significant difference between the two age groups was seen. Abnormal reflux index was an independent predictor of histopathological esophagitis. However, we cannot recommend the use of pH-metry as a substitute for esophageal biopsies; future studies are needed to elucidate if esophageal biopsies might be postponed in infants with normal reflux index.
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Affiliation(s)
- Felipe Donoso
- Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
- Section of Pediatric Surgery, Uppsala University Children’s Hospital, Uppsala, Sweden
| | - Anna Beckman
- Department of Medical Sciences, Clinical Physiology, Uppsala University, Uppsala, Sweden
| | - Andrei Malinovschi
- Department of Medical Sciences, Clinical Physiology, Uppsala University, Uppsala, Sweden
| | - Helene Engstrand Lilja
- Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
- Section of Pediatric Surgery, Uppsala University Children’s Hospital, Uppsala, Sweden
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30
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Nissen M, Rogge P, Sander V, Alrefai M, Romanova A, Tröbs RB. Pediatric Urachal Anomalies: Monocentric Experience and Mini-Review of Literature. CHILDREN 2022; 9:children9010072. [PMID: 35053696 PMCID: PMC8774176 DOI: 10.3390/children9010072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 12/31/2021] [Accepted: 01/02/2022] [Indexed: 11/16/2022]
Abstract
Background: Surgery is the current mainstay for the treatment of urachal anomalies (UA). Recent literature data support the theory of a spontaneous resolution within the first year of life. The aim of this study, comprising solely surgically treated children, was to identify age specific patterns regarding symptoms and outcomes that may support the non-surgical treatment of UA. Methods: Retrospective review on the clinico-laboratory characteristics of 52 children aged < 17 years undergoing resection of symptomatic UA at our pediatric surgical unit during 2006–2017. Data was dichotomized into age > 1 (n = 17) versus < 1 year (n = 35), and complicated (pre-/post-surgical abscess formation or peritonitis, n = 10) versus non-complicated course (n = 42). Results: Children aged < 1 year comprised majority (67%) of cohort and had lower complication rates (p = 0.062). Complicated course at surgery exclusively occurred in patients aged > 1 year (p = 0.003). Additionally, complicated group was older (p = 0.018), displayed leukocytosis (p < 0.001) and higher frequencies regarding presence of abdominal pain (p = 0.008) and abdominal mass (p = 0.034) on admission. Regression analysis identified present abdominal pain (OR (95% CI), 11.121 (1.152–107.337); p = 0.037) and leukocytosis (1.435 (1.070–1.925); p = 0.016) being associated with complicated course. Conclusions: This study provides evidence that symptomatic disease course follows an age-dependent complication pattern with lower complication rates at age < 1 year. Larger, studies have to clarify, if waiting for spontaneous urachal obliteration during the first year of life comprises a reasonable alternative to surgery.
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Affiliation(s)
- Matthias Nissen
- Department of Pediatric Surgery, Marien Hospital Witten, St. Elisabeth Group, Ruhr-University of Bochum, Marienplatz 2, D-58452 Witten, Germany; (P.R.); (V.S.); (M.A.); (A.R.)
- Correspondence: or ; Tel.: +49-23021733709; Fax: +49-23021731699
| | - Phillip Rogge
- Department of Pediatric Surgery, Marien Hospital Witten, St. Elisabeth Group, Ruhr-University of Bochum, Marienplatz 2, D-58452 Witten, Germany; (P.R.); (V.S.); (M.A.); (A.R.)
| | - Volker Sander
- Department of Pediatric Surgery, Marien Hospital Witten, St. Elisabeth Group, Ruhr-University of Bochum, Marienplatz 2, D-58452 Witten, Germany; (P.R.); (V.S.); (M.A.); (A.R.)
| | - Mohamad Alrefai
- Department of Pediatric Surgery, Marien Hospital Witten, St. Elisabeth Group, Ruhr-University of Bochum, Marienplatz 2, D-58452 Witten, Germany; (P.R.); (V.S.); (M.A.); (A.R.)
| | - Anna Romanova
- Department of Pediatric Surgery, Marien Hospital Witten, St. Elisabeth Group, Ruhr-University of Bochum, Marienplatz 2, D-58452 Witten, Germany; (P.R.); (V.S.); (M.A.); (A.R.)
| | - Ralf-Bodo Tröbs
- Department of Pediatric Surgery, St. Johannes Hospital, Helios Group, An der Abtei 7-11, D-47166 Duisburg, Germany;
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31
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Yu Y, Yang M, Zhuang X, Pan J, Feng J, Yu J, Yu Y. Neurotoxic 18-kDa apolipoprotein E fragment production contributes to anesthetic sevoflurane-induced tau phosphorylation and neuroinflammation in vitro. Hum Exp Toxicol 2022; 41:9603271221102519. [PMID: 35575159 DOI: 10.1177/09603271221102519] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Anesthesia may induce neuronal tau phosphorylation and neurotoxicity in the developing brain. Apolipoprotein E (ApoE) may play a protective role in neuronal activity and injury repair, whereas its 18-kDa fragments are reported to induce neurodegeneration and neuroinflammation in Alzheimer's disease patients. We aimed to test the hypothesis that differences in 18-kDa ApoE fragment levels, but not full-length ApoE, in primary neurons contribute to differences in tau phosphorylation and neuroinflammation with or without sevoflurane administration. Neurons extracted from wild-type (WT), ApoE knockout (ApoE-KO), and ApoE ε3-and ε2-targeted replacement (ApoE ε3, ApoE ε2) mice were divided into control and sevoflurane groups. Neurons in the sevoflurane group were treated with 21% O2, 5% CO2, and 4.1% sevoflurane, whereas those in the control group were treated with 21% O2 and 5% CO2 only on day 5 of neuronal culture. ApoE mRNA, full-length ApoE, 18-kDa ApoE fragments, Tau-PS202/PT205 (AT8), Tau-PSer396/404 (PHF1), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 and IL-1β levels were measured. The data showed that sevoflurane-induced AT8 and PHF1 increases, and TNF-α, IL-6, and IL-1β increases in WT or ApoE ε3 neurons (both expressing full-length and 18-kDa fragmented ApoE) could be mitigated in ApoE ε2 (only expressing full-length ApoE), but not in ApoE-KO neurons, indicating that differences in 18-kDa ApoE fragments, but not full-length ApoE, in primary mouse neurons contributed to differences in tau phosphorylation and neuroinflammation with or without 4.1% sevoflurane administration.
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Affiliation(s)
- Yang Yu
- Department of Anesthesiology, 117865Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Anesthesiology, Tianjin, China
| | - M Yang
- Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, China
| | - X Zhuang
- Department of Anesthesiology, 117865Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Anesthesiology, Tianjin, China
| | - J Pan
- Department of Anesthesiology, 117865Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Anesthesiology, Tianjin, China
| | - J Feng
- Department of Anesthesiology, 117865Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Anesthesiology, Tianjin, China
| | - J Yu
- Department of Anesthesiology, 117865Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Anesthesiology, Tianjin, China
| | - Yonghao Yu
- Department of Anesthesiology, 117865Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Institute of Anesthesiology, Tianjin, China
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32
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Schroepf S, Mayle PM, Kurz M, Wermelt JZ, Hubertus J. Prematurity is a critical risk factor for respiratory failure after early inguinal hernia repair under general anesthesia. Front Pediatr 2022; 10:843900. [PMID: 35958181 PMCID: PMC9357901 DOI: 10.3389/fped.2022.843900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
INTRODUCTION The purpose of this study was to determine the earliest timing of inguinal hernia repair under general anesthesia with minimized risk for respiratory complications during postoperative course. METHODS We performed a monocentric analysis of patient records of premature and full-term infants undergoing inguinal hernia repair between 2009 and 2016. In addition to demographic and medical parameters, preexisting conditions and the perioperative course were recorded. RESULTS The study included 499 infants (preterm n = 285; full term n = 214). The number of subsequently ventilated patients was particularly high among preterm infants with bronchopulmonary dysplasia, up to 45.3% (p < 0.001). Less than 10% of subsequent ventilation occurred in preterm infants after 45 weeks of postmenstrual age at the time of surgery or in patients with a body weight of more than 4,100 g. Preterm infants with a bronchopulmonary dysplasia had an increased risk of apneas (p < 0.05). Only 10% of the preterm babies with postoperative apneas weighed more than 3,600 g at the time of surgery or were older than 44 weeks of postmenstrual age. CONCLUSION Our data indicate that after the 45th week of postmenstrual age and a weight above 4,100 g, the risk for respiratory failure after general anesthesia seems to be significantly decreased in preterm infants.
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Affiliation(s)
- Sebastian Schroepf
- Department of Pediatrics and Neonatology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Paulina M Mayle
- Department of Pediatrics and Neonatology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.,Department of Internal Medicine, University Hospital Augsburg, Augsburg, Germany
| | - Matthias Kurz
- Department of Anesthesiology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Julius Z Wermelt
- Department of Anesthesiology and Pediatric Anesthesiology, Bürgerhospital Frankfurt am Main, Frankfurt am Main, Germany
| | - Jochen Hubertus
- Department of Pediatric Surgery, Ruhr-University Bochum, Bochum, Germany
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Schüttler C, Münster T, Gall C, Trollmann R, Schüttler J. General Anesthesia in the First 36 Months of Life–a Study of Cognitive Performance in Children Aged 7-11 Years (ANFOLKI-36). DEUTSCHES ARZTEBLATT INTERNATIONAL 2021; 118:835-841. [PMID: 34743788 DOI: 10.3238/arztebl.m2021.0355] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 03/28/2021] [Accepted: 10/04/2021] [Indexed: 01/20/2023]
Abstract
BACKGROUND Experimental data have shown that the developing brain is especially vulnerable to exogenous noxious substances. The potential effects of anesthetic drugs on brain growth and development are a matter of concern. Clinical studies of children who underwent general anesthesia in their earliest years can make a major contribution to our understanding of the effects of anesthetic drugs on infants and toddlers (i.e., children under age 5). METHODS Children born at term during the years 2007-2011 who were exposed to general anesthesia before their third birthday were included in the study. Data on general anesthesia were retrospectively evaluated, and the overall intelligence quotient (IQ) was determined prospectively as the primary target parameter. Children who had not been exposed to general anesthesia were recruited as a control group. The non-inferiority threshold was set at a difference of 5 IQ points out of a consideration of clinical relevance. RESULTS 430 complete data sets were available from exposed children and 67 from members of the control group. The exposed group achieved a mean IQ score of 108.2, with a 95% confidence interval of [107; 109.4]; the corresponding values in the control group were 113 [110; 116.1]. Both groups achieved a mean score that was higher than the expected 100 points. After adjustment for age, socioeconomic status, and sex, the difference between the two groups was 2.9 points [0.2; 5.6], indicating a significantly better outcome in the control group than in the exposed group. The non-inferiority threshold of 5 IQ points was within the confidence interval; thus, non-inferiority was not demonstrated. CONCLUSION The fact that both groups achieved a higher IQ score than the expected 100 points may be attributable, at least in part, to the restriction of the study to children born at term. The results indicate that general anesthesia in early childhood is not associated with markedly reduced intelligence in later years, although non-inferiority could not be demonstrated.
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Gao Z, Zhang J, Wang X, Yao M, Sun L, Ren Y, Qiu D. A retrospective study of electroencephalography burst suppression in children undergoing general anesthesia. Pediatr Investig 2021; 5:271-276. [PMID: 34938968 PMCID: PMC8666939 DOI: 10.1002/ped4.12287] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 05/20/2021] [Indexed: 12/19/2022] Open
Abstract
IMPORTANCE In children, anesthesia dosages are based on population pharmacokinetics and patient hemodynamics rather than patient-specific brain activity. Brain function is highly susceptible to the effects of anesthetics. OBJECTIVE The primary objective of this retrospective pilot study was to assess the prevalence of electroencephalography (EEG) burst suppression-a sign of deep anesthesia-in children undergoing general anesthesia. METHODS We analyzed EEG in patients aged 1-36 months who received sevoflurane or propofol as the primary anesthetic. Patient enrollment was stratified into two age groups: 1-12 months and 13-36 months. Burst suppression (voltage ≤ 5.0 mV, lasting > 0.5 seconds) was characterized by occurrence over anesthesia time. Associations with patient demographics and anesthetics were determined. RESULTS In total, 54 patients (33 males and 21 females) were included in the study [age 11.0 (5.0-19.5) months; weight 9.2 (6.5-11.0) kg]. The total prevalence of burst suppression was 56% (30/54). Thirty-three percent of patients experienced burst suppression during the surgical phase. The greatest proportion of burst suppression occurred during the induction phase. More burst suppression event occurrences (18/30) were observed in the patient under sevoflurane anesthesia (P = 0.024). Virtually all patients who received propofol boluses had burst suppression (P = 0.033). More burst suppression occurred in patients with hypotension (P < 0.001). During the surgical phase, a younger age was associated with more burst suppression (P = 0.002). INTERPRETATION EEG burst suppression was associated with younger age, inhalation anesthetics, propofol bolus, and lower arterial pressure.
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Affiliation(s)
- Zhengzheng Gao
- Department of AnesthesiologyBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Jianmin Zhang
- Department of AnesthesiologyBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Xiaoxue Wang
- Department of AnesthesiologyBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Mengnan Yao
- Department of AnesthesiologyBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Lan Sun
- Department of AnesthesiologyBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Yi Ren
- Department of AnesthesiologyBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Dongyu Qiu
- Department of AnesthesiologyBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
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Early Development of the GABAergic System and the Associated Risks of Neonatal Anesthesia. Int J Mol Sci 2021; 22:ijms222312951. [PMID: 34884752 PMCID: PMC8657958 DOI: 10.3390/ijms222312951] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/19/2021] [Accepted: 11/25/2021] [Indexed: 12/30/2022] Open
Abstract
Human and animal studies have elucidated the apparent neurodevelopmental effects resulting from neonatal anesthesia. Observations of learning and behavioral deficits in children, who were exposed to anesthesia early in development, have instigated a flurry of studies that have predominantly utilized animal models to further interrogate the mechanisms of neonatal anesthesia-induced neurotoxicity. Specifically, while neonatal anesthesia has demonstrated its propensity to affect multiple cell types in the brain, it has shown to have a particularly detrimental effect on the gamma aminobutyric acid (GABA)ergic system, which contributes to the observed learning and behavioral deficits. The damage to GABAergic neurons, resulting from neonatal anesthesia, seems to involve structure-specific changes in excitatory-inhibitory balance and neurovascular coupling, which manifest following a significant interval after neonatal anesthesia exposure. Thus, to better understand how neonatal anesthesia affects the GABAergic system, we first review the early development of the GABAergic system in various structures that have been the focus of neonatal anesthesia research. This is followed by an explanation that, due to the prolonged developmental curve of the GABAergic system, the entirety of the negative effects of neonatal anesthesia on learning and behavior in children are not immediately evident, but instead take a substantial amount of time (years) to fully develop. In order to address these concerns going forward, we subsequently offer a variety of in vivo methods which can be used to record these delayed effects.
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Assessing the Safety of a Novel Neonatal Anesthesia Protocol: A Review of 101 Patients With Early Cleft Lip Repair. J Craniofac Surg 2021; 32:2682-2686. [PMID: 34727471 DOI: 10.1097/scs.0000000000007964] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
PURPOSE Our study introduces a novel anesthetic protocol for neonates without using volatile agents with the goal to minimize potentially neurotoxic and pro-apoptotic agents. The authors evaluated the short-term safety and efficacy of our anesthetic protocol in patients undergoing early cleft lip repair (ECLR). METHODS A retrospective review of ECLR patients who underwent repair before 2.5 months of age within the last 4.3 years was performed. This sample was comprised of 2 groups, those who received either a standard volatile gas-based regimen or a dexmedetomidine-based neonatal anesthetic protocol (DBNAP). Patient demographics, medication dosing, anesthetic time (induction to extubation), major and minor complications, and medication side effects were compared between the 2 cohorts. RESULTS A total of 101 patients underwent ECLR. All patients were American Society of Anesthesiologists class 1 or 2. Mean age at surgery was 31 ± 13 days and mean anesthetic time was 179 ± 36 minutes. DBNAP was used in 65 patients while the standard anesthetic protocol was used in 36 patients. Patient weight was significantly lower in the DBNAP group (4.01 ± 0.61 versus 4.38 ± 0.72 kg, P = 0.007). There were no significant differences between the 2 cohorts when comparing anesthetic time, emergence time, complication rate, or medication side effects. CONCLUSION For patients undergoing ECLR, DBNAP is perioperatively equivalent to the anesthetic standard of care, demonstrating no major complications and acceptable rates of minor complications and medication side effects.
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Yang Y, Liang F, Gao J, Dong Y, Zhang Y, Yang G, Soriano SG, Feng HJ, Xie Z. Testosterone attenuates sevoflurane-induced tau phosphorylation and cognitive impairment in neonatal male mice. Br J Anaesth 2021; 127:929-941. [PMID: 34686310 DOI: 10.1016/j.bja.2021.08.028] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 08/14/2021] [Accepted: 08/26/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Sevoflurane anaesthesia induces phosphorylation of the microtubule-associated protein tau and cognitive impairment in neonatal, but not adult, mice. The underlying mechanisms remain largely to be determined. Sex hormones can be neuroprotective, but little is known about the influence of testosterone on age-dependent anaesthesia effects. METHODS Six- and 60-day-old male mice received anaesthesia with sevoflurane 3% for 2 h daily for 3 days. Morris water maze, immunoassay, immunoblotting, co-immunoprecipitation, nanobeam technology, and electrophysiology were used to assess cognition; testosterone concentrations; tau phosphorylation; glycogen synthase kinase-3β (GSK3β) activation; binding or interaction between tau and GSK3β; and neuronal activation in mice, cells, and neurones. RESULTS Compared with 60-day-old male mice, 6-day-old male mice had lower testosterone concentrations (3.03 [0.29] vs 0.44 [0.12] ng ml-1; P<0.01), higher sevoflurane-induced tau phosphorylation in brain (133 [20]% vs 100 [6]% in 6-day-old mice, P<0.01; 103 [8]% vs 100 [13]% in 60-day-old mice, P=0.77), and sevoflurane-induced cognitive impairment. Testosterone treatment increased brain testosterone concentrations (1.76 [0.10] vs 0.39 [0.05] ng ml-1; P<0.01) and attenuated the sevoflurane-induced tau phosphorylation and cognitive impairment in neonatal male mice. Testosterone inhibited the interaction between tau and GSK3β, and attenuated sevoflurane-induced inhibition of excitatory postsynaptic currents in hippocampal neurones. CONCLUSIONS Lower brain testosterone concentrations in neonatal compared with adult male mice contributed to age-dependent tau phosphorylation and cognitive impairment after sevoflurane anaesthesia. Testosterone might attenuate the sevoflurane-induced tau phosphorylation and cognitive impairment by inhibiting the interaction between tau and GSK3β.
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Affiliation(s)
- Yongyan Yang
- Department of Anesthesia, Tianjin Medical University General Hospital, Tianjin, People's Republic of China; Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Feng Liang
- Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Jie Gao
- Department of Anesthesiology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Yuanlin Dong
- Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Yiying Zhang
- Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Guang Yang
- Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA
| | - Sulpicio G Soriano
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Hua-Jun Feng
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Zhongcong Xie
- Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
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Li G, Cao F, Jin Y, Wang Y, Wang D, Zhou L. Role of NR2B/ERK signaling in the neuroprotective effect of dexmedetomidine against sevoflurane induced neurological dysfunction in the developing rat brain. Acta Neurobiol Exp (Wars) 2021; 81:271-278. [PMID: 34672297 DOI: 10.21307/ane-2021-025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Dexmedetomidine (DEX) is a potent α‑2 adrenergic receptor agonist and has been widely applied in clinic. The present study explored the protective effect of DEX on sevoflurane‑induced learning and cognitive impairment and examined its underlying mechanism. Sprague‑Dawley rat pups were exposed to 0.85% sevoflurane for 6 h and injected with DEX in different doses. The Morris water maze test was performed to evaluate the learning and memory function of rats. Western blot was used for the measurement of protein levels. The water maze results indicated that sevoflurane treatment increased the escape latency but reduced the time spent in the original quadrant of rats. The protein levels of NR2B, phosphorylated ERK were significantly influenced by sevoflurane. Ifenprodil administration alleviated sevoflurane‑induced neurological impairment. DEX treatment reversed the effect of sevoflurane on both escape latency and time in original quadrant in a dose manner, and pretreatment with DEX had the most dramatic effect. DEX regulated the NR2B/ERK signaling in sevoflurane treated rats. NR2B/ERK signaling is involved in sevoflurane induced neurological impairment. DEX may protect against sevoflurane induced neurological dysfunction in the developing rat brain via regulating the NR2B/ERK signaling.
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Affiliation(s)
- Guohua Li
- Department of Anesthesiology, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong, P.R. China
| | - Fang Cao
- Department of Orthopaedics, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong, P.R. China
| | - Yanwu Jin
- Department of Anesthesiology, the Second Hospital of Shandong University, Shandong University, Jinan, Shandong, P.R. China
| | - Yu Wang
- Department of Anesthesiology, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong, P.R. China
| | - Dawei Wang
- Department of Obstetrics, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, P.R. China
| | - Limin Zhou
- Department of Anesthesiology, the Second Affiliated Hospital of Shandong First Medical University, Taian, Shandong, P.R. China;
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Laporta ML, Sprung J, Fejedelem CA, Henning DT, Weaver AL, Hanson AC, Schroeder DR, Myers SM, Voigt RG, Weingarten TN, Flick RP, Warner DO. Association Between Exposure of Children to General Anesthesia and Autism Spectrum Disorder. J Autism Dev Disord 2021; 52:4301-4310. [PMID: 34618293 DOI: 10.1007/s10803-021-05305-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2021] [Indexed: 12/27/2022]
Abstract
This study tested the hypothesis that exposure of children prior to their third birthday to procedures requiring general anesthesia is associated with an increased incidence of autism spectrum disorder (ASD) in later life. This study employed a nested, 1:2 matched-case control study design using ASD cases identified in a population-based birth cohort of children born in Olmsted County, MN from 1976 to 2000. Matching variables included sex, date of birth, and mother's age in conditional logistic regression including 499 ASD cases and 998 controls. After adjusting for birth weight and health status, there was no significant association between exposure and ASD (OR 1.27 [95% CI 0.92-1.76]), indicating that general anesthesia is not associated with an increased risk of ASD.
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Affiliation(s)
- Mariana L Laporta
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Juraj Sprung
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Caroline A Fejedelem
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Dustin T Henning
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Amy L Weaver
- Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science, 200 First St SW, Rochester, MN, 55905, USA
| | - Andrew C Hanson
- Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science, 200 First St SW, Rochester, MN, 55905, USA
| | - Darrell R Schroeder
- Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science, 200 First St SW, Rochester, MN, 55905, USA
| | - Scott M Myers
- Geisinger Autism & Developmental Medicine Institute, 120 Hamm Drive Suite 2, Lewisburg, PA, 17837, USA
| | - Robert G Voigt
- Meyer Center for Developmental Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
| | - Toby N Weingarten
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Randall P Flick
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - David O Warner
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Dreuning KMA, van Tulder MW, Been JV, Rovers MM, de Graaff JC, Stevens MF, Anema JR, Twisk JWR, van Heurn LWE, Derikx JPM. Contralateral surgical exploration during inguinal hernia repair in infants (HERNIIA trial): study protocol for a multi-centre, randomised controlled trial. Trials 2021; 22:670. [PMID: 34593022 PMCID: PMC8481323 DOI: 10.1186/s13063-021-05606-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 09/05/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The incidence of metachronous contralateral inguinal hernia (MCIH) is high in infants with an inguinal hernia (5-30%), with the highest risk in infants aged 6 months or younger. MCIH is associated with the risk of incarceration and necessitates a second operation. This might be avoided by contralateral exploration during primary surgery. However, contralateral exploration may be unnecessary, leads to additional operating time and costs and may result in additional complications of surgery and anaesthesia. Thus, there is no consensus whether contralateral exploration should be performed routinely. METHODS The Hernia-Exploration-oR-Not-In-Infants-Analysis (HERNIIA) study is a multicentre randomised controlled trial with an economic evaluation alongside to study the (cost-)effectiveness of contralateral exploration during unilateral hernia repair. Infants aged 6 months or younger who need to undergo primary unilateral hernia repair will be randomised to contralateral exploration or no contralateral exploration (n = 378 patients). Primary endpoint is the proportion of infants that need to undergo a second operation related to inguinal hernia within 1 year after primary repair. Secondary endpoints include (a) total duration of operation(s) (including anaesthesia time) and hospital admission(s); (b) complications of anaesthesia and surgery; and (c) participants' health-related quality of life and distress and anxiety of their families, all assessed within 1 year after primary hernia repair. Statistical testing will be performed two-sided with α = .05 and according to the intention-to-treat principle. Logistic regression analysis will be performed adjusted for centre and possible confounders. The economic evaluation will be performed from a societal perspective and all relevant costs will be measured, valued and analysed. DISCUSSION This study evaluates the effectiveness and cost-effectiveness of contralateral surgical exploration during unilateral inguinal hernia repair in children younger than 6 months with a unilateral inguinal hernia. TRIAL REGISTRATION ClinicalTrials.gov NCT03623893 . Registered on August 9, 2018 Netherlands Trial Register NL7194. Registered on July 24, 2018 Central Committee on Research Involving Human Subjects (CCMO) NL59817.029.18. Registered on July 3, 2018.
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Affiliation(s)
- Kelly M A Dreuning
- Department of Paediatric Surgery, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam & Vrije Universiteit Amsterdam, Amsterdam Reproduction and Development Research Institute and the Amsterdam Public Health Research Institute, P.O. Box 22660, 1100 DD, Amsterdam, The Netherlands.
| | - Maurits W van Tulder
- Department of Health Sciences and Amsterdam Movement Science research institute, Faculty of Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.,Department of Physiotherapy & Occupational Therapy, Aarhus University Hospital, Aarhus, Denmark
| | - Jasper V Been
- Division of Neonatology, Department of Paediatrics, Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, The Netherlands.,Department of Public Health, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.,Department of Obstetrics and Gynaecology, Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | - Maroeska M Rovers
- Radboud Institute for Health Sciences, Department of Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Jurgen C de Graaff
- Department of Anaesthesiology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Markus F Stevens
- Department of Anaesthesiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Johannes R Anema
- Department of Public and Occupational Health, and the Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Jos W R Twisk
- Department of Methodology and Applied Biostatistics, and the Amsterdam Public Health research institute, Vrije Universiteit, Amsterdam, The Netherlands
| | - L W Ernest van Heurn
- Department of Paediatric Surgery, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam & Vrije Universiteit Amsterdam, Amsterdam Reproduction and Development Research Institute and the Amsterdam Public Health Research Institute, P.O. Box 22660, 1100 DD, Amsterdam, The Netherlands
| | - Joep P M Derikx
- Department of Paediatric Surgery, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam & Vrije Universiteit Amsterdam, Amsterdam Reproduction and Development Research Institute and the Amsterdam Public Health Research Institute, P.O. Box 22660, 1100 DD, Amsterdam, The Netherlands
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Quantitative behavioural phenotyping to investigate anaesthesia induced neurobehavioural impairment. Sci Rep 2021; 11:19398. [PMID: 34588499 PMCID: PMC8481492 DOI: 10.1038/s41598-021-98405-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 09/01/2021] [Indexed: 11/16/2022] Open
Abstract
Anaesthesia exposure to the developing nervous system causes neuroapoptosis and behavioural impairment in vertebrate models. Mechanistic understanding is limited, and target-based approaches are challenging. High-throughput methods may be an important parallel approach to drug-discovery and mechanistic research. The nematode worm Caenorhabditis elegans is an ideal candidate model. A rich subset of its behaviour can be studied, and hundreds of behavioural features can be quantified, then aggregated to yield a 'signature'. Perturbation of this behavioural signature may provide a tool that can be used to quantify the effects of anaesthetic regimes, and act as an outcome marker for drug screening and molecular target research. Larval C. elegans were exposed to: isoflurane, ketamine, morphine, dexmedetomidine, and lithium (and combinations). Behaviour was recorded, and videos analysed with automated algorithms to extract behavioural features. Anaesthetic exposure during early development leads to persisting behavioural variation (in total, 125 features across exposure combinations). Higher concentrations, and combinations of isoflurane with ketamine, lead to persistent change in a greater number of features. Morphine and dexmedetomidine do not appear to lead to behavioural impairment. Lithium rescues the neurotoxic phenotype produced by isoflurane. Findings correlate well with vertebrate research: impairment is dependent on agent, is concentration-specific, is more likely with combination therapies, and can potentially be rescued by lithium. These results suggest that C. elegans may be an appropriate model with which to pursue phenotypic screens for drugs that mitigate the neurobehavioural impairment. Some possibilities are suggested for how high-throughput platforms might be organised in service of this field.
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Yamasaki Y, Kamitani T, Sagiyama K, Matsuura Y, Hida T, Nagata H. Model-based iterative reconstruction for 320-detector row CT angiography reduces radiation exposure in infants with complex congenital heart disease. ACTA ACUST UNITED AC 2021; 27:42-49. [PMID: 33290239 DOI: 10.5152/dir.2020.19633] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE We investigated the impact of model-based iterative reconstruction (MBIR) on 320-detector row computed tomography angiography (CTA) in infants with complex congenital heart disease (CHD). METHODS Seventy infants with complex CHD who underwent 320-detector row CTA (40 boys and 30 girls; age range, 0-22 months; median age, 60 days) were retrospectively evaluated. First, the images were reconstructed by filtered back projection (FBP), hybrid iterative reconstruction (HIR), or MBIR in 20 cases, and variables were compared among the three iterative reconstruction methods (IR test). Second, the variables were compared between 25 cases scanned using HIR and 25 cases scanned using MBIR, with a 20 standard deviation noise level for both. Attenuation values and contrast-to-noise ratios (CNRs) of the great vessels and heart chambers were calculated. Total dose-length products were recorded for all patients (radiation dose: RD test). RESULTS In the IR test, the mean CNR values were 4.8±1.3 for FBP, 6.9±1.4 for HIR, and 8.2±1.7 for MBIR (P < 0.0001). The best subjective image qualities in the great vessels and heart chambers were obtained with MBIR. In RD testing, no significant differences between HIR and MBIR in image quality (CNR: HIR, 8.4±2.4; MBIR, 8.3±2.4) were observed. The effective dose was significantly lower for MBIR than for HIR (0.7±0.2 vs. 1.1±0.3 mSv; P < 0.001). CONCLUSION The MBIR algorithm significantly improved image quality and decreased radiation exposure in 320-row CTA of infants with complex CHD, providing an alternative to FBP or HIR that is both safer and produces better results.
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Affiliation(s)
- Yuzo Yamasaki
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Kamitani
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koji Sagiyama
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuko Matsuura
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoyuki Hida
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hazumu Nagata
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Platholi J, Hemmings HC. Effects of general anesthetics on synaptic transmission and plasticity. Curr Neuropharmacol 2021; 20:27-54. [PMID: 34344292 PMCID: PMC9199550 DOI: 10.2174/1570159x19666210803105232] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/26/2021] [Accepted: 08/02/2021] [Indexed: 11/22/2022] Open
Abstract
General anesthetics depress excitatory and/or enhance inhibitory synaptic transmission principally by modulating the function of glutamatergic or GABAergic synapses, respectively, with relative anesthetic agent-specific mechanisms. Synaptic signaling proteins, including ligand- and voltage-gated ion channels, are targeted by general anesthetics to modulate various synaptic mechanisms, including presynaptic neurotransmitter release, postsynaptic receptor signaling, and dendritic spine dynamics to produce their characteristic acute neurophysiological effects. As synaptic structure and plasticity mediate higher-order functions such as learning and memory, long-term synaptic dysfunction following anesthesia may lead to undesirable neurocognitive consequences depending on the specific anesthetic agent and the vulnerability of the population. Here we review the cellular and molecular mechanisms of transient and persistent general anesthetic alterations of synaptic transmission and plasticity.
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Affiliation(s)
- Jimcy Platholi
- Cornell University Joan and Sanford I Weill Medical College Ringgold standard institution - Anesthesiology New York, New York. United States
| | - Hugh C Hemmings
- Cornell University Joan and Sanford I Weill Medical College Ringgold standard institution - Anesthesiology New York, New York. United States
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Sun JJ, Zhu CY, Jiang HY. Exposure to general anaesthesia in childhood and the subsequent risk of attention-deficit hyperactivity disorder: A meta-analysis of cohort studies. Asian J Psychiatr 2021; 62:102708. [PMID: 34052708 DOI: 10.1016/j.ajp.2021.102708] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 05/10/2021] [Accepted: 05/21/2021] [Indexed: 11/20/2022]
Abstract
BACKGROUND The evidence for a relationship between general anaesthesia induced in childhood and the risk of attention-deficit hyperactivity disorder (ADHD) in later life is inconsistent. We systematically assessed whether such an association existed. METHODS We searched the PubMed and EMBASE databases for relevant cohort studies. Relative risks (RRs) and 95 % confidence intervals (CIs) were calculated to determine the relationship between induction of childhood general anaesthesia and the risk of ADHD in later life. RESULTS Seven studies (eight publications) on developmental outcomes after the induction of childhood general anaesthesia met our inclusion criteria but not our exclusion criteria. Repeat childhood general anaesthesia (RR = 1.84, 95 CI% 1.14-2.97; P < 0.001; I2 = 74.8 %), but not one-off general anaesthesia (RR = 1.09, 95 CI% 0.93-1.27; P = 0.301; I2 = 0%), was associated with an increased risk of ADHD in later life. The association was evident only when the total general anaesthesia exposure exceeded 90 min. CONCLUSIONS Our meta-analysis indicated that the effect of general anaesthesia on the risk of ADHD is dose- or duration-dependent.
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Affiliation(s)
- Ji-Jun Sun
- No.3 Psychiatry Department, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Chun-Yan Zhu
- No.6 Psychiatry Department, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Hai-Yin Jiang
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Anesthetic Exposure in Staged Versus Single-Stage Cleft Lip and Palate Repair: Can We Reduce Risk of Anesthesia-Induced Developmental Neurotoxicity? J Craniofac Surg 2021; 32:521-524. [PMID: 33704974 DOI: 10.1097/scs.0000000000007156] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
ABSTRACT Cleft lip and palate (CLP) repair is typically performed in a staged fashion, which requires multiple instances of anesthetic exposure during a critical period of infant neurodevelopment. One solution to this concern includes the implementation of a single-stage CLP repair performed between 6 and 12 months of age. This study aimed to compare total anesthetic exposure between single-stage and staged CLP repairs. A retrospective review of unilateral CLP repairs between 2013 and 2018 conducted at a single institution was performed. Patients underwent either traditional, staged lip and palate repair, or single-stage complete cleft repair, where palate, lip, alveolus, and nasal repair was performed simultaneously. Primary endpoints included: total surgical time and total anesthetic exposure. Secondary endpoints included: excess anesthesia time, recovery room time, length of stay, and type of anesthetic administered. Two hundred twenty-five (n = 225) unilateral CLP repairs were conducted at the Loma Linda University. Detailed anesthetic data for eighty-six (n = 86) single-stage and twenty-eight (n = 28) staged operations were available. There was a statistically significant decrease in anesthetic exposure in single-stage versus staged repairs (316 minutes versus 345 minutes, P = 0.017), despite similar procedure times (260 minutes versus 246 minutes, P = 0.224). This resulted in near double excess anesthetic exposure time in the staged group (98 minutes versus 56 minutes, P < 0.001), primarily occurring during induction. This analysis suggests that single-stage CLP repair can reduce wasted time under general anesthesia and potentially reduce harmful neuronal toxicity in the developmental period in this at-risk population.
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Wen X, Lawal OD, Belviso N, Matson KL, Wang S, Quilliam BJ, Meador KJ. Association Between Prenatal Opioid Exposure and Neurodevelopmental Outcomes in Early Childhood: A Retrospective Cohort Study. Drug Saf 2021; 44:863-875. [PMID: 34100263 DOI: 10.1007/s40264-021-01080-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2021] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Several studies have reported increasing prevalence of prescription opioid use among pregnant women. However, little is known regarding the effects of maternal opioid use on neurodevelopmental disorders in early childhood in pregnant women with no evidence of opioid use disorders or drug dependence. OBJECTIVE The aim of this study was to quantify the association between prenatal opioid exposure from maternal prescription use and neurodevelopmental outcomes in early childhood. METHODS This retrospective study included pregnant women aged 12-55 years and their live-birth infants born from 2010 to 2012 present in Optum's deidentified Clinformatics® Data Mart database. Eligible infants born to mothers without opioid use disorders or drug dependence were followed till occurrence of neurodevelopmental disorders, loss to follow-up, or study end (December 31, 2017), whichever came first. Propensity score by fine stratification was applied to adjust for confounding by demographic characteristics, obstetric characteristics, maternal comorbid mental and pain conditions, and measures of burden of illnesses and to obtain adjusted hazard ratios (HR) and 95% confidence intervals (CI). Exposed and unexposed infants were compared on the incidence of neurodevelopmental disorders. RESULTS Of 24,910 newborns, 7.6% (1899) were prenatally exposed to prescription opioids. Overall, 1562 children were diagnosed with neurodevelopmental disorders, with crude incidence rates of 2.9 per 100 person-years in exposed children versus 2.5 per 100 person-years in unexposed children. After adjustment, we observed no association between fetal opioid exposure and the risk of neurodevelopmental disorders (HR 1.10; 95% CI 0.92-1.32). However, increased risk of neurodevelopmental disorders were observed in children with longer cumulative exposure duration (HR 1.70; 95% CI 1.05-2.96) or high cumulative opioid doses (HR 1.22; 95% CI 1.01-1.54). CONCLUSION AND RELEVANCE In pregnant women without opioid use disorders or drug dependence, maternal opioid use was not associated with increased risk of neurodevelopmental disorders in early childhood. However, increased risks of early neurodevelopmental disorders were observed in children born to women receiving prescription opioids for longer duration and at higher doses during pregnancy.
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Affiliation(s)
- Xuerong Wen
- Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Suite 265F, Kingston, RI, 02881, USA.
| | - Oluwadolapo D Lawal
- Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Suite 265F, Kingston, RI, 02881, USA
| | - Nicholas Belviso
- Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Suite 265F, Kingston, RI, 02881, USA
| | - Kelly L Matson
- Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Suite 265F, Kingston, RI, 02881, USA
| | - Shuang Wang
- Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Suite 265F, Kingston, RI, 02881, USA
| | - Brian J Quilliam
- College of Health Sciences, University of Rhode Island, Kingston, RI, USA
| | - Kimford J Meador
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, California, CA, USA
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Wen J, Xu J, Mathena RP, Choi JH, Mintz CD. Early Isoflurane Exposure Impairs Synaptic Development in Fmr1 KO Mice via the mTOR Pathway. Neurochem Res 2021; 46:1577-1588. [PMID: 33791908 DOI: 10.1007/s11064-021-03301-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/23/2021] [Accepted: 03/17/2021] [Indexed: 12/16/2022]
Abstract
General anesthetics (GAs) may cause disruptions in brain development, and the effect of GA exposure in the setting of pre-existing neurodevelopmental disease is unknown. We tested the hypothesis that synaptic development is more vulnerable to GA-induced deficits in a mouse model of fragile X syndrome than in WT mice and asked whether they were related to the mTOR pathway, a signaling system implicated in both anesthesia toxicity and fragile X syndrome. Early postnatal WT and Fmr1-KO mice were exposed to isoflurane and brain slices were collected in adulthood. Primary neuron cultures isolated from WT and Fmr1-KO mice were exposed to isoflurane during development, in some cases treated with rapamycin, and processed for immunohistochemistry at maturity. Quantitative immunofluorescence microscopy was conducted for synaptic markers and markers of mTOR pathway activity. Isoflurane exposure caused reduction in Synpasin-1, PSD-95, and Gephyrin puncta that was significantly lower in Fmr1-KO mice than in WT mice. Similar results were found in cell culture, where synapse loss was ameliorated with rapamycin treatment. Early developmental exposure to isoflurane causes more profound synapse loss in Fmr1- KO than WT mice, and this effect is mediated by a pathologic increase in mTOR pathway activity.
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Affiliation(s)
- Jieqiong Wen
- Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Jing Xu
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - R Paige Mathena
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Jun H Choi
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - C David Mintz
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
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Zhou H, Xie Z, Brambrink AM, Yang G. Behavioural impairments after exposure of neonatal mice to propofol are accompanied by reductions in neuronal activity in cortical circuitry. Br J Anaesth 2021; 126:1141-1156. [PMID: 33641936 PMCID: PMC8216302 DOI: 10.1016/j.bja.2021.01.017] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 12/23/2020] [Accepted: 01/16/2021] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Both animal and retrospective human studies have linked extended and repeated general anaesthesia during early development with cognitive and behavioural deficits later in life. However, the neuronal circuit mechanisms underlying this anaesthesia-induced behavioural impairment are poorly understood. METHODS Neonatal mice were administered one or three doses of propofol, a commonly used i.v. general anaesthetic, over Postnatal days 7-11. Control mice received Intralipid® vehicle injections. At 4 months of age, the mice were subjected to a series of behavioural tests, including motor learning. During the process of motor learning, calcium activity of pyramidal neurones and three classes of inhibitory interneurones in the primary motor cortex were examined in vivo using two-photon microscopy. RESULTS Repeated, but not a single, exposure of neonatal mice to propofol i.p. caused motor learning impairment in adulthood, which was accompanied by a reduction of pyramidal neurone number and activity in the motor cortex. The activity of local inhibitory interneurone networks was also altered: somatostatin-expressing and parvalbumin-expressing interneurones were hypoactive, whereas vasoactive intestinal peptide-expressing interneurones were hyperactive when the mice were performing a motor learning task. Administration of low-dose pentylenetetrazol to attenuate γ-aminobutyric acid A receptor-mediated inhibition or CX546 to potentiate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-subtype glutamate receptor function during emergence from anaesthesia ameliorated neuronal dysfunction in the cortex and prevented long-term behavioural deficits. CONCLUSIONS Repeated exposure of neonatal mice to propofol anaesthesia during early development causes cortical circuit dysfunction and behavioural impairments in later life. Potentiation of neuronal activity during recovery from anaesthesia reduces these adverse effects of early-life anaesthesia.
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Affiliation(s)
- Hang Zhou
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Zhongcong Xie
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - Ansgar M Brambrink
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Guang Yang
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA.
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Neudecker V, Perez-Zoghbi JF, Brambrink AM. Recent advances in understanding cognitive and behavioural alterations after early-in-life anaesthesia exposure and new mitigation/alternative strategies in preclinical studies. Curr Opin Anaesthesiol 2021; 34:402-408. [DOI: 10.1097/aco.0000000000001016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Aksenov DP. Normal Development of Local Neurovascular Interactions and the Diagnostic Value of Resting State Functional MRI in Neurovascular Deficiency Based on the Example of Neonatal Anesthesia Exposure. Front Neurol 2021; 12:664706. [PMID: 33995262 PMCID: PMC8116565 DOI: 10.3389/fneur.2021.664706] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 04/08/2021] [Indexed: 01/25/2023] Open
Affiliation(s)
- Daniil P Aksenov
- Department of Radiology, NorthShore University HealthSystem, Evanston, IL, United States.,Department of Anesthesiology, NorthShore University HealthSystem, Evanston, IL, United States
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