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Huang S, Zhou Y, Ji H, Zhang T, Liu S, Ma L, Deng D, Ding Y, Han L, Shu S, Wang Y, Chen X. Decoding mechanisms and protein markers in lung-brain axis. Respir Res 2025; 26:190. [PMID: 40390067 PMCID: PMC12090670 DOI: 10.1186/s12931-025-03272-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 05/08/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND The lung-brain axis represents a complex bidirectional communication network that is pivotal in the crosstalk between respiratory and neurological functions. This review summarizes the current understanding of the mechanisms and protein markers that mediate the effects of lung diseases on brain health. MAIN FINDINGS In this review, we explore the mechanisms linking lung injury to neurocognitive impairments, focusing on neural pathways, immune regulation and inflammatory responses, microorganism pathways, and hypoxemia. Specifically, we highlight the role of the vagus nerve in modulating the central nervous system response to pulmonary stimuli; Additionally, the regulatory function of the immune system is underscored, with evidence suggesting that lung-derived immune mediators can traverse the blood-brain barrier, induce neuroinflammation and cognitive decline; Furthermore, we discuss the potential of lung microbiota to influence brain diseases through microbial translocation and immune activation; Finally, the impact of hypoxemia is examined, with findings indicating that it can exacerbate cerebral injury via oxidative stress and impaired perfusion. Moreover, we analyze how pulmonary conditions, such as pneumonia, ALI/ARDS, and asthma, contribute to neurological dysfunction. Prolonged mechanical ventilation can also contribute to cognitive impairment. Conversely, brain diseases (e.g., stroke, traumatic brain injury) can lead to acute respiratory complications. In addition, protein markers such as TLR4, ACE2, A-SAA, HMGB1, and TREM2 are crucial to the lung-brain axis and correlate with disease severity. We also discuss emerging therapeutic strategies targeting this axis, including immunomodulation and microbiome engineering. Overall, understanding the lung-brain interplay is crucial for developing integrated treatment strategies and improving patient outcomes. Further research is needed to elucidate the molecular mechanisms and foster interdisciplinary collaboration.
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Affiliation(s)
- Shiqian Huang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Wuhan, 430022, China
| | - Yuxi Zhou
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Wuhan, 430022, China
| | - Haipeng Ji
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Wuhan, 430022, China
| | - Tianhao Zhang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Wuhan, 430022, China
| | - Shiya Liu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Wuhan, 430022, China
| | - Lulin Ma
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Wuhan, 430022, China
| | - Daling Deng
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Wuhan, 430022, China
| | - Yuanyuan Ding
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Wuhan, 430022, China
| | - Linlin Han
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Wuhan, 430022, China
| | - Shaofang Shu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Wuhan, 430022, China
| | - Yu Wang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Wuhan, 430022, China.
| | - Xiangdong Chen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, Wuhan, 430022, China.
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Ghazvineh S, Mooziri M, Salimi A, Mirnajafi-Zadeh J, Raoufy MR. Olfactory epithelium electrical stimulation mitigates memory and synaptic deficits caused by mechanical ventilation. Sci Rep 2025; 15:12197. [PMID: 40204831 PMCID: PMC11982190 DOI: 10.1038/s41598-025-96661-9] [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: 12/30/2024] [Accepted: 03/31/2025] [Indexed: 04/11/2025] Open
Abstract
Mechanical ventilation (MV) causes a wide range of cognitive impairments. Unfortunately, to date, we are lacking knowledge about its underlying neural mechanisms and significant treatment options for the condition. Here, we show that MV-induced memory impairment in rats stems from dysfunctions in the olfactory bulb-medial prefrontal cortex-ventral hippocampus network and hippocampal synaptic currents imbalance. More importantly, we introduce a novel treatment approach, namely olfactory epithelium electrical stimulation (OEES) that shows promising preclinical results in mitigating the mentioned behavioral and neural disorders caused by MV. These results pave the way for research on non-invasive brain stimulation approaches and introduce the olfactory system as a potential target for treating cognitive or psychiatric disorders induced by MV.
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Affiliation(s)
- Sepideh Ghazvineh
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Morteza Mooziri
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Alireza Salimi
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Javad Mirnajafi-Zadeh
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
- Institute for Brain and Cognition, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Reza Raoufy
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
- Institute for Brain and Cognition, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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Khwaja SA, Habib MA, Gupta R, Mahay HS, Singla D. Unraveling Ventilator-Induced Diaphragmatic Dysfunction: A Comprehensive Narrative Review on Pathogenesis, Diagnosis and Management of Ventilator-Induced Diaphragmatic Dysfunction. PHYSIOTHERAPY RESEARCH INTERNATIONAL 2025; 30:e70046. [PMID: 40099967 DOI: 10.1002/pri.70046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/28/2025] [Accepted: 03/07/2025] [Indexed: 03/20/2025]
Abstract
INTRODUCTION Mechanical ventilation (MV) is a crucial intervention for patients with respiratory failure to ensure optimal gas exchange. However, there is strong evidence that MV exerts significant structural and functional alterations on the diaphragm, leading to a notable decline in its contractile force and the consequent atrophy of its muscle fibers. This condition, referred to as ventilator-induced diaphragmatic dysfunction (VIDD), is an integral factor contributing to challenges in weaning patients off MV, a reduction in their quality of life, and escalated Mortality Risks. OBJECTIVES This review highlights the complications of MV, with a focus on VIDD and its clinical implications. It explores bedside diagnostic tools for VIDD and examines exercise-based interventions aimed at preventing or reversing daiphragmatic weakness. DISCUSSION Rehabilitation programs, including early mobilization and inspiratory muscle training (IMT) for critically ill patients, have the potential to prevent or mitigate the adverse effects of prolonged Mechanical ventilator and improve clinical outcomes. Numerous studies have demonstrated that these interventions are both safe and feasible, offering benefits such as enhanced physical functioning, reduced duration of mechanical ventilation, and shorter stays in intensive care and hospital settings. However, despite these demonstrated advantages, the implementation of rehabilitation programs remains infrequent in routine clinical practice, often hindered by various perceived barriers. CONCLUSION Recognizing and addressing respiratory muscle weakness is crucial, as it represents a reversible and treatable factor that can significantly improve patient outcomes.
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Affiliation(s)
- Sajad Ahmad Khwaja
- Department of Physiotherapy, Jamia Hamdard, New Delhi, India
- Department of Medicine HIMSR, Jamia Hamdard, New Delhi, India
- Department of Medicine, Pentamed Hospital, New Delhi, India
| | | | - Rajesh Gupta
- Department of Medicine, Pentamed Hospital, New Delhi, India
| | | | - Deepika Singla
- Department of Physiotherapy, Jamia Hamdard, New Delhi, India
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Silva PL, Chiumello D, Pozzi T, Rocco PRM. Beyond the Lungs: Extrapulmonary Effects of Non-Invasive and Invasive Ventilation Strategies. J Clin Med 2025; 14:1242. [PMID: 40004773 PMCID: PMC11856178 DOI: 10.3390/jcm14041242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 02/03/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Non-invasive respiratory support and invasive mechanical ventilation are critical interventions that can induce significant changes not only in the lungs but also in extra-pulmonary organs, which are often overlooked. Understanding the extra-pulmonary effects of non-invasive respiratory support and invasive mechanical ventilation is crucial since it can help prevent or mitigate complications and improve outcomes. This narrative review explores these consequences in detail and highlights areas that require further research. Main Text: Non-invasive respiratory support and invasive mechanical ventilation can significantly impact various extrapulmonary organs. For instance, some ventilation strategies can affect venous return from the brain, which may lead to neurological sequelae. In the heart, regardless of the chosen ventilation method, increased intrathoracic pressure (ITP) can also reduce venous return to the heart. This reduction in turn can decrease cardiac output, resulting in hypotension and diminished perfusion of vital organs. Conversely, in certain situations, both ventilation strategies may enhance cardiac function by decreasing the work of breathing and lowering oxygen consumption. In the kidneys, these ventilation methods can impair renal perfusion and function through various mechanisms, including hemodynamic changes and the release of stress hormones. Such alterations can lead to acute kidney injury or exacerbate pre-existing renal conditions. Conclusions: This review emphasizes the critical importance of understanding the extensive mechanisms by which non-invasive respiratory support and invasive mechanical ventilation affect extrapulmonary organs, including neurological, cardiovascular, and renal systems. Such knowledge is essential for optimizing patient care and improving outcomes in critical care settings.
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Affiliation(s)
- Pedro Leme Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941, Brazil; (P.L.S.); (P.R.M.R.)
| | - Davide Chiumello
- Department of Anesthesia and Intensive Care, ASST Santi Paolo e Carlo, San Paolo University Hospital Milan, 20142 Milan, Italy
| | - Tommaso Pozzi
- Department of Anesthesia and Intensive Care, ASST Santi Paolo e Carlo, San Paolo University Hospital Milan, 20142 Milan, Italy
| | - Patricia Rieken Macedo Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro 21941, Brazil; (P.L.S.); (P.R.M.R.)
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van Rijn CM, Roberts JHM, Coulthard MG, Lambert HJ, McKeown DS, Howard DJ, van Egmond J. Negative Pressure Ventilation Can Prevent Ventilator-associated Brain Injury. Am J Respir Crit Care Med 2024; 210:954-955. [PMID: 39079128 PMCID: PMC11506893 DOI: 10.1164/rccm.202405-1016le] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 07/24/2024] [Indexed: 10/02/2024] Open
Affiliation(s)
- Clementina M. van Rijn
- Donders Institute for Brain, Cognition and Behaviour, DCC, Radboud University, Nijmegen, The Netherlands
| | - James H. M. Roberts
- The Royal National Ear, Nose and Throat & Eastman Dental Hospitals, University College London Hospital, London, United Kingdom
| | - Malcolm G. Coulthard
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Heather J. Lambert
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | | | | | - Jan van Egmond
- Donders Institute for Brain, Cognition and Behaviour, DCC, Radboud University, Nijmegen, The Netherlands
- Department of Anesthesiology, Radboud University Medical Centre, Nijmegen, The Netherlands
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Chen YC, Chen JH, Tsai CF, Wu CY, Chang CN, Wu CT, Yeh WL. Protective effects of paeonol against cognitive impairment in lung diseases. J Pharmacol Sci 2024; 155:101-112. [PMID: 38797534 DOI: 10.1016/j.jphs.2024.04.006] [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: 02/16/2024] [Revised: 04/14/2024] [Accepted: 04/30/2024] [Indexed: 05/29/2024] Open
Abstract
Pulmonary inflammation may lead to neuroinflammation resulting in neurological dysfunction, and it is associated with a variety of acute and chronic lung diseases. Paeonol is a herbal phenolic compound with anti-inflammatory and anti-oxidative properties. The aim of this study is to understand the beneficial effects of paeonol on cognitive impairment, pulmonary inflammation and its underlying mechanisms. Pulmonary inflammation-associated cognitive deficit was observed in TNFα-stimulated mice, and paeonol mitigated the cognitive impairment by reducing the expressions of interleukin (IL)-1β, IL-6, and NOD-like receptor family pyrin domain-containing 3 (NLRP3) in hippocampus. Moreover, elevated plasma miR-34c-5p in lung-inflamed mice was also reduced by paeonol. Pulmonary inflammation induced by intratracheal instillation of TNFα in mice resulted in immune cells infiltration in bronchoalveolar lavage fluid, pulmonary edema, and acute fibrosis, and these inflammatory responses were alleviated by paeonol orally. In MH-S alveolar macrophages, tumor necrosis factor (TNF) α- and phorbol myristate acetate (PMA)-induced inflammasome activation was ameliorated by paeonol. In addition, the expressions of antioxidants were elevated by paeonol, and reactive oxygen species production was reduced. In this study, paeonol demonstrates protective effects against cognitive deficits and pulmonary inflammation by exerting anti-inflammatory and anti-oxidative properties, suggesting a powerful benefit as a potential therapeutic agent.
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Affiliation(s)
- Yen-Chang Chen
- Institute of New Drug Development, China Medical University, No.91 Hsueh-Shih Road, Taichung, 404333, Taiwan
| | - Jia-Hong Chen
- Department of General Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 88, Sec. 1, Fengxing Road, Taichung, 427213, Taiwan
| | - Cheng-Fang Tsai
- Department of Medical Laboratory Science and Biotechnology, Asia University, No.500 Lioufeng Road, Taichung, 413305, Taiwan
| | - Chen-Yun Wu
- Institute of New Drug Development, China Medical University, No.91 Hsueh-Shih Road, Taichung, 404333, Taiwan
| | - Chen-Ni Chang
- Institute of New Drug Development, China Medical University, No.91 Hsueh-Shih Road, Taichung, 404333, Taiwan
| | - Chen-Teng Wu
- Department of Surgery, China Medical University Hospital, No. 2, Yude Road, Taichung, 404332, Taiwan
| | - Wei-Lan Yeh
- Institute of New Drug Development, China Medical University, No.91 Hsueh-Shih Road, Taichung, 404333, Taiwan; Department of Biochemistry, School of Medicine, China Medical University, No.91 Hsueh-Shih Road, Taichung, 404333, Taiwan.
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Bassi T, Taran S, Girard TD, Robba C, Goligher EC. Ventilator-associated Brain Injury: A New Priority for Research in Mechanical Ventilation. Am J Respir Crit Care Med 2024; 209:1186-1188. [PMID: 38526447 PMCID: PMC11146544 DOI: 10.1164/rccm.202401-0069vp] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 03/21/2024] [Indexed: 03/26/2024] Open
Affiliation(s)
- Thiago Bassi
- Department of Medicine, Division of Respirology, University Health Network, Toronto, Ontario, Canada
- Interdepartmental Division of Critical Care Medicine and
- Lungpacer Medical Inc., Vancouver, British Columbia, Canada
| | - Shaurya Taran
- Department of Medicine, Division of Respirology, University Health Network, Toronto, Ontario, Canada
- Interdepartmental Division of Critical Care Medicine and
| | - Timothy D. Girard
- Center for Research, Investigation, and Systems Modeling of Acute Illness, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Chiara Robba
- Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy
- Anesthesia and Critical Care, Scientific Institute for Research, Hospitalization and Healthcare Policlinico San Martino, Genoa, Italy; and
| | - Ewan C. Goligher
- Department of Medicine, Division of Respirology, University Health Network, Toronto, Ontario, Canada
- Interdepartmental Division of Critical Care Medicine and
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada
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Taran S, Stevens RD, Perrot B, McCredie VA, Cinotti R, Asehnoune K, Pelosi P, Robba C, for the ENIO Study Group, on behalf of the PROtective VENTilation network, the European Society of Intensive Care Medicine, the Colegio Mexicano de Medicina Critica, the Atlanréa group, and the La Société Française d’Anesthésie et de Réanimation (SFAR) research network. Incidence and Outcomes of Acute Respiratory Distress Syndrome in Brain-Injured Patients Receiving Invasive Ventilation: A Secondary Analysis of the ENIO Study. J Intensive Care Med 2024; 39:136-145. [PMID: 37563968 PMCID: PMC10771027 DOI: 10.1177/08850666231194532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
Background: Acute respiratory distress syndrome (ARDS) is an important pulmonary complication in brain-injured patients receiving invasive mechanical ventilation (IMV). We aimed to evaluate the incidence and association between ARDS and clinical outcomes in patients with different forms of acute brain injury requiring IMV in the intensive care unit (ICU). Methods: This was a preplanned secondary analysis of a prospective, multicenter, international cohort study (NCT03400904). We included brain-injured patients receiving IMV for ≥ 24 h. ARDS was the main exposure of interest and was identified during index ICU admission using the Berlin definition. We examined the incidence and adjusted association of ARDS with ICU mortality, ICU length of stay, duration of IMV, and extubation failure. Outcomes were evaluated using mixed-effect logistic regression and cause-specific Cox proportional hazards models. Results: 1492 patients from 67 hospitals and 16 countries were included in the analysis, of whom 137 individuals developed ARDS (9.2% of overall cohort). Across countries, the median ARDS incidence was 5.1% (interquartile range [IQR] 0-10; range 0-27.3). ARDS was associated with increased ICU mortality (adjusted odds ratio (OR) 2.66; 95% confidence interval [CI], 1.29-5.48), longer ICU length of stay (adjusted hazard ratio [HR] 0.59; 95% CI, 0.48-0.73), and longer duration of IMV (adjusted HR 0.54; 95% CI, 0.44-0.67). The association between ARDS and extubation failure approached statistical significance (adjusted HR 1.48; 95% CI 0.99-2.21). Higher ARDS severity was associated with incrementally longer ICU length of stay and longer cumulative duration of IMV. Findings remained robust in a sensitivity analysis evaluating the magnitude of unmeasured confounding. Conclusions: In this cohort of acutely brain-injured patients, the incidence of ARDS was similar to that reported in other mixed cohorts of critically ill patients. Development of ARDS was associated with worse outcomes.
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Affiliation(s)
- Shaurya Taran
- Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Robert D. Stevens
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Biomedical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Bastien Perrot
- UMR 1246 MethodS in Patient-centered outcomes and HEalth REsearch, SPHERE, Nantes Université, Tours Université, Nantes, France
| | - Victoria A. McCredie
- Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada
| | - Raphael Cinotti
- UMR 1246 MethodS in Patient-centered outcomes and HEalth REsearch, SPHERE, Nantes Université, Tours Université, Nantes, France
- Department of Anaesthesia and Critical Care, CHU Nantes, Nantes Université, Hôtel-Dieu, Nantes, France
| | - Karim Asehnoune
- Department of Anaesthesia and Critical Care, CHU Nantes, Nantes Université, Hôtel-Dieu, Nantes, France
| | - Paolo Pelosi
- Anesthesia and Critical Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, Genoa, Italy
- Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy
| | - Chiara Robba
- Anesthesia and Critical Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, Genoa, Italy
- Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy
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Li H, Le L, Marrero M, David-Bercholz J, Caceres AI, Lim C, Chiang W, Majewska AK, Terrando N, Gelbard HA. Neutrophilia with damage to the blood-brain barrier and neurovascular unit following acute lung injury. RESEARCH SQUARE 2023:rs.3.rs-3459515. [PMID: 37961257 PMCID: PMC10635322 DOI: 10.21203/rs.3.rs-3459515/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Background Links between acute lung injury (ALI), infectious disease, and neurological outcomes have been frequently discussed over the past few years, especially due to the COVID-19 pandemic. Yet, much of the cross-communication between organs, particularly the lung and the brain, has been understudied. Here, we have focused on the role of neutrophils in driving changes to the brain endothelium with ensuing microglial activation and neuronal loss in a model of ALI. Methods We have applied a three-dose paradigm of 10μg/40μl intranasal lipopolysaccharide (LPS) to induce neutrophilia accompanied by proteinaceous exudate in bronchoalveolar lavage fluid (BALF) in adult C57BL/6 mice. Brain endothelial markers, microglial activation, and neuronal cytoarchitecture were evaluated 24hr after the last intranasal dose of LPS or saline. C57BL/6-Ly6g(tm2621(Cre-tdTomato)Arte (Catchup mice) were used to measure neutrophil and blood-brain barrier permeability following LPS exposure with intravital 2-photon imaging. Results Three doses of intranasal LPS induced robust neutrophilia accompanied by proteinaceous exudate in BALF. ALI triggered central nervous system pathology as highlighted by robust activation of the cerebrovascular endothelium (VCAM1, CD31), accumulation of plasma protein (fibrinogen), microglial activation (IBA1, CD68), and decreased expression of proteins associated with postsynaptic terminals (PSD-95) in the hippocampal stratum lacunosum moleculare, a relay station between the entorhinal cortex and CA1 of the hippocampus. 2-photon imaging of Catchup mice revealed neutrophil homing to the cerebral endothelium in the blood-brain barrier and neutrophil extravasation from cerebral vasculature 24hr after the last intranasal treatment. Conclusions Overall, these data demonstrate ensuing brain pathology resulting from ALI, highlighting a key role for neutrophils in driving brain endothelial changes and subsequent neuroinflammation. This paradigm may have a considerable translational impact on understanding how infectious disease with ALI can lead to neurodegeneration, particularly in the elderly.
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Affiliation(s)
- Herman Li
- Center for Neurotherapeutics Discovery, University of Rochester Medical Center, Rochester, NY United States
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY United States
| | - Linh Le
- Department of Neurology, University of Rochester Medical Center, Rochester, NY United States
| | - Mariah Marrero
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY United States
| | | | - Ana I Caceres
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States
| | - Claire Lim
- Department of Neurology, University of Rochester Medical Center, Rochester, NY United States
| | - Wesley Chiang
- Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY United States
| | - Ania K Majewska
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY United States
| | - Niccolò Terrando
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States
- Department of Cell Biology, Duke University Medical Center, Durham, NC, United States
- Department of Immunology, Duke University Medical Center, Durham, NC, United States
| | - Harris A Gelbard
- Center for Neurotherapeutics Discovery, University of Rochester Medical Center, Rochester, NY United States
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY United States
- Department of Neurology, University of Rochester Medical Center, Rochester, NY United States
- Department of Immmunology, Microbiology, and Virology, University of Rochester Medical Center, Rochester, NY United States
- Department of Pediatrics, University of Rochester Medical Center, Rochester, NY United States
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Li H, Le L, Marrero M, David-Bercholz J, Caceres AI, Lim C, Chiang W, Majewska AK, Terrando N, Gelbard HA. Neutrophilia with damage to the blood-brain barrier and neurovascular unit following acute lung injury. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.16.562508. [PMID: 37905036 PMCID: PMC10614777 DOI: 10.1101/2023.10.16.562508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
Background Links between acute lung injury (ALI), infectious disease, and neurological outcomes have been frequently discussed over the past few years, especially due to the COVID-19 pandemic. Yet, much of the cross-communication between organs, particularly the lung and the brain, has been understudied. Here, we have focused on the role of neutrophils in driving changes to the brain endothelium with ensuing microglial activation and neuronal loss in a model of ALI. Methods We have applied a three-dose paradigm of 10μg/40μl intranasal lipopolysaccharide (LPS) to induce neutrophilia accompanied by proteinaceous exudate in bronchoalveolar lavage fluid (BALF) in adult C57BL/6 mice. Brain endothelial markers, microglial activation, and neuronal cytoarchitecture were evaluated 24hr after the last intranasal dose of LPS or saline. C57BL/6-Ly6g(tm2621(Cre-tdTomato)Arte (Catchup mice) were used to measure neutrophil and blood-brain barrier permeability following LPS exposure with intravital 2-photon imaging. Results Three doses of intranasal LPS induced robust neutrophilia accompanied by proteinaceous exudate in BALF. ALI triggered central nervous system pathology as highlighted by robust activation of the cerebrovascular endothelium (VCAM1, CD31), accumulation of plasma protein (fibrinogen), microglial activation (IBA1, CD68), and decreased expression of proteins associated with postsynaptic terminals (PSD-95) in the hippocampal stratum lacunosum moleculare, a relay station between the entorhinal cortex and CA1 of the hippocampus. 2-photon imaging of Catchup mice revealed neutrophil homing to the cerebral endothelium in the blood-brain barrier and neutrophil extravasation from cerebral vasculature 24hr after the last intranasal treatment. Conclusions Overall, these data demonstrate ensuing brain pathology resulting from ALI, highlighting a key role for neutrophils in driving brain endothelial changes and subsequent neuroinflammation. This paradigm may have a considerable translational impact on understanding how infectious disease with ALI can lead to neurodegeneration, particularly in the elderly.
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Affiliation(s)
- Herman Li
- Center for Neurotherapeutics Discovery, University of Rochester Medical Center, Rochester, NY United States
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY United States
| | - Linh Le
- Department of Neurology, University of Rochester Medical Center, Rochester, NY United States
| | - Mariah Marrero
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY United States
| | | | - Ana I Caceres
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States
| | - Claire Lim
- Department of Neurology, University of Rochester Medical Center, Rochester, NY United States
| | - Wesley Chiang
- Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, NY United States
| | - Ania K Majewska
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY United States
| | - Niccolò Terrando
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States
- Department of Cell Biology, Duke University Medical Center, Durham, NC, United States
- Department of Immunology, Duke University Medical Center, Durham, NC, United States
| | - Harris A Gelbard
- Center for Neurotherapeutics Discovery, University of Rochester Medical Center, Rochester, NY United States
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY United States
- Department of Neurology, University of Rochester Medical Center, Rochester, NY United States
- Department of Immmunology, Microbiology, and Virology, University of Rochester Medical Center, Rochester, NY United States
- Department of Pediatrics, University of Rochester Medical Center, Rochester, NY United States
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11
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Villalba N, Ma Y, Gahan SA, Joly-Amado A, Spence S, Yang X, Nash KR, Yuan SY. Lung infection by Pseudomonas aeruginosa induces neuroinflammation and blood-brain barrier dysfunction in mice. J Neuroinflammation 2023; 20:127. [PMID: 37245027 PMCID: PMC10223932 DOI: 10.1186/s12974-023-02817-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 05/23/2023] [Indexed: 05/29/2023] Open
Abstract
BACKGROUND Severe lung infection can lead to brain dysfunction and neurobehavioral disorders. The mechanisms that regulate the lung-brain axis of inflammatory response to respiratory infection are incompletely understood. This study examined the effects of lung infection causing systemic and neuroinflammation as a potential mechanism contributing to blood-brain barrier (BBB) leakage and behavioral impairment. METHODS Lung infection in mice was induced by instilling Pseudomonas aeruginosa (PA) intratracheally. We determined bacterial colonization in tissue, microvascular leakage, expression of cytokines and leukocyte infiltration into the brain. RESULTS Lung infection caused alveolar-capillary barrier injury as indicated by leakage of plasma proteins across pulmonary microvessels and histopathological characteristics of pulmonary edema (alveolar wall thickening, microvessel congestion, and neutrophil infiltration). PA also caused significant BBB dysfunction characterized by leakage of different sized molecules across cerebral microvessels and a decreased expression of cell-cell junctions (VE-cadherin, claudin-5) in the brain. BBB leakage peaked at 24 h and lasted for 7 days post-inoculation. Additionally, mice with lung infection displayed hyperlocomotion and anxiety-like behaviors. To test whether cerebral dysfunction was caused by PA directly or indirectly, we measured bacterial load in multiple organs. While PA loads were detected in the lungs up to 7 days post-inoculation, bacteria were not detected in the brain as evidenced by negative cerebral spinal fluid (CSF) cultures and lack of distribution in different brain regions or isolated cerebral microvessels. However, mice with PA lung infection demonstrated increased mRNA expression in the brain of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), chemokines (CXCL-1, CXCL-2) and adhesion molecules (VCAM-1 and ICAM-1) along with CD11b + CD45+ cell recruitment, corresponding to their increased blood levels of white cells (polymorphonuclear cells) and cytokines. To confirm the direct effect of cytokines on endothelial permeability, we measured cell-cell adhesive barrier resistance and junction morphology in mouse brain microvascular endothelial cell monolayers, where administration of IL-1β induced a significant reduction of barrier function coupled with tight junction (TJ) and adherens junction (AJ) diffusion and disorganization. Combined treatment with IL-1β and TNFα augmented the barrier injury. CONCLUSIONS Lung bacterial infection is associated with BBB disruption and behavioral changes, which are mediated by systemic cytokine release.
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Affiliation(s)
- Nuria Villalba
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL USA
| | - Yonggang Ma
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL USA
| | - Sarah A. Gahan
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL USA
| | - Aurelie Joly-Amado
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL USA
| | - Sam Spence
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL USA
| | - Xiaoyuan Yang
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL USA
| | - Kevin R. Nash
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL USA
| | - Sarah Y. Yuan
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL USA
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL USA
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Bassi TG, Rohrs EC, Fernandez KC, Ornowska M, Nicholas M, Wittmann J, Gani M, Evans D, Reynolds SC. Phrenic nerve stimulation mitigates hippocampal and brainstem inflammation in an ARDS model. Front Physiol 2023; 14:1182505. [PMID: 37215178 PMCID: PMC10196250 DOI: 10.3389/fphys.2023.1182505] [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: 03/08/2023] [Accepted: 04/20/2023] [Indexed: 05/24/2023] Open
Abstract
Rationale: In porcine healthy-lung and moderate acute respiratory distress syndrome (ARDS) models, groups that received phrenic nerve stimulation (PNS) with mechanical ventilation (MV) showed lower hippocampal apoptosis, and microglia and astrocyte percentages than MV alone. Objectives: Explore whether PNS in combination with MV for 12 h leads to differences in hippocampal and brainstem tissue concentrations of inflammatory and synaptic markers compared to MV-only animals. Methods: Compare tissue concentrations of inflammatory markers (IL-1α, IL-1β, IL-6, IL-8, IL-10, IFN-γ, TNFα and GM-CSF), pre-synaptic markers (synapsin and synaptophysin) and post-synaptic markers (disc-large-homolog 4, N-methyl-D-aspartate receptors 2A and 2B) in the hippocampus and brainstem in three groups of mechanically ventilated pigs with injured lungs: MV only (MV), MV plus PNS every other breath (MV + PNS50%), and MV plus PNS every breath (MV + PNS100%). MV settings in volume control were tidal volume 8 ml/kg, and positive end-expiratory pressure 5 cmH2O. Moderate ARDS was achieved by infusing oleic acid into the pulmonary artery. Measurements and Main Results: Hippocampal concentrations of GM-CSF, N-methyl-D-aspartate receptor 2B, and synaptophysin were greater in the MV + PNS100% group compared to the MV group, p = 0.0199, p = 0.0175, and p = 0.0479, respectively. The MV + PNS100% group had lower brainstem concentrations of IL-1β, and IL-8 than the MV group, p = 0.0194, and p = 0.0319, respectively; and greater brainstem concentrations of IFN-γ and N-methyl-D-aspartate receptor 2A than the MV group, p = 0.0329, and p = 0.0125, respectively. Conclusion: In a moderate-ARDS porcine model, MV is associated with hippocampal and brainstem inflammation, and phrenic nerve stimulation on every breath mitigates that inflammation.
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Affiliation(s)
| | - Elizabeth C. Rohrs
- Advancing Innovation in Medicine Institute, New Westminster, BC, Canada
- Fraser Health Authority, Royal Columbian Hospital, New Westminster, BC, Canada
| | - Karl C. Fernandez
- Fraser Health Authority, Royal Columbian Hospital, New Westminster, BC, Canada
- Biomedical, Physiology, and Kinesiology Department, Simon Fraser University, Burnaby, BC, Canada
| | - Marlena Ornowska
- Fraser Health Authority, Royal Columbian Hospital, New Westminster, BC, Canada
| | - Michelle Nicholas
- Fraser Health Authority, Royal Columbian Hospital, New Westminster, BC, Canada
- Biomedical, Physiology, and Kinesiology Department, Simon Fraser University, Burnaby, BC, Canada
| | - Jessica Wittmann
- Biomedical, Physiology, and Kinesiology Department, Simon Fraser University, Burnaby, BC, Canada
| | - Matt Gani
- Lungpacer Medical Inc., Vancouver, BC, Canada
| | - Doug Evans
- Lungpacer Medical Inc., Vancouver, BC, Canada
| | - Steven C. Reynolds
- Advancing Innovation in Medicine Institute, New Westminster, BC, Canada
- Fraser Health Authority, Royal Columbian Hospital, New Westminster, BC, Canada
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Villalba N, Ma Y, Gahan SA, Joly-Amado A, Spence S, Yang X, Nash K, Yuan SY. Lung infection by P. aeruginosa induces neuroinflammation and blood-brain barrier dysfunction in mice. RESEARCH SQUARE 2023:rs.3.rs-2511441. [PMID: 36778380 PMCID: PMC9915779 DOI: 10.21203/rs.3.rs-2511441/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Background Severe lung infection can lead to brain dysfunction and neurobehavioral disorders. The mechanisms that regulate the lung-brain axis of inflammatory response to respiratory infection are incompletely understood. This study examined the effects of lung infection causing systemic and neuroinflammation as a potential mechanism contributing to blood-brain barrier (BBB) leakage and behavioral impairment. Methods Pneumonia was induced in adult C57BL/6 mice by intratracheal inoculation of Pseudomonas aeruginosa (PA). Solute extravasation, histology, immunofluorescence, RT-PCR, multiphoton imaging and neurological testing were performed in this study. Results Lung infection caused alveolar-capillary barrier injury as indicated by leakage of plasma proteins across pulmonary microvessels and histopathological characteristics of pulmonary edema (alveolar wall thickening, microvessel congestion, and neutrophil infiltration). PA also caused significant BBB dysfunction characterized by leakage of different sized molecules across cerebral microvessels and a decreased expression of cell-cell junctions (VE-cadherin, claudin-5) in the brain. BBB leakage peaked at 24 hours and lasted for 7 days post-inoculation. Additionally, mice with lung infection displayed hyperlocomotion and anxiety-like behaviors. To test whether cerebral dysfunction was caused by PA directly or indirectly, we measured bacterial load in multiple organs. While PA loads were detected in the lungs up to 7 days post-inoculation, bacteria were not detected in the brain as evidenced by negative cerebral spinal fluid (CSF) cultures and lack of distribution in different brain regions or isolated cerebral microvessels. However, mice with PA lung infection demonstrated increased mRNA expression in the brain of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), chemokines (CXCL-1, CXCL-2) and adhesion molecules (VCAM-1 and ICAM-1) along with CD11b + cell recruitment, corresponding to their increased blood levels of white cells (polymorphonuclear cells) and cytokines. To confirm the direct effect of cytokines on endothelial permeability, we measured cell-cell adhesive barrier resistance and junction morphology in mouse brain microvascular endothelial cell monolayers, where administration of IL-1β induced a significant reduction of barrier function coupled with tight junction (TJ) diffusion and disorganization. Combined treatment with IL-1β and TNFα augmented the barrier injury. Conclusions These results suggest that lung bacterial infection causes cerebral microvascular leakage and neuroinflammation via a mechanism involving cytokine-induced BBB injury.
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Affiliation(s)
| | - Yonggang Ma
- University of South Florida Morsani College of Medicine
| | - Sarah A Gahan
- University of South Florida Morsani College of Medicine
| | | | - Sam Spence
- University of South Florida Morsani College of Medicine
| | - Xiaoyuan Yang
- University of South Florida Morsani College of Medicine
| | - Kevin Nash
- University of South Florida Morsani College of Medicine
| | - Sarah Y Yuan
- University of South Florida Morsani College of Medicine
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14
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Villalba N, Ma Y, Gahan SA, Joly-Amado A, Spence S, Yang X, Nash K, Yuan SY. Lung infection by P. aeruginosa induces neuroinflammation and blood-brain barrier dysfunction in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.23.524949. [PMID: 36747856 PMCID: PMC9900744 DOI: 10.1101/2023.01.23.524949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Background Severe lung infection can lead to brain dysfunction and neurobehavioral disorders. The mechanisms that regulate the lung-brain axis of inflammatory response to respiratory infection are incompletely understood. This study examined the effects of lung infection causing systemic and neuroinflammation as a potential mechanism contributing to blood-brain barrier (BBB) leakage and behavioral impairment. Methods Pneumonia was induced in adult C57BL/6 mice by intratracheal inoculation of Pseudomonas aeruginosa (PA). Solute extravasation, histology, immunofluorescence, RT-PCR, multiphoton imaging and neurological testing were performed in this study. Results Lung infection caused alveolar-capillary barrier injury as indicated by leakage of plasma proteins across pulmonary microvessels and histopathological characteristics of pulmonary edema (alveolar wall thickening, microvessel congestion, and neutrophil infiltration). PA also caused significant BBB dysfunction characterized by leakage of different sized molecules across cerebral microvessels and a decreased expression of cell-cell junctions (VE-cadherin, claudin-5) in the brain. BBB leakage peaked at 24 hours and lasted for 7 days post-inoculation. Additionally, mice with lung infection displayed hyperlocomotion and anxiety-like behaviors. To test whether cerebral dysfunction was caused by PA directly or indirectly, we measured bacterial load in multiple organs. While PA loads were detected in the lungs up to 7 days post-inoculation, bacteria were not detected in the brain as evidenced by negative cerebral spinal fluid (CSF) cultures and lack of distribution in different brain regions or isolated cerebral microvessels. However, mice with PA lung infection demonstrated increased mRNA expression in the brain of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), chemokines (CXCL-1, CXCL-2) and adhesion molecules (VCAM-1 and ICAM-1) along with CD11b+ cell recruitment, corresponding to their increased blood levels of white cells (polymorphonuclear cells) and cytokines. To confirm the direct effect of cytokines on endothelial permeability, we measured cell-cell adhesive barrier resistance and junction morphology in mouse brain microvascular endothelial cell monolayers, where administration of IL-1β induced a significant reduction of barrier function coupled with tight junction (TJ) diffusion and disorganization. Combined treatment with IL-1β and TNFα augmented the barrier injury. Conclusions These results suggest that lung bacterial infection causes cerebral microvascular leakage and neuroinflammation via a mechanism involving cytokine-induced BBB injury.
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15
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Anwar F, Sparrow NA, Rashid MH, Guidry G, Gezalian MM, Ley EJ, Koronyo-Hamaoui M, Danovitch I, Ely EW, Karumanchi SA, Lahiri S. Systemic interleukin-6 inhibition ameliorates acute neuropsychiatric phenotypes in a murine model of acute lung injury. Crit Care 2022; 26:274. [PMID: 36100846 PMCID: PMC9469063 DOI: 10.1186/s13054-022-04159-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 09/04/2022] [Indexed: 11/10/2022] Open
Abstract
Acute neuropsychiatric impairments occur in over 70% of patients with acute lung injury. Mechanical ventilation is a well-known precipitant of acute lung injury and is strongly associated with the development of acute delirium and anxiety phenotypes. In prior studies, we demonstrated that IL-6 mediates neuropathological changes in the frontal cortex and hippocampus of animals with mechanical ventilation-induced brain injury; however, the effect of systemic IL-6 inhibition on structural and functional acute neuropsychiatric phenotypes is not known. We hypothesized that a murine model of mechanical ventilation-induced acute lung injury (VILI) would induce neural injury to the amygdala and hippocampus, brain regions that are implicated in diverse neuropsychiatric conditions, and corresponding delirium- and anxiety-like functional impairments. Furthermore, we hypothesized that these structural and functional changes would reverse with systemic IL-6 inhibition. VILI was induced using high tidal volume (35 cc/kg) mechanical ventilation. Cleaved caspase-3 (CC3) expression was quantified as a neural injury marker and found to be significantly increased in the VILI group compared to spontaneously breathing or anesthetized and mechanically ventilated mice with 10 cc/kg tidal volume. VILI mice treated with systemic IL-6 inhibition had significantly reduced amygdalar and hippocampal CC3 expression compared to saline-treated animals and demonstrated amelioration in acute neuropsychiatric behaviors in open field, elevated plus maze, and Y-maze tests. Overall, these data provide evidence of a pathogenic role of systemic IL-6 in mediating structural and functional acute neuropsychiatric symptoms in VILI and provide preclinical justification to assess IL-6 inhibition as a potential intervention to ameliorate acute neuropsychiatric phenotypes following VILI.
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Ziaka M, Exadaktylos A. ARDS associated acute brain injury: from the lung to the brain. Eur J Med Res 2022; 27:150. [PMID: 35964069 PMCID: PMC9375183 DOI: 10.1186/s40001-022-00780-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 07/29/2022] [Indexed: 01/10/2023] Open
Abstract
A complex interrelation between lung and brain in patients with acute lung injury (ALI) has been established by experimental and clinical studies during the last decades. Although, acute brain injury represents one of the most common insufficiencies in patients with ALI and acute respiratory distress syndrome (ARDS), the underlying pathophysiology of the observed crosstalk remains poorly understood due to its complexity. Specifically, it involves numerous pathophysiological parameters such as hypoxemia, neurological adverse events of lung protective ventilation, hypotension, disruption of the BBB, and neuroinflammation in such a manner that the brain of ARDS patients-especially hippocampus-becomes very vulnerable to develop secondary lung-mediated acute brain injury. A protective ventilator strategy could reduce or even minimize further systemic release of inflammatory mediators and thus maintain brain homeostasis. On the other hand, mechanical ventilation with low tidal volumes may lead to self-inflicted lung injury, hypercapnia and subsequent cerebral vasodilatation, increased cerebral blood flow, and intracranial hypertension. Therefore, by describing the pathophysiology of ARDS-associated acute brain injury we aim to highlight and discuss the possible influence of mechanical ventilation on ALI-associated acute brain injury.
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Affiliation(s)
- Mairi Ziaka
- Department of Internal Medicine, Thun General Hospital, Thun, Switzerland
| | - Aristomenis Exadaktylos
- Department of Emergency Medicine, Inselspital, University Hospital, University of Bern, Bern, Switzerland
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Rissel R, Schaefer M, Kamuf J, Ruemmler R, Riedel J, Mohnke K, Renz M, Hartmann EK, Ziebart A. Lung-brain 'cross-talk': systemic propagation of cytokines in the ARDS via the bloodstream using a blood transfusion model does not influence cerebral inflammatory response in pigs. PeerJ 2022; 10:e13024. [PMID: 35265399 PMCID: PMC8900612 DOI: 10.7717/peerj.13024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 02/07/2022] [Indexed: 01/11/2023] Open
Abstract
Background Interorgan cross-talk describes the phenomenon in which a primarily injured organ causes secondary damage to a distant organ. This cross-talk is well known between the lung and brain. One theory suggests that the release and systemic distribution of cytokines via the bloodstream from the primarily affected organ sets in motion proinflammatory cascades in distant organs. In this study, we analysed the role of the systemic distribution of cytokines via the bloodstream in a porcine ARDS model for organ cross-talk and possible inflammatory changes in the brain. Methods After approval of the State and Institutional Animal Care Committee, acute respiratory distress syndrome (ARDS) induction with oleic acid injection was performed in seven animals. Eight hours after ARDS induction, blood (35-40 ml kg-1) was taken from these seven 'ARDS donor' pigs. The collected 'ARDS donor' blood was transfused into seven healthy 'ARDS-recipient' pigs. Three animals served as a control group, and blood from these animals was transfused into three healthy pigs after an appropriate ventilation period. All animals were monitored for 8 h using advanced cardiorespiratory monitoring. Postmortem assessment included cerebral (hippocampal and cortex) mediators of early inflammatory response (IL-6, TNF-alpha, iNOS, sLCN-2), wet-to-dry ratio and lung histology. TNF-alpha serum concentration was measured in all groups. Results ARDS was successfully induced in the 'ARDS donor' group, and serum TNF-alpha levels were elevated compared with the 'ARDS-recipient' group. In the 'ARDS-recipient' group, neither significant ARDS alterations nor upregulation of inflammatory mediators in the brain tissue were detected after high-volume random allogenic 'ARDS-blood' transfusion. The role of the systemic distribution of inflammatory cytokines from one affected organ to another could not be confirmed in this study.
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Wei W, Sun Z, He S, Zhang W, Chen S, Cao YN, Wang N. Mechanical ventilation induces lung and brain injury through ATP production, P2Y1 receptor activation and dopamine release. Bioengineered 2022; 13:2346-2359. [PMID: 35034579 PMCID: PMC8974168 DOI: 10.1080/21655979.2021.2022269] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Mechanical ventilation can induce lung injury and exacerbate brain injury due to lung-brain interaction. The current study sought to investigate the mechanism of lung-brain interaction induced by mechanical ventilation and offer theoretical insight into the management of ventilator-induced brain injury. The experimental mice were assigned into the spontaneously breathing group and the mechanical ventilation group and injected with dopamine (DA) receptor antagonist haloperidol or P2Y1 receptor antagonist MRS2279 before ventilation. In vitro assay was conducted using lung epithelial cells MLE-12 hippocampal neuron cells and HT-22. Mouse recognition function and lung injury were examined. The condition and concentration of neurons in the hippocampus were observed. The levels of several inflammatory factors, DA, adenosine triphosphate (ATP), P2Y1R, and dysbindin-1 were detected. Mechanical ventilation induced lung and brain injury in mice, manifested in increased inflammatory factors in the bronchoalveolar lavage fluid and hippocampus, prolonged escape latency, and swimming distance and time in the target quadrant with a weakened concentration of neurons in the hippocampus. Our results presented elevated ATP and P2Y1R expressions in the mechanically ventilated mice and stretched MLE-12 cells. The mechanically ventilated mice and P2Y1 receptor activator MRS2365-treated HT-22 cells presented with elevated levels of DA and dysbindin-1. Inactivation of P2Y1 receptor in the hippocampus or blockage of DA receptor alleviated brain injury induced by mechanical ventilation in mice. To conclude, the current study elicited that lung injury induced by mechanical ventilation exacerbated brain injury in mice by increasing ATP production, activating the P2Y1 receptor, and thus promoting DA release.
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Affiliation(s)
- Wei Wei
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhentao Sun
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Shifeng He
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Wanyue Zhang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Sai Chen
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ya-Nan Cao
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ning Wang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Taran S, McCredie VA, Goligher EC. Noninvasive and invasive mechanical ventilation for neurologic disorders. HANDBOOK OF CLINICAL NEUROLOGY 2022; 189:361-386. [PMID: 36031314 DOI: 10.1016/b978-0-323-91532-8.00015-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Patients with acute neurologic injuries frequently require mechanical ventilation due to diminished airway protective reflexes, cardiopulmonary failure secondary to neurologic insults, or to facilitate gas exchange to precise targets. Mechanical ventilation enables tight control of oxygenation and carbon dioxide levels, enabling clinicians to modulate cerebral hemodynamics and intracranial pressure with the goal of minimizing secondary brain injury. In patients with acute spinal cord injuries, neuromuscular conditions, or diseases of the peripheral nerve, mechanical ventilation enables respiratory support under conditions of impending or established respiratory failure. Noninvasive ventilatory approaches may be carefully considered for certain disease conditions, including myasthenia gravis and amyotrophic lateral sclerosis, but may be inappropriate in patients with Guillain-Barré syndrome or when relevant contra-indications exist. With regard to discontinuing mechanical ventilation, considerable uncertainty persists about the best approach to wean patients, how to identify patients ready for extubation, and when to consider primary tracheostomy. Recent consensus guidelines highlight these and other knowledge gaps that are the focus of active research efforts. This chapter outlines important general principles to consider when initiating, titrating, and discontinuing mechanical ventilation in patients with acute neurologic injuries. Important disease-specific considerations are also reviewed where appropriate.
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Affiliation(s)
- Shaurya Taran
- Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON, Canada; Department of Medicine, University Health Network, Toronto, ON, Canada
| | - Victoria A McCredie
- Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON, Canada; Department of Medicine, University Health Network, Toronto, ON, Canada
| | - Ewan C Goligher
- Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON, Canada; Department of Medicine, University Health Network, Toronto, ON, Canada.
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Martín-Vicente P, López-Martínez C, Lopez-Alonso I, López-Aguilar J, Albaiceta GM, Amado-Rodríguez L. Molecular mechanisms of postintensive care syndrome. Intensive Care Med Exp 2021; 9:58. [PMID: 34859298 PMCID: PMC8639215 DOI: 10.1186/s40635-021-00423-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 11/16/2021] [Indexed: 11/10/2022] Open
Affiliation(s)
- Paula Martín-Vicente
- Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.,Centro de Investigación Biomédica en Red (CIBER)-Enfermedades Respiratorias, Madrid, Spain
| | - Cecilia López-Martínez
- Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.,Centro de Investigación Biomédica en Red (CIBER)-Enfermedades Respiratorias, Madrid, Spain
| | - Inés Lopez-Alonso
- Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain.,Centro de Investigación Biomédica en Red (CIBER)-Enfermedades Respiratorias, Madrid, Spain.,Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain
| | - Josefina López-Aguilar
- Centro de Investigación Biomédica en Red (CIBER)-Enfermedades Respiratorias, Madrid, Spain.,Critical Care Center, Hospital Universitari Parc Taulí, Institut d'Investigació I Innovació Parc Taulí I3PT, Sabadell, Spain
| | - Guillermo M Albaiceta
- Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain. .,Centro de Investigación Biomédica en Red (CIBER)-Enfermedades Respiratorias, Madrid, Spain. .,Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain. .,Unidad de Cuidados Intensivos Cardiológicos, Hospital Universitario Central de Asturias, Oviedo, Spain.
| | - Laura Amado-Rodríguez
- Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain. .,Centro de Investigación Biomédica en Red (CIBER)-Enfermedades Respiratorias, Madrid, Spain. .,Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain. .,Unidad de Cuidados Intensivos Cardiológicos, Hospital Universitario Central de Asturias, Oviedo, Spain.
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21
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Albaiceta GM, Brochard L, Dos Santos CC, Fernández R, Georgopoulos D, Girard T, Jubran A, López-Aguilar J, Mancebo J, Pelosi P, Skrobik Y, Thille AW, Wilcox ME, Blanch L. The central nervous system during lung injury and mechanical ventilation: a narrative review. Br J Anaesth 2021; 127:648-659. [PMID: 34340836 DOI: 10.1016/j.bja.2021.05.038] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/03/2021] [Accepted: 05/24/2021] [Indexed: 11/26/2022] Open
Abstract
Mechanical ventilation induces a number of systemic responses for which the brain plays an essential role. During the last decade, substantial evidence has emerged showing that the brain modifies pulmonary responses to physical and biological stimuli by various mechanisms, including the modulation of neuroinflammatory reflexes and the onset of abnormal breathing patterns. Afferent signals and circulating factors from injured peripheral tissues, including the lung, can induce neuronal reprogramming, potentially contributing to neurocognitive dysfunction and psychological alterations seen in critically ill patients. These impairments are ubiquitous in the presence of positive pressure ventilation. This narrative review summarises current evidence of lung-brain crosstalk in patients receiving mechanical ventilation and describes the clinical implications of this crosstalk. Further, it proposes directions for future research ranging from identifying mechanisms of multiorgan failure to mitigating long-term sequelae after critical illness.
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Affiliation(s)
- Guillermo M Albaiceta
- Unidad de Cuidados Intensivos Cardiológicos, Hospital Universitario Central de Asturias, Oviedo, Spain; Departamento de Biología Funcional, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain; Centro de Investigación Biomédica en Red-Enfermedades Respiratorias (CIBER)-Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
| | - Laurent Brochard
- Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada; Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada
| | - Claudia C Dos Santos
- Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada; Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada
| | - Rafael Fernández
- Centro de Investigación Biomédica en Red-Enfermedades Respiratorias (CIBER)-Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Critical Care Department, Althaia Xarxa Assistencial Universitaria de Manresa, Universitat Internacional de Catalunya, Manresa, Spain
| | - Dimitris Georgopoulos
- Intensive Care Medicine Department, University Hospital of Heraklion, School of Medicine, University of Crete, Heraklion, Crete, Greece
| | - Timothy Girard
- Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Amal Jubran
- Division of Pulmonary and Critical Care Medicine, Hines VA Hospital, Hines, IL, USA; Loyola University of Chicago, Stritch School of Medicine, Maywood, IL, USA
| | - Josefina López-Aguilar
- Centro de Investigación Biomédica en Red-Enfermedades Respiratorias (CIBER)-Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Critical Care Center, Hospital Universitari Parc Taulí, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain
| | - Jordi Mancebo
- Servei Medicina Intensiva, University Hospital Sant Pau, Barcelona, Spain
| | - Paolo Pelosi
- Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy; Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences, Genoa, Italy
| | - Yoanna Skrobik
- Department of Medicine, McGill University, Regroupement de Soins Critiques Respiratoires, Réseau de Soins Respiratoires FRQS, Montreal, QC, Canada
| | - Arnaud W Thille
- CHU de Poitiers, Médecine Intensive Réanimation, Poitiers, France; INSERM CIC 1402 ALIVE, Université de Poitiers, Poitiers, France
| | - Mary E Wilcox
- Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada; Department of Medicine, Division of Respirology (Critical Care Medicine), University Health Network, Toronto, ON, Canada
| | - Lluis Blanch
- Centro de Investigación Biomédica en Red-Enfermedades Respiratorias (CIBER)-Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Critical Care Center, Hospital Universitari Parc Taulí, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain
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22
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Sparrow NA, Anwar F, Covarrubias AE, Rajput PS, Rashid MH, Nisson PL, Gezalian MM, Toossi S, Ayodele MO, Karumanchi SA, Ely EW, Lahiri S. Interleukin-6 Inhibition Reduces Neuronal Injury In A Murine Model of Ventilator-Induced Lung Injury. Am J Respir Cell Mol Biol 2021; 65:403-412. [PMID: 34014798 DOI: 10.1165/rcmb.2021-0072oc] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by frontal cortex and hippocampal dysfunction. Although interleukin-6 (IL-6) is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether inhibition of systemic IL-6 mitigates delirium-relevant neuropathology. To histologically define neuropathological effects of IL-6 inhibition in an experimental VILI model. VILI was simulated in anesthetized adult mice using a 35cc/kg tidal volume mechanical ventilation model. There were two controls groups: 1) spontaneously breathing, or 2) anesthetized and mechanically ventilated with 10cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours prior to inducing VILI, mice were treated with either anti-IL-6 antibody, anti-IL-6 receptor antibody, or saline. Neuronal injury, stress, and inflammation were assessed using immunohistochemistry. Cleaved caspase-3 (CC3), a neuronal apoptosis marker, was significantly increased in the frontal (p<0.001) and hippocampal (p<0.0001) brain regions and accompanied by significant increases in c-Fos and heat shock protein-90 in the frontal cortices of VILI mice compared to controls (p<0.001). These findings were not related to cerebral hypoxia and there was no evidence of irreversible neuronal death. Frontal and hippocampal neuronal CC3 were significantly reduced with anti-IL-6 antibody (p<0.01 and p<0.0001, respectively), anti-IL-6 receptor antibody (p<0.05 and p<0.0001, respectively) compared to saline VILI mice. VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.
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Affiliation(s)
- Nicklaus A Sparrow
- Cedars-Sinai Medical Center, 22494, Neurology, West Hollywood, California, United States
| | - Faizan Anwar
- Cedars-Sinai Medical Center, 22494, Los Angeles, California, United States
| | | | - Padmesh S Rajput
- Cedars-Sinai Health System, 5149, Neurology, Los Angeles, California, United States
| | | | - Peyton L Nisson
- Cedars-Sinai Medical Center, 22494, West Hollywood, California, United States
| | - Michael M Gezalian
- Cedars-Sinai Medical Center, 22494, Neurology, West Hollywood, California, United States
| | - Shahed Toossi
- Cedars-Sinai Medical Center, 22494, West Hollywood, California, United States
| | - Maranatha O Ayodele
- Cedars-Sinai Medical Center, 22494, West Hollywood, California, United States
| | | | - E Wesley Ely
- Vanderbilt University School of Medicine, 12327, Nashville, Tennessee, United States
| | - Shouri Lahiri
- Cedars-Sinai Health System, 5149, Neurology and Neurosurgery, Los Angeles, California, United States;
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23
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Giordano G, Pugliese F, Bilotta F. Neuroinflammation, neuronal damage or cognitive impairment associated with mechanical ventilation: A systematic review of evidence from animal studies. J Crit Care 2021; 62:246-255. [PMID: 33454552 DOI: 10.1016/j.jcrc.2020.12.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 11/25/2020] [Accepted: 12/19/2020] [Indexed: 01/01/2023]
Abstract
PURPOSE Long-term cognitive impairment is a complication of critical illness survivors. Beside its lifesaving role, mechanical ventilation has potential complications. The aim of this study is to systematically review the evidence collected in animal studies that correlate mechanical ventilation with neuroinflammation, neuronal damage and cognitive impairment. METHODS We searched MEDLINE and EMBASE databases for studies published from inception until August 31st, 2020, that enrolled mechanically ventilated animals and reported on neuroinflammation or neuronal damage markers changes or cognitive-behavioural impairment. RESULTS Of 5583 studies, 11 met inclusion criteria. Mice, rats, pigs were used. Impact of MV: 4 out of 7 studies reported higher neuroinflammation markers in MV-treated animals and 3 studies reported no differences; 7 out of 8 studies reported a higher neuronal damage and 1 reported no differences; 2 out of 2 studies reported cognitive decline up to 3 days after MV. Higher Tidal volumes are associated with higher changes in brain or serum markers. CONCLUSION Preclinical evidence suggests that MV induces neuroinflammation, neuronal damage and cognitive impairment and these are worsened if sub-optimal MV settings are applied. Future studies, with appropriate methodology, are necessary to evaluate for serum monitoring strategies. TRIAL REGISTRATION NUMBER CRD42019148935.
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Affiliation(s)
- Giovanni Giordano
- Department of Anaesthesia and Intensive Care, Sapienza University of Rome, Roma, Italy.
| | - Francesco Pugliese
- Department of Anaesthesia and Intensive Care, Sapienza University of Rome, Roma, Italy
| | - Federico Bilotta
- Department of Anaesthesia and Intensive Care, Sapienza University of Rome, Roma, Italy
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24
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Bassi TG, Rohrs EC, Reynolds SC. Systematic review of cognitive impairment and brain insult after mechanical ventilation. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2021; 25:99. [PMID: 33691752 PMCID: PMC7945325 DOI: 10.1186/s13054-021-03521-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 03/01/2021] [Indexed: 12/11/2022]
Abstract
We conducted a systematic review following the PRISMA protocol primarily to identify publications that assessed any links between mechanical ventilation (MV) and either cognitive impairment or brain insult, independent of underlying medical conditions. Secondary objectives were to identify possible gaps in the literature that can be used to inform future studies and move toward a better understanding of this complex problem. The preclinical literature suggests that MV is associated with neuroinflammation, cognitive impairment, and brain insult, reporting higher neuroinflammatory markers, greater evidence of brain injury markers, and lower cognitive scores in subjects that were ventilated longer, compared to those ventilated less, and to never-ventilated subjects. The clinical literature suggests an association between MV and delirium, and that delirium in mechanically ventilated patients may be associated with greater likelihood of long-term cognitive impairment; our systematic review found no clinical study that demonstrated a causal link between MV, cognitive dysfunction, and brain insult. More studies should be designed to investigate ventilation-induced brain injury pathways as well as any causative linkage between MV, cognitive impairment, and brain insult.
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Affiliation(s)
- Thiago G Bassi
- Simon Fraser University, Burnaby, Canada.,Lungpacer Medical Inc, Vancouver, Canada
| | - Elizabeth C Rohrs
- Simon Fraser University, Burnaby, Canada.,Royal Columbian Hospital, Fraser Health Authority, 260 Sherbrooke Street, New Westminster, BC, V3L 3M2, Canada
| | - Steven C Reynolds
- Simon Fraser University, Burnaby, Canada. .,Royal Columbian Hospital, Fraser Health Authority, 260 Sherbrooke Street, New Westminster, BC, V3L 3M2, Canada.
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25
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Crosstalk Between Lung and Extrapulmonary Organs in Infection and Inflammation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1303:333-350. [PMID: 33788201 DOI: 10.1007/978-3-030-63046-1_18] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Acute and chronic lung inflammation is a risk factor for various diseases involving lungs and extrapulmonary organs. Intercellular and interorgan networks, including crosstalk between lung and brain, intestine, heart, liver, and kidney, coordinate host immunity against infection, protect tissue, and maintain homeostasis. However, this interaction may be counterproductive and cause acute or chronic comorbidities due to dysregulated inflammation in the lung. In this chapter, we review the relationship of the lung with other key organs during normal cell processes and disease development. We focus on how pneumonia may lead to a systemic pathophysiological response to acute lung injury and chronic lung disease through organ interactions, which can facilitate the development of undesirable and even deleterious extrapulmonary sequelae.
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26
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Robba C, Battaglini D, Samary CS, Silva PL, Ball L, Rocco PRM, Pelosi P. Ischaemic stroke-induced distal organ damage: pathophysiology and new therapeutic strategies. Intensive Care Med Exp 2020; 8:23. [PMID: 33336314 PMCID: PMC7746424 DOI: 10.1186/s40635-020-00305-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 05/20/2020] [Indexed: 01/09/2023] Open
Abstract
Acute ischaemic stroke is associated with a high risk of non-neurological complications, which include respiratory failure, cardiovascular dysfunction, kidney and liver injury, and altered immune and endocrine function. The aim of this manuscript is to provide an overview of the main forms of stroke-induced distal organ damage, providing new pathophysiological insights and recommendations for clinical management.Non-neurological complications of stroke can affect outcomes, with potential for serious short-term and long-term consequences. Many of these complications can be prevented; when prevention is not feasible, early detection and proper management can still be effective in mitigating their adverse impact. The general care of stroke survivors entails not only treatment in the acute setting but also prevention of secondary complications that might hinder functional recovery. Acute ischaemic stroke triggers a cascade of events-including local and systemic activation of the immune system-which results in a number of systemic consequences and, ultimately, may cause organ failure. Understanding the pathophysiology and clinical relevance of non-neurological complications is a crucial component in the proper treatment of patients with acute stroke.Little evidence-based data is available to guide management of these complications. There is a clear need for improved surveillance and specific interventions for the prevention, early diagnosis, and proper management of non-neurological complications during the acute phase of ischaemic stroke, which should reduce morbidity and mortality.
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Affiliation(s)
- Chiara Robba
- Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, Largo Rosanna Benzi 10, 16100, Genoa, Italy.
| | - Denise Battaglini
- Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, Largo Rosanna Benzi 10, 16100, Genoa, Italy.,Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy
| | - Cynthia S Samary
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Pedro L Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Lorenzo Ball
- Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, Largo Rosanna Benzi 10, 16100, Genoa, Italy.,Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy
| | - Patricia R M Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Paolo Pelosi
- Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, Largo Rosanna Benzi 10, 16100, Genoa, Italy.,Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy
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27
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Hippocampal Damage During Mechanical Ventilation in Trendelenburg Position: A Secondary Analysis of an Experimental Study on the Prevention of Ventilator-Associated Pneumonia. Shock 2020; 52:75-82. [PMID: 30052585 DOI: 10.1097/shk.0000000000001237] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
We previously corroborated benefits of the Trendelenburg position in the prevention of ventilator-associated pneumonia (VAP). We now investigate its potential effects on the brain versus the semirecumbent position. We studied 17 anesthetized pigs and randomized to be ventilated and positioned as follows: duty cycle (TI/TTOT) of 0.33, without positive end-expiratory pressure (PEEP), placed with the bed oriented 30° in anti-Trendelenburg (control group); positioned as in the control group, with TI/TTOT adjusted to achieve an expiratory flow bias, PEEP of 5 cm H2O (IRV-PEEP); positioned in 5° TP and ventilated as in the control group (TP). Animals were challenged into the oropharynx with Pseudomonas aeruginosa. We assessed hemodynamic parameters and systemic inflammation throughout the study. After 72 h, we evaluated incidence of microbiological/histological VAP and brain injury. Petechial hemorrhages score was greater in the TP group (P = 0.013). Analysis of the dentate gyrus showed higher cell apoptosis and deteriorating neurons in TP animals (P < 0.05 vs. the other groups). No differences in systemic inflammation were found among groups. Cerebral perfusion pressure was higher in TP animals (P < 0.001), mainly driven by higher mean arterial pressure. Microbiological/histological VAP developed in 0%, 67%, and 86% of the animals in the TP, control, and IRV-PEEP groups, respectively (P = 0.003). In conclusion, the TP prevents VAP; yet, we found deleterious neural effects in the dentate gyrus, likely associated with cerebrovascular modification in such position. Further laboratory and clinical studies are mandatory to appraise potential neurological risks associated with long-term TP.
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28
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Abstract
Mechanical ventilation can cause ventilator-induced brain injury via afferent vagal signaling and hippocampal neurotransmitter imbalances. The triggering mechanisms for vagal signaling during mechanical ventilation are unknown. The objective of this study was to assess whether pulmonary transient receptor potential vanilloid type-4 (TRPV4) mechanoreceptors and vagal afferent purinergic receptors (P2X) act as triggers of ventilator-induced brain injury.
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29
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Vaillancourt M, Chia P, Medzikovic L, Cao N, Ruffenach G, Younessi D, Umar S. Experimental Pulmonary Hypertension Is Associated With Neuroinflammation in the Spinal Cord. Front Physiol 2019; 10:1186. [PMID: 31616310 PMCID: PMC6764190 DOI: 10.3389/fphys.2019.01186] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Accepted: 09/02/2019] [Indexed: 02/02/2023] Open
Abstract
Rationale Pulmonary hypertension (PH) is a rare but fatal disease characterized by elevated pulmonary pressures and vascular remodeling, leading to right ventricular failure and death. Recently, neuroinflammation has been suggested to be involved in the sympathetic activation in experimental PH. Whether PH is associated with neuroinflammation in the spinal cord has never been investigated. Methods/Results PH was well-established in adult male Wistar rats 3-week after pulmonary endothelial toxin Monocrotaline (MCT) injection. Using the thoracic segments of the spinal cord, we found a 5-fold increase for the glial fibrillary acidic protein (GFAP) in PH rats compared to controls (p < 0.05). To further determine the region of the spinal cord where GFAP was expressed, we performed immunofluorescence and found a 3 to 3.5-fold increase of GFAP marker in the gray matter, and a 2 to 3-fold increase in the white matter in the spinal cord of PH rats compared to controls. This increase was due to PH (MCT vs. Control; p < 0.01), and there was no difference between the dorsal versus ventral region. PH rats also had an increase in the pro-inflammatory marker chemokine (C-C motif) ligand 3 (CCL3) protein expression (∼ 3-fold) and (2.8 to 4-fold, p < 0.01) in the white matter. Finally, angiogenesis was increased in PH rat spinal cords assessed by the adhesion molecule CD31 expression (1.5 to 2.3-fold, p < 0.01). Conclusion We report for the first time evidence for neuroinflammation in the thoracic spinal cord of pulmonary hypertensive rats. The impact of spinal cord inflammation on cardiopulmonary function in PH remains elusive.
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Affiliation(s)
- Mylene Vaillancourt
- Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Pamela Chia
- Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Lejla Medzikovic
- Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Nancy Cao
- Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Gregoire Ruffenach
- Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - David Younessi
- Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Soban Umar
- Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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30
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Ziebart A, Schaefer MM, Thomas R, Kamuf J, Garcia-Bardon A, Möllmann C, Ruemmler R, Heid F, Schad A, Hartmann EK. Random allogeneic blood transfusion in pigs: characterisation of a novel experimental model. PeerJ 2019; 7:e7439. [PMID: 31440432 PMCID: PMC6699485 DOI: 10.7717/peerj.7439] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 07/08/2019] [Indexed: 12/29/2022] Open
Abstract
Background Organ cross-talk describes interactions between a primary affected organ and a secondarily injured remote organ, particularly in lung-brain interactions. A common theory is the systemic distribution of inflammatory mediators that are released by the affected organ and transferred through the bloodstream. The present study characterises the baseline immunogenic effects of a novel experimental model of random allogeneic blood transfusion in pigs designed to analyse the role of the bloodstream in organ cross-talk. Methods After approval of the State and Institutional Animal Care Committee, 20 anesthetized pig were randomized in a donor and an acceptor (each n = 8): the acceptor animals each received high-volume whole blood transfusion from the donor (35–40 ml kg−1). Four animals received balanced electrolyte solution instead of blood transfusion (control group; n = 4). Afterwards the animals underwent extended cardiorespiratory monitoring for eight hours. Post mortem assessment included pulmonary, cerebral and systemic mediators of early inflammatory response (IL-6, TNF-alpha, iNOS), wet to dry ratio, and lung histology. Results No adverse events or incompatibilities occurred during the blood transfusion procedures. Systemic cytokine levels and pulmonary function were unaffected. Lung histopathology scoring did not display relevant intergroup differences. Neither within the lung nor within the brain an up-regulation of inflammatory mediators was detected. High volume random allogeneic blood transfusion in pigs neither impaired pulmonary integrity nor induced systemic, lung, or brain inflammatory response. Conclusion This approach can represent a novel experimental model to characterize the blood-bound transmission in remote organ injury.
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Affiliation(s)
- Alexander Ziebart
- Department of Anesthesiology, Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
| | - Moritz M Schaefer
- Department of Anesthesiology, Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
| | - Rainer Thomas
- Department of Anesthesiology, Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
| | - Jens Kamuf
- Department of Anesthesiology, Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
| | - Andreas Garcia-Bardon
- Department of Anesthesiology, Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
| | - Christian Möllmann
- Department of Anesthesiology, Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
| | - Robert Ruemmler
- Department of Anesthesiology, Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
| | - Florian Heid
- Department of Anesthesiology, Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
| | - Arno Schad
- Institute of Pathology, Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
| | - Erik K Hartmann
- Department of Anesthesiology, Medical Centre of the Johannes Gutenberg-University, Mainz, Germany
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31
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Bilotta F, Giordano G, Sergi PG, Pugliese F. Harmful effects of mechanical ventilation on neurocognitive functions. Crit Care 2019; 23:273. [PMID: 31387627 PMCID: PMC6685219 DOI: 10.1186/s13054-019-2546-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 07/18/2019] [Indexed: 12/18/2022] Open
Affiliation(s)
- Federico Bilotta
- Department of Anesthesiology, Critical Care and Pain Medicine, Sapienza University of Rome, Rome, Italy
| | - Giovanni Giordano
- Department of Anesthesiology, Critical Care and Pain Medicine, Sapienza University of Rome, Rome, Italy
| | - Paola Giuseppina Sergi
- Department of Anesthesiology, Critical Care and Pain Medicine, Sapienza University of Rome, Rome, Italy
| | - Francesco Pugliese
- Department of Anesthesiology, Critical Care and Pain Medicine, Sapienza University of Rome, Rome, Italy
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32
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Westhoff D, Engelen-Lee JY, Hoogland ICM, Aronica EMA, van Westerloo DJ, van de Beek D, van Gool WA. Systemic infection and microglia activation: a prospective postmortem study in sepsis patients. Immun Ageing 2019; 16:18. [PMID: 31384283 PMCID: PMC6664744 DOI: 10.1186/s12979-019-0158-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 07/17/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Systemic infection is associated with long-term cognitive deficits and functional decline. In this study we hypothesized that severe systemic inflammation leads to a neuroinflammatory response that is characterized by microglial activation, and that these effects might be more pronounced in patients using medication with anticholinergic side-effects. METHODS Based on the results of a pilot study in 8 patients, we assessed the number of MHC-II and CD-68 positive cells by immunohistochemistry and compared the number of microglia in specific brain regions of 16 well-characterized patients with septic shock and 15 controls. RESULTS In the pilot study, patients with sepsis tended to have higher density of MHC-II and CD-68 positive microglia in the basal ganglia (putamen, caudate nucleus and globus pallidus) and of MHC-II positive microglia in the hippocampus. In the validation study, patients with sepsis had a significantly higher number of CD-68 positive cells in hippocampus (1.5 fold; p = 0.012), putamen (2.2 fold; p = 0.008) and cerebellum (2.5 fold; p = 0.011) than control patients. The density of MHC-II positive microglia was similar between sepsis and control groups. There was no consistent correlation between microglia counts and anti-cholinergic activity drugs score. CONCLUSION In patients who die during septic shock, severe systemic inflammation is accompanied by localized and strong upregulation of CD-68 positive microglia, but not of MHC-II positive microglia. We identified regional differences in the brain with increased microglial activation in putamen, hippocampus and cerebellum.
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Affiliation(s)
- D. Westhoff
- Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - J. Y. Engelen-Lee
- Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - I. C. M. Hoogland
- Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - E. M. A. Aronica
- Department of Neuropathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
- Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, Netherlands
| | - D. J. van Westerloo
- Department of Intensive Care medicine, Leiden University Medical Center, Leiden, Netherlands
| | - D. van de Beek
- Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - W. A. van Gool
- Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
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de Haro C, Ochagavia A, López-Aguilar J, Fernandez-Gonzalo S, Navarra-Ventura G, Magrans R, Montanyà J, Blanch L. Patient-ventilator asynchronies during mechanical ventilation: current knowledge and research priorities. Intensive Care Med Exp 2019; 7:43. [PMID: 31346799 PMCID: PMC6658621 DOI: 10.1186/s40635-019-0234-5] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 03/07/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Mechanical ventilation is common in critically ill patients. This life-saving treatment can cause complications and is also associated with long-term sequelae. Patient-ventilator asynchronies are frequent but underdiagnosed, and they have been associated with worse outcomes. MAIN BODY Asynchronies occur when ventilator assistance does not match the patient's demand. Ventilatory overassistance or underassistance translates to different types of asynchronies with different effects on patients. Underassistance can result in an excessive load on respiratory muscles, air hunger, or lung injury due to excessive tidal volumes. Overassistance can result in lower patient inspiratory drive and can lead to reverse triggering, which can also worsen lung injury. Identifying the type of asynchrony and its causes is crucial for effective treatment. Mechanical ventilation and asynchronies can affect hemodynamics. An increase in intrathoracic pressure during ventilation modifies ventricular preload and afterload of ventricles, thereby affecting cardiac output and hemodynamic status. Ineffective efforts can decrease intrathoracic pressure, but double cycling can increase it. Thus, asynchronies can lower the predictive accuracy of some hemodynamic parameters of fluid responsiveness. New research is also exploring the psychological effects of asynchronies. Anxiety and depression are common in survivors of critical illness long after discharge. Patients on mechanical ventilation feel anxiety, fear, agony, and insecurity, which can worsen in the presence of asynchronies. Asynchronies have been associated with worse overall prognosis, but the direct causal relation between poor patient-ventilator interaction and worse outcomes has yet to be clearly demonstrated. Critical care patients generate huge volumes of data that are vastly underexploited. New monitoring systems can analyze waveforms together with other inputs, helping us to detect, analyze, and even predict asynchronies. Big data approaches promise to help us understand asynchronies better and improve their diagnosis and management. CONCLUSIONS Although our understanding of asynchronies has increased in recent years, many questions remain to be answered. Evolving concepts in asynchronies, lung crosstalk with other organs, and the difficulties of data management make more efforts necessary in this field.
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Affiliation(s)
- Candelaria de Haro
- Critical Care Center, Hospital Universitari Parc Taulí, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí 1, 08208, Sabadell, Spain. .,CIBERES, Instituto de Salud Carlos III, Madrid, Spain.
| | - Ana Ochagavia
- Critical Care Center, Hospital Universitari Parc Taulí, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí 1, 08208, Sabadell, Spain.,CIBERES, Instituto de Salud Carlos III, Madrid, Spain
| | - Josefina López-Aguilar
- Critical Care Center, Hospital Universitari Parc Taulí, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí 1, 08208, Sabadell, Spain.,CIBERES, Instituto de Salud Carlos III, Madrid, Spain
| | - Sol Fernandez-Gonzalo
- Critical Care Center, Hospital Universitari Parc Taulí, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí 1, 08208, Sabadell, Spain.,CIBERSAM, Instituto de Salud Carlos III, Madrid, Spain
| | - Guillem Navarra-Ventura
- Critical Care Center, Hospital Universitari Parc Taulí, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí 1, 08208, Sabadell, Spain
| | - Rudys Magrans
- Critical Care Center, Hospital Universitari Parc Taulí, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí 1, 08208, Sabadell, Spain.,CIBERES, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Lluís Blanch
- Critical Care Center, Hospital Universitari Parc Taulí, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí 1, 08208, Sabadell, Spain.,CIBERES, Instituto de Salud Carlos III, Madrid, Spain
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Ventilatory Strategies in the Brain-injured Patient. Int Anesthesiol Clin 2019; 56:131-146. [PMID: 29227316 DOI: 10.1097/aia.0000000000000169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Turon M, Fernández-Gonzalo S, de Haro C, Magrans R, López-Aguilar J, Blanch L. Mechanisms involved in brain dysfunction in mechanically ventilated critically ill patients: implications and therapeutics. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:30. [PMID: 29430447 DOI: 10.21037/atm.2017.12.10] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Critical illness may lead to significant long-term neurological morbidity and patients frequently develop neuropsychological disturbances including acute delirium or memory impairment after intensive care unit (ICU) discharge. Mechanical ventilation (MV) is a risk factor to the development of adverse neurocognitive outcomes. Patients undergoing MV for long periods present neurologic impairment with memory and cognitive alteration. Delirium is considered an acute form of brain dysfunction and its prevalence rises in mechanically ventilated patients. Delirium duration is an independent predictor of mortality, ventilation time, ICU length of stay and short- and long-term cognitive impairment in the ICU survivors. Although, neurocognitive sequelae tend to improve after hospital discharge, residual deficits persist even 6 years after ICU stay. ICU-related neurocognitive impairments occurred in many cognitive domains and are particularly pronounced with regard to memory, executive functions, attentional functions, and processing speed. These sequelae have an important impact on patients' lives and ICU survivors often require institutionalization and hospitalization. Experimental studies have served to explore the possible mechanisms or pathways involved in this lung to brain interaction. This communication can be mediated via a complex web of signaling events involving neural, inflammatory, immunologic and neuroendocrine pathways. MV can affect respiratory networks and the application of protective ventilation strategies is mandatory in order to prevent adverse effects. Therefore, strategies focused to minimize lung stretch may improve outcomes, avoiding failure of distal organ, including the brain. Long-term neurocognitive impairments experienced by critically ill survivors may be mitigated by early interventions, combining cognitive and physical therapies. Inpatient rehabilitation interventions in ICU promise to improve outcomes in critically ill patients. The cross-talk between lung and brain, involving specific pathways during critical illness deserves further efforts to evaluate, prevent and improve cognitive alterations after ICU admission, and highlights the crucial importance of tailoring MV to prevent adverse outcomes.
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Affiliation(s)
- Marc Turon
- Critical Care Center, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.,CIBERES, Instituto de Salud Carlos III, Madrid, Spain
| | - Sol Fernández-Gonzalo
- Critical Care Center, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.,CIBERSAM, Instituto de Salud Carlos III, Madrid, Spain
| | - Candelaria de Haro
- Critical Care Center, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.,CIBERES, Instituto de Salud Carlos III, Madrid, Spain
| | - Rudys Magrans
- Critical Care Center, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.,CIBERES, Instituto de Salud Carlos III, Madrid, Spain
| | - Josefina López-Aguilar
- Critical Care Center, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.,CIBERES, Instituto de Salud Carlos III, Madrid, Spain
| | - Lluís Blanch
- Critical Care Center, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.,CIBERES, Instituto de Salud Carlos III, Madrid, Spain
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Johnson NJ, Carlbom DJ, Gaieski DF. Ventilator Management and Respiratory Care After Cardiac Arrest: Oxygenation, Ventilation, Infection, and Injury. Chest 2017; 153:1466-1477. [PMID: 29175085 DOI: 10.1016/j.chest.2017.11.012] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 10/16/2017] [Accepted: 11/10/2017] [Indexed: 01/14/2023] Open
Abstract
Return of spontaneous circulation after cardiac arrest results in a systemic inflammatory state called the post-cardiac arrest syndrome, which is characterized by oxidative stress, coagulopathy, neuronal injury, and organ dysfunction. Perturbations in oxygenation and ventilation may exacerbate secondary injury after cardiac arrest and have been shown to be associated with poor outcome. Further, patients who experience cardiac arrest are at risk for a number of other pulmonary complications. Up to 70% of patients experience early infection after cardiac arrest, and the respiratory tract is the most common source. Vigilance for early-onset pneumonia, as well as aggressive diagnosis and early antimicrobial agent administration are important components of critical care in this population. Patients who experience cardiac arrest are at risk for the development of ARDS. Risk factors include aspiration, pulmonary contusions (from chest compressions), systemic inflammation, and reperfusion injury. Early evidence suggests that they may benefit from ventilation with low tidal volumes. Meticulous attention to mechanical ventilation, early assessment and optimization of respiratory gas exchange, and therapies targeted at potential pulmonary complications may improve outcomes after cardiac arrest.
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Affiliation(s)
- Nicholas J Johnson
- Department of Emergency Medicine, University of Washington, Seattle, WA; Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle, WA.
| | - David J Carlbom
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle, WA
| | - David F Gaieski
- Department of Emergency Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA
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Abstract
Sepsis-associated organ dysfunction involves multiple responses to inflammation, including endothelial and microvascular dysfunction, immune and autonomic dysregulation, and cellular metabolic reprogramming. The effect of targeting these mechanistic pathways on short- and long-term outcomes depends highly on the timing of therapeutic intervention. Furthermore, there is a need to understand the adaptive or maladaptive character of these mechanisms, to discover phase-specific biomarkers to guide therapy, and to conceptualize these mechanisms in terms of resistance and tolerance.
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Affiliation(s)
- Rachel Pool
- Department of Anesthesiology, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA
| | - Hernando Gomez
- Center for Critical Care Nephrology, The CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Center, Department of Critical Care Medicine, University of Pittsburgh, 3347 Forbes Avenue, Suite 220, Pittsburgh, PA 15213, USA.
| | - John A Kellum
- Center for Critical Care Nephrology, The CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Center, Department of Critical Care Medicine, University of Pittsburgh, 3347 Forbes Avenue, Suite 220, Pittsburgh, PA 15213, USA
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The Effect of Mechanical Ventilation on TASK-1 Expression in the Brain in a Rat Model. Can Respir J 2017; 2017:8530352. [PMID: 29093631 PMCID: PMC5637865 DOI: 10.1155/2017/8530352] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 08/05/2017] [Accepted: 08/13/2017] [Indexed: 12/30/2022] Open
Abstract
Background and Objective TWIK-related acid-sensitive potassium channel 1 (TASK-1) is closely related to respiratory central control and neuronal injury. We investigated the effect of MV on TASK-1's functions and explored the mechanism using a rat model. Methods Male Sprague-Dawley rats were randomized to three groups: (1) high tidal volume (HVt): MV for four hours with Vt at 10 mL/kg; (2) low Vt (LVt): MV for four hours with Vt at 5 mL/kg; (3) basal (BAS): anesthetized and unventilated animals. We measured lung histology and plasma and brain levels of proteins (IL-6, TNF-α, and S-100B) and determined TASK-1 levels in rat brainstems as a marker of respiratory centre activity. Results The LISs (lung injury scores) were significantly higher in the HVt group. Brain inflammatory cytokines levels were different to those in serum. TASK-1 levels were significantly lower in the MV groups (P = 0.002) and the HVt group tended to have a lower level of TASK-1 than the LVt group. Conclusion MV causes not only lung injury, but also brain injury. MV affects the regulation of the respiratory centre, perhaps causing damage to it. Inflammation is probably not the main mechanism of ventilator-related brain injury.
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Fernandez-Gonzalo S, Turon M, De Haro C, López-Aguilar J, Jodar M, Blanch L. Do sedation and analgesia contribute to long-term cognitive dysfunction in critical care survivors? Med Intensiva 2017; 42:114-128. [PMID: 28851588 DOI: 10.1016/j.medin.2017.06.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 06/23/2017] [Accepted: 06/29/2017] [Indexed: 01/22/2023]
Abstract
Deep sedation during stay in the Intensive Care Unit (ICU) may have deleterious effects upon the clinical and cognitive outcomes of critically ill patients undergoing mechanical ventilation. Over the last decade a vast body of literature has been generated regarding different sedation strategies, with the aim of reducing the levels of sedation in critically ill patients. There has also been a growing interest in acute brain dysfunction, or delirium, in the ICU. However, the effect of sedation during ICU stay upon long-term cognitive deficits in ICU survivors remains unclear. Strategies for reducing sedation levels in the ICU do not seem to be associated with worse cognitive and psychological status among ICU survivors. Sedation strategy and management efforts therefore should seek to secure the best possible state in the mechanically ventilated patient and lower the prevalence of delirium, in order to prevent long-term cognitive alterations.
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Affiliation(s)
- S Fernandez-Gonzalo
- Research Department, Institut d'Investigació i Innovació Sanitària Parc Taulí (I3PT), Fundació Parc Taulí, Corporació Sanitària Universitària ParcTaulí, Sabadell, Spain; Centro de Investigación Biomédica En Red en Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
| | - M Turon
- Research Department, Institut d'Investigació i Innovació Sanitària Parc Taulí (I3PT), Fundació Parc Taulí, Corporació Sanitària Universitària ParcTaulí, Sabadell, Spain; Centro de Investigación Biomédica En Red en Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
| | - C De Haro
- Critical Care Department, ParcTaulí Sabadell, Hospital Universitari, Universitat Autònoma de Barcelona, Sabadell, Barcelona, Spain
| | - J López-Aguilar
- Research Department, Institut d'Investigació i Innovació Sanitària Parc Taulí (I3PT), Fundació Parc Taulí, Corporació Sanitària Universitària ParcTaulí, Sabadell, Spain; Centro de Investigación Biomédica En Red en Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
| | - M Jodar
- Centro de Investigación Biomédica En Red en Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain; Department of Clinical and Health Psychology, Universitat Autònoma de Barcelona, International Excellence Campus, Bellaterra, Spain; Neurology Department, ParcTaulí Sabadell, Hospital Universitari, Universitat Autònoma de Barcelona, Sabadell, Barcelona, Spain
| | - L Blanch
- Research Department, Institut d'Investigació i Innovació Sanitària Parc Taulí (I3PT), Fundació Parc Taulí, Corporació Sanitària Universitària ParcTaulí, Sabadell, Spain; Centro de Investigación Biomédica En Red en Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Critical Care Department, ParcTaulí Sabadell, Hospital Universitari, Universitat Autònoma de Barcelona, Sabadell, Barcelona, Spain
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Beitler JR, Ghafouri TB, Jinadasa SP, Mueller A, Hsu L, Anderson RJ, Joshua J, Tyagi S, Malhotra A, Sell RE, Talmor D. Favorable Neurocognitive Outcome with Low Tidal Volume Ventilation after Cardiac Arrest. Am J Respir Crit Care Med 2017; 195:1198-1206. [PMID: 28267376 DOI: 10.1164/rccm.201609-1771oc] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
RATIONALE Neurocognitive outcome after out-of-hospital cardiac arrest (OHCA) is often poor, even when initial resuscitation succeeds. Lower tidal volumes (Vts) attenuate extrapulmonary organ injury in other disease states and are neuroprotective in preclinical models of critical illness. OBJECTIVE To evaluate the association between Vt and neurocognitive outcome after OHCA. METHODS We performed a propensity-adjusted analysis of a two-center retrospective cohort of patients experiencing OHCA who received mechanical ventilation for at least the first 48 hours of hospitalization. Vt was calculated as the time-weighted average over the first 48 hours, in milliliters per kilogram of predicted body weight (PBW). The primary endpoint was favorable neurocognitive outcome (cerebral performance category of 1 or 2) at discharge. MEASUREMENTS AND MAIN RESULTS Of 256 included patients, 38% received time-weighted average Vt greater than 8 ml/kg PBW during the first 48 hours. Lower Vt was independently associated with favorable neurocognitive outcome in propensity-adjusted analysis (odds ratio, 1.61; 95% confidence interval [CI], 1.13-2.28 per 1-ml/kg PBW decrease in Vt; P = 0.008). This finding was robust to several sensitivity analyses. Lower Vt also was associated with more ventilator-free days (β = 1.78; 95% CI, 0.39-3.16 per 1-ml/kg PBW decrease; P = 0.012) and shock-free days (β = 1.31; 95% CI, 0.10-2.51; P = 0.034). Vt was not associated with hypercapnia (P = 1.00). Although the propensity score incorporated several biologically relevant covariates, only height, weight, and admitting hospital were independent predictors of Vt less than or equal to 8 ml/kg PBW. CONCLUSIONS Lower Vt after OHCA is independently associated with favorable neurocognitive outcome, more ventilator-free days, and more shock-free days. These findings suggest a role for low-Vt ventilation after cardiac arrest.
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Affiliation(s)
| | - Tiffany Bita Ghafouri
- 2 Department of Medicine, University of California, San Diego, San Diego, California; and
| | - Sayuri P Jinadasa
- 3 Department of Anesthesia and Critical Care Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Ariel Mueller
- 3 Department of Anesthesia and Critical Care Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Leeyen Hsu
- 2 Department of Medicine, University of California, San Diego, San Diego, California; and
| | - Ryan J Anderson
- 2 Department of Medicine, University of California, San Diego, San Diego, California; and
| | - Jisha Joshua
- 2 Department of Medicine, University of California, San Diego, San Diego, California; and
| | - Sanjeev Tyagi
- 2 Department of Medicine, University of California, San Diego, San Diego, California; and
| | - Atul Malhotra
- 1 Division of Pulmonary and Critical Care Medicine and
| | | | - Daniel Talmor
- 3 Department of Anesthesia and Critical Care Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
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Abstract
Neuropulmonology refers to the complex interconnection between the central nervous system and the respiratory system. Neurologic injury includes traumatic brain injury, hemorrhage, stroke, and seizures, and in each there are far-reaching effects that can result in pulmonary dysfunction. Systemic changes can induce impairment of pulmonary function due to changes in the core structure and function of the lung. The conditions and disorders that often occur in these patients include aspiration pneumonia, neurogenic pulmonary edema, and acute respiratory distress syndrome, but also several abnormal respiratory patterns and sleep-disordered breathing. Lung infections, pulmonary edema - neurogenic or cardiogenic - and pulmonary embolus all are a serious barrier to recovery and can have significant effects on outcomes such as hospital course, prognosis, and mortality. This review presents the spectrum of pulmonary abnormalities seen in neurocritical care.
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Moderate Peep After Tracheal Lipopolysaccharide Instillation Prevents Inflammation and Modifies the Pattern of Brain Neuronal Activation. Shock 2016; 44:601-8. [PMID: 26398809 PMCID: PMC4851224 DOI: 10.1097/shk.0000000000000469] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background: Ventilatory strategy and specifically positive end-expiratory pressure (PEEP) can modulate the inflammatory response and pulmonary-to-systemic translocation of lipopolysaccharide (LPS). Both inflammation and ventilatory pattern may modify brain activation, possibly worsening the patient's outcome and resulting in cognitive sequelae. Methods: We prospectively studied Sprague–Dawley rats randomly assigned to undergo 3 h mechanical ventilation with 7 mL/kg tidal ventilation and either 2 cmH2O or 7 cmH2O PEEP after intratracheal instillation of LPS or saline. Healthy nonventilated rats served as baseline. We analyzed lung mechanics, gas exchange, lung and plasma cytokine levels, lung apoptotic cells, and lung neutrophil infiltration. To evaluate brain neuronal activation, we counted c-Fos immunopositive cells in the retrosplenial cortex (RS), thalamus, supraoptic nucleus (SON), nucleus of the solitary tract (NTS), paraventricular nucleus (PVN), and central amygdala (CeA). Results: LPS increased lung neutrophilic infiltration, lung and systemic MCP-1 levels, and neuronal activation in the CeA and NTS. LPS-instilled rats receiving 7 cmH2O PEEP had less lung and systemic inflammation and more c-Fos-immunopositive cells in the RS, SON, and thalamus than those receiving 2 cmH2O PEEP. Applying 7 cmH2O PEEP increased neuronal activation in the CeA and NTS in saline-instilled rats, but not in LPS-instilled rats. Conclusions: Moderate PEEP prevented lung and systemic inflammation secondary to intratracheal LPS instillation. PEEP also modified the neuronal activation pattern in the RS, SON, and thalamus. The relevance of these differential brain c-Fos expression patterns in neurocognitive outcomes should be explored.
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Lung-brain cross talk in the critically ill. Intensive Care Med 2016; 43:557-559. [PMID: 27714405 DOI: 10.1007/s00134-016-4583-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 09/28/2016] [Indexed: 12/13/2022]
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Chen T, Chen C, Zhang Z, Zou Y, Peng M, Wang Y. Toll-like receptor 4 knockout ameliorates neuroinflammation due to lung-brain interaction in mechanically ventilated mice. Brain Behav Immun 2016; 56:42-55. [PMID: 27067748 DOI: 10.1016/j.bbi.2016.04.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 03/31/2016] [Accepted: 04/08/2016] [Indexed: 02/07/2023] Open
Abstract
Toll-like receptor 4 (TLR4) is a crucial receptor in the innate immune system, and increasing evidence supports its role in inflammation, stress, and tissue injury, including injury to the lung and brain. We aimed to investigate the effects of TLR4 on neuroinflammation due to the lung-brain interaction in mechanically ventilated mice. Male wild-type (WT) C57BL/6 and TLR4 knockout (TLR4 KO) mice were divided into three groups: (1) control group (C): spontaneous breathing; (2) anesthesia group (A): spontaneous breathing under anesthesia; and (3) mechanical ventilation group (MV): 6h of MV under anesthesia. The behavioral responses of mice were tested with fear conditioning tests. The histological changes in the lung and brain were assessed using hematoxylin-eosin (HE) staining. The level of TLR4 mRNA in tissue was measured using reverse transcription-polymerase chain reaction (RT-PCR). The levels of inflammatory cytokines were measured with an enzyme-linked immunosorbent assay (ELISA). Microgliosis, astrocytosis, and the TLR4 immunoreactivity in the hippocampus were measured by double immunofluorescence. MV mice exhibited impaired cognition, and this impairment was less severe in TLR4 KO mice than in WT mice. In WT mice, MV increased TLR4 mRNA expression in the lung and brain. MV induced mild lung injury, which was prevented in TLR4 KO mice. MV mice exhibited increased levels of inflammatory cytokines, increased microglia and astrocyte activation. Microgliosis was alleviated in TLR4 KO mice. MV mice exhibited increased TLR4 immunoreactivity, which was expressed in microglia and astrocytes. These results demonstrate that TLR4 is involved in neuroinflammation due to the lung-brain interaction and that TLR4 KO ameliorates neuroinflammation due to lung-brain interaction after prolonged MV. In addition, Administration of a TLR4 antagonist (100μg/mice) to WT mice also significantly attenuated neuroinflammation of lung-brain interaction due to prolonged MV. TLR4 antagonism may be a new and novel approach for the treatment and management of neuroinflammation in long-term mechanically ventilated patients.
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Affiliation(s)
- Ting Chen
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, Hubei 430071, China.
| | - Chang Chen
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, Hubei 430071, China.
| | - Zongze Zhang
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, Hubei 430071, China.
| | - Yufeng Zou
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, Hubei 430071, China
| | - Mian Peng
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, Hubei 430071, China
| | - Yanlin Wang
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, Hubei 430071, China
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Koutsoukou A, Katsiari M, Orfanos SE, Kotanidou A, Daganou M, Kyriakopoulou M, Koulouris NG, Rovina N. Respiratory mechanics in brain injury: A review. World J Crit Care Med 2016; 5:65-73. [PMID: 26855895 PMCID: PMC4733457 DOI: 10.5492/wjccm.v5.i1.65] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Revised: 10/08/2015] [Accepted: 12/11/2015] [Indexed: 02/06/2023] Open
Abstract
Several clinical and experimental studies have shown that lung injury occurs shortly after brain damage. The responsible mechanisms involve neurogenic pulmonary edema, inflammation, the harmful action of neurotransmitters, or autonomic system dysfunction. Mechanical ventilation, an essential component of life support in brain-damaged patients (BD), may be an additional traumatic factor to the already injured or susceptible to injury lungs of these patients thus worsening lung injury, in case that non lung protective ventilator settings are applied. Measurement of respiratory mechanics in BD patients, as well as assessment of their evolution during mechanical ventilation, may lead to preclinical lung injury detection early enough, allowing thus the selection of the appropriate ventilator settings to avoid ventilator-induced lung injury. The aim of this review is to explore the mechanical properties of the respiratory system in BD patients along with the underlying mechanisms, and to translate the evidence of animal and clinical studies into therapeutic implications regarding the mechanical ventilation of these critically ill patients.
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Quilez ME, Fuster G, Villar J, Flores C, Martí-Sistac O, Blanch L, López-Aguilar J. Erratum to: Injurious mechanical ventilation affects neuronal activation in ventilated rats. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2015; 19:379. [PMID: 26506991 PMCID: PMC4624182 DOI: 10.1186/s13054-015-1076-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 09/23/2015] [Indexed: 11/10/2022]
Affiliation(s)
- María Elisa Quilez
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, C/ Sinesio Delgado 6, Madrid, 28029, Spain. .,Critical Care Center, Corporació Sanitaria Parc Taulí, Institut Universitari, Esfera UAB. Parc Taulí sn, Sabadell, 08208, Spain. .,Universitat Autònoma de Barcelona, Campus de la UAB, Bellaterra, 08193, Spain.
| | - Gemma Fuster
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, C/ Sinesio Delgado 6, Madrid, 28029, Spain. .,Critical Care Center, Corporació Sanitaria Parc Taulí, Institut Universitari, Esfera UAB. Parc Taulí sn, Sabadell, 08208, Spain.
| | - Jesús Villar
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, C/ Sinesio Delgado 6, Madrid, 28029, Spain. .,Research Unit, Hospital Universitario Dr.Negrín, Barranco de la Ballena s/n, Las Palmas de Gran Canaria, 35010, Spain.
| | - Carlos Flores
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, C/ Sinesio Delgado 6, Madrid, 28029, Spain. .,Research Unit, Hospital Universitario N.S. de Candelaria, Carretera del Rosario 145, Santa Cruz de Tenerife, 38010, Spain.
| | - Octavi Martí-Sistac
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, C/ Sinesio Delgado 6, Madrid, 28029, Spain. .,Critical Care Center, Corporació Sanitaria Parc Taulí, Institut Universitari, Esfera UAB. Parc Taulí sn, Sabadell, 08208, Spain. .,Universitat Autònoma de Barcelona, Campus de la UAB, Bellaterra, 08193, Spain.
| | - Lluís Blanch
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, C/ Sinesio Delgado 6, Madrid, 28029, Spain. .,Critical Care Center, Corporació Sanitaria Parc Taulí, Institut Universitari, Esfera UAB. Parc Taulí sn, Sabadell, 08208, Spain.
| | - Josefina López-Aguilar
- CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, C/ Sinesio Delgado 6, Madrid, 28029, Spain. .,Critical Care Center, Corporació Sanitaria Parc Taulí, Institut Universitari, Esfera UAB. Parc Taulí sn, Sabadell, 08208, Spain.
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Mrozek S, Constantin JM, Geeraerts T. Brain-lung crosstalk: Implications for neurocritical care patients. World J Crit Care Med 2015; 4:163-178. [PMID: 26261769 PMCID: PMC4524814 DOI: 10.5492/wjccm.v4.i3.163] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2015] [Revised: 04/29/2015] [Accepted: 05/28/2015] [Indexed: 02/06/2023] Open
Abstract
Major pulmonary disorders may occur after brain injuries as ventilator-associated pneumonia, acute respiratory distress syndrome or neurogenic pulmonary edema. They are key points for the management of brain-injured patients because respiratory failure and mechanical ventilation seem to be a risk factor for increased mortality, poor neurological outcome and longer intensive care unit or hospital length of stay. Brain and lung strongly interact via complex pathways from the brain to the lung but also from the lung to the brain. Several hypotheses have been proposed with a particular interest for the recently described “double hit” model. Ventilator setting in brain-injured patients with lung injuries has been poorly studied and intensivists are often fearful to use some parts of protective ventilation in patients with brain injury. This review aims to describe the epidemiology and pathophysiology of lung injuries in brain-injured patients, but also the impact of different modalities of mechanical ventilation on the brain in the context of acute brain injury.
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Lopez-Aguilar J, Blanch L. Brain injury requires lung protection. ANNALS OF TRANSLATIONAL MEDICINE 2015; 3:S5. [PMID: 26046092 DOI: 10.3978/j.issn.2305-5839.2015.02.24] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 02/06/2015] [Indexed: 12/26/2022]
Abstract
The paper entitled "The high-mobility group protein B1-Receptor for advanced glycation endproducts (HMGB1-RAGE) axis mediates traumatic brain injury (TBI)-induced pulmonary dysfunction in lung transplantation" published recently in Science Translational Medicine links lung failure after transplantation with alterations in the axis HMGB1-RAGE after TBI, opening a new field for exploring indicators for the early detection of patients at risk of developing acute lung injury (ALI). The lung is one of the organs most vulnerable to the inflammatory cascade triggered by TBI. HMGB1 is an alarm in that can be released from activated immune cells in response to tissue injury. Increased systemic HMGB1 concentration correlates with poor lung function before and after lung transplant, confirming its role in acute ALI after TBI. HMGB1 exerts its influence by interacting with several receptors, including the RAGE receptor. RAGE also plays an important role in the onset of innate immune inflammatory responses, and systemic levels of RAGE are strongly associated with ALI and clinical outcomes in ventilator-induced lung injury. RAGE ligation to HMGB1 triggers the amplification of the inflammatory cascade involving nuclear factor-κB (NF-κB) activation. Identifying early biomarkers that mediate pulmonary dysfunction will improve outcomes not only in lung transplantation, but also in other scenarios. These novel findings show that upregulation of the HMGB1-RAGE axis plays an important role in brain-lung crosstalk.
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Affiliation(s)
- Josefina Lopez-Aguilar
- 1 Critical Care Center, Hospital de Sabadell and Fundació Parc Taulí, Corporació Sanitaria Universitària Parc Taulí, Sabadell, Spain ; 2 Universitat Autònoma de Barcelona, Campus d'Excelència Internacional 08193, Bellaterra, Spain ; 3 CIBER Enfermedades Respiratorias, ISCIII, Madrid, Spain
| | - Lluis Blanch
- 1 Critical Care Center, Hospital de Sabadell and Fundació Parc Taulí, Corporació Sanitaria Universitària Parc Taulí, Sabadell, Spain ; 2 Universitat Autònoma de Barcelona, Campus d'Excelència Internacional 08193, Bellaterra, Spain ; 3 CIBER Enfermedades Respiratorias, ISCIII, Madrid, Spain
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Sperber J, Lipcsey M, Larsson A, Larsson A, Sjölin J, Castegren M. Evaluating the effects of protective ventilation on organ-specific cytokine production in porcine experimental postoperative sepsis. BMC Pulm Med 2015; 15:60. [PMID: 25958003 PMCID: PMC4434882 DOI: 10.1186/s12890-015-0052-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 04/22/2015] [Indexed: 12/04/2022] Open
Abstract
Background Protective ventilation with lower tidal volume (VT) and higher positive end-expiratory pressure (PEEP) reduces the negative additive effects of mechanical ventilation during systemic inflammatory response syndrome. We hypothesised that protective ventilation during surgery would affect the organ-specific immune response in an experimental animal model of endotoxin-induced sepsis-like syndrome. Methods 30 pigs were laparotomised for 2 hours (h), after which a continuous endotoxin infusion was started at 0.25 micrograms × kg−1 × h−1 for 5 h. Catheters were placed in the carotid artery, hepatic vein, portal vein and jugular bulb. Animals were randomised to two protective ventilation groups (n = 10 each): one group was ventilated with VT 6 mL × kg−1 during the whole experiment while the other group was ventilated during the surgical phase with VT of 10 mL × kg−1. In both groups PEEP was 5 cmH2O during surgery and increased to 10 cmH2O at the start of endotoxin infusion. A control group (n = 10) was ventilated with VT of 10 mL × kg−1 and PEEP 5 cm H20 throughout the experiment. In four sample locations we a) simultaneously compared cytokine levels, b) studied the effect of protective ventilation initiated before and during endotoxemia and c) evaluated protective ventilation on organ-specific cytokine levels. Results TNF-alpha levels were highest in the hepatic vein, IL-6 levels highest in the artery and jugular bulb and IL-10 levels lowest in the artery. Protective ventilation initiated before and during endotoxemia did not differ in organ-specific cytokine levels. Protective ventilation led to lower levels of TNF-alpha in the hepatic vein compared with the control group, whereas no significant differences were seen in the artery, portal vein or jugular bulb. Conclusions Variation between organs in cytokine output was observed during experimental sepsis. We see no implication from cytokine levels for initiating protective ventilation before endotoxemia. However, during endotoxemia protective ventilation attenuates hepatic inflammatory cytokine output contributing to a reduced total inflammatory burden.
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Affiliation(s)
- Jesper Sperber
- Centre for Clinical Research Sörmland, Uppsala University, Uppsala, Sweden. .,Department of Medical Sciences, Infectious Diseases, Uppsala University, Uppsala, Sweden. .,Department of Anaesthesiology and Intensive Care, Mälarsjukhuset Eskilstuna, Sweden.
| | - Miklós Lipcsey
- Department of Surgical Sciences, Hedenstierna laboratory, Anaesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden.
| | - Anders Larsson
- Department of Surgical Sciences, Hedenstierna laboratory, Anaesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden.
| | - Anders Larsson
- Department of Medical Sciences, Biochemical structure and function, Uppsala University, Uppsala, Sweden.
| | - Jan Sjölin
- Department of Medical Sciences, Infectious Diseases, Uppsala University, Uppsala, Sweden.
| | - Markus Castegren
- Centre for Clinical Research Sörmland, Uppsala University, Uppsala, Sweden. .,Department of Medical Sciences, Infectious Diseases, Uppsala University, Uppsala, Sweden. .,Department of Anaesthesiology and Intensive Care, Mälarsjukhuset Eskilstuna, Sweden.
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López-Aguilar J, Bassi GL, Quílez ME, Martí JD, Rigol M, Tavares-Ranzani O, Aguilera E, Ferrer I, Blanch L, Torres A. 0468. Cerebral effects of lateral trendelenburg vs semirecumbent position in an experimental model of ventilator-associated pneumonia. Intensive Care Med Exp 2014. [PMCID: PMC4796195 DOI: 10.1186/2197-425x-2-s1-o14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
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