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Wang G, Han Y, Peng K, Jiang Z, Wang T, Zheng Q, Li W, Xu H, Ji F, Li Z. Astragalin-functionalized ultrasmall nanoparticles modulate the complement pathway to inhibit microglial synaptic phagocytosis for reducing anesthetic neurotoxicity. Mater Today Bio 2025; 32:101714. [PMID: 40230643 PMCID: PMC11994406 DOI: 10.1016/j.mtbio.2025.101714] [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: 10/04/2024] [Revised: 03/10/2025] [Accepted: 03/28/2025] [Indexed: 04/16/2025] Open
Abstract
Synaptic impairment is identified as a primary pathology in sevoflurane-induced neurotoxicity, contributing to neurobehavioral and neurodevelopmental deficits. Synaptic loss in neurons occurs through microglia-mediated synaptic phagocytosis via the complement pathway. Astragalin, a natural flavonoid compound, exhibits diverse bioactivities, such as anti-tumor, anti-complement, and anti-inflammatory effects. Herein, astragalin-functionalized Cu 2-x Se nanoparticles (CSPA NPs) can effectively inhibit the complement pathway, mitigating microglia-mediated synaptic phagocytosis and promoting synaptic restoration to repair sevoflurane-induced neurotoxicity. They efficiently target and reduce microglial activation and phagocytosis. By downregulating sortilin, CSPA NPs increase progranulin expression, promoting TFEB cytoplasmic translocation to decrease lysosomal activity and microglial phagocytosis. Furthermore, CSPA NPs decrease complement C1q and C3 levels, inhibiting microglial synaptic engulfment and ameliorating cognition dysfunction in sevoflurane-treated mice. This study illustrates that CSPA NPs inhibit microglial synaptic elimination via the complement pathway, alleviating sevoflurane-induced neurotoxicity and providing insights into treating complement pathway-related diseases.
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Affiliation(s)
- Gang Wang
- Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Institute of Anesthesiology, Soochow University, Suzhou, Jiangsu, China
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Suzhou Medical College, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, China
| | - Yaobao Han
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Suzhou Medical College, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, China
| | - Ke Peng
- Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Institute of Anesthesiology, Soochow University, Suzhou, Jiangsu, China
| | - Zhilin Jiang
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Suzhou Medical College, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, China
| | - Tingting Wang
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Suzhou Medical College, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, China
| | - Qing Zheng
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Suzhou Medical College, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, China
| | - Wenting Li
- Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Institute of Anesthesiology, Soochow University, Suzhou, Jiangsu, China
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Suzhou Medical College, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, China
| | - Hanbing Xu
- Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Institute of Anesthesiology, Soochow University, Suzhou, Jiangsu, China
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Suzhou Medical College, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, China
| | - Fuhai Ji
- Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Institute of Anesthesiology, Soochow University, Suzhou, Jiangsu, China
| | - Zhen Li
- Center for Molecular Imaging and Nuclear Medicine, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Suzhou Medical College, Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, 215123, China
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Mares-Barbosa TB, Cuellar-Santoyo AO, Ruiz-Rodríguez VM, Hernández-Balderas K, González-Hernández O, Portales-Pérez DP, Estrada-Sánchez AM. Repeated administration of a subanesthetic dose of ketamine results in impaired motor and cognitive behavior and differential expression of hippocampal P2X1 and P2X7 receptors in adult mice. Behav Brain Res 2025; 482:115441. [PMID: 39842642 DOI: 10.1016/j.bbr.2025.115441] [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: 06/08/2024] [Revised: 12/31/2024] [Accepted: 01/17/2025] [Indexed: 01/24/2025]
Abstract
Ketamine hydrochloride serves multiple purposes, including its use as a general anesthetic, treatment for depression, and recreational drug. In studies involving rodents, ketamine is utilized as a model for schizophrenia. However, it is unclear whether age affects the behavioral response induced by repeated ketamine administration and if it modifies the expression levels of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and purinergic receptors (P2X1, P2X4, P2X7). In the present study, we evaluated the effect of intraperitoneal administration of subanesthetic ketamine dose (30 mg/Kg) for fourteen days on young (35 days of age) and adult (76 days of age) mice on different behavioral tests. Nest-building behavior was evaluated during the fourteen-day treatment; short-term memory and social interaction tests were assessed twenty-four hours after the last administration of ketamine. Interestingly, only adult mice treated with ketamine showed impaired nest-building and novel object recognition. In the hippocampus, an area related to memory and cognition, ketamine administration showed no changes in the relative expression of GluN1, P2X4, and P2X7 while increasing GluA2 and P2X1 only in young mice. In contrast, when assessing the protein levels of P2X1 and P2X7 in the hippocampus following ketamine treatment, young mice exhibited a decrease in P2X1 levels while P2X7 levels increased. In contrast, adult mice showed the opposite pattern; P2X1 levels were higher, and P2X7 levels decreased. These results suggest that adult mice are more vulnerable to repeated ketamine administration than young mice and that a differential response of P2X1 and P2X7 might contribute to ketamine-induced behavioral changes.
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Affiliation(s)
- Teresa Belem Mares-Barbosa
- Laboratorio de Neurobiología, División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica (IPICYT), San Luis Potosí, Mexico; Laboratorio de Medicina Molecular y Traslacional, Centro de Investigación en Ciencias de la Salud y Biomedicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
| | - Ares Orlando Cuellar-Santoyo
- Laboratorio de Neurobiología, División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica (IPICYT), San Luis Potosí, Mexico
| | - Victor Manuel Ruiz-Rodríguez
- Laboratorio de Neurobiología, División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica (IPICYT), San Luis Potosí, Mexico
| | - Karen Hernández-Balderas
- Laboratorio de Neurobiología, División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica (IPICYT), San Luis Potosí, Mexico
| | - Osiel González-Hernández
- Laboratorio de Medicina Molecular y Traslacional, Centro de Investigación en Ciencias de la Salud y Biomedicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
| | - Diana Patricia Portales-Pérez
- Laboratorio de Medicina Molecular y Traslacional, Centro de Investigación en Ciencias de la Salud y Biomedicina, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
| | - Ana María Estrada-Sánchez
- Laboratorio de Neurobiología, División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica (IPICYT), San Luis Potosí, Mexico.
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Bai H, Chen H, Du S, Qiu D, Li S, Ma T, Gao R, Zhang Z. N-Acetylcysteine Mitigates Ketamine Neurotoxicity in Young Rats by Modulating ROS-Mediated Pyroptosis and Ferroptosis. Mol Neurobiol 2025:10.1007/s12035-025-04860-2. [PMID: 40111652 DOI: 10.1007/s12035-025-04860-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 03/14/2025] [Indexed: 03/22/2025]
Abstract
Ketamine, an N-methyl-D-aspartate receptor antagonist with anesthetic and analgesic properties, is extensively utilized for the induction and maintenance of pediatric perioperative anesthesia. Increasing evidence suggests that prolonged exposure to ketamine may induce neurotoxicity in developing animals, adversely affecting their long-term cognitive function. N-acetylcysteine (NAC) is an organic sulfur compound in the Allium genus; however, the mechanisms through which it alleviates ketamine-induced neurotoxicity during developmental stages remain inadequately understood. Refine the investigation of the mechanisms by which Nac mitigates ketamine-induced neurotoxicity during development via ferroptosis and pyroptosis pathways. Postnatal day 7 in SD rats PC12 cells and HAPI cells were used in this study. The neuroprotective mechanism of Nac was elucidated through pathological, histological, and molecular biological methodologies to assess pyroptosis, ferroptosis, hippocampal tissue damage, and behavioral modifications in adulthood. The results suggest that prior administration of Nac reduced lipid peroxidation and mitochondrial injury, along with pyroptosis activated by the NLRP3/caspase-1 pathway, hippocampal damage, and cognitive deficits after exposure to ketamine. In summary, our findings from both in vivo and in vitro studies indicate that ROS plays a significant regulatory role in the neurotoxic effects of ketamine during development. Furthermore, Nac mitigates hippocampal damage and cognitive deficits associated with ketamine exposure by inhibiting ROS-mediated ferroptosis and pyroptosis.
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Affiliation(s)
- Hui Bai
- College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, China
- Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Hui Chen
- College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, China
- Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China
| | - Shan Du
- College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, China
- Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China
| | - Di Qiu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Siyao Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Tianwen Ma
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Ruifeng Gao
- College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, China.
- Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China.
| | - Zhiheng Zhang
- College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, China.
- Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, Hohhot, China.
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China.
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Cai Y, Yu F, Wu W, Chen W. Study on the mechanism of Dexmedetomidine's effect on postoperative cognitive dysfunction in elderly people. Front Physiol 2025; 16:1508661. [PMID: 40144543 PMCID: PMC11936804 DOI: 10.3389/fphys.2025.1508661] [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: 10/09/2024] [Accepted: 02/19/2025] [Indexed: 03/28/2025] Open
Abstract
Postoperative cognitive dysfunction (POCD) is a common complication among elderly patients following surgical procedures, significantly impairing postoperative recovery and quality of life. The selection and dosage of intraoperative anaesthetic drugs are frequently implicated as contributing factors in the development of POCD. In recent years, dexmedetomidine (DEX), a novel α2-adrenoceptor agonist, has been increasingly utilized in surgical anaesthesia for elderly patients, showing potential as both a preventive and therapeutic agent for POCD. This paper provides a comprehensive review of current research on the mechanisms by which DEX affects POCD in the elderly. Additionally, it explores DEX's mechanisms of action in the context of neuroprotection, anti-inflammation, antioxidative stress, and the regulation of apoptosis, autophagy, and analgesia. The objective is to provide reliable theoretical support and a reference point for the clinical application of DEX in POCD among the elderly, thereby promoting its broader use in clinical practice to improve outcomes and enhance quality of life.
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Affiliation(s)
- Yuanbin Cai
- Department of Anesthesiology, Putuo District Central Hospital, Shanghai, China
| | - Fan Yu
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Wei Wu
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Wurong Chen
- Department of Anesthesiology, Putuo District Central Hospital, Shanghai, China
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Nagai T, Yoda Y, Tokuda N, Takeshima Y, Hirose M, Shima M. Association between general anesthesia in early childhood and neurodevelopment up to 4 years of age: the Japan Environment and Children's Study. J Anesth 2024; 38:609-621. [PMID: 38847849 PMCID: PMC11415522 DOI: 10.1007/s00540-024-03359-9] [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: 09/28/2023] [Accepted: 05/29/2024] [Indexed: 09/01/2024]
Abstract
PURPOSE The effects of general anesthesia on neurodevelopment in children remain controversial. We explored the relationship between general anesthesia and neurodevelopment in children participating in the Japan Environment and Children's Study (JECS). METHODS This study enrolled children born between 37 and 41 weeks of pregnancy via single-vaginal delivery to pregnant women registered in the JECS between January 2011 and March 2014. Data were collected from mother-completed questionnaires and medical transcripts. Neurodevelopment in five domains was assessed every 6 months between 12 and 48 months of age, using the Ages and Stages Questionnaires. The associations between general anesthesia exposure during early childhood and neurodevelopment in children were evaluated at each time point. Adjusted odds ratios and 95% confidence intervals were estimated after covariate adjustment using logistic regression models. RESULTS Children who received general anesthesia before age 1 year had higher risks of neurodevelopmental delay in all five domains throughout the observational period. The largest risk was for gross motor delay at 18 months (adjusted odds ratio: 3.51; 95% confidence interval: 2.75-4.49). The effects on the incidence of neurodevelopmental delays after age 3 were not observed except for problem solving at 48 months. The risk of neurodevelopmental delay in children who first received general anesthesia after age 1 was considerably small. CONCLUSIONS This study suggests that general anesthesia administration before age 1 is associated with neurodevelopmental delay during 1-4 years of age. The risk of general anesthesia after age 1 may be small.
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Affiliation(s)
- Takahisa Nagai
- Department of Public Health, School of Medicine, Hyogo Medical University, Nishinomiya, 663-8501, Japan
| | - Yoshiko Yoda
- Department of Public Health, School of Medicine, Hyogo Medical University, Nishinomiya, 663-8501, Japan
- Hyogo Regional Center for the Japan Environment and Children's Study, Hyogo Medical University, Nishinomiya, 663-8501, Japan
| | - Narumi Tokuda
- Hyogo Regional Center for the Japan Environment and Children's Study, Hyogo Medical University, Nishinomiya, 663-8501, Japan
| | - Yasuhiro Takeshima
- Hyogo Regional Center for the Japan Environment and Children's Study, Hyogo Medical University, Nishinomiya, 663-8501, Japan
- Department of Pediatrics, School of Medicine, Hyogo Medical University, Nishinomiya, 663-8501, Japan
| | - Munetaka Hirose
- Hyogo Regional Center for the Japan Environment and Children's Study, Hyogo Medical University, Nishinomiya, 663-8501, Japan
- Department of Anesthesiology and Pain Medicine, School of Medicine, Hyogo Medical University, Nishinomiya, 663-8501, Japan
| | - Masayuki Shima
- Department of Public Health, School of Medicine, Hyogo Medical University, Nishinomiya, 663-8501, Japan.
- Hyogo Regional Center for the Japan Environment and Children's Study, Hyogo Medical University, Nishinomiya, 663-8501, Japan.
- School of Nursing, Hyogo Medical University, 1-3-6 Minatojima, Chuo-Ku, Kobe, Hyogo, 650-8530, Japan.
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Chen DX, Tan ZM, Lin XM. General Anesthesia Exposure in Infancy and Childhood: A 10-year Bibliometric Analysis. J Perianesth Nurs 2024; 39:772-781. [PMID: 38520467 DOI: 10.1016/j.jopan.2023.12.006] [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: 07/04/2023] [Revised: 11/23/2023] [Accepted: 12/04/2023] [Indexed: 03/25/2024]
Abstract
PURPOSE Heated discussions have divided health care providers and policymakers on the risks versus benefits of general anesthesia in pediatric populations. We conducted this study to provide a comprehensive bibliometric analysis of general anesthesia in this specific population over the past decade. DESIGN We summarized and quantitatively analyzed the studies related to general anesthesia in children and infants over the past decade. METHODS Using the Web of Science Core Collection as the data source, we analyzed the literature using CiteSpace software, focusing on authors, countries, institutions, keywords, and references to identify hotspots and predict research trends. FINDINGS A total of 2,364 publications on pediatric anesthesia were included in the analysis. The number of related publications and citations steadily increased from 2013 to 2022. The United States was the leading country in terms of output, and University of Toronto was the primary contributing institution. Co-citation analysis revealed that over the past decade research has mainly focused on the long-term adverse effects of general anesthesia on neurodevelopment and acute perioperative crisis events. Keyword analysis identified infant sedation and drug selection and compatibility as promising areas for development. In addition, improving the quality of perioperative anesthesia will be a major research focus in the future. CONCLUSIONS Recent research in pediatric anesthesia has focused on mitigating the adverse effects of general anesthesia in infants and young children and studying the pharmacological compatibility of anesthetics. Our study results would assist researchers and clinicians in understanding the current research status and optimizing clinical practice in this field.
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Affiliation(s)
- Dong X Chen
- Department of Anesthesiology, West China Second Hospital of Sichuan University, Chengdu, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan Province, China
| | - Zhi M Tan
- Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China
| | - Xue M Lin
- Department of Anesthesiology, West China Second Hospital of Sichuan University, Chengdu, Sichuan Province, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan Province, China.
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Colletti G, Di Bartolomeo M, Negrello S, Geronemus RG, Cohen B, Chiarini L, Anesi A, Feminò R, Mariotti I, Levitin GM, Rozell-Shannon L, Nocini R. Multiple General Anesthesia in Children: A Systematic Review of Its Effect on Neurodevelopment. J Pers Med 2023; 13:jpm13050867. [PMID: 37241037 DOI: 10.3390/jpm13050867] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 05/15/2023] [Accepted: 05/19/2023] [Indexed: 05/28/2023] Open
Abstract
The effect of multiple general anesthesia (mGA) procedures administered in early life is a critical theme and has led the Food and Drug Administration (FDA) to issue an alert. This systematic review seeks to explore the potential effects on neurodevelopment of mGA on patients under 4 years. The Medline, Embase and Web of Science databases were searched for publications up to 31 March 2021. The databases were searched for publications regarding "children multiple general anesthesia OR pediatric multiple general anesthesia". Case reports, animal studies and expert opinions were excluded. Systematic reviews were not included, but they were screened to identify any possible additional information. A total of 3156 studies were identified. After removing the duplicates, screening the remaining records and analyzing the systematic reviews' bibliography, 10 studies were considered suitable for inclusion. Comprehensively, a total cohort of 264.759 unexposed children and 11.027 exposed children were assessed for neurodevelopmental outcomes. Only one paper did not find any statistically significant difference between exposed and unexposed children in terms of neurodevelopmental alterations. Controlled studies on mGA administered before 4 years of age support that there might be a greater risk of neurodevelopmental delay in children receiving mGA, warranting the need for careful risk/benefit considerations.
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Affiliation(s)
- Giacomo Colletti
- Department of Medical and Surgical Sciences for Children & Adults, Cranio-Maxillo-Facial Surgery, University of Modena and Reggio Emilia, Largo del Pozzo 71, 41124 Modena, Italy
- The Vascular Birthmark Foundation, P.O. Box 106, Latham, NY 12110, USA
| | - Mattia Di Bartolomeo
- Unit of Dentistry and Maxillo-Facial Surgery, Surgery, Dentistry, Maternity and Infant Department, University of Verona, P.le L.A. Scuro 10, 37134 Verona, Italy
| | - Sara Negrello
- Cranio-Maxillo-Facial Surgery Unit, University Hospital of Modena, 41124 Modena, Italy
| | - Roy G Geronemus
- Laser and Skin Surgery Center of New York, New York, NY 10016, USA
| | - Bernard Cohen
- Pediatric Dermatology and Cutaneous Laser Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Luigi Chiarini
- Department of Medical and Surgical Sciences for Children & Adults, Cranio-Maxillo-Facial Surgery, University of Modena and Reggio Emilia, Largo del Pozzo 71, 41124 Modena, Italy
| | - Alexandre Anesi
- Department of Medical and Surgical Sciences for Children & Adults, Cranio-Maxillo-Facial Surgery, University of Modena and Reggio Emilia, Largo del Pozzo 71, 41124 Modena, Italy
| | - Raimondo Feminò
- Anesthesia and Intensive Care Unit, Department of General and Specialist Surgeries, University Hospital of Modena, 41124 Modena, Italy
| | - Ilaria Mariotti
- Onco-Hematology Paediatric Unit, Department of Medical and Surgical Sciences for Mothers, Children and Adults, University Hospital of Modena, 41124 Modena, Italy
| | - Gregory M Levitin
- The Vascular Birthmark Foundation, P.O. Box 106, Latham, NY 12110, USA
| | | | - Riccardo Nocini
- Section of Ear Nose and Throat (ENT), Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, 37124 Verona, Italy
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Fine-Raquet B, Manzella FM, Joksimovic SM, Dietz RM, Orfila JE, Sampath D, Tesic V, Atluri N, Covey DF, Raol YH, Jevtovic-Todorovic V, Herson PS, Todorovic SM. Neonatal exposure to a neuroactive steroid alters low-frequency oscillations in the subiculum. Exp Biol Med (Maywood) 2023; 248:578-587. [PMID: 37309730 PMCID: PMC10350800 DOI: 10.1177/15353702231177009] [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] [Indexed: 06/14/2023] Open
Abstract
Preclinical studies have established that neonatal exposure to contemporary sedative/hypnotic drugs causes neurotoxicity in the developing rodent and primate brains. Our group recently reported that novel neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) induced effective hypnosis in both neonatal and adult rodents but did not cause significant neurotoxicity in vulnerable brain regions such as subiculum, an output region of hippocampal formation particularly sensitive to commonly used sedatives/hypnotics. Despite significant emphasis on patho-morphological changes, little is known about long-term effects on subicular neurophysiology after neonatal exposure to neuroactive steroids. Hence, we explored the lasting effects of neonatal exposure to 3β-OH on sleep macrostructure as well as subicular neuronal oscillations in vivo and synaptic plasticity ex vivo in adolescent rats. At postnatal day 7, we exposed rat pups to either 10 mg/kg of 3β-OH over a period of 12 h or to volume-matched cyclodextrin vehicle. At weaning age, a cohort of rats was implanted with a cortical electroencephalogram (EEG) and subicular depth electrodes. At postnatal day 30-33, we performed in vivo assessment of sleep macrostructure (divided into wake, non-rapid eye movement, and rapid eye movement sleep) and power spectra in cortex and subiculum. In a second cohort of 3β-OH exposed animals, we conducted ex vivo studies of long-term potentiation (LTP) in adolescent rats. Overall, we found that neonatal exposure to 3β-OH decreased subicular delta and sigma oscillations during non-rapid eye movement sleep without altering sleep macrostructure. Furthermore, we observed no significant changes in subicular synaptic plasticity. Interestingly, our previous study found that neonatal exposure to ketamine increased subicular gamma oscillations during non-rapid eye movement sleep and profoundly suppressed subicular LTP in adolescent rats. Together these results suggest that exposure to different sedative/hypnotic agents during a critical period of brain development may induce distinct functional changes in subiculum circuitry that may persist into adolescent age.
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Affiliation(s)
- Brier Fine-Raquet
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Francesca M Manzella
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Srdjan M Joksimovic
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Robert M Dietz
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - James E Orfila
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Dayalan Sampath
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University, College Station, TX 77843, USA
| | - Vesna Tesic
- Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA
| | - Navya Atluri
- Department of Anesthesiology, University of Virginia, Charlottesville, VA 22903, USA
| | - Douglas F Covey
- Department of Developmental Biology, St. Louis School of Medicine, Washington University, St. Louis, MO 63130, USA
- Taylor Family Institute for Innovative Psychiatric Research, St. Louis School of Medicine, Washington University, St. Louis, MO 63130, USA
| | - Yogendra H Raol
- Department of Pediatrics, Division of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Rockville, MD 20824, USA
| | - Vesna Jevtovic-Todorovic
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Paco S Herson
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Slobodan M Todorovic
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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Vutskits L, Davidson A. Clinical investigations on anesthesia-induced developmental neurotoxicity: the knowns, the unknowns and future prospects. Best Pract Res Clin Anaesthesiol 2023. [DOI: 10.1016/j.bpa.2023.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
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10
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Fehr T, Janssen WG, Park J, Baxter MG. Neonatal exposures to sevoflurane in rhesus monkeys alter synaptic ultrastructure in later life. iScience 2022; 25:105685. [PMID: 36567715 PMCID: PMC9772858 DOI: 10.1016/j.isci.2022.105685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 11/02/2022] [Accepted: 11/24/2022] [Indexed: 12/02/2022] Open
Abstract
Repeated or prolonged early life exposure to anesthesia is neurotoxic in animals and associated with neurocognitive impairment in later life in humans. We used electron microscopy with unbiased stereological sampling to assess synaptic ultrastructure in dorsolateral prefrontal cortex (dlPFC) and hippocampal CA1 of female and male rhesus monkeys, four years after three 4-h exposures to sevoflurane during the first five postnatal weeks. This allowed us to ascertain long-term consequences of anesthesia exposure without confounding effects of surgery or illness. Synapse areas were reduced in the largest synapses in CA1 and dlPFC, predominantly in perforated spinous synapses in CA1 and nonperforated spinous synapses in dlPFC. Mitochondrial morphology and localization changed subtly in both areas. Synapse areas in CA1 correlated with response to a mild social stressor. Thus, exposure to anesthesia in infancy can cause long-term ultrastructural changes in primates, which may be substrates for long-term alterations in synaptic transmission and behavioral deficits.
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Affiliation(s)
- Tristan Fehr
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA,Section on Comparative Medicine, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - William G.M. Janssen
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Janis Park
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Mark G. Baxter
- Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA,Section on Comparative Medicine, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA,Corresponding author
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11
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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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12
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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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13
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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: 51] [Impact Index Per Article: 17.0] [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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14
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Abstract
Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins.
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15
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Bradford V, Gaiser R. Preservation of Fetal Viability During Noncardiac Surgery. Perioper Med (Lond) 2022. [DOI: 10.1016/b978-0-323-56724-4.00030-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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16
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Wali B, Sayeed I, Stein DG, Raper J. Prophylactic progesterone prevents adverse behavioural and neurocognitive effects of neonatal anaesthesia exposure in rat. Br J Anaesth 2021; 128:301-310. [PMID: 34920856 DOI: 10.1016/j.bja.2021.10.030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 10/02/2021] [Accepted: 10/28/2021] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Evidence from animal models and human studies suggests an association between early general anaesthesia exposure and development of long-lasting neurocognitive problems including learning and memory impairments and an anxious phenotype. Because millions of children each year undergo procedures that require anaesthesia, it is important to investigate ways to protect the vulnerable developing brain. We evaluated whether progesterone treatment administered before general anaesthesia exposure could prevent long-term anaesthesia-induced neurocognitive and behavioural changes. METHODS Female and male Long-Evans rat pups were repeatedly exposed to 2 h of sevoflurane or control procedures at postnatal days 7, 10, and 13. Subcutaneous injections of progesterone or vehicle were administered immediately before general anaesthesia exposure or control procedures. Neurobehavioural and cognitive outcomes were evaluated using elevated plus maze and Morris water maze tests. RESULTS Prophylactic progesterone treatment attenuated the chemokine (C-X-C motif) ligand 1 (CXCL1) response to sevoflurane exposure. Rats given vehicle treatment with general anaesthesia exposure exhibited increased anxiety on the elevated plus maze and learning and memory impairments on the Morris water maze. However, rats treated with progesterone before general anaesthesia lacked these impairments and performed in a similar manner to controls on both tasks. CONCLUSIONS Progesterone attenuated the anaesthesia-induced, acute peripheral inflammatory response and prevented cognitive and behavioural alterations associated with early repeated general anaesthesia exposure. Importantly, our results suggest that progesterone treatments given before general anaesthesia may help to protect the developing brain.
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Affiliation(s)
- Bushra Wali
- Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Iqbal Sayeed
- Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Donald G Stein
- Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, USA; Neuroscience and Behavioral Biology Program, Emory College of Arts and Sciences, Atlanta, GA, USA
| | - Jessica Raper
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
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17
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Shaw PH. Sedation and lumbar punctures for pediatric leukemia patients: The challenge of unintended consequences. Pediatr Blood Cancer 2021; 68:e29343. [PMID: 34519432 DOI: 10.1002/pbc.29343] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 08/25/2021] [Indexed: 11/11/2022]
Affiliation(s)
- Peter H Shaw
- Cancer and Blood Disorders Institute, Johns Hopkins All Children's Hospital, St. Petersburg, Florida, USA
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18
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Peng L, Liu X, Yang Y, Guo Q, Zhong T. Histone Deacetylase 2-Mediated Epigenetic Regulation is Involved in the Early Isoflurane Exposure-Related Increase in Susceptibility to Anxiety-Like Behaviour Evoked by Chronic Variable Stress in Mice. Neurochem Res 2021; 46:2333-2347. [PMID: 34101131 DOI: 10.1007/s11064-021-03368-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/14/2021] [Accepted: 05/28/2021] [Indexed: 10/21/2022]
Abstract
Increasing studies report that prolonged or multiple anaesthetic exposures early in life are associated with detrimental effects on brain function. Although studies have evaluated the detrimental effects on neurocognitive function, few have focused on long-term neuropsychiatric effects. In the present study, C57BL/6 mice received either three neonatal isoflurane exposures or control exposure. Starting on postnatal day 45, the mice were either exposed or not to a chronic variable stress (CVS) paradigm, and CVS-related neuropsychiatric performance was evaluated using a series of behavioural tests. The expression levels of histone 3 lysine 9 acetylation (acetyl-H3K9), brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein-binding protein, and histone deacetylases 1-4 in the amygdala were measured by immunoblotting or immunohistochemistry analysis. In mice with neonatal isoflurane exposure, the effects of sodium butyrate (NaB), a commonly used HDAC inhibitor, were examined on CVS-related behavioural and molecular alterations. The results showed that repeated neonatal isoflurane exposure did not affect innate depression-like and anxiety-like behaviours under non-stress conditions but facilitated the CVS-induced anxiety-like behavioural phenotype. Increased HDAC2 expression in the amygdala was associated with an increase in the CVS-induced repression of acetyl-H3K9 and BDNF expression and an enhanced CVS-evoked anxiety-like behavioural phenotype in mice neonatal isoflurane exposure. NaB significantly decreased the CVS-induced anxiety level by elevating acetyl-H3K9 and BDNF expression. These results suggested that early anaesthesia exposure facilitated chronic stress-induced neuropsychiatric outcomes, and the HDAC2-related epigenetic dysregulation of BDNF gene expression is involved in the underlying mechanism.
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Affiliation(s)
- Luofang Peng
- Teaching and Research Section of Clinical Nursing, Xiangya Hospital of Central South University, Xiangya Road, 87#, Changsha City, 410008, Hunan Province, People's Republic of China
- Department of Anaesthesiology and Operating Theatre Services, Xiangya Hospital of Central South University, Xiangya Road, 87#, Changsha City, 410008, Hunan Province, People's Republic of China
| | - Xian Liu
- Department of Anaesthesiology and Operating Theatre Services, Xiangya Hospital of Central South University, Xiangya Road, 87#, Changsha City, 410008, Hunan Province, People's Republic of China
- Teaching and Research Section of Anaesthesia and Critical Care Medicine, Xiangya Hospital of Central South University, Changsha City, Hunan Province, People's Republic of China
| | - Yong Yang
- Department of Anaesthesiology and Operating Theatre Services, Xiangya Hospital of Central South University, Xiangya Road, 87#, Changsha City, 410008, Hunan Province, People's Republic of China
- Teaching and Research Section of Anaesthesia and Critical Care Medicine, Xiangya Hospital of Central South University, Changsha City, Hunan Province, People's Republic of China
| | - Qulian Guo
- Department of Anaesthesiology and Operating Theatre Services, Xiangya Hospital of Central South University, Xiangya Road, 87#, Changsha City, 410008, Hunan Province, People's Republic of China
- Teaching and Research Section of Anaesthesia and Critical Care Medicine, Xiangya Hospital of Central South University, Changsha City, Hunan Province, People's Republic of China
| | - Tao Zhong
- Department of Anaesthesiology and Operating Theatre Services, Xiangya Hospital of Central South University, Xiangya Road, 87#, Changsha City, 410008, Hunan Province, People's Republic of China.
- Teaching and Research Section of Anaesthesia and Critical Care Medicine, Xiangya Hospital of Central South University, Changsha City, Hunan Province, People's Republic of China.
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19
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Wei Q, Chen J, Xiao F, Tu Y, Zhong Y, Xie Y. High-Dose Dexmedetomidine Promotes Apoptosis in Fetal Rat Hippocampal Neurons. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:2433-2444. [PMID: 34135573 PMCID: PMC8197572 DOI: 10.2147/dddt.s300247] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 05/04/2021] [Indexed: 11/23/2022]
Abstract
Objective Dexmedetomidine (DEX) is a potent a2-adrenoceptor agonist that has sedative, analgesic, and anxiolytic effects. Its primary clinical use is as an adjunct to general anesthesia to reduce anesthetic doses, provide analgesia and sedation in the preoperative and postoperative periods, it also used in intensive care units (ICUs). However, high concentrations of DEX may have toxic effects on neurons and cause neuronal apoptosis. This study aimed to evaluate the potential proapoptotic effects of DEX on fetal rat hippocampal neurons. Methods Primary hippocampal were cultured in vitro for 8 days and incubated with different DEX concentrations for 3 h. Cell viability was measured using cell counting kit-8 assays. Cell apoptosis was evaluated using flow cytometry. The expression of apoptosis-related proteins, such as cleaved caspase-3, caspase-9, Cyt-c, Bax, and Bcl-2, was measured by Western blotting. The mitochondrial ATP levels, Δψm, and ROS analyzed were conducted. Results High concentrations of DEX (≥100 μM) significantly reduced cell viability, induced neuronal apoptosis, upregulated the protein expression of cleaved caspase 3, Bax, cleaved caspase 9, and Cyt-c. DEX also considerably promoted the release of ROS. However, DEX (≥100 μM) downregulated the protein expression of Bcl-2, decreased the mitochondrial membrane potential (MTP), and reduced ATP synthesis. Conclusion High concentrations of dexmedetomidine produced toxic effects on neurons and caused neuronal apoptosis.
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Affiliation(s)
- Qiufeng Wei
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Jing Chen
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Fei Xiao
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Youbing Tu
- Department of Anesthesiology, Shenzhen People's Hospital, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, 518020, People's Republic of China
| | - Yu Zhong
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Yubo Xie
- Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People's Republic of China
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20
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Peng L, Zhu M, Yang Y, Lu F, Liu X, Guo Q, Zhong T. Repeated Neonatal Isoflurane Exposure is Associated with Higher Susceptibility to Chronic Variable Stress-induced Behavioural and Neuro-inflammatory Alterations. Neuroscience 2021; 465:166-176. [PMID: 33951503 DOI: 10.1016/j.neuroscience.2021.04.024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/11/2021] [Accepted: 04/21/2021] [Indexed: 01/22/2023]
Abstract
Numerous studies have reported that prolonged or multiple exposures to anaesthetics in early life lead to detrimental effects on brain function, most having focused on neurocognitive function, and relatively few on long term neuropsychiatric performance. The present study investigated the impact of repeated neonatal isoflurane exposure on chronic variable stress (CVS)-induced psychiatric and behavioural outcomes together with CVS-related neuronal activity and neuro-inflammatory reactivity in relevant brain circuits. In the present study, C57BL/6J mice received either three exposures to isoflurane at postnatal days 7, 8, and 9 or a control exposure. From postnatal day 45, mice were exposed to a mild, 3-week, CVS paradigm or none and the CVS-related neuropsychiatric performance was evaluated using a series of behavioural tests. The neuronal activity in relevant brain regions was measured by ΔFosB immunopositivity and CVS-related neuroinflammation was assessed by analysing levels of pro-inflammatory cytokines IL-1α, IL-1β, IL-6, and TNF-α. In mice experiencing serial neonatal isoflurane exposure, we detected a significant enhancement in anxiety levels following CVS procedures, together with enhanced neuronal activity, and exacerbated neuroinflammation in the basolateral amygdaloid nuclei (BLA) and hippocampal dentate gyrus (DG) regions. No such change was found in control mice. These results indicate an association between early multiple isoflurane exposures in infant mice and susceptibility to a CVS-evoked anxious phenotype accompanied by enhanced neuronal activity in BLA and DG regions and high inflammatory reactivity in response to CVS.
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Affiliation(s)
- Luofang Peng
- Teaching and Research Section of Clinical Nursing, Xiangya Hospital of Central South University, Changsha City, Hunan Province, PR China; Department of Anaesthesiology and Operating Theatre Services, Xiangya Hospital of Central South University, Changsha City, Hunan Province, PR China
| | - Maoen Zhu
- Department of Anaesthesiology and Operating Theatre Services, Xiangya Hospital of Central South University, Changsha City, Hunan Province, PR China; Teaching and Research Section of Anesthesia and Critical Care Medicine, Xiangya Hospital of Central South University, Changsha City, Hunan Province, PR China
| | - Yong Yang
- Department of Anaesthesiology and Operating Theatre Services, Xiangya Hospital of Central South University, Changsha City, Hunan Province, PR China; Teaching and Research Section of Anesthesia and Critical Care Medicine, Xiangya Hospital of Central South University, Changsha City, Hunan Province, PR China
| | - Feng Lu
- Department of Anaesthesiology and Operating Theatre Services, Xiangya Hospital of Central South University, Changsha City, Hunan Province, PR China; Teaching and Research Section of Anesthesia and Critical Care Medicine, Xiangya Hospital of Central South University, Changsha City, Hunan Province, PR China
| | - Xian Liu
- Department of Anaesthesiology and Operating Theatre Services, Xiangya Hospital of Central South University, Changsha City, Hunan Province, PR China; Teaching and Research Section of Anesthesia and Critical Care Medicine, Xiangya Hospital of Central South University, Changsha City, Hunan Province, PR China
| | - Qulian Guo
- Department of Anaesthesiology and Operating Theatre Services, Xiangya Hospital of Central South University, Changsha City, Hunan Province, PR China; Teaching and Research Section of Anesthesia and Critical Care Medicine, Xiangya Hospital of Central South University, Changsha City, Hunan Province, PR China
| | - Tao Zhong
- Department of Anaesthesiology and Operating Theatre Services, Xiangya Hospital of Central South University, Changsha City, Hunan Province, PR China; Teaching and Research Section of Anesthesia and Critical Care Medicine, Xiangya Hospital of Central South University, Changsha City, Hunan Province, PR China.
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21
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Neudecker V, Perez-Zoghbi JF, Coleman K, Neuringer M, Robertson N, Bemis A, Glickman B, Schenning KJ, Fair DA, Martin LD, Dissen GA, Brambrink AM. Infant isoflurane exposure affects social behaviours, but does not impair specific cognitive domains in juvenile non-human primates. Br J Anaesth 2020; 126:486-499. [PMID: 33198945 DOI: 10.1016/j.bja.2020.10.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 10/05/2020] [Accepted: 10/15/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Clinical studies show that children exposed to anaesthetics for short times at young age perform normally on intelligence tests, but display altered social behaviours. In non-human primates (NHPs), infant anaesthesia exposure for several hours causes neurobehavioural impairments, including delayed motor reflex development and increased anxiety-related behaviours assessed by provoked response testing. However, the effects of anaesthesia on spontaneous social behaviours in juvenile NHPs have not been investigated. We hypothesised that multiple, but not single, 5 h isoflurane exposures in infant NHPs are associated with impairments in specific cognitive domains and altered social behaviours at juvenile age. METHODS Eight Rhesus macaques per group were anaesthetised for 5 h using isoflurane one (1×) or three (3×) times between postnatal days 6 and 12 or were exposed to room air (control). Cognitive testing, behavioural assessments in the home environment, and provoked response testing were performed during the first 2 yr of life. RESULTS The cognitive functions tested did not differ amongst groups. However, compared to controls, NHPs in the 3× group showed less close social behaviour (P=0.016), and NHPs in the 1× group displayed increased anxiety-related behaviours (P=0.038) and were more inhibited towards novel objects (P<0.001). CONCLUSIONS 5 h exposures of NHPs to isoflurane during infancy are associated with decreased close social behaviour after multiple exposures and more anxiety-related behaviours and increased behavioural inhibition after single exposure, but they do not affect the cognitive domains tested. Our findings are consistent with behavioural alterations in social settings reported in clinical studies, which may guide future research.
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Affiliation(s)
- Viola Neudecker
- Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA
| | - Jose F Perez-Zoghbi
- Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA
| | - Kristine Coleman
- Division of Neuroscience, USA; Division of Comparative Medicine, Oregon National Primate Research Center, Beaverton, OR, USA
| | | | - Nicola Robertson
- Division of Comparative Medicine, Oregon National Primate Research Center, Beaverton, OR, USA
| | | | | | | | - Damien A Fair
- Department of Behavioural Neuroscience, Oregon Health & Science University, Portland, OR, USA
| | - Lauren D Martin
- Division of Comparative Medicine, Oregon National Primate Research Center, Beaverton, OR, USA
| | | | - Ansgar M Brambrink
- Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA.
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22
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Zhang X, Kong Y, He G, Zhou Z. Neonatal exposure to ketamine disrupts developmental synapse unsilencing and predisposes adult mice for stressor-evoked anxiety. Neuropharmacology 2020; 180:108300. [PMID: 32910951 DOI: 10.1016/j.neuropharm.2020.108300] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 08/05/2020] [Accepted: 09/04/2020] [Indexed: 11/25/2022]
Abstract
Accumulating evidence suggests long-lasting impairments in brain development and cognition caused by neonatal exposure to general anesthetics. To date, very little is known about potential abnormal psychiatric manifestations attributable to neonatal anesthesia. In this study, we used ketamine to induce anesthesia in neonatal mice. By applying mild stressors one day before behavioral tests, we found that adult mice exhibit significant anxiety-like behaviors that were indistinguishable at basal level. Recruitment of AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) type glutamate receptors into silent synapses is a prominent cellular process during neonatal neurodevelopment. We found that exposure to ketamine significantly disrupted synapse unsilencing, and impaired the expression of unsilencing-mediated long-term potentiation (LTP). Pharmacologically enhancement of neural activities by AMPAkine drug CX546 [1-(1,4-benzodioxan-6-ylcarbonyl) piperidine] effectively rescued disrupted developmental synapse unsilencing and LTP at neonatal age, and prevented stressor-evoked anxiety-like behaviors in adult mice. Together, our results indicate that neonatal exposure to ketamine may predispose individuals for psychiatric conditions via disrupting synapse unsilencing, and potentiation of neural activities during the anesthesia-recovery period may be an effective approach to manage adverse effects on brain development. This article is part of the special issue on 'Stress, Addiction and Plasticity'.
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Affiliation(s)
- Xiaoyun Zhang
- The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Yue Kong
- The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Guiqin He
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zikai Zhou
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
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23
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Lee HH, Faundez L, LoSasso AT. A Cross-Sectional Analysis of Community Water Fluoridation and Prevalence of Pediatric Dental Surgery Among Medicaid Enrollees. JAMA Netw Open 2020; 3:e205882. [PMID: 32785633 PMCID: PMC7424407 DOI: 10.1001/jamanetworkopen.2020.5882] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
IMPORTANCE Dental surgery under general anesthesia (DGA) is an ineffective, costly treatment for caries. Interventions to reduce the need for DGA are challenging because children's parents may not seek care until surgery is required. Community water fluoridation (CWF) effectively prevents early childhood caries, but its effectiveness in reducing severe early childhood caries is unknown. OBJECTIVE To determine whether access to CWF is associated with the prevalence of DGA. DESIGN, SETTING, AND PARTICIPANTS This is a cross-sectional analysis of Medicaid claims data from 2011 to 2012. Deidentified data were derived from Medicaid claims and enrollee files for Massachusetts, Texas, Connecticut, Illinois, and Florida for children aged 9 years and younger enrolled in either a fee-for-service or managed care plan through their state's Medicaid program. Linear regression models tested for associations between CWF and covariates. Multivariable linear regression models tested for associations between CWF and outcomes. Regression models included clustered SEs at the county level. Data analysis was performed from December 2018 to March 2020. EXPOSURES Access to CWF was determined by estimating the proportion of a county's total population that had access to a fluoridated public water system. MAIN OUTCOMES AND MEASURES The main outcome was county-level DGA prevalence. Other outcomes were caries-related visit prevalence and patient quality indicators (asthma and diabetes). Covariates included county-level demographic, socioeconomic, and dental practitioner variables. RESULTS A total of 436 counties within 5 states per year (872 county-year observations), were included in the analysis. Adjusted analysis revealed that a 10% increase in the proportion of county's population access to CWF was associated with lower caries-related visit prevalence (-0.45 percentage points; 95% CI, -0.59 to -0.31 percentage points; P < .001). Increasing CWF access in 10% increments was associated with decreased DGA prevalence in unadjusted analysis (-0.39 percentage points; 95% CI, -0.67 to -0.12 percentage points; P = .006) but not in adjusted analysis (-0.23 percentage points; 95% CI, -0.49 to 0.02 percentage points; P = .07). Increasing the proportion of county's access to CWF by 10% was not associated with the prevalence of asthma-related exacerbations (-0.02 percentage points; 95% CI, -0.10 to 0.05 percentage points; P = .53) or diabetes-related exacerbations (-0.0003 percentage points; 95% CI, -0.0014 to 0.0009 percentage points; P = .66). CONCLUSIONS AND RELEVANCE This study extends our understanding of CWF's benefits for children's oral health. Specifically, these findings suggest that increasing a population's access to CWF's is associated with decreased caries-related visits and may also be associated with use of dental surgical services within high-risk populations.
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Affiliation(s)
- Helen H. Lee
- Department of Anesthesiology, University of Illinois at Chicago, Chicago
| | - Luis Faundez
- Department of Economics, University of Illinois at Chicago, Chicago
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24
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Kimia R, Butler PD, Guajardo I, Magee L, Lowe K, Scott M, Wes A, Jackson OA. Sociodemographic Factors That Influence the Choice to Pursue Nasoalveolar Molding: One Pediatric Hospital's Experience. Cleft Palate Craniofac J 2020; 57:1069-1077. [PMID: 32618203 DOI: 10.1177/1055665620936056] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
OBJECTIVE To identify demographic factors that influence choosing nasoalveolar molding (NAM) in the treatment of cleft lip with or without cleft palate (CL±P), and NAM treatment compliance. DESIGN This work is a retrospective cohort study. SETTING Tertiary pediatric hospital. PATIENTS, PARTICIPANTS One hundred forty-nine patients with a diagnosis of unilateral complete CL±P receiving treatment when NAM was offered (January 1, 2008-July 26, 2016). MAIN OUTCOME MEASURE(S) Demographic variables collected included race, ethnicity, ZIP code, number of caregivers, caregiver employment status, and health insurance status. Medical variables collected included diagnosis, treatment pursued, compliance with NAM, completion of NAM, and the treating cleft surgeon and orthodontist. Data were analyzed via Fisher exact tests, χ2 tests, and multivariate logistic regression to identify factors that influence the decision to pursue NAM and treatment compliance. RESULTS Univariate analyses identified the following significant factors predicting the pursuit of NAM: race and insurance type (both P < .001), surgeon (P = .005), income level (P = .009), comorbidities (P = .015), and syndromic diagnosis (P = .033). Driving distance trended toward significance (P = .078). Multivariate regression analyses indicated that Asian race (P = .047), insurance type (P = .046), driving distance (P = .019), and surgeon (P = .017) were significant predictors of pursuit of NAM. CONCLUSIONS There are disparities in patient choice of NAM at our center for children with complete cleft lip. African American patient families were less likely to pursue this intervention. A stronger understanding of the barriers that lower income and minority patients face is needed in order to better characterize disparities in cleft care.
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Affiliation(s)
- Rotem Kimia
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Paris D Butler
- Division of Plastic and Reconstructive Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Isabella Guajardo
- Department of Surgery, UC San Diego School of Medicine, La Jolla, CA, USA
| | - Leanne Magee
- Division of Plastic and Reconstructive Surgery, The Children's Hospital of Philadelphia, PA, USA
| | - Kristen Lowe
- Division of Plastic and Reconstructive Surgery, Children's Hospital Colorado, Aurora, CO, USA
| | - Michelle Scott
- Division of Plastic and Reconstructive Surgery, The Children's Hospital of Philadelphia, PA, USA
| | - Ari Wes
- Division of Plastic and Reconstructive Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Oksana A Jackson
- Division of Plastic and Reconstructive Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.,Division of Plastic and Reconstructive Surgery, The Children's Hospital of Philadelphia, PA, USA
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25
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Manzella FM, Joksimovic SM, Orfila JE, Fine BR, Dietz RM, Sampath D, Fiedler HK, Tesic V, Atluri N, Raol YH, Jevtovic-Todorovic V, Herson PS, Todorovic SM. Neonatal Ketamine Alters High-Frequency Oscillations and Synaptic Plasticity in the Subiculum But Does not Affect Sleep Macrostructure in Adolescent Rats. Front Syst Neurosci 2020; 14:26. [PMID: 32528257 PMCID: PMC7264261 DOI: 10.3389/fnsys.2020.00026] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 04/21/2020] [Indexed: 11/13/2022] Open
Abstract
Exposure to sedative/hypnotic and anesthetic drugs, such as ketamine, during the critical period of synaptogenesis, causes profound neurotoxicity in the developing rodent and primate brains and is associated with poor cognitive outcomes later in life. The subiculum is especially vulnerable to acute neurotoxicity after neonatal exposure to sedative/hypnotic and anesthetic drugs. The subiculum acts as a relay center between the hippocampal complex and various cortical and subcortical brain regions and is also an independent generator of gamma oscillations. Gamma oscillations are vital in neuronal synchronization and play a role in learning and memory during wake and sleep. However, there has been little research examining long-term changes in subicular neurophysiology after neonatal exposure to ketamine. Here we explore the lasting effects of neonatal ketamine exposure on sleep macrostructure as well as subicular neuronal oscillations and synaptic plasticity in rats. During the peak of rodent synaptogenesis at postnatal day 7, rat pups were exposed to either 40 mg/kg of ketamine over 12 h or to volume matched saline vehicle. At weaning age, a subset of rats were implanted with a cortical and subicular electroencephalogram electrode, and at postnatal day 31, we performed in vivo experiments that included sleep macrostructure (divided into the wake, non-rapid eye movement, and rapid eye movement sleep) and electroencephalogram power spectra in cortex and subiculum. In a second subset of ketamine exposed animals, we conducted ex vivo studies of long-term potentiation (LTP) experiments in adolescent rats. Overall, we found that neonatal exposure to ketamine increased subicular gamma oscillations during non-rapid eye movement sleep but it did not alter sleep macrostructure. Also, we observed a significant decrease in subicular LTP. Gamma oscillations during non-rapid eye movement sleep are implicated in memory formation and consolidation, while LTP serves as a surrogate for learning and memory. Together these results suggest that lasting functional changes in subiculum circuitry may underlie neurocognitive impairments associated with neonatal exposure to anesthetic agents.
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Affiliation(s)
- Francesca M Manzella
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Srdjan M Joksimovic
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - James E Orfila
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Brier R Fine
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Robert M Dietz
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Dayalan Sampath
- Department of Neuroscience and Experimental Therapeutics, University of Texas A&M, College Station, TX, United States
| | - Hanna K Fiedler
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Vesna Tesic
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Navya Atluri
- Department of Anesthesiology, University of Virginia, Charlottesville, VA, United States
| | - Yogendra H Raol
- Department of Pediatrics, Division of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Vesna Jevtovic-Todorovic
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Paco S Herson
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Slobodan M Todorovic
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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26
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Martynyuk AE, Ju LS, Morey TE, Zhang JQ. Neuroendocrine, epigenetic, and intergenerational effects of general anesthetics. World J Psychiatry 2020; 10:81-94. [PMID: 32477904 PMCID: PMC7243620 DOI: 10.5498/wjp.v10.i5.81] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/18/2020] [Accepted: 03/26/2020] [Indexed: 02/05/2023] Open
Abstract
The progress of modern medicine would be impossible without the use of general anesthetics (GAs). Despite advancements in refining anesthesia approaches, the effects of GAs are not fully reversible upon GA withdrawal. Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly. Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research, but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects. The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents, which are far more extensively studied than any other species. Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated. Specifically, we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities (somatic effects), but also epigenetic reprogramming of germ cells (germ cell effects). The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring, who may be affected even at levels of anesthesia that are not harmful to the exposed parents. The large number of patients who require general anesthesia, the even larger number of their future unexposed offspring whose health may be affected, and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs. In this mini review, we discuss emerging experimental findings on neuroendocrine, epigenetic, and intergenerational effects of GAs.
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Affiliation(s)
- Anatoly E Martynyuk
- Department of Anesthesiology and the McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Jia-Qiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, Henan Province, China
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27
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Kobayashi Y, Tokuda N, Adachi S, Takeshima Y, Hirose M, Shima M. Association between surgical procedures under general anesthesia in infancy and developmental outcomes at 1 year: the Japan Environment and Children's Study. Environ Health Prev Med 2020; 25:32. [PMID: 32711462 PMCID: PMC7382792 DOI: 10.1186/s12199-020-00873-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 07/14/2020] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND The neurotoxicity of general anesthesia to the developing human brains is controversial. We assessed the associations between surgery under general anesthesia in infancy and development at age 1 year using the Japan Environment and Children's Study (JECS), a large-scale birth cohort study. METHODS In the JECS, 103,062 pregnancies and 104,065 fetuses were enrolled between January 2011 and March 2014. Of the 100,144 registered live births, we excluded preterm or post-term infants, multiple births, and infants with chromosomal anomalies and/or anomalies of the head or brain. Data on surgical procedures under general anesthesia in infancy were collected from self-administered questionnaires by parents at the 1-year follow-up. Developmental delay at age 1 year was assessed using the Japanese translation of the Ages and Stages Questionnaires, Third Edition (J-ASQ-3), comprising five developmental domains. RESULTS Among the 64,141 infants included, 746 infants had surgery under general anesthesia once, 90 twice, and 71 three or more times. The percentage of developmental delay in the five domains of the J-ASQ-3 significantly increased with the number of surgical procedures. After adjusting for potential confounding factors, the risk of developmental delays in all five domains was significantly increased in infants who had surgery under general anesthesia three times or more (adjusted odds ratios: for communication domain 3.32; gross motor domain 4.69; fine motor domain 2.99; problem solving domain 2.47; personal-social domain 2.55). CONCLUSIONS Surgery under general anesthesia in infancy was associated with an increased likelihood of developmental delay in all five domains of the J-ASQ-3, especially the gross motor domain at age 1 year. The neurodevelopment with the growth should be further evaluated among the children who had surgery under general anesthesia. TRIAL REGISTRATION UMIN Clinical Trials Registry (number: UMIN000030786 ).
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Affiliation(s)
- Yoshiko Kobayashi
- grid.272264.70000 0000 9142 153XHyogo Regional Center for the Japan Environment and Children’s Study, Hyogo College of Medicine, Nishinomiya, Japan ,grid.272264.70000 0000 9142 153XDepartment of Anesthesiology and Pain Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Narumi Tokuda
- grid.272264.70000 0000 9142 153XHyogo Regional Center for the Japan Environment and Children’s Study, Hyogo College of Medicine, Nishinomiya, Japan
| | - Sho Adachi
- grid.272264.70000 0000 9142 153XHyogo Regional Center for the Japan Environment and Children’s Study, Hyogo College of Medicine, Nishinomiya, Japan ,grid.272264.70000 0000 9142 153XDepartment of Public Health, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo 663-8501 Japan
| | - Yasuhiro Takeshima
- grid.272264.70000 0000 9142 153XHyogo Regional Center for the Japan Environment and Children’s Study, Hyogo College of Medicine, Nishinomiya, Japan ,grid.272264.70000 0000 9142 153XDepartment of Pediatrics, Hyogo College of Medicine, Nishinomiya, Japan
| | - Munetaka Hirose
- grid.272264.70000 0000 9142 153XHyogo Regional Center for the Japan Environment and Children’s Study, Hyogo College of Medicine, Nishinomiya, Japan ,grid.272264.70000 0000 9142 153XDepartment of Anesthesiology and Pain Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Masayuki Shima
- Hyogo Regional Center for the Japan Environment and Children's Study, Hyogo College of Medicine, Nishinomiya, Japan. .,Department of Public Health, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
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28
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Holmer N, Artola E, Christianson E, Lynn AM, Whitlock KB, Norton S. Feasibility of Acupuncture to Induce Sleep for Brainstem Auditory Evoked Response Testing. Am J Audiol 2019; 28:895-907. [PMID: 31747523 DOI: 10.1044/2019_aja-19-0069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Purpose Brainstem auditory evoked response (BAER) testing is often performed under general anesthesia for children unable to complete behavioral audiologic evaluation. Alternatively, acupuncture treatment may be considered appropriate for BAER. Reports of acupuncture treatment in pediatric patients are scarce but are needed to demonstrate effectiveness. This study had 2 main objectives: (a) to examine the feasibility and effectiveness of acupuncture to achieve sleep to perform diagnostic BAER testing in medically complex (Cohort I) and nonmedically complex (Cohort II) children and (b) to assess acceptability to parents and audiologists of acupuncture as an alternative to anesthesia for BAER testing. Method A prospective feasibility study at Seattle Children's Hospital Outpatient Audiology Clinic from August 2015 through December 2018 was performed. A total of 31 pediatric patients were included. The median age for Cohort I was 29 months (interquartile range: 19-37 months), and the median age for Cohort II was 25.5 months (interquartile range: 16-32 months). Variables included number of BAER thresholds obtained, sleep indicators, and acceptability. The cost of BAER with acupuncture and the cost of BAER under anesthesia were compared. Results Acupuncture treatment effectively contributed to an adequate sleep state to obtain BAER results for most patients in both cohorts. Across cohorts, most patients (81%) fell asleep after acupuncture treatment. Complete test results were obtained in 48% of patients. Audiologists and parents reported high satisfaction rates with this procedure (87%). There were no adverse safety effects. Acupuncture treatment was less costly than anesthesia for BAER testing. Conclusions Acupuncture to induce sleep for BAER testing is effective, safe, and cost-efficient in small samples of medically and nonmedically complex pediatric patients. This procedure allowed earlier detection of hearing status and avoided potential adverse effects of anesthesia. Audiologists and parents reported that acupuncture treatment was an acceptable alternative to anesthesia for the BAER procedure.
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Affiliation(s)
- Nicole Holmer
- Division of Audiology, Seattle Children's Hospital, WA
| | - Elizabeth Artola
- Department of Anesthesia and Pain Medicine, Seattle Children's Hospital, WA
| | | | - Anne M. Lynn
- Department of Anesthesia and Pain Medicine, Seattle Children's Hospital, WA
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle
| | - Kathryn B. Whitlock
- Department of Otolaryngology–Head and Neck Surgery, Seattle Children's Hospital, WA
- Center for Clinical and Translational Research, Seattle Children's Hospital, WA
| | - Susan Norton
- Division of Audiology, Seattle Children's Hospital, WA
- Childhood Communication Center, Seattle Children's Hospital, WA
- Department of Otolaryngology–Head and Neck Surgery, Seattle Children's Hospital, WA
- Department of Speech & Hearing Sciences, University of Washington, Seattle
- Department of Otolaryngology–Head and Neck Surgery, University of Washington, Seattle
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Abstract
General anesthesia has been unequivocally linked to abnormal development of the central nervous system, leading to neurocognitive impairments in laboratory models. In vitro and in vivo studies have consistently shown that exposure to GABA agonists (eg, volatile anesthetics, midazolam, and propofol) or NMDA antagonists (eg, ketamine, isoflurane, and nitrous oxide) produces dose dependent and developmental age dependent effects on various neuronal transmission systems. Exposure to these drugs increases neuronal cell death in juvenile animals including rats, mice, and non-human primates. The possibility of anesthetic induced neurotoxicity occurring in children has led to concerns about the safety of pediatric anesthesia. A spectrum of behavioral changes has been documented after general anesthetic exposure in young children, including emergence delirium, which may be evidence of toxicity. Most clinical studies are retrospective; specifics about medications or monitoring are unavailable and many of the outcomes may not be sensitive to detect small neurocognitive deficits. Some of these retrospective studies have shown an association between anesthesia exposure at a young age and neurocognitive deficits, but others have not. Practitioners and families should be reassured that although general anesthetics have the potential to induce neurotoxicity, very little clinical evidence exists to support this.
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Affiliation(s)
- Mary Ellen McCann
- Department of Anesthesia, Harvard Medical School, Boston, MA, USA
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA
| | - Sulpicio G Soriano
- Department of Anesthesia, Harvard Medical School, Boston, MA, USA
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA
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30
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Clausen NG, Hansen TG, Disma N. Anesthesia Neurotoxicity in the Developing Brain: Basic Studies Relevant for Neonatal or Perinatal Medicine. Clin Perinatol 2019; 46:647-656. [PMID: 31653300 DOI: 10.1016/j.clp.2019.08.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Diagnostic and invasive procedures in premature infants may require general anesthesia. General anesthetics interfere with the development of the immature animal brain. Accelerated apoptosis, disturbed synaptogenesis, and cytoarchitecture are among the mechanisms suspected to underlie this phenomenon. The implications for humans are unknown. This article presents current suspected mechanisms of anesthesia-induced neurotoxicity and elaborates on the difficulties in translating results from animal research to human. Ethical considerations limit the conduct of such experiments in human neonates, but the use of animal models is still considered feasible. Vulnerable periods in brain development need further identification as do neurotoxic and neuroprotective interventions.
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Affiliation(s)
- Nicola Groes Clausen
- Department of Anesthesiology and Intensive Care, Odense University Hospital, J.B. Winsløwsvej 4, Odense C 5000, Denmark
| | - Tom G Hansen
- Department of Anesthesiology and Intensive Care - Pediatrics, Odense University Hospital, J.B. Winsløwsvej 4, Odense C 5000, Denmark; Department of Clinical Research - Anesthesiology, University of Southern Denmark, Odense C 5000, Denmark
| | - Nicola Disma
- Department of Anesthesia, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, Genoa 16100, Italy.
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31
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Esmonde N, Jedrzejewski B, Fitzpatrick B, Koh J, Bardo D, Urbinelli L, Crupi L, Oliverio M, Selden NR, Kuang A. Feed and Swaddle: An Alternative to Infant Sedation for Craniofacial Imaging. Cleft Palate Craniofac J 2019; 56:1373-1376. [DOI: 10.1177/1055665619857651] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Objective: The gold standard for diagnosis of craniosynostosis is a clinical examination and motionless head computed tomography (CT). Computed tomography sedation is associated with increased cost, resource utilization, medical, and possible developmental risks. This study investigates whether a “feed and swaddle” protocol can be used to achieve diagnostic quality craniofacial imaging without the use of infant sedation. Design: Prospective cohort study. Setting: Tertiary academic medical center. Patients: Ninety patients <18 months of age undergoing evaluation for craniosynostosis from 2012 to 2018. Interventions: A feed and swaddle protocol. Main Outcome Measures: Diagnostic level imaging without the use of infant sedation. Results: Eighty-five (94%) achieved a diagnostic quality craniofacial CT scan using the “feed and swaddle” method. Mean patient age was 24.0 ± 10.0 weeks. Craniosynostosis was diagnosed in 74% of patients. Mean age of patients with successful completion of a CT scan was 23.7 ± 9.6 weeks, compared to 27.2 ± 17.1 weeks for unsuccessful completion. Mean weight for the successful group was 15.6 ± 2.9 pounds and 15.9 ± 2.5 pounds for the unsuccessful group. Mean travel distance was 59.2 ± 66.5 miles for successful patients and 66.5 ± 61.5 miles for unsuccessful patients. For the unsuccessful patients, there were no delays in surgical planning or scheduling. Conclusion: The “feed and swaddle” protocol described here is an effective alternative to infant sedation for motionless craniofacial CT imaging.
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Affiliation(s)
- Nick Esmonde
- Oregon Health & Science University, Portland, OR, USA
| | | | | | - Jeffrey Koh
- Oregon Health & Science University, Portland, OR, USA
| | | | - Leo Urbinelli
- Oregon Health & Science University, Portland, OR, USA
| | - Lisa Crupi
- Oregon Health & Science University, Portland, OR, USA
| | | | | | - Anna Kuang
- Oregon Health & Science University, Portland, OR, USA
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32
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General anesthetic neurotoxicity in the young: Mechanism and prevention. Neurosci Biobehav Rev 2019; 107:883-896. [PMID: 31606415 DOI: 10.1016/j.neubiorev.2019.10.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 08/27/2019] [Accepted: 10/04/2019] [Indexed: 12/17/2022]
Abstract
General anesthesia (GA) is usually considered to safely induce a reversible unconscious state allowing surgery to be performed without pain. A growing number of studies, in particular pre-clinical studies, however, demonstrate that general anesthetics can cause neuronal death and even long-term neurological deficits. Herein, we report our literature review and meta-analysis data of the neurological outcomes after anesthesia in the young. We also review available mechanistic and epigenetic data of GA exposure related to cognitive impairment per se and the potential preventive strategies including natural herbal compounds to attenuate those side effects. In summary, anesthetic-induced neurotoxicity may be treatable and natural herbal compounds and other medications may have great potential for such use but warrants further study before clinical applications can be initiated.
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Banerjee P, Rossi MG, Anghelescu DL, Liu W, Breazeale AM, Reddick WE, Glass JO, Phillips NS, Jacola LM, Sabin ND, Inaba H, Srivastava D, Robison LL, Pui CH, Hudson MM, Krull KR. Association Between Anesthesia Exposure and Neurocognitive and Neuroimaging Outcomes in Long-term Survivors of Childhood Acute Lymphoblastic Leukemia. JAMA Oncol 2019; 5:1456-1463. [PMID: 31219514 PMCID: PMC6587141 DOI: 10.1001/jamaoncol.2019.1094] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 03/08/2019] [Indexed: 11/14/2022]
Abstract
IMPORTANCE Limited studies have reported associations between anesthesia and neurocognitive and neuroimaging outcomes, particularly in pediatric patients who undergo multiple exposures to anesthesia as part of chronic disease management. OBJECTIVE To investigate whether general anesthesia is associated with neurocognitive impairment and neuroimaging abnormalities in long-term survivors of childhood acute lymphoblastic leukemia. DESIGN, SETTING, AND PARTICIPANTS A cohort study of 212 survivors of childhood acute lymphoblastic leukemia who received treatment between July 7, 2000, and November 3, 2010, and follow-up at a mean (SD) of 7.7 (1.7) years post diagnosis, was conducted at an academic medical center. Of 301 survivors who were alive and eligible for participation, 217 individuals (72.1%) agreed to participate in long-term follow-up. Data analysis was performed from August 23, 2017, to May 3, 2018. EXPOSURES For 5699 anesthesia procedures, data on duration and cumulative doses of all anesthetics, sedatives, analgesics, anxiolytics, and neuromuscular blockers were abstracted, along with cumulative doses of high-dose intravenous methotrexate and number of triple intrathecal chemotherapy treatments. MAIN OUTCOMES AND MEASURES Neurocognitive measures of attention, processing speed, executive function, and intelligence were examined. Brain volumes, cortical thickness, and diffusion tensor imaging of the whole brain, corpus callosum, frontal lobes, and parietal lobes were evaluated. RESULTS Of the 217 study participants, 212 were included in both neurocognitive and brain imaging analysis. Of these, 105 were female (49.5%); mean (SD) age at diagnosis was 14.36 (4.79) years; time since diagnosis was 7.7 (1.7) years. Adjusting for chemotherapy doses and age at diagnosis, neurocognitive impairment was associated with higher propofol cumulative dose (relative risk [RR], 1.40 per 100 mg/kg; 95% CI, 1.11-1.75), flurane exposure (RR, 1.10 per exposure; 95% CI, 1.01-1.21), and longer anesthesia duration (RR, 1.03 per cumulative hour; 95% CI, 1.00-1.06). Slower processing speed was associated with higher propofol dose (estimate [est], -0.30; P = .04), greater number of exposures to fluranes (est, -0.14; P = .01), and longer anesthesia duration (est, -0.04; P = .003). Higher corpus callosum white matter diffusivity was associated with dose of propofol (est, 2.55; P = .01) and duration of anesthesia (est, 2.40; P = .02). Processing speed was significantly correlated with corpus callosum diffusivity (r = -0.26, P < .001). CONCLUSIONS AND RELEVANCE Higher cumulative anesthesia exposure and duration may be associated with neurocognitive impairment and neuroimaging abnormalities in long-term survivors of childhood acute lymphoblastic leukemia, beyond the known outcomes associated with neurotoxic chemotherapies. Anesthesia exposures should be limited in pediatric populations with chronic health conditions who undergo multiple medical procedures.
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Affiliation(s)
- Pia Banerjee
- Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Michael G. Rossi
- Department of Pediatric Medicine, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Doralina L. Anghelescu
- Department of Pediatric Medicine, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Wei Liu
- Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Ashley M. Breazeale
- Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Wilburn E. Reddick
- Department of Diagnostic Imaging, St Jude Children's Research Hospital, Memphis, Tennessee
| | - John O. Glass
- Department of Diagnostic Imaging, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Nicholas S. Phillips
- Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Lisa M. Jacola
- Department of Psychology, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Noah D. Sabin
- Department of Diagnostic Imaging, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Hiroto Inaba
- Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Deokumar Srivastava
- Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Leslie L. Robison
- Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Ching-Hon Pui
- Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Melissa M. Hudson
- Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee
- Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Kevin R. Krull
- Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee
- Department of Psychology, St Jude Children's Research Hospital, Memphis, Tennessee
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Premedication with neuromuscular blockade and sedation during neonatal intubation is associated with fewer adverse events. J Perinatol 2019; 39:848-856. [PMID: 30940929 DOI: 10.1038/s41372-019-0367-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 02/20/2019] [Accepted: 02/25/2019] [Indexed: 01/24/2023]
Abstract
OBJECTIVE To determine the impact of premedication for tracheal intubation (TI) on adverse TI associated events, severe oxygen desaturations, and first attempt success STUDY DESIGN: Retrospective cohort study in neonatal intensive care units (NICU) participating in the National Emergency Airway Registry for Neonates from 10/2014 to 6/2017. Premedication for TI was categorized as sedation with neuromuscular blockade, sedation only, or no medication. RESULTS 2260 TIs were reported from 11 NICUs. Adverse TI associated events occurred less often in sedation with neuromuscular blockade group (10%) as compared to sedation only (29%), or no medication group (23%), p < 0.001. The adjusted odds ratio (aOR) for adverse TI associated events were: sedation with neuromuscular blockade aOR 0.48 (95%CI 0.34-0.65, p < 0.001) compared to no medication. CONCLUSION Use of sedation with neuromuscular blockade was associated with favorable TI outcomes. This study supports the recommendation for the standard use of sedation with neuromuscular blockade in non-emergency TIs.
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Mayo Anesthesia Safety in Kids continued: two new studies and a potential redirection of the field. Br J Anaesth 2019; 122:716-719. [DOI: 10.1016/j.bja.2019.03.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 03/11/2019] [Indexed: 11/21/2022] Open
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Abstract
PURPOSE OF REVIEW Compelling evidence in animal models that, under some conditions, general anesthetics and sedatives produce changes in the brain and persistent impairments in learning, memory, and behavior. The present review summarizes recent clinical studies investigating whether the use of these agents in children causes similar neurotoxicities. RECENT FINDINGS Although the results of retrospective studies are somewhat mixed, multiple exposures to general anesthesia were generally found to confer greater risk than single exposures with regard to learning disability, attention deficit hyperactivity disorder, school readiness, and academic achievement. Recent clinical studies, including a large randomized controlled trial, are consistent in confirming that a single exposure in infancy to general anesthesia lasting less than 1 h is not associated with neurodevelopmental impairments in later childhood. These studies do not, however, clarify the potential impacts of longer exposures or multiple exposures. SUMMARY Given that approximately half of the anesthetic exposures in young US children are 1 h or less in duration, the results of the recent clinical studies are reassuring. Because of the clinical necessity of administering general anesthetics and sedatives for longer periods for many surgical, procedural, or diagnostic purposes, the identification of adjuvants that prevent or reduce the potential neurotoxicity of these agents is an area of active research.
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Zens TJ, Rogers A, Cartmill R, Ostlie D, Muldowney BL, Nichol P, Kohler JE. Age-dependent outcomes in asymptomatic umbilical hernia repair. Pediatr Surg Int 2019; 35:463-468. [PMID: 30430281 DOI: 10.1007/s00383-018-4413-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/02/2018] [Indexed: 11/24/2022]
Abstract
PURPOSE Umbilical hernias are common in young children. Many resolve spontaneously by age four with very low risk of symptoms or incarceration. Complications associated with surgical repair of asymptomatic umbilical hernias have not been well elucidated. We analyzed data from one hospital to test the hypothesis that repair at younger ages is associated with increased complication rates. METHODS A retrospective chart review of all umbilical hernia repairs performed during 2007-2015 was conducted at a tertiary care children's hospital. Patients undergoing repairs as a single procedure for asymptomatic hernia were evaluated for post-operative complications by age, demographics, and co-morbidities. RESULTS Of 308 umbilical hernia repairs performed, 204 were isolated and asymptomatic. Postoperative complications were more frequent in children < 4 years (12.3%) compared to > 4 years (3.1%, p = 0.034). All respiratory complications (N = 4) and readmissions (N = 1) were in children < 4 years. CONCLUSIONS Age of umbilical hernia repair in children varied widely even within a single institution, demonstrating that timing of repair may be a surgeon-dependent decision. Patients < 4 years were more likely to experience post-operative complications. Umbilical hernias often resolve over time and can safely be monitored with watchful waiting. Formal guidelines are needed to support delayed repair and prevent unnecessary, potentially harmful operations.
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Affiliation(s)
- Tiffany J Zens
- Division of Pediatric Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue Madison, Madison, WI, 53792-7375, USA
| | - Andrew Rogers
- Division of Pediatric Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue Madison, Madison, WI, 53792-7375, USA
| | - Randi Cartmill
- Division of Pediatric Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue Madison, Madison, WI, 53792-7375, USA
| | - Daniel Ostlie
- Division of Pediatric Surgery, Phoenix Children's Hospital, Phoenix, AZ, USA
| | - Bridget L Muldowney
- Division of Pediatric Anesthesiology, Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Peter Nichol
- Division of Pediatric Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue Madison, Madison, WI, 53792-7375, USA
| | - Jonathan E Kohler
- Division of Pediatric Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue Madison, Madison, WI, 53792-7375, USA.
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Zens TJ, Cartmill R, Muldowney BL, Fernandes-Taylor S, Nichol P, Kohler JE. Practice Variation in Umbilical Hernia Repair Demonstrates a Need for Best Practice Guidelines. J Pediatr 2019; 206:172-177. [PMID: 30448274 PMCID: PMC6389373 DOI: 10.1016/j.jpeds.2018.10.049] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 09/08/2018] [Accepted: 10/24/2018] [Indexed: 11/19/2022]
Abstract
OBJECTIVE To evaluate and better understand variations in practice patterns, we analyzed ambulatory surgery claims data from 3 demographically diverse states to assess the relationship between age at umbilical hernia repair and patient, hospital, and geographic characteristics. STUDY DESIGN We performed a cross-sectional descriptive study of uncomplicated hernia repairs performed as a single procedure in 2012-2014, using the State Ambulatory Surgery and Services Database for Wisconsin, New York, and Florida. Age and demographic characteristics of umbilical hernia repair patients are described. RESULTS The State Ambulatory Surgery and Services Database analysis included 6551 patients. Across 3 states, 8.2% of hernia repairs were performed in children <2 years, 18.7% in children age 2-3 years, and 73.0% in children age ≥4 years, but there was significant variability (P < .001) in practice patterns by state. In regression analysis, race, Medicaid insurance and rural residence were predictive of early repair, with African American patients less likely to have a repair before age 2 (OR 0.62, P = .046) and rural children (OR 1.53, P = .009) and Medicaid patients (OR 2.01, P < .001) more likely to do so. State of residence predicted early repair even when holding these variables constant. CONCLUSIONS The age of pediatric umbilical hernia repair varies widely. As hernias may resolve over time and can be safely monitored with watchful waiting, formal guidelines are needed to support delayed repair and prevent unnecessary operations.
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Affiliation(s)
- Tiffany J Zens
- Division of Pediatric Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Randi Cartmill
- Wisconsin Surgical Outcomes Research Program, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI.
| | - Bridget L Muldowney
- Division of Pediatric Anesthesiology, Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Sara Fernandes-Taylor
- Wisconsin Surgical Outcomes Research Program, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Peter Nichol
- Division of Pediatric Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Jonathan E Kohler
- Division of Pediatric Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI; Wisconsin Surgical Outcomes Research Program, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
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Kouri A, Herron JS, Lempert N, Oliver M, Hubbard EW, Talwalkar VR, Muchow RD, Iwinski HJ. Magnetic Resonance Imaging in Infantile Idiopathic Scoliosis: Is Universal Screening Necessary? Spine Deform 2019; 6:651-655. [PMID: 30348339 DOI: 10.1016/j.jspd.2018.04.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 04/18/2018] [Accepted: 04/21/2018] [Indexed: 11/30/2022]
Abstract
STUDY DESIGN Retrospective chart review. OBJECTIVE Determine if there is a subset of presumed infantile idiopathic scoliosis (IIS) patients who have a low incidence of neural axis abnormalities (NAAs) such that screening magnetic resonance imaging (MRI) may be delayed. SUMMARY OF BACKGROUND DATA Individuals with presumed IIS have an increased incidence of NAA. Because of the increased incidence, screening MRI is recommended for all patients. We follow these guidelines at our institution. However, MRI screening in this age group is not without cost or risk. METHODS This is a retrospective study of 53 presumed IIS (onset ≤3 years) patients who had screening MRIs. Demographic and radiographic characteristics were collected. A binary regression using continuous and categorical variables was used to determine if a model could be created to accurately predict MRI necessity. A receiver operating characteristic (ROC) analysis was performed to determine if a threshold Cobb angle exists that is associated with an increased likelihood of NAA. RESULTS Of the 53 patients, 13 had NAA findings, resulting in a 24.5% incidence of NAAs. Significantly fewer abnormal MRIs were found in patients with Cobb angles <29.5° than those with Cobb angles >29.5° (13/33 [39%] vs. 0/20 [0%], p = .0008). Patients with Cobb angles >29.5° were 27 times more likely to have NAAs than those with angles <29.5° (odds ratio = 27.0 [95% CI = 1.5-486.0], p = .03). No other parameters have a predictive value for NAA (p > .05). CONCLUSION This is the first study in IIS patients to identify a radiographic parameter that helps select out a subgroup for MRI screening. Additionally, we report an incidence of 24.5% NAAs in these patients, which is higher than previously reported.
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Affiliation(s)
- Anthony Kouri
- University of Toledo Medical Center, 3000 Arlington Ave, Toledo, OH 43614, USA.
| | - Joseph S Herron
- University of Toledo Medical Center, 3000 Arlington Ave, Toledo, OH 43614, USA
| | - Nathaniel Lempert
- University of Toledo Medical Center, 3000 Arlington Ave, Toledo, OH 43614, USA
| | - Mark Oliver
- University of Toledo Medical Center, 3000 Arlington Ave, Toledo, OH 43614, USA
| | | | - Vish R Talwalkar
- Shriners Hospital for Children, 110 Conn Terrace, Lexington, KY 40508, USA
| | - Ryan D Muchow
- Shriners Hospital for Children, 110 Conn Terrace, Lexington, KY 40508, USA
| | - Henry J Iwinski
- Shriners Hospital for Children, 110 Conn Terrace, Lexington, KY 40508, USA
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Yu D, Xiao R, Huang J, Cai Y, Bao X, Jing S, Du Z, Yang T, Fan X. Neonatal exposure to propofol affects interneuron development in the piriform cortex and causes neurobehavioral deficits in adult mice. Psychopharmacology (Berl) 2019; 236:657-670. [PMID: 30415279 DOI: 10.1007/s00213-018-5092-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 10/25/2018] [Indexed: 11/24/2022]
Abstract
RATIONALE Animal studies have shown that early postnatal propofol administration is involved in neurobehavioral alterations in adults. However, the underlying mechanism is not clear. METHODS We used c-Fos immunohistochemistry to identify activated neurons in brain regions of neonatal mice under propofol exposure and performed behavioral tests to observe the long-term consequences. RESULTS Exposure to propofol (30g or 60 mg/kg) on P7 produced significant c-Fos expression in the deep layers of the piriform cortex on P8. Double immunofluorescence of c-Fos with interneuron markers in the piriform cortex revealed that c-Fos was specifically induced in calbindin (CB)-positive interneurons. Repeated propofol exposure from P7 to P9 induced behavioral deficits in adult mice, such as olfactory function deficit in a buried food test, decreased sociability in a three-chambered choice task, and impaired recognitive ability of learning and memory in novel object recognition tests. However, locomotor activity in the open-field test was not generally affected. Propofol treatment also significantly decreased the number of CB-positive interneurons in the piriform cortex of mice on P21 and adulthood. CONCLUSIONS These results suggest that CB-positive interneurons in the piriform cortex are vulnerable to propofol exposure during the neonatal period, and these neurons are involved in the damage effects of propofol on behavior changes. These data provide a new target of propofol neurotoxicity and may elucidate the mechanism of neurobehavioral deficits in adulthood.
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Affiliation(s)
- Dan Yu
- Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China.,Department of Anesthesiology, Wuhan No.4 Hospital, Wuhan Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430033, People's Republic of China
| | - Rui Xiao
- Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China.,Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Jing Huang
- Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Yulong Cai
- Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Xiaohang Bao
- Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China.,Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Sheng Jing
- Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Zhiyong Du
- Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Tiande Yang
- Department of Anesthesiology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China.
| | - Xiaotang Fan
- Department of Developmental Neuropsychology, School of Psychology, Third Military Medical University, Chongqing, 400038, People's Republic of China.
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O'Leary JD, Warner DO. What do recent human studies tell us about the association between anaesthesia in young children and neurodevelopmental outcomes? Br J Anaesth 2019; 119:458-464. [PMID: 28969310 DOI: 10.1093/bja/aex141] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Anaesthetic and sedative drugs transiently disrupt normal neural activity to facilitate healthcare procedures in children, but they can also cause long-term brain injury in experimental animal models. The US Food and Drug Administration (FDA) has recently advised that repeated or lengthy exposures to anaesthetic and sedative drugs prior to 3 yr of age have the potential to harm the development of children's brains and added warnings to these drug labels. Paediatric anaesthesia toxicity could represent a significant public health issue, and concern about this potential injury in children has become an important issue for families, paediatric clinicians and healthcare regulators. Since late 2015, important new data from five major clinical studies have been published. This narrative review aims to provide a brief overview of the preclinical and clinical literature, including a comprehensive review of these recent additions to the human literature. We integrate these new data with prior studies to provide further insights into how these clinical findings can be applied to children.
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Affiliation(s)
- J D O'Leary
- Department of Anaesthesia and Pain Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.,Department of Anaesthesia, University of Toronto, 12th Floor, 123 Edward Street, Toronto, Ontario M5G 1E2, Canada
| | - D O Warner
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic Rochester, 200?1ST ST SW, Rochester, MN 55905, USA
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Ing C, Hegarty MK, Perkins JW, Whitehouse AJO, DiMaggio CJ, Sun M, Andrews H, Li G, Sun LS, von Ungern-Sternberg BS. Duration of general anaesthetic exposure in early childhood and long-term language and cognitive ability. Br J Anaesth 2019; 119:532-540. [PMID: 28969309 DOI: 10.1093/bja/aew413] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2016] [Indexed: 12/31/2022] Open
Abstract
Background The anaesthetic dose causing neurotoxicity in animals has been evaluated, but the relationship between duration of volatile anaesthetic (VA) exposure and neurodevelopment in children remains unclear. Methods Data were obtained from the Western Australian Pregnancy Cohort (Raine) Study, with language (Clinical Evaluation of Language Fundamentals: Receptive [CELF-R] and Expressive [CELF-E] and Total [CELF-T]) and cognition (Coloured Progressive Matrices [CPM]) assessed at age 10 yr. Medical records were reviewed, and children divided into quartiles based on total VA exposure duration before age three yr. The association between test score and exposure duration quartile was evaluated using linear regression, adjusting for patient characteristics and comorbidity. Results Of 1622 children with available test scores, 148 had documented VA exposure and were split into the following quartiles: ≤25, >25 to ≤35, >35 to ≤60 and >60 min. Compared with unexposed children, CELF-T scores for children in the first and second quartiles did not differ, but those in the third and fourth quartiles had significantly lower scores ([3 rd quartile - Unexposed] -5.3; 95% confidence interval [CI], (-10.2 - -0.4), [4 th quartile - Unexposed] -6.2; 95% CI, (-11.6 - -0.9). CELF-E showed similar findings, but significant differences were not found in CELF-R or CPM for any quartile. Conclusions Children with VA exposures ≤35 min did not differ from unexposed children, but those with exposures >35 min had lower total and expressive language scores. It remains unclear if this is a dose-response relationship, or if children requiring longer exposures for longer surgeries have other clinical reasons for lower scores.
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Affiliation(s)
- C Ing
- Departments of Anesthesiology and Epidemiology, Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY, USA
| | - M K Hegarty
- Department of Anaesthesia and Pain Management, Princess Margaret Hospital for Children, Perth, Australia
| | - J W Perkins
- Department of Anaesthesia and Pain Management, Princess Margaret Hospital for Children, Perth, Australia
| | - A J O Whitehouse
- Telethon Kids Institute, University of Western Australia, Perth, Australia
| | - C J DiMaggio
- Departments of Anesthesiology and Epidemiology, Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY, USA
| | - M Sun
- Departments of Anesthesiology and Biostatistics, Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY, USA
| | - H Andrews
- Department of Biostatistics, Mailman School of Public Health, New York, NY, USA
| | - G Li
- Departments of Anesthesiology and Epidemiology, Columbia University College of Physicians and Surgeons and Mailman School of Public Health, New York, NY, USA
| | - L S Sun
- Departments of Anesthesiology and Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - B S von Ungern-Sternberg
- School of Medicine and Pharmacology, The University of Western Australia, Perth, Australia and Department of Anaesthesia and Pain Management, Princess Margaret Hospital for Children, Perth, Australia
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Alvarado MC, Murphy KL, Baxter MG. Visual recognition memory is impaired in rhesus monkeys repeatedly exposed to sevoflurane in infancy. Br J Anaesth 2019; 119:517-523. [PMID: 28575197 DOI: 10.1093/bja/aew473] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Background Experimental studies in animals have shown that exposure to general anaesthesia in infancy can cause loss of cells in the central nervous system and long-term impairments in neurocognitive function. Some human epidemiological studies have shown increased risk of learning disability after repeated anaesthesia exposure in early childhood. Thus, we investigated in a highly translational rhesus monkey model, whether repeated exposure in infancy to the inhalation anaesthetic sevoflurane is associated with impaired visual recognition memory during the first two yr of life. Methods Rhesus monkeys of both sexes were exposed to sevoflurane inhalation anaesthesia on approximately postnatal day 7 and then again 14 and 28 days later, for four h each time. Visual recognition memory was tested using the visual paired comparison task, which measures memory by assessing preference for looking at a new image over a previously-viewed image. Monkeys were tested at 6-10 months of age, again at 12-18 months of age, and again at 24-30 months of age. Results No memory impairment was detected at 6-10 months old, but significant impairment (reduced time looking at the novel image) was observed at 12-18 and 24-30 months old. Conclusions Repeated exposure of infant rhesus monkeys to sevoflurane results in visual recognition memory impairment that emerges after the first yr of life. This is consistent with epidemiological studies that show increased risk of learning disability after repeated exposure to anaesthesia in infancy/early childhood. Moreover, these deficits may emerge at later developmental stages, even when memory performance is unaffected earlier in development.
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Affiliation(s)
- M C Alvarado
- Division of Developmental and Cognitive Neuroscience, Yerkes National Primate Research Centre, Emory University, Atlanta, GA, USA
| | - K L Murphy
- Comparative Biology Centre, Newcastle University, Newcastle, UK
| | - M G Baxter
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Zens T, Nichol P, Leys C, Haines K, Brinkman A. Fractured pediatric central venous catheters - Repair or replace? J Pediatr Surg 2019; 54:165-169. [PMID: 30466713 DOI: 10.1016/j.jpedsurg.2018.10.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 10/01/2018] [Indexed: 01/18/2023]
Abstract
INTRODUCTION Central venous catheter (CVC) fracture is a common complication. The aim of this study is to examine risk factors resulting in CVC fracture and compare outcomes of children undergoing CVC repair versus replacement. METHODS A retrospective chart review was conducted from 2000 to 2016 for children with tunneled CVCs. Children with CVC fractures were compared to those without to identify risk factors resulting in fracture. Children with fractured CVCs were divided into repair or replacement treatment groups and outcomes compared. A logistic regression model determined independent predictors of CVC-associated bloodstream infections (CLABSI) after fracture. RESULTS In the 236 children with CVCs, the fracture rate was 29.2%. Fractured CVCs were more common with double lumen CVC (p = 0.040) and children whose indication was total parenteral nutrition (p = 0.003). Given children often underwent multiple repairs or replacements. 98 CVC repairs and 41 replacements were analyzed. CVC replacements had longer durability than repair (181.98 vs. 98.9 days, p = 0.038). There were no differences in CLABSI incidence for repair vs. replacement (OR 0.5 CI 0.05-4.97) after controlling for other factors. CONCLUSIONS CVC fracture is a frequent complication in children with tunneled CVCs. CVC repair has no increased incidence of CLABSI but eliminates the intraoperative and anesthetic risks of CVC replacement. TYPE OF STUDY Retrospective cohort study. LEVEL OF EVIDENCE Level III.
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Affiliation(s)
- Tiffany Zens
- Division of Pediatric Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Division of General Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Peter Nichol
- Division of Pediatric Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Division of General Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Charles Leys
- Division of Pediatric Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Division of General Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Krista Haines
- Division of Pediatric Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Division of General Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Adam Brinkman
- Division of Pediatric Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Division of General Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
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Impact of fellow training level on adverse events and operative time for common pediatric GI endoscopic procedures. Gastrointest Endosc 2018; 88:787-794. [PMID: 30031806 DOI: 10.1016/j.gie.2018.07.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 07/11/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Previous studies on pediatric endoscopic training have not examined in detail if adverse events (AEs) are affected by the fellow's training level. We aimed to determine whether trainee presence and educational level increase AEs or operative time (OT) for pediatric intestinal endoscopy. METHODS This was a prospective observational study of AEs for all endoscopic procedures and retrospective analysis of OT (time of endoscope insertion until removal) for a sample of specified procedures at a tertiary children's hospital. AEs were categorized by severity grades: 1, home management; 2, outpatient evaluation; 3, hospitalization and/or repeat endoscopy; 4, surgery and/or intensive care unit admission; and 5, death. RESULTS A total of 15,886 procedures (6257 with trainee) including 1627 therapeutic procedures (733 with trainee) were analyzed for AEs. Four hundred thirteen total AEs (2.60%) and 213 AEs grade 2 to 4 (1.34%) were identified. Fellow presence at any training level did not increase AE rates for any procedures. Median OT for 3762 EGDs decreased from 17 to 11 minutes from the first quarter to the fourth quarter of first-year fellowship and then remained stable. EGDs without fellows were shorter (9 minutes, P < .0001) compared with any training level. Median times of 1291 colonoscopies with EGD decreased from 55 to 51 to 47 minutes for fellows in the first half, second half of first-year fellowship, and second and third year, respectively. Attendings alone were faster (37 minutes, P < .0001). CONCLUSIONS Current pediatric endoscopic training for is safe regardless of fellow training level. Trainee efficiency improves during and after fellowship.
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Affiliation(s)
- Susan Lei
- Division of Pediatric Anesthesiology, Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA
| | - Riva Ko
- Division of Pediatric Anesthesiology, Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA
| | - Lena S Sun
- Division of Pediatric Anesthesiology, Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA; Department of Pediatrics, Columbia University Medical Center, New York, NY 01132, USA.
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Castellheim A, Lundström S, Molin M, Kuja-Halkola R, Gillberg C, Gillberg C. The role of general anesthesia on traits of neurodevelopmental disorders in a Swedish cohort of twins. J Child Psychol Psychiatry 2018; 59:966-972. [PMID: 29465765 DOI: 10.1111/jcpp.12885] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/24/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND The role of general anesthetics as a risk factor for possible neurodevelopmental disorders (NDDs) in humans is unresolved. The investigation of the role of anesthetics in the development of postgeneral anesthesia (anesthesia onward) NDDs has proven to be complicated, partly because of the inherent confounding in clinical cohort studies, and partly by the fact that anesthetics are only one part in the complex process of anesthesia-surgery. METHODS Utilizing the Swedish databases Child and Adolescent Twins Study in Sweden (CATSS) and National Patient Register (NPR), we investigated twins discordant for anesthesia, born between 1997 and 2004 for traits of NDDs. We identified 68 twin pairs discordant for anesthesia and explored traits of Attention-Deficit/Hyperactivity Disorder (ADHD), Learning Disability (LD), and Autism Spectrum Disorder (ASD) in them while simultaneously taking congenital abnormalities and systemic disorders (CSDs) into account. We analyzed the possible effect of anesthesia on neurodevelopmental problems, and we analyzed the within-pair differences using conditional linear regression. RESULTS Twins with a recorded episode of anesthesia had higher traits of NDDs than twins without; similarly twins with CSDs had higher mean scores on all traits than twins without CSDs. The within-pair analyses suggested that exposure to anesthesia was associated with higher scores of ADHD (regression coefficient 1.02 and 95% confidence intervals: 0.27-1.78) in monozygotic (MZ) twins discordant for anesthesia. This effect remained when adjusting for congenital abnormalities. DISCUSSION Our finding that traits of ADHD were slightly associated with anesthesia in a genetically sensitive design is in need of replication and warrants further investigation. Future studies should aim to elucidate mechanisms behind this possible association (e.g. anesthetics doses, age at exposure, exposure duration).
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Affiliation(s)
- Albert Castellheim
- Department of Anesthesiology and Intensive Care, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Sebastian Lundström
- Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Centre for Ethics, Law, and Mental Health, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | | | - Ralf Kuja-Halkola
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
| | - Carina Gillberg
- Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Christopher Gillberg
- Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Lee JR, Loepke AW. Does pediatric anesthesia cause brain damage? - Addressing parental and provider concerns in light of compelling animal studies and seemingly ambivalent human data. Korean J Anesthesiol 2018; 71:255-273. [PMID: 29969889 PMCID: PMC6078876 DOI: 10.4097/kja.d.18.00165] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 07/04/2018] [Indexed: 02/07/2023] Open
Abstract
Anesthesia facilitates surgery in millions of young children every year. Structural brain abnormalities and functional impairment observed in animals have created substantial concerns among clinicians, parents, and government regulators. Clinical studies seemed ambivalent; it remains unclear whether differential species effects exist towards anesthetic exposure. The current literature search and analysis attempts to unify the available clinical and animal studies, which currently comprise of > 530 in vivo animal studies and > 30 clinical studies. The prevalence of abnormalities was lowest for exposures < 1 hour, in both animals and humans, while studies with injurious findings increased in frequency with exposure time. Importantly, no exposure time, anesthetic technique, or age during exposure was clearly identifiable to be entirely devoid of any adverse outcomes. Moreover, the age dependence of maximum injury clearly identified in animal studies, combined with the heterogeneity in age in most human studies, may impede the discovery of a specific human neurological phenotype. In summary, animal and human research studies identify a growing prevalence of injurious findings with increasing exposure times. However, the existing lack of definitive data regarding safe exposure durations, unaffected ages, and non-injurious anesthetic techniques precludes any evidence-based recommendations for drastically changing current clinical anesthesia management. Animal studies focusing on brain maturational states more applicable to clinical practice, as well as clinical studies focusing on prolonged exposures during distinct developmental windows of vulnerability, are urgently needed to improve the safety of perioperative care for thousands of young children requiring life-saving and quality of life-improving procedures daily.
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Affiliation(s)
- Jeong-Rim Lee
- Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Andreas W Loepke
- Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Abstract
Considering that growing population of very young children is exposed to general anesthesia every year, it is of utmost importance to understand how and whether such practice may affect the development and growth of their very immature and vulnerable brains. Compelling evidence from animal studies suggests that an early exposure to general anesthesia is detrimental to normal brain development leading to structural and functional impairments of neurons and glia, and long-lasting impairments in normal emotional and cognitive development. Although the evidence from animal studies is overwhelming and confirmed across species examined from rodents to non-human primates, the evidence from human studies is inconsistent and not conclusive at present. In this review we focus on new developments in animal studies of anesthesia-induced developmental neurotoxicity and summarize recent clinical studies while focusing on outcome measures and exposure variables in terms of their utility for assessing cognitive and behavioral development in children.
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Affiliation(s)
| | - Ansgar Brambrick
- Department of Anesthesiology, Columbia University Medical Center, New York, NY USA
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