359 results on '"Zarbock"'
Search Results
2. ADAM8 signaling drives neutrophil migration and ARDS severity
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Catharina Conrad, Daniela Yildiz, Simon J. Cleary, Andreas Margraf, Lena Cook, Uwe Schlomann, Barry Panaretou, Jessica L. Bowser, Harry Karmouty-Quintana, Jiwen Li, Nathaniel K. Berg, Samuel C. Martin, Ahmad Aljohmani, S. Farshid Moussavi-Harami, Kristin M. Wang, Jennifer J. Tian, Mélia Magnen, Colin Valet, Longhui Qiu, Jonathan P. Singer, Holger K. Eltzschig, CAPSys Study Group, Wilhelm Bertrams, Susanne Herold, Norbert Suttorp, Bernd Schmeck, Zachary T. Ball, Alexander Zarbock, Mark R. Looney, and Jörg W. Bartsch
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Inflammation ,Pulmonology ,Medicine - Abstract
Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8–/– mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain.
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- 2022
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3. Resolving immune cells with patrolling behaviour by magnetic resonance time-lapse single cell tracking
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Max Masthoff, Felix Noah Freppon, Lisa Zondler, Enrica Wilken, Lydia Wachsmuth, Silke Niemann, Christian Schwarz, Ina Fredrich, Asli Havlas, Helena Block, Mirjam Gerwing, Anne Helfen, Walter Heindel, Alexander Zarbock, Moritz Wildgruber, and Cornelius Faber
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patrolling monocytes ,time-lapse MRI ,single cell tracking ,immune response ,iron oxide nanoparticles ,Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Immune cells show distinct motion patterns that change upon inflammatory stimuli. Monocytes patrol the vasculature to screen for pathogens, thereby exerting an early task of innate immunity. Here, we aimed to non-invasively analyse single patrolling monocyte behaviour upon inflammatory stimuli. Methods: We used time-lapse Magnetic Resonance Imaging (MRI) of the murine brain to dynamically track single patrolling monocytes within the circulation distant to the actual site of inflammation in different inflammatory conditions, ranging from a subcutaneous pellet model to severe peritonitis and bacteraemia. Findings: Single patrolling immune cells with a velocity of
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- 2021
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4. Protocol for a prospective, international cohort study on the Management and Outcomes of Perioperative Care among European Diabetic Patients (MOPED)
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Alexander Zarbock, Mark Coburn, Malachy Columb, Markus W Hollman, Jeroen Hermanides, Donal J Buggy, and Rachel Nolan
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Medicine - Published
- 2021
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5. Real-time feedback improves chest compression quality in out-of-hospital cardiac arrest: A prospective cohort study.
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Felix Lakomek, Roman-Patrik Lukas, Peter Brinkrolf, Andreas Mennewisch, Nicole Steinsiek, Peter Gutendorf, Hendrik Sudowe, Michael Heller, Robert Kwiecien, Alexander Zarbock, and Andreas Bohn
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Medicine ,Science - Abstract
BACKGROUND:Current guidelines underline the importance of high-quality chest compression during cardiopulmonary resuscitation (CPR), to improve outcomes. Contrary to this many studies show that chest compression is often carried out poorly in clinical practice, and long interruptions in compression are observed. This prospective cohort study aimed to analyse whether chest compression quality changes when a real-time feedback system is used to provide simultaneous audiovisual feedback on chest compression quality. For this purpose, pauses in compression, compression frequency and compression depth were compared. METHODS:The study included 292 out-of-hospital cardiac arrests in three consecutive study groups: first group, conventional resuscitation (no-sensor CPR); second group, using a feedback sensor to collect compression depth data without real-time feedback (sensor-only CPR); and third group, with real-time feedback on compression quality (sensor-feedback CPR). Pauses and frequency were analysed using compression artefacts on electrocardiography, and compression depth was measured using the feedback sensor. With this data, various parameters were determined in order to be able to compare the chest compression quality between the three consecutive groups. RESULTS:The compression fraction increased with sensor-only CPR (group 2) in comparison with no-sensor CPR (group 1) (80.1% vs. 87.49%; P < 0.001), but there were no further differences belonging compression fraction after activation of sensor-feedback CPR (group 3) (P = 1.00). Compression frequency declined over the three study groups, reaching the guideline recommendations (127.81 comp/min vs. 122.96 comp/min, P = 0.02 vs. 119.15 comp/min, P = 0.008) after activation of sensor-feedback CPR (group 3). Mean compression depth only changed minimally with sensor-feedback (52.49 mm vs. 54.66 mm; P = 0.16), but the fraction of compressions with sufficient depth (at least 5 cm) and compressions within the recommended 5-6 cm increased significantly with sensor-feedback CPR (56.90% vs. 71.03%; P = 0.003 and 28.74% vs. 43.97%; P < 0.001). CONCLUSIONS:The real-time feedback system improved chest compression quality regarding pauses in compression and compression frequency and facilitated compliance with the guideline recommendations. Compression depth did not change significantly after activation of the real-time feedback. Even the sole use of a CPR-feedback-sensor ("sensor-only CPR") improved performance regarding pauses in compression and compression frequency, a phenomenon known as the 'Hawthorne effect'. Based on this data real-time feedback systems can be expected to raise the quality level in some parts of chest compression quality. TRIAL REGISTRATION:International Clinical Trials Registry Platform of the World Health Organisation and German Register of Clinical Trials (DRKS00009903), Registered 09 February 2016 (retrospectively registered).
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- 2020
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6. Correction: Real-time feedback improves chest compression quality in out-of-hospital cardiac arrest: A prospective cohort study.
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Felix Lakomek, Roman-Patrik Lukas, Peter Brinkrolf, Andreas Mennewisch, Nicole Steinsiek, Peter Gutendorf, Hendrik Sudowe, Michael Heller, Robert Kwiecien, Alexander Zarbock, and Andreas Bohn
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Medicine ,Science - Abstract
[This corrects the article DOI: 10.1371/journal.pone.0229431.].
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- 2020
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7. Reticulocyte and Erythrocyte Hemoglobin Parameters for Iron Deficiency and Anemia Diagnostics in Patient Blood Management. A Narrative Review
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Christian Hoenemann, Norbert Ostendorf, Alexander Zarbock, Dietrich Doll, Olaf Hagemann, Mathias Zimmermann, and Markus Luedi
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anemia ,iron deficiency ,patient blood management ,reticulocyte hemoglobin (Ret He) ,anemia of inflammation (ACD, anemia of chronic decease) ,hospital acquired anemia ,Medicine - Abstract
Anemia, iron deficiency and other hematinic deficiencies are a major cause of perioperative transfusion needs and are associated with increased morbidity and mortality. Anemia can be caused either by decreased production of hemoglobin or red blood cells or by increased consumption and blood loss. Decreased production can involve anything from erythropoietin or vitamin B12 insufficiency to absolute or functional lack of iron. Thus, to achieve the goal of patient blood management, anemia must be addressed by addressing its causes. The traditional parameters to diagnose anemia, despite offering elaborate options, are not ideally suited to giving a simple overview of the causes of anemia, e.g., iron status for erythropoiesis, especially during the acute phase of inflammation, acute blood loss or iron deficiency. Reticulocyte hemoglobin can thus help to uncover the cause of the anemia and to identify the main factors inhibiting erythropoiesis. Regardless of the cause of anemia, reticulocyte hemoglobin can also quickly track the success of therapy and, together with the regular full blood count it is measured alongside, help in clearing the patient for surgery.
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- 2021
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8. Diagnosis of Cardiac Surgery-Associated Acute Kidney Injury
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Christina Massoth and Alexander Zarbock
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cardiac surgery ,acute kidney injury ,biomarkers ,cardiopulmonary bypass ,Medicine - Abstract
Acute kidney injury after cardiac surgery is characterized by specific patterns of damage and recovery that are important to consider for management and outcome. The Kidney Disease: Improving Global Outcomes (KDIGO) classification covers only part of the conceptual framework and is thus insufficient for a comprehensive diagnosis. This review highlights the strengths and limitations of the recent criteria and provides an overview of biomarkers of cardiac surgery-associated acute kidney injury (CSA-AKI). The evolving understanding of CSA-AKI as a time-sensitive condition has increased the demand to enhance the diagnostic criteria and translate biomarkers into clinical practice.
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- 2021
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9. Neutrophils in acute inflammation: current concepts and translational implications
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Andreas Margraf, Clifford A. Lowell, and Alexander Zarbock
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Integrins ,Chemokine ,Neutrophils ,Immunology ,Integrin ,Inflammation ,medicine.disease_cause ,Biochemistry ,Neutrophil Activation ,Autoimmunity ,Sepsis ,medicine ,Animals ,Humans ,Receptor ,biology ,Cell Biology ,Hematology ,medicine.disease ,Phenotype ,Cell biology ,Neutrophil Infiltration ,biology.protein ,medicine.symptom ,Function (biology) - Abstract
Modulation of neutrophil recruitment and function is crucial for targeting inflammatory cells to sites of infection to combat invading pathogens while, at the same time, limiting host tissue injury or autoimmunity. The underlying mechanisms regulating recruitment of neutrophils, 1 of the most abundant inflammatory cells, have gained increasing interest over the years. The previously described classical recruitment cascade of leukocytes has been extended to include capturing, rolling, adhesion, crawling, and transmigration, as well as a reverse-transmigration step that is crucial for balancing immune defense and control of remote organ endothelial leakage. Current developments in the field emphasize the importance of cellular interplay, tissue environmental cues, circadian rhythmicity, detection of neutrophil phenotypes, differential chemokine sensing, and contribution of distinct signaling components to receptor activation and integrin conformations. The use of therapeutics modulating neutrophil activation responses, as well as mutations causing dysfunctional neutrophil receptors and impaired signaling cascades, have been defined in translational animal models. Human correlates of such mutations result in increased susceptibility to infections or organ damage. This review focuses on current advances in the understanding of the regulation of neutrophil recruitment and functionality and translational implications of current discoveries in the field with a focus on acute inflammation and sepsis.
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- 2022
10. Perioperatives Management der postmortalen Organspende
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Christian Ertmer, Christian Lanckohr, Alexander Zarbock, and Jan Sönke Englbrecht
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Brain dead ,business.industry ,General Medicine ,Perioperative ,law.invention ,Anesthesiology and Pain Medicine ,Pharmacotherapy ,Randomized controlled trial ,law ,Donation ,Intensive care ,Anesthesia ,Medicine ,Justice (ethics) ,Organ donation ,business - Abstract
Background The number of organs donated after brain death in Germany is far lower than the demand. This underlines the importance of providing the brain-dead donor with optimal medical care throughout the donation process to decrease the risk of graft dysfunction. Several international guidelines and national recommendations guide the intensivists in organ-protective intensive care management of the brain-dead donor. Objective The anesthetist is a key member during organ retrieval procedures and plays a crucial role in physiological donor management; however, evidence-based recommendations for the perioperative anesthetic management, drug treatment strategies and target values are lacking. Anesthesia literature about donor management is scarce and predominantly composed of reviews of practice, with little exploration of the scientific foundations. The aim of this review is to guide the anesthetist in the organ-protective perioperative therapy. The pathophysiological changes in patients who progress to brain death are briefly summarized. The available evidence, guidelines and expert opinions regarding medical treatment strategies and therapeutic goals in organ-protective therapy are reviewed. The ethical and pathophysiological considerations regarding the performance of anesthesia during organ retrieval are discussed. Methods This review is based on a selective literature search in PubMed for publications regarding organ donation after brain death (keywords: "brain dead donor", "organ procurement", "organ protective therapy", "donor preconditioning", "perioperative donor management", "ethical considerations of brain dead donor"). International guidelines, national recommendations and expert opinions were given special consideration. Results Overall, the evidence for optimal perioperative organ-protective care of the brain-dead donor is limited. Most elements in the current recommendations and guidelines are based on pathophysiological reasoning, epidemiological observations or extrapolations from general organ-protective management strategies, and not on evidence from randomized controlled trials. National and international recommendations on treatment goals and drug therapy differ considerably in some aspects. The therapy concepts applied are very heterogeneous. Apart from medical challenges, the ethical circumstances are an additional burden for the entire treatment team. Whether anesthesia is reasonable during organ retrieval remains unclear. There is uncertainty about possible organ-protective effects of anesthetic drugs. Furthermore, ethical considerations raise the question of whether the determination of brain death and the use of anesthetic drugs during the procedure of organ retrieval are compatible with each other. Conclusion Due to the lack of evidence, perioperative treatment should be guided by intensive care therapy strategies. The discussion about using anesthetic drugs during organ retrieval remains controversial. Pathophysiological considerations support the use of volatile anesthetics because of possible organ-protective effects. The use of neuromuscular blocking is justified to control any possible motor response resulting from spinal cord reflexes, whereas there is no evidence for a benefit from using opioids. Apart from that, it seems ethically problematic to anesthetise a brain-dead donor. Consequently, knowledge about the pathophysiological processes caused by brain death and about organ-protective therapy concepts are just as much a basic requirement as the consideration of ethical problems in organ donation after brain death. Only then are the caregivers able to do justice to both the organ recipient and the organ donor, as well as their relatives in this challenging situation.
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- 2021
11. Perioperative renal protection
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Alexander Zarbock and Khaschayar Saadat-Gilani
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medicine.medical_specialty ,business.industry ,Hemodynamics ,Acute kidney injury ,Renal function ,Perioperative ,Acute Kidney Injury ,Kidney ,Critical Care and Intensive Care Medicine ,medicine.disease ,Nephrotoxicity ,Blood pressure ,medicine ,Fluid Therapy ,Humans ,Renal protection ,Intensive care medicine ,business ,Biomarkers ,Kidney disease - Abstract
Purpose of review Acute kidney injury (AKI) is a common but underestimated syndrome in the perioperative setting. AKI can be induced by different causes and is associated with increased morbidity and mortality. Unfortunately, no specific treatment options are available at the moment. Recent findings AKI is now understood as being a continuum ranging from normal kidney function over AKI and acute kidney disease to ultimately chronic kidney disease. The KDIGO organization recommend in 2012 implementation of preventive bundles in patients at high risk for AKI. In the perioperative setting, relevant measures include hemodynamic optimization, with careful consideration of blood pressure targets, adequate fluid therapy to maintain organ perfusion and avoidance of hyperglycaemia. These measures are most effective if patients at risk are identified as soon as possible and measures are implemented accordingly. Although current point of care functional biomarkers can detect patients at risk earlier than the established damage biomarkers, some components of the preventive bundle are still under investigation. Summary Good evidence exists for the use of biomarkers to identify individual patients at risk for AKI and for the implementation of haemodynamic optimization, abdication of nephrotoxins, adequate fluid administration using balanced crystalloid solutions and glycaemic control. The data for using colloids or the degree of nephrotoxicity of contrast media still remain inconclusive.
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- 2021
12. <scp>SKAP2</scp> as a new regulator of oligodendroglial migration and myelin sheath formation
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Farina Windener, Alexander Zarbock, Laureen Grewing, Julia Ghelman, Stefanie Albrecht, and Tanja Kuhlmann
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Central Nervous System ,Cell type ,Integrin ,Central nervous system ,Population ,Biology ,Cellular and Molecular Neuroscience ,Myelin ,Downregulation and upregulation ,medicine ,Axon ,Progenitor cell ,education ,Cytoskeleton ,Myelin Sheath ,education.field_of_study ,Chemistry ,Cell Differentiation ,Cell biology ,Oligodendroglia ,stomatognathic diseases ,medicine.anatomical_structure ,Spinal Cord ,nervous system ,Neurology ,biology.protein - Abstract
Oligodendroglial progenitor cells (OPC) are highly proliferative and migratory bipolar cells, which differentiate into complex myelin forming and axon ensheathing mature oligodendrocytes during myelination. Recent studies indicate that the oligodendroglial cell population is heterogeneous on transcriptional and functional level depending on the location in the CNS. Here, we compared intrinsic properties of OPC from spinal cord and brain on functional and transcriptional level. Spinal cord OPC demonstrated increased migration as well as differentiation capacity. Moreover, transcriptome analysis revealed differential expression of several genes between both OPC populations. In spinal cord OPC we confirmed upregulation of SKAP2, a cytoplasmatic adaptor protein known for its implication in cytoskeletal remodelling and migration in other cell types. Recent findings suggest that actin dynamics determine not only oligodendroglial migration, but also differentiation: Whereas actin polymerization is important for process extension, actin destabilization and depolymerization is required for myelin sheath formation. Downregulation or complete lack of SKAP2 in OPC resulted in reduced migration and impaired morphological maturation in oligodendrocytes. In contrast, overexpression of SKAP2 as well as constitutively active SKAP2 increased OPC migration suggesting that SKAP2 function is dependent on activation by phosphorylation. Furthermore, lack of SKAP2 enhanced the positive effect on OPC migration after integrin activation suggesting that SKAP2 acts as modulator of integrin dependent migration. In summary, we demonstrate the presence of intrinsic differences between spinal cord and brain OPC and identified SKAP2 as a new regulator of oligodendroglial migration and sheath formation.Significance statementOPC play an important role in many still incurable diseases, such as multiple sclerosis, leukodystrophies or neurodegenerative diseases. Their heterogeneity in different CNS regions has recently been identified. Here, we observed increased migration and differentiation capabilities of OPC isolated from the spinal cord compared to brain OPC and confirmed differences in the transcriptome between these two cell populations. Furthermore, we identified SKAP2 as potential modulator of actin dynamics in oligodendrocytes. Whereas knockdown or lack of SKAP2 impairs migration and myelin sheath formation in mouse and human oligodendrocytes, overexpression of wildtype or constitutively active SKAP2 enhances the migratory capacity of murine oligodendrocytes. In summary, we present SKAP2 as modulator of cytoskeletal dynamics regulating OPC migration, differentiation and myelin sheath formation.
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- 2021
13. Potential Renoprotective Strategies in Adult Cardiac Surgery: A Survey of Society of Cardiovascular Anesthesiologists Members to Explore the Rationale and Beliefs Driving Current Clinical Decision-Making
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Alexander Zarbock, Bennett Roman, Amanda A. Fox, Bruce A. Bollen, Linda Shore-Lesserson, Hong Liu, Frederic T. Billings, David R. McIlroy, Mariya Geube, and Andrew D. Shaw
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medicine.medical_specialty ,business.industry ,Psychological intervention ,Acute kidney injury ,Renal function ,Perioperative ,Affect (psychology) ,medicine.disease ,Cardiac surgery ,Anesthesiology and Pain Medicine ,Blood pressure ,Cardiothoracic surgery ,medicine ,Cardiology and Cardiovascular Medicine ,Intensive care medicine ,business - Abstract
Objectives The authors sought to (1) characterize the rationale underpinning anesthesiologists’ use of various perioperative strategies hypothesized to affect renal function in adult patients undergoing cardiac surgery, (2) characterize existing belief about the quality of evidence addressing the renal impact of these strategies, and (3) identify potentially renoprotective strategies for which anesthesiologists would most value a detailed, evidence-based review. Design Survey of perioperative practice in adult patients undergoing cardiac surgery. Setting Online survey. Participants Members of the Society of Cardiovascular Anesthesiologists (SCA). Interventions None. Measurements & Main Results The survey was distributed to more than 2,000 SCA members and completed in whole or in part by 202 respondents. Selection of target intraoperative blood pressure (and relative hypotension avoidance) was the strategy most frequently reported to reflect belief about its potential renal effect (79%; 95% CI: 72-85). Most respondents believed the evidence supporting an effect on renal injury of intraoperative target blood pressure during cardiac surgery was of high or moderate quality. Other factors, including a specific nonrenal rationale, surgeon preference, department- or institution-level decisions, tradition, or habit, also frequently were reported to affect decision making across queried strategies. Potential renoprotective strategies most frequently requested for inclusion in a subsequent detailed, evidence-based review were intraoperative target blood pressure and choice of vasopressor agent to achieve target pressure. Conclusions A large number of perioperative strategies are believed to variably affect renal injury in adult patients undergoing cardiac surgery, with wide variation in perceived quality of evidence for a renal effect of these strategies.
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- 2021
14. Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury
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Starrt-Aki Investigators, Jean-Pierre Quenot, Bin Du, Paul J Young, Bruno R. da Costa, Stéphane Gaudry, Sean M. Bagshaw, Michael Joannidis, Eric Hoste, Haibo Qiu, Bram Rochwerg, Daniel F. McAuley, Didier Dreyfuss, Ron Wald, Antoine G. Schneider, Matthew A. Weir, Rinaldo Bellomo, Neill K.J. Adhikari, Kathleen D. Liu, Fernando Thomé, Marlies Ostermann, Suvi T. Vaara, Kevin E. Thorpe, Martin Gallagher, Amanda Y. Wang, Alexander Zarbock, Javier A. Neyra, Shay McGuinness, Francois Lamontagne, Ville Pettilä, Paul M. Palevsky, Orla Smith, Alistair Nichol, Giovanni Landoni, Bagshaw, S. M., Wald, R., Adhikari, N. K. J., Bellomo, R., da Costa, B. R., Dreyfuss, D., Du, B., Gallagher, M. P., Gaudry, S., Hoste, E. A., Lamontagne, F., Joannidis, M., Landoni, G., Liu, K. D., Mcauley, D. F., Mcguinness, S. P., Neyra, J. A., Nichol, A. D., Ostermann, M., Palevsky, P. M., Pettila, V., Quenot, J. -P., Qiu, H., Rochwerg, B., Schneider, A. G., Smith, O. M., Thome, F., Thorpe, K. E., Vaara, S., Weir, M., Wang, A. Y., Young, P., Zarbock, A (STARRT-AKI Investigators), and Zangrillo, A
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medicine.medical_specialty ,medicine.medical_treatment ,610 Medicine & health ,030204 cardiovascular system & hematology ,Lower risk ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,360 Social problems & social services ,law ,Internal medicine ,DIALYSIS ,Medicine and Health Sciences ,medicine ,030212 general & internal medicine ,Renal replacement therapy ,Adverse effect ,Dialysis ,Intention-to-treat analysis ,business.industry ,MORTALITY ,Acute kidney injury ,General Medicine ,medicine.disease ,TRIALS ,Relative risk ,business ,CRITICALLY-ILL PATIENTS - Abstract
Background Acute kidney injury is common in critically ill patients, many of whom receive renal-replacement therapy. However, the most effective timing for the initiation of such therapy remains uncertain. Methods We conducted a multinational, randomized, controlled trial involving critically ill patients with severe acute kidney injury. Patients were randomly assigned to receive an accelerated strategy of renal-replacement therapy (in which therapy was initiated within 12 hours after the patient had met eligibility criteria) or a standard strategy (in which renal-replacement therapy was discouraged unless conventional indications developed or acute kidney injury persisted for >72 hours). The primary outcome was death from any cause at 90 days. Results Of the 3019 patients who had undergone randomization, 2927 (97.0%) were included in the modified intention-to-treat analysis (1465 in the accelerated-strategy group and 1462 in the standard-strategy group). Of these patients, renal-replacement therapy was performed in 1418 (96.8%) in the accelerated-strategy group and in 903 (61.8%) in the standard-strategy group. At 90 days, death had occurred in 643 patients (43.9%) in the accelerated-strategy group and in 639 (43.7%) in the standard-strategy group (relative risk, 1.00; 95% confidence interval [CI], 0.93 to 1.09; P=0.92). Among survivors at 90 days, continued dependence on renal-replacement therapy was confirmed in 85 of 814 patients (10.4%) in the accelerated-strategy group and in 49 of 815 patients (6.0%) in the standard-strategy group (relative risk, 1.74; 95% CI, 1.24 to 2.43). Adverse events occurred in 346 of 1503 patients (23.0%) in the accelerated-strategy group and in 245 of 1489 patients (16.5%) in the standard-strategy group (P
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- 2020
15. Prevention of Cardiac Surgery–Associated Acute Kidney Injury by Implementing the KDIGO Guidelines in High-Risk Patients Identified by Biomarkers: The PrevAKI-Multicenter Randomized Controlled Trial
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Wim Vandenberghe, Fabrizio Monaco, Alexander Zarbock, Shrijit Nair, Carola Wempe, Gianluca Lucchese, Joachim Gerss, Jordi Miralles Bagan, Ronak Rajani, Gudrun Kunst, Lui G. Forni, Armando Cennamo, Hinnerk Wulf, Marlies Ostermann, Christina Massoth, Melanie Meersch, Camilla L'Acqua, John A. Kellum, Patrick M. Honore, Christian Arndt, Marc Irqsusi, Philippe Grieshaber, Stefano Italiano, Stuart McCorkell, Ambra Licia Di Prima, Mira Küllmar, Mercedes Garcia Alvarez, Kamran Baig, Raphael Weiss, and Eric Hoste
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Male ,medicine.medical_specialty ,Time Factors ,Risk Assessment ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Predictive Value of Tests ,Risk Factors ,030202 anesthesiology ,law ,Internal medicine ,Clinical endpoint ,Humans ,Medicine ,Cardiac Surgical Procedures ,Aged ,Tissue Inhibitor of Metalloproteinase-2 ,business.industry ,Acute kidney injury ,Absolute risk reduction ,Guideline ,Acute Kidney Injury ,Middle Aged ,medicine.disease ,Confidence interval ,Cardiac surgery ,Europe ,Insulin-Like Growth Factor Binding Proteins ,Treatment Outcome ,Anesthesiology and Pain Medicine ,Practice Guidelines as Topic ,Feasibility Studies ,Female ,Guideline Adherence ,business ,Biomarkers ,Patient Care Bundles ,030217 neurology & neurosurgery ,Kidney disease - Abstract
BACKGROUND: Prospective, single-center trials have shown that the implementation of the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations in high-risk patients significantly reduced the development of acute kidney injury (AKI) after surgery. We sought to evaluate the feasibility of implementing a bundle of supportive measures based on the KDIGO guideline in high-risk patients undergoing cardiac surgery in a multicenter setting in preparation for a large definitive trial. METHODS: In this multicenter, multinational, randomized controlled trial, we examined the adherence to the KDIGO bundle consisting of optimization of volume status and hemodynamics, functional hemodynamic monitoring, avoidance of nephrotoxic drugs, and prevention of hyperglycemia in high-risk patients identified by the urinary biomarkers tissue inhibitor of metalloproteinases-2 [TIMP-2] and insulin growth factor-binding protein 7 [IGFBP7] after cardiac surgery. The primary end point was the adherence to the bundle protocol and was evaluated by the percentage of compliant patients with a 95% confidence interval (CI) according to Clopper-Pearson. Secondary end points included the development and severity of AKI. RESULTS: In total, 278 patients were included in the final analysis. In the intervention group, 65.4% of patients received the complete bundle as compared to 4.2% in the control group (absolute risk reduction [ARR] 61.2 [95% CI, 52.6-69.9]; P < .001). AKI rates were statistically not different in both groups (46.3% intervention versus 41.5% control group; ARR -4.8% [95% CI, -16.4 to 6.9]; P = .423). However, the occurrence of moderate and severe AKI was significantly lower in the intervention group as compared to the control group (14.0% vs 23.9%; ARR 10.0% [95% CI, 0.9-19.1]; P = .034). There were no significant effects on other specified secondary outcomes. CONCLUSIONS: Implementation of a KDIGO-derived treatment bundle is feasible in a multinational setting. Furthermore, moderate to severe AKI was significantly reduced in the intervention group.
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- 2021
16. Kinetic Changes of Plasma Renin Concentrations Predict Acute Kidney Injury in Cardiac Surgery Patients
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Manuel Núñez Cortés, Joachim Gerss, Danilo Fliser, Raphael Weiss, Anas Lagan, Mira Küllmar, Alexander Zarbock, Lakhmir S. Chawla, Khaschayar Saadat-Gilani, Christina Massoth, and Melanie Meersch
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,Fluid homeostasis ,Acute kidney injury ,Renal function ,Critical Care and Intensive Care Medicine ,medicine.disease ,Plasma renin activity ,Cardiac surgery ,03 medical and health sciences ,0302 clinical medicine ,Blood pressure ,030228 respiratory system ,Internal medicine ,Renin–angiotensin system ,medicine ,Cardiology ,030212 general & internal medicine ,business - Abstract
Rationale: The renin–angiotensin–aldosterone system is a major pathway in regulating blood pressure, glomerular filtration, and fluid homeostasis. During inflammatory diseases, generation of angiot...
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- 2021
17. Comparison of C-C motif chemokine ligand 14 with other biomarkers for adverse kidney events after cardiac surgery
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Christina Massoth, Mira Küllmar, Dominic Enders, John A. Kellum, Lui G. Forni, Melanie Meersch, Alexander Zarbock, Raphael Weiss, Khaschayar Saadat-Gilani, Tamara Roy-Ali, and Jan Rossaint
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Pulmonary and Respiratory Medicine ,Chemokine ,medicine.medical_specialty ,medicine.medical_treatment ,030204 cardiovascular system & hematology ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Clinical endpoint ,Renal replacement therapy ,Kidney ,biology ,business.industry ,Acute kidney injury ,Area under the curve ,medicine.disease ,medicine.anatomical_structure ,030228 respiratory system ,biology.protein ,Biomarker (medicine) ,Surgery ,Cardiology and Cardiovascular Medicine ,business ,Kidney disease - Abstract
Objective Outcomes after acute kidney injury are affected by both the severity and the duration of the insult. Patients with persistent acute kidney injury have higher major adverse kidney events, including 90-day mortality, renal replacement therapy, and persistent kidney dysfunction. Methods to identify these patients are urgently needed to improve outcomes. The purpose of this study was to evaluate whether biomarkers, including C-C motif chemokine ligand 14, were able to predict persistent acute kidney injury and major adverse kidney events after cardiac surgery. Methods This study was a single-center, prospective, observational study. Patients who developed moderate or severe acute kidney injury (Kidney Disease Improving Global Outcomes 2 or 3) within 72 hours after cardiac surgery were enrolled with a primary end point of persistent severe acute kidney injury (Kidney Disease Improving Global Outcomes 3) lasting 72 hours or more. Results A total of 100 patients were available for the primary analysis, and 37 met the primary end point. C-C motif chemokine ligand 14 was the most predictive biomarker for the primary end point with an area under the curve of 0.930 (95% confidence interval, 0.881-0.979). The area under the curve of C-C motif chemokine ligand 14 was significantly higher than the area under the curve for the other biomarkers analyzed. C-C motif chemokine ligand 14 was significantly higher in end point positive patients at enrollment (4.47 ng/mL [2.35-11.5] vs 0.67 ng/mL [0.38-1.07]; P = .001). Sensitivity and specificity were 78% and 95% at a cutoff value of 2.21 ng/mL, respectively. C-C motif chemokine ligand 14 was also highly accurate for predicting renal replacement therapy within 7 days (area under the curve, 0.915; 95% confidence interval, 0.858-0.972; P Conclusions Elevated C-C motif chemokine ligand 14 levels predict persistent acute kidney injury in cardiac surgery patients with moderate or severe acute kidney injury. This new biomarker may help stratify patients destined to receive renal replacement therapy and identify patients who may benefit from novel therapeutic approaches to acute kidney injury.
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- 2023
18. Systemic Inflammatory Response Syndrome After Surgery: Mechanisms and Protection
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Nadine Ludwig, Jan Rossaint, Alexander Zarbock, and Andreas Margraf
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Organ dysfunction ,Inflammation ,medicine.disease ,Systemic inflammation ,Proinflammatory cytokine ,Surgery ,Systemic inflammatory response syndrome ,03 medical and health sciences ,0302 clinical medicine ,Anesthesiology and Pain Medicine ,Cytokine ,Immune system ,030202 anesthesiology ,medicine ,medicine.symptom ,Endothelial dysfunction ,business ,030217 neurology & neurosurgery - Abstract
The immune system is an evolutionary hallmark of higher organisms that defends the host against invading pathogens and exogenous infections. This defense includes the recruitment of immune cells to the site of infection and the initiation of an inflammatory response to contain and eliminate pathogens. However, an inflammatory response may also be triggered by noninfectious stimuli such as major surgery, and, in case of an overshooting, still not comprehensively understood reaction, lead to tissue destruction and organ dysfunction. Unfortunately, in some cases, the immune system may not effectively distinguish between stimuli elicited by major surgery, which ideally should only require a modest inflammatory response, and those elicited by trauma or pathogenic infection. Surgical procedures thus represent a potential trigger for systemic inflammation that causes the secretion of proinflammatory cytokines, endothelial dysfunction, glycocalyx damage, activation of neutrophils, and ultimately tissue and multisystem organ destruction. In this review, we discuss and summarize currently available mechanistic knowledge on surgery-associated systemic inflammation, demarcation toward other inflammatory complications, and possible therapeutic options. These options depend on uncovering the underlying mechanisms and could include pharmacologic agents, remote ischemic preconditioning protocols, cytokine blockade or clearance, and optimization of surgical procedures, anesthetic regimens, and perioperative inflammatory diagnostic assessment. Currently, a large gap between basic science and clinically confirmed data exists due to a limited evidence base of translational studies. We thus summarize important steps toward the understanding of the precise time- and space-regulated processes in systemic perioperative inflammation.
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- 2020
19. Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19
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Natalio Garbi, Stav Kozlovski, Mike Sportiello, David J. Topham, Emma C. Reilly, Ronen Alon, Ashwin B. R. Kumar, and Alexander Zarbock
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History ,Virus ,Education ,Immune system ,Cell Movement ,Leukocyte Trafficking ,Influenza, Human ,Leukocytes ,Medicine ,Animals ,Humans ,Respiratory system ,Epidemics ,Pathological ,Lung ,Molecular medicine ,business.industry ,SARS-CoV-2 ,COVID-19 ,Epithelium ,Computer Science Applications ,medicine.anatomical_structure ,Immunology ,Perspective ,Cytokines ,Airway ,business ,Influenza virus - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Understanding of the fundamental processes underlying the versatile clinical manifestations of COVID-19 is incomplete without comprehension of how different immune cells are recruited to various compartments of virus-infected lungs, and how this recruitment differs among individuals with different levels of disease severity. As in other respiratory infections, leukocyte recruitment to the respiratory system in people with COVID-19 is orchestrated by specific leukocyte trafficking molecules, and when uncontrolled and excessive it results in various pathological complications, both in the lungs and in other organs. In the absence of experimental data from physiologically relevant animal models, our knowledge of the trafficking signals displayed by distinct vascular beds and epithelial cell layers in response to infection by SARS-CoV-2 is still incomplete. However, SARS-CoV-2 and influenza virus elicit partially conserved inflammatory responses in the different respiratory epithelial cells encountered early in infection and may trigger partially overlapping combinations of trafficking signals in nearby blood vessels. Here, we review the molecular signals orchestrating leukocyte trafficking to airway and lung compartments during primary pneumotropic influenza virus infections and discuss potential similarities to distinct courses of primary SARS-CoV-2 infections. We also discuss how an imbalance in vascular activation by leukocytes outside the airways and lungs may contribute to extrapulmonary inflammatory complications in subsets of patients with COVID-19. These multiple molecular pathways are potential targets for therapeutic interventions in patients with severe COVID-19., In this Perspective, Alon and colleagues discuss how insights into immune cell trafficking during pneumotropic influenza virus infections may inform our understanding of immune cell recruitment to the respiratory tract in patients with coronavirus disease 2019 (COVID-19). Moreover, they examine the emerging knowledge of vascular pathologies beyond the lung caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
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- 2020
20. Qualitätsverbessernde Maßnahmen in der Versorgung von kritisch kranken Intensivpatienten mit Nierenersatztherapie bei akuter Nierenschädigung
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Peter Heering, Michael Schmitz, S. John, Alexander Zarbock, Michael Oppert, Achim Jörres, Detlef Kindgen-Milles, Melanie Meersch-Dini, and Carsten Willam
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Gynecology ,03 medical and health sciences ,medicine.medical_specialty ,0302 clinical medicine ,business.industry ,Emergency Medicine ,Internal Medicine ,Medicine ,030212 general & internal medicine ,Emergency Nursing ,Critical Care and Intensive Care Medicine ,business - Abstract
ZusammenfassungDie Nierenersatztherapie ist neben der Beatmung eines der wichtigsten und am häufigsten angewendeten Organersatzverfahren in der täglichen Praxis in der Intensivmedizin. Im Gegensatz zur Beatmungstherapie sind Qualitätsstandards für die Nierenersatztherapie weniger gut definiert und bekannt. In diesem Positionspapier der Deutschen Interdisziplinären Vereinigung für Intensivmedizin (DIVI) beschreiben wir Qualitätsstandards zur Nierenersatztherapie mit dem Ziel die Behandlungsqualität der Patienten mit einem schweren akuten Nierenversagen zu verbessern.
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- 2020
21. COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup
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Xose L. Perez-Fernandez, John R. Prowle, Shruti Gupta, John A. Kellum, Kianoush Kashani, Nattachai Srisawat, Ashita Tolwani, Faeq Husain-Syed, Nuttha Lumlertgul, Li Yang, Mitra K. Nadim, Claudio Ronco, Matthieu Legrand, Eric Hoste, Thiago Reis, Gianluca Villa, Kathleen D. Liu, Jay L. Koyner, Michael Joannidis, Peter Pickkers, Stuart L. Goldstein, Neesh Pannu, Marlies Ostermann, Sumit Mohan, Lui G. Forni, Zhiyong Peng, Michael J. Germain, Thomas Rimmelé, Ravindra L. Mehta, Vincenzo Cantaluppi, Anitha Vijayan, Michael J. Connor, Azra Bihorac, Alexander Zarbock, and Samira Bell
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Kidney Disease ,Scientific community ,medicine.medical_treatment ,030232 urology & nephrology ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,CORONAVIRUS ,Disease ,urologic and male genital diseases ,Acute renal failure ,0302 clinical medicine ,Risk Factors ,INFECTION ,Medicine and Health Sciences ,030212 general & internal medicine ,RENAL-REPLACEMENT THERAPY ,PERITONEAL-DIALYSIS ,Proteinuria ,Acute kidney injury ,Acute Kidney Injury ,Urology & Nephrology ,female genital diseases and pregnancy complications ,Renal Replacement Therapy ,Insuficiència renal aguda ,Nephrology ,Infectious diseases ,medicine.symptom ,CRITICALLY-ILL PATIENTS ,medicine.medical_specialty ,Consensus ,POLYMYXIN-B HEMOPERFUSION ,Clinical Sciences ,Renal and urogenital ,Peritoneal dialysis ,03 medical and health sciences ,medicine ,Humans ,Renal replacement therapy ,Risk factor ,Intensive care medicine ,Dialysis ,Septic shock ,business.industry ,urogenital system ,SARS-CoV-2 ,Prevention ,SEPTIC SHOCK ,Consensus Statement ,Anticoagulants ,COVID-19 ,medicine.disease ,BALANCED CRYSTALLOIDS ,business - Abstract
Kidney involvement in patients with coronavirus disease 2019 (COVID-19) is common, and can range from the presence of proteinuria and haematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT; also known as kidney replacement therapy). COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and serves as an independent risk factor for all-cause in-hospital death in patients with COVID-19. The pathophysiology and mechanisms of AKI in patients with COVID-19 have not been fully elucidated and seem to be multifactorial, in keeping with the pathophysiology of AKI in other patients who are critically ill. Little is known about the prevention and management of COVID-19 AKI. The emergence of regional ‘surges’ in COVID-19 cases can limit hospital resources, including dialysis availability and supplies; thus, careful daily assessment of available resources is needed. In this Consensus Statement, the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI based on current literature. We also make recommendations for areas of future research, which are aimed at improving understanding of the underlying processes and improving outcomes for patients with COVID-19 AKI., COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and is an independent risk factor for all-cause in-hospital death in patients with COVID-19. This Consensus Statement from the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI and for areas of future research, with the aim of improving understanding of the underlying processes and outcomes for patients with COVID-19 AKI.
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- 2020
22. Effects of Different Doses of Remote Ischemic Preconditioning on Kidney Damage Among Patients Undergoing Cardiac Surgery: A Single-Center Mechanistic Randomized Controlled Trial
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Melanie Meersch, John A. Kellum, Laura Kerschke, Sven Martens, Pia Klausmeyer, Mira Küllmar, Jan Rossaint, Hermann Pavenstädt, Elisa A Schmidt, and Alexander Zarbock
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Male ,medicine.medical_specialty ,Urinary system ,Critical Care and Intensive Care Medicine ,Single Center ,law.invention ,Double-Blind Method ,Randomized controlled trial ,law ,Internal medicine ,Clinical endpoint ,medicine ,Cardiopulmonary bypass ,Humans ,Cardiac Surgical Procedures ,Ischemic Preconditioning ,Aged ,Tissue Inhibitor of Metalloproteinase-2 ,Cardiopulmonary Bypass ,business.industry ,Acute kidney injury ,Acute Kidney Injury ,medicine.disease ,Cardiac surgery ,Insulin-Like Growth Factor Binding Proteins ,Cardiology ,Ischemic preconditioning ,Female ,business - Abstract
We have previously shown that remote ischemic preconditioning reduces acute kidney injury (acute kidney injury) in high-risk patients undergoing cardiopulmonary bypass and that the protective effect is confined to patients who exhibit an increased urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 in response to remote ischemic preconditioning. The purpose of this study was to determine the optimal intensity of remote ischemic preconditioning to induce required [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] changes and further explore mechanisms of remote ischemic preconditioning.Observational and randomized controlled, double-blind clinical trial.University Hospital of Muenster, Germany.High-risk patients undergoing cardiac surgery as defined by the Cleveland Clinic Foundation Score.In the interventional part, patients were randomized to receive either one of four different remote ischemic preconditioning doses (3 × 5 min, 3 × 7 min, 3 × 10 min remote ischemic preconditioning, or 3 × 5 min remote ischemic preconditioning + 2 × 10 min remote ischemic preconditioning in nonresponders) or sham-remote ischemic preconditioning (control).The primary endpoint of the interventional part was change in urinary [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] between pre- and postintervention. To examine secondary objectives including acute kidney injury incidence, we included an observational cohort. A total of 180 patients were included in the trial (n = 80 observational and n = 100 randomized controlled part [20 patients/group]). The mean age was 69.3 years (10.5 yr), 119 were men (66.1%). Absolute changes in [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] were significantly higher in all remote ischemic preconditioning groups when compared with controls (p0.01). Although we did not observe a dose-response relationship on absolute changes in [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] across the four different remote ischemic preconditioning groups, in the 15 patients failing to respond to the lowest dose, nine (60%) responded to a subsequent treatment at a higher intensity. Compared with controls, fewer patients receiving remote ischemic preconditioning developed acute kidney injury within 72 hours after surgery as defined by both Kidney Disease: Improving Global Outcomes criteria (30/80 [37.5%] vs 61/100 [61.0%]; p = 0.003).All doses of remote ischemic preconditioning significantly increased [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] and significantly decreased acute kidney injury compared with controls. High-dose remote ischemic preconditioning could stimulate [tissue inhibitor of metalloproteinases-2]*[insulin-like growth factor-binding protein 7] increases in patients refractory to low-dose remote ischemic preconditioning.
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- 2020
23. A Multinational Observational Study Exploring Adherence With the Kidney Disease
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Mercedes García-Alvarez, Patrick M. Honore, Mar Felipe Correoso, Marc Irqsusi, Gary Thomson, Neus Grau Novellas, Mira Küllmar, Marlies Ostermann, Eric Hoste, Carola Wempe, Melanie Meersch, John A. Kellum, Shrijit Nair, Christian Arndt, Ambra Licia Di Prima, Gudrun Kunst, Philippe Grieshaber, Sara Campos, Lui G. Forni, Camilla L'Acqua, Wim Vandenberghe, Hinnerk Wulf, Stefano Italiano, Michael Haffner, Alexander Zarbock, Fabrizio Monaco, and Raphael Weiß
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Adult ,Male ,medicine.medical_specialty ,Acute Lung Injury ,Renal function ,Kidney Function Tests ,law.invention ,Cohort Studies ,03 medical and health sciences ,Postoperative Complications ,0302 clinical medicine ,Randomized controlled trial ,030202 anesthesiology ,law ,Prevalence ,Humans ,Medicine ,Prospective Studies ,Cardiac Surgical Procedures ,Prospective cohort study ,Aged ,Monitoring, Physiologic ,business.industry ,Incidence ,Acute kidney injury ,Postoperative complication ,Length of Stay ,Middle Aged ,medicine.disease ,Clinical trial ,Anesthesiology and Pain Medicine ,Creatinine ,Emergency medicine ,Female ,Kidney Diseases ,Guideline Adherence ,business ,030217 neurology & neurosurgery ,Cohort study ,Kidney disease - Abstract
BACKGROUND: The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend a bundle of different measures for patients at increased risk of acute kidney injury (AKI). Prospective, single-center, randomized controlled trials (RCTs) have shown that management in accordance with the KDIGO recommendations was associated with a significant reduction in the incidence of postoperative AKI in high-risk patients. However, compliance with the KDIGO bundle in routine clinical practice is unknown. METHODS: This observational prevalence study was performed in conjunction with a prospective RCT investigating the role of the KDIGO bundle in high-risk patients undergoing cardiac surgery. A 2-day observational prevalence study was performed in all participating centers before the RCT to explore routine clinical practice. The participating hospitals provided the following data: demographics and surgical characteristics, AKI rates, and compliance rates with the individual components of the bundle. RESULTS: Ninety-five patients were enrolled in 12 participating hospitals. The incidence of AKI within 72 hours after cardiac surgery was 24.2%. In 5.3% of all patients, clinical management was fully compliant with all 6 components of the bundle. Nephrotoxic drugs were discontinued in 52.6% of patients, volume optimization was performed in 70.5%, 52.6% of the patients underwent functional hemodynamic monitoring, close monitoring of serum creatinine and urine output was undertaken in 24.2% of patients, hyperglycemia was avoided in 41.1% of patients, and no patient received radiocontrast agents. The patients received on average 3.4 (standard deviation [SD] +/- 1.1) of 6 supportive measures as recommended by the KDIGO guidelines. There was no significant difference in the number of applied measures between AKI and non-AKI patients (3.2 [SD +/- 1.1] vs 3.5 [SD +/- 1.1]; P = .347). CONCLUSIONS: In patients after cardiac surgery, compliance with the KDIGO recommendations was low in routine clinical practice.
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- 2020
24. Coronaviruses and SARS-CoV-2: A Brief Overview
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Alexander Zarbock and Stephan Ludwig
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Critical Care ,Coronavirus disease 2019 (COVID-19) ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,Disease ,medicine.disease_cause ,Virus ,Betacoronavirus ,Special Article ,Basic Science ,Pandemic ,medicine ,Humans ,Pandemics ,Coronavirus ,biology ,SARS-CoV-2 ,business.industry ,COVID-19 ,virus diseases ,medicine.disease ,biology.organism_classification ,Virology ,Anesthesiologists ,Pneumonia ,Anesthesiology and Pain Medicine ,Coronavirus Infections ,business - Abstract
In late December 2019, several cases of pneumonia of unknown origin were reported from China, which in early January 2020 were announced to be caused by a novel coronavirus. The virus was later denominated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and defined as the causal agent of Coronavirus Disease 2019 (COVID-19). Despite massive attempts to contain the disease in China, the virus has spread globally, and COVID-19 was declared a pandemic by the World Health Organization (WHO) in March 2020. Here we provide a short background on coronaviruses, and describe in more detail the novel SARS-CoV-2 and attempts to identify effective therapies against COVID-19.
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- 2020
25. Organersatzverfahren: Update Nierenersatztherapie
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Alexander Zarbock and Christina Massoth
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Gynecology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Acute kidney injury ,030208 emergency & critical care medicine ,General Medicine ,Critical Care and Intensive Care Medicine ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Anesthesiology and Pain Medicine ,Emergency Medicine ,medicine ,030212 general & internal medicine ,Renal replacement therapy ,business - Abstract
ZusammenfassungDie steigende Inzidenz der schweren akuten Nierenschädigung in Verbindung mit weiterhin hohen Mortalitätsraten stellt die intensivmedizinische Versorgung vor eine wachsende Herausforderung. Nierenersatzverfahren sind die wichtigste Therapiemaßnahme und kommen gleichermaßen zunehmend zum Einsatz – ungeachtet dessen werden wesentliche Aspekte ihrer Umsetzung infolge einer eingeschränkten Evidenzlage kontrovers diskutiert.
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- 2020
26. Intravascular adhesion and recruitment of neutrophils in response to CXCL1 depends on their TRPC6 channels
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Alexander Zarbock, Jan Rossaint, Mike Wälte, Verena Hofschröer, Otto Lindemann, Benedikt Fels, Sandra Schimmelpfennig, Albrecht Schwab, Hans Oberleithner, and Karolina Najder
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Neutrophils ,Chemokine CXCL1 ,Integrin ,Inflammation ,Kidney ,Mice ,03 medical and health sciences ,Transient receptor potential channel ,0302 clinical medicine ,Drug Discovery ,Cell Adhesion ,TRPC6 Cation Channel ,medicine ,Animals ,Central element ,Genetics (clinical) ,TRPC ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,CXCR2 ,biology ,Chemistry ,Chemotaxis ,TRPC6 channel ,CXCL1 ,Cell biology ,Mice, Inbred C57BL ,Neutrophil recruitment ,Reperfusion Injury ,biology.protein ,Molecular Medicine ,Original Article ,Calcium ,Kidney Diseases ,medicine.symptom ,Signal transduction ,030215 immunology - Abstract
Abstract Here we report a novel role for TRPC6, a member of the transient receptor potential (TRPC) channel family, in the CXCL1-dependent recruitment of murine neutrophil granulocytes. Representing a central element of the innate immune system, neutrophils are recruited from the blood stream to a site of inflammation. The recruitment process follows a well-defined sequence of events including adhesion to the blood vessel walls, migration, and chemotaxis to reach the inflammatory focus. A common feature of the underlying signaling pathways is the utilization of Ca2+ ions as intracellular second messengers. However, the required Ca2+ influx channels are not yet fully characterized. We used WT and TRPC6−/− neutrophils for in vitro and TRPC6−/− chimeric mice (WT mice with WT or TRPC6−/− bone marrow cells) for in vivo studies. After renal ischemia and reperfusion injury, TRPC6−/− chimeric mice had an attenuated TRPC6−/− neutrophil recruitment and a better outcome as judged from the reduced increase in the plasma creatinine concentration. In the cremaster model CXCL1-induced neutrophil adhesion, arrest and transmigration were also decreased in chimeric mice with TRPC6−/− neutrophils. Using atomic force microscopy and microfluidics, we could attribute the recruitment defect of TRPC6−/− neutrophils to the impact of the channel on adhesion to endothelial cells. Mechanistically, TRPC6−/− neutrophils exhibited lower Ca2+ transients during the initial adhesion leading to diminished Rap1 and β2 integrin activation and thereby reduced ICAM-1 binding. In summary, our study reveals that TRPC6 channels in neutrophils are crucial signaling modules in their recruitment from the blood stream in response to CXCL1. Key point Neutrophil TRPC6 channels are crucial for CXCL1-triggered activation of integrins during the initial steps of neutrophil recruitment.
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- 2020
27. Salvaging remote ischaemic preconditioning as a therapy for perioperative acute kidney injury
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John A. Kellum, Gareth L. Ackland, Alexander Zarbock, and Alexander V. Gourine
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Critical Care ,business.industry ,Acute kidney injury ,MEDLINE ,Perioperative ,Acute Kidney Injury ,medicine.disease ,Endotoxemia ,Anesthesiology and Pain Medicine ,Anesthesia ,Humans ,Medicine ,Ischemic preconditioning ,Ischemic Preconditioning ,business ,Biomarkers - Abstract
BACKGROUND: Remote ischaemic preconditioning (RIPC) consists of repeated cycles of limb ischaemia and reperfusion, which may reduce perioperative myocardial ischaemic damage and kidney injury. We hypothesised that RIPC may be beneficial by attenuating the systemic inflammatory response. We investigated whether RIPC affects the response in humans to bacterial endotoxin (lipopolysaccharide [LPS]) by measuring plasma cytokines and renal cell-cycle arrest mediators, which reflect renal tubular stress. METHODS: Healthy male volunteers were randomised to receive either daily RIPC for 6 consecutive days (RIPC(multiple), n=10) plus RIPC during the 40 min preceding i.v. LPS (2 ng kg(−1)), RIPC only during the 40 min before LPS (RIPC(single), n=10), or no RIPC preceding LPS (control, n=10). As a surrogate marker of renal tubular stress, the product of urinary concentrations of two cell-cycle arrest markers was calculated (tissue inhibitor of metalloproteinases-2 [TIMP2]*insulin-like growth factor binding protein-7 [IGFBP7]). Data are presented as median (inter-quartile range). RESULTS: In both RIPC groups, RIPC alone increased [TIMP2]*[IGFBP7]. LPS administration resulted in fever, flu-like symptoms, and haemodynamic alterations. Plasma cytokine concentrations increased profoundly during endotoxaemia (control group: tumor necrosis factor alpha [TNF-α] from 14 [9–16] pg ml(−1) at baseline to 480 [284–709] pg ml(−1) at 1.5 h after LPS; interleukin-6 [IL-6] from 4 [4–4] pg ml(−1) at baseline to 659 [505–1018] pg ml(−1) at 2 h after LPS). LPS administration also increased urinary [TIMP2[*[IGFBP7]. RIPC had no effect on LPS-induced cytokine release or [TIMP2]*[IGFBP7]. CONCLUSIONS: RIPC neither modulated systemic cytokine release nor attenuated inflammation-induced tubular stress after LPS. However, RIPC alone induced renal markers of cell-cycle arrest. CLINICAL TRIAL REGISTRATION: NCT 02602977.
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- 2020
28. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial
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François-Xavier Lescure, Hitoshi Honda, Robert A Fowler, Jennifer Sloane Lazar, Genming Shi, Peter Wung, Naimish Patel, Owen Hagino, Ignacio J. Bazzalo, Marcelo M. Casas, Sebastián A. Nuñez, Yael Pere, Carlos M. Ibarrola, Marco A. Solis Aramayo, Maria C. Cuesta, Andrea E. Duarte, Pablo M. Gutierrez Fernandez, Maria A. Iannantuono, Erica A. Miyazaki, Javier P. Silvio, Dario G. Scublinsky, Alessandra Bales, Daniela Catarino, Elie Fiss, Sara Mohrbacher, Victor Sato, Antonio Baylao, Adilson Cavalcante, Francini Correa, Celso A. de Andrade, Juvencio Furtado, Nelson Ribeiro Filho, Valéria Telles, Leopoldo T. Trevelin, Ricardo Vipich, Rodrigo Boldo, Paula Borges, Suzana Lobo, Graziela Luckemeyer, Luana Machado, Maysa B. Alves, Ana C. Iglessias, Marianna M. Lago, Daniel W. Santos, Hugo Chapdelaine, Emilia L. Falcone, Rahima Jamal, Me-Linh Luong, Madeleine Durand, Stephane Doucet, François-Martin Carrier, Bryan A. Coburn, Lorenzo Del Sorbo, Sharon L. Walmsley, Sara Belga, Luke Y. Chen, Allison D. Mah, Theodore Steiner, Alissa J. Wright, J. Hajek, Neill Adhikari, Robert A. Fowler, Nick Daneman, Kosar A. Khwaja, Jason Shahin, Carolina Gonzalez, Rafael Silva, Marcelo Lindh, Gabriel Maluenda, Patricia Fernandez, Maite Oyonarte, Martin Lasso, Alexandre Boyer, Didier Bronnimann, Hoang-Nam Bui, Charles Cazanave, Helene Chaussade, Arnaud Desclaux, Mailys Ducours, Alexandre Duvignaud, Denis Malvy, Lisa Martin, Didier Neau, Duc Nguyen, Thierry Pistone, Gaetane Soubrane-Wirth, Julie Leitao, Clotilde Allavena, Charlotte Biron, Sabelline Bouchez, Benjamin Gaborit, Antoine Gregoire, Paul Le Turnier, Anne-Sophie Lecompte, Raphael Lecomte, Maeva Lefebvre, Francois Raffi, David Boutoille, Pascale H. Morineau, Romain Guéry, Emmanuel Chatelus, Nathalie Dumoussaud, Renaud Felten, Florina Luca, Bernard Goichot, Francis Schneider, Marie-Caroline Taquet, Matthieu Groh, Mathilde Roumier, Mathilde Neuville, Antoine Bachelard, Valentina Isernia, F-Xavier Lescure, Bao-Chau Phung, Anne Rachline, Aurelie Sautereau, Dorothee Vallois, Yves Bleher, Delphine Boucher, Clémentine Coudon, Jean Esnault, Thomas Guimard, Sophie Leautez-Nainville, Dominique Merrien, Marine Morrier, Pauline Motte-Vincent, Romain Gabeff, Hélène Leclerc, Céline Cozic, Romain Decours, Ronan Février, Gwenhael Colin, Sophie Abgrall, Dorothee Vignes, Raluca Sterpu, Mira Kuellmar, Melanie Meersch-Dini, Raphael Weiss, Alexander Zarbock, Christiane Antony, Marc Berger, Thorsten Brenner, Christian Taube, Frank Herbstreit, Sebastian Dolff, Margarethe Konik, Karsten Schmidt, Markus Zettler, Oliver Witzke, Boris Boell, Jorge Garcia Borrega, Philipp Koehler, Thomas Zander, Fabian Dusse, Othman Al-Sawaf, Philipp Köhler, Dennis Eichenauer, Matthias Kochanek, Alexander Shimabukuro-Vornhagen, Sibylle Mellinghoff, Annika Claßen, Jan-Michel Heger, Charlotte Meyer-Schwickerath, Paul Liedgens, Katrin Heindel, Ana Belkin, Asaf Biber, Mayan Gilboa, Itzchak Levy, Vladislav Litachevsky, Galia Rahav, Anat Finesod Wiedner, Tal Zilberman-Daniels, Yonatan Oster, Jacob Strahilevitz, Sigal Sviri, Elena M. Baldissera, Corrado Campochiaro, Giulio Cavalli, Lorenzo Dagna, Giacomo De Luca, Emanuel Della Torre, Alessandro Tomelleri, Davide Bernasconi De Luca, Amedeo F. Capetti, Massimo Coen, Maria V. Cossu, Massimo Galli, Andrea Giacomelli, Guido A. Gubertini, Stefano Rusconi, Giulia J. Burastero, Margherita Digaetano, Giovanni Guaraldi, Marianna Meschiari, Cristina Mussini, Cinzia Puzzolante, Sara Volpi, Marina Aiello, Alarico Ariani, Alfredo A. Chetta, Annalisa Frizzelli, Andrea Ticinesi, Domenico Tuttolomondo, Stefano Aliberti, Francesco B. Blasi, Marta F. Di Pasquale, Sofia Misuraca, Tommaso Pilocane, Edoardo Simonetta, Alessio M. Aghelmo, Claudio Angelini, Enrico Brunetta, Giorgio W. Canonica, Michele Ciccarelli, Sara Dal Farra, Maria De Santis, Sebastian Ferri, Marco Folci, Giacomo M. Guidelli, Enrico M. Heffler, Ferdinando Loiacono, Giacomo Malipiero, Giovanni Paoletti, Rosa Pedale, Francesca A. Puggioni, Francesca Racca, Aurora Zumbo, Morihiko Satou, Tatyana Lisun, Denis Protsenko, Nikolay Rubtsov, Irina Beloglazova, Daria Fomina, Mariana Lysenko, Sofia Serdotetskova, Vitali Firstov, Ivan Gordeev, Ilia Kokorin, Ksenia Komissarova, Nina Lapochkina, Elena Luchinkina, Valentin Malimon, Sevinch Mamedguseyinova, Ksenia Polubatonova, Natalia Suvorova, Jose Arribas, Alberto M. Borobia Perez, Fernando de la Calle Prieto, Juan Carlos Figueira, Rocio Motejano Sanchez, Marta Mora-Rillo, Concepcion Prados Sanchez, Javier Queiruga Parada, Francisco Fernandez Arnalich, Maria Guerro Barrientos, Alejandro Bendala Estrada, Aranzazu Caballero Marcos, Maria E. Garcia Leoni, Rita García-Martínez, Ana María Collado, Patricia Munoz Garcia, Ana Torres do Rego, María V. Villalba García, Almudena Burrillo, Maricela Valerio Minero, Paloma Gijon Vidaurreta, Sonsoles Infante Herrero, Elena Velilla, Marina Machado, Maria Olmedo, Blanca Pinilla, Benito Almirante Gragera, Maria de la Esperanza Cañas Ruano, Sofia Contreras Medina, Alejandro Cortés Herrera, Vicenç Falcó Ferrer, Ricard Ferrer Roca, Xavier Nuvials Casals, Esteve Ribera Pascuet, Paula Suanzes Diez, Pedro Rebollo Castro, Felipe Garcia Alcaide, Alejandro Soriano, Aina Oliver Caldes, Ana González Cordón, Celia Cardozo, Lorena De la Mora Cañizo, Romina Pena López, Sandra Chamorro, Clara Crespillo-Andujar, Rosa Escudero Sanchez, Jesús Fortún-Abete, Begoña Monge-Maillo, Ana Moreno Zamora, Francesca Norman, Matilde Sanchez Conde, Sergio Serrano Villar, Pilar Vizcarra, Lescure, F. -X., Honda, H., Fowler, R. A., Lazar, J. S., Shi, G., Wung, P., Patel, N., Hagino, O., Bazzalo, I. J., Casas, M. M., Nunez, S. A., Pere, Y., Ibarrola, C. M., Solis Aramayo, M. A., Cuesta, M. C., Duarte, A. E., Gutierrez Fernandez, P. M., Iannantuono, M. A., Miyazaki, E. A., Silvio, J. P., Scublinsky, D. G., Bales, A., Catarino, D., Fiss, E., Mohrbacher, S., Sato, V., Baylao, A., Cavalcante, A., Correa, F., de Andrade, C. A., Furtado, J., Ribeiro Filho, N., Telles, V., Trevelin, L. T., Vipich, R., Boldo, R., Borges, P., Lobo, S., Luckemeyer, G., Machado, L., Alves, M. B., Iglessias, A. C., Lago, M. M., Santos, D. W., Chapdelaine, H., Falcone, E. L., Jamal, R., Luong, M. -L., Durand, M., Doucet, S., Carrier, F. -M., Coburn, B. A., Del Sorbo, L., Walmsley, S. L., Belga, S., Chen, L. Y., Mah, A. D., Steiner, T., Wright, A. J., Hajek, J., Adhikari, N., Daneman, N., Khwaja, K. A., Shahin, J., Gonzalez, C., Silva, R., Lindh, M., Maluenda, G., Fernandez, P., Oyonarte, M., Lasso, M., Boyer, A., Bronnimann, D., Bui, H. -N., Cazanave, C., Chaussade, H., Desclaux, A., Ducours, M., Duvignaud, A., Malvy, D., Martin, L., Neau, D., Nguyen, D., Pistone, T., Soubrane-Wirth, G., Leitao, J., Allavena, C., Biron, C., Bouchez, S., Gaborit, B., Gregoire, A., Le Turnier, P., Lecompte, A. -S., Lecomte, R., Lefebvre, M., Raffi, F., Boutoille, D., Morineau, P. H., Guery, R., Chatelus, E., Dumoussaud, N., Felten, R., Luca, F., Goichot, B., Schneider, F., Taquet, M. -C., Groh, M., Roumier, M., Neuville, M., Bachelard, A., Isernia, V., Phung, B. -C., Rachline, A., Sautereau, A., Vallois, D., Bleher, Y., Boucher, D., Coudon, C., Esnault, J., Guimard, T., Leautez-Nainville, S., Merrien, D., Morrier, M., Motte-Vincent, P., Gabeff, R., Leclerc, H., Cozic, C., Decours, R., Fevrier, R., Colin, G., Abgrall, S., Vignes, D., Sterpu, R., Kuellmar, M., Meersch-Dini, M., Weiss, R., Zarbock, A., Antony, C., Berger, M., Brenner, T., Taube, C., Herbstreit, F., Dolff, S., Konik, M., Schmidt, K., Zettler, M., Witzke, O., Boell, B., Garcia Borrega, J., Koehler, P., Zander, T., Dusse, F., Al-Sawaf, O., Kohler, P., Eichenauer, D., Kochanek, M., Shimabukuro-Vornhagen, A., Mellinghoff, S., Classen, A., Heger, J. -M., Meyer-Schwickerath, C., Liedgens, P., Heindel, K., Belkin, A., Biber, A., Gilboa, M., Levy, I., Litachevsky, V., Rahav, G., Finesod Wiedner, A., Zilberman-Daniels, T., Oster, Y., Strahilevitz, J., Sviri, S., Baldissera, E. M., Campochiaro, C., Cavalli, G., Dagna, L., De Luca, Giacomo., Della Torre, E., Tomelleri, A., Bernasconi De Luca, D., Capetti, A. F., Coen, M., Cossu, M. V., Galli, M., Giacomelli, A., Gubertini, G. A., Rusconi, S., Burastero, G. J., Digaetano, M., Guaraldi, G., Meschiari, M., Mussini, C., Puzzolante, C., Volpi, S., Aiello, M., Ariani, A., Chetta, A. A., Frizzelli, A., Ticinesi, A., Tuttolomondo, D., Aliberti, S., Blasi, F. B., Di Pasquale, M. F., Misuraca, S., Pilocane, T., Simonetta, E., Aghelmo, A. M., Angelini, C., Brunetta, E., Canonica, G. W., Ciccarelli, M., Dal Farra, S., De Santis, M., Ferri, S., Folci, M., Guidelli, G. M., Heffler, E. M., Loiacono, F., Malipiero, G., Paoletti, G., Pedale, R., Puggioni, F. A., Racca, F., Zumbo, A., Satou, M., Lisun, T., Protsenko, D., Rubtsov, N., Beloglazova, I., Fomina, D., Lysenko, M., Serdotetskova, S., Firstov, V., Gordeev, I., Kokorin, I., Komissarova, K., Lapochkina, N., Luchinkina, E., Malimon, V., Mamedguseyinova, S., Polubatonova, K., Suvorova, N., Arribas, J., Borobia Perez, A. M., de la Calle Prieto, F., Figueira, J. C., Motejano Sanchez, R., Mora-Rillo, M., Prados Sanchez, C., Queiruga Parada, J., Fernandez Arnalich, F., Guerro Barrientos, M., Bendala Estrada, A., Caballero Marcos, A., Garcia Leoni, M. E., Garcia-Martinez, R., Collado, A. M., Munoz Garcia, P., Torres do Rego, A., Villalba Garcia, M. V., Burrillo, A., Valerio Minero, M., Gijon Vidaurreta, P., Infante Herrero, S., Velilla, E., Machado, M., Olmedo, M., Pinilla, B., Almirante Gragera, B., Canas Ruano, M. D. L. E., Contreras Medina, S., Cortes Herrera, A., Falco Ferrer, V., Ferrer Roca, R., Nuvials Casals, X., Ribera Pascuet, E., Suanzes Diez, P., Rebollo Castro, P., Garcia Alcaide, F., Soriano, A., Oliver Caldes, A., Gonzalez Cordon, A., Cardozo, C., De la Mora Canizo, L., Pena Lopez, R., Chamorro, S., Crespillo-Andujar, C., Escudero Sanchez, R., Fortun-Abete, J., Monge-Maillo, B., Moreno Zamora, A., Norman, F., Sanchez Conde, M., Serrano Villar, S., and Vizcarra, P.
- Subjects
Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Critical Care ,International Cooperation ,Population ,Antibodies, Monoclonal, Humanized ,Placebo ,Severity of Illness Index ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Intensive care ,Severity of illness ,medicine ,Clinical endpoint ,Humans ,Immunologic Factors ,030212 general & internal medicine ,Mortality ,education ,Respiratory Distress Syndrome ,education.field_of_study ,Dose-Response Relationship, Drug ,SARS-CoV-2 ,business.industry ,Hazard ratio ,COVID-19 ,Articles ,Middle Aged ,Receptors, Interleukin-6 ,Sarilumab ,Treatment Outcome ,030228 respiratory system ,Female ,Drug Monitoring ,Cytokine Release Syndrome ,business - Abstract
Summary Background Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding Sanofi and Regeneron Pharmaceuticals.
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- 2021
29. Vascular Adhesion Protein-1 Is Associated With Acute Kidney Injury in High-Risk Patients After Cardiac Surgery
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Eike Bormann, Ronny W. Renfurm, Melanie Meersch, Andreas Margraf, Mira Küllmar, and Alexander Zarbock
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Male ,medicine.medical_specialty ,Time Factors ,Urology ,Vascular Cell Adhesion Molecule-1 ,Adhesion (medicine) ,Risk Assessment ,law.invention ,chemistry.chemical_compound ,Risk Factors ,law ,Cardiopulmonary bypass ,Humans ,Medicine ,Prospective Studies ,Cardiac Surgical Procedures ,Aged ,Randomized Controlled Trials as Topic ,Creatinine ,Cardiopulmonary Bypass ,business.industry ,Acute kidney injury ,Acute Kidney Injury ,Middle Aged ,medicine.disease ,Up-Regulation ,Cardiac surgery ,Treatment Outcome ,Anesthesiology and Pain Medicine ,chemistry ,Ischemic preconditioning ,Female ,business ,Complication ,Biomarkers ,Kidney disease - Abstract
Acute kidney injury is a common complication after cardiac surgery, with a high impact on morbidity and mortality. Vascular adhesion protein-1 is involved in inflammation, which, in turn, is part of the development of acute kidney injury after cardiac surgery.In this ancillary study to the RENal effects of Remote Ischemic Preconditioning in cardiac surgery trial, we investigated whether vascular adhesion protein-1 might be associated with the development of acute kidney injury in high-risk patients after cardiac surgery. In total, 114 patients were included in this data set. Acute kidney injury was defined by the Kidney Disease: Improving Global Outcomes criteria serum creatinine and/or urine output. Vascular adhesion protein-1 concentrations were measured at baseline (before surgery), 4 hours, and 12 hours after cardiopulmonary bypass.Vascular adhesion protein-1 levels at 12 hours were significantly higher in patients with acute kidney injury (no acute kidney injury, 271 ng/mL [Q1, Q3, 179, 364 ng/mL] versus acute kidney injury, 384 ng/mL [Q1, Q3, 311, 478 ng/mL]; P.001). Moreover, patients developing acute kidney injury had higher differences in vascular adhesion protein-1 levels between 12 hours and baseline (P.001) and between 12 and 4 hours (P.001) after cardiopulmonary bypass. At a cut point difference value of 99 ng/mL (95% CI, 63-133) between 12 hours and baseline, patients with differences99 ng/mL showed a higher occurrence rate of acute kidney injury (acute kidney injury, 78.6% versus no acute kidney injury, 31.5%; P.001). Receiver-operating characteristic curve analyses demonstrated best performance for vascular adhesion protein-1 levels at 12 hours for acute kidney injury within 72 hours after surgery, especially in the subgroup of patients with chronic kidney disease (area under the receiver-operating characteristic curve, 0.78; P.001).Vascular adhesion protein-1 is elevated in patients developing acute kidney injury assuming that vascular adhesion protein-1 plays a crucial role in the development of acute kidney injury in high-risk patients after cardiac surgery.
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- 2019
30. Platelets in Inflammation and Resolution
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Andreas Margraf and Alexander Zarbock
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Blood Platelets ,Inflammation ,Hemostasis ,Inflammasomes ,Platelet Count ,Chemistry ,Immunology ,Cell Communication ,medicine.disease ,Proinflammatory cytokine ,Cell biology ,Extracellular Vesicles ,medicine.anatomical_structure ,Leukocytes ,medicine ,Humans ,Immunology and Allergy ,Macrophage ,Secretion ,Platelet ,Thrombus ,medicine.symptom ,Blood vessel - Abstract
Platelets have long been known for their role in hemostasis. In this, platelet adhesion and activation leads to the formation of a firm thrombus and thus the sealing of a damaged blood vessel. More recently, inflammatory modes of function have been attributed to these non–nuclei-containing cellular fragments. Interaction with leukocytes, secretion of proinflammatory mediators, and migratory behavior are some of the recent discoveries. Nonetheless, platelets also have anti-inflammatory potential by regulating macrophage functions, regulatory T cells, and secretion of proresolving mediators. This review summarizes current knowledge of platelet functions with a special focus on inflammation and resolution of inflammation.
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- 2019
31. Chronic Kidney Disease and Coronary Artery Disease
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Mark J. Sarnak, Kerstin Amann, Sripal Bangalore, João L. Cavalcante, David M. Charytan, Jonathan C. Craig, John S. Gill, Mark A. Hlatky, Alan G. Jardine, Ulf Landmesser, L. Kristin Newby, Charles A. Herzog, Michael Cheung, David C. Wheeler, Wolfgang C. Winkelmayer, Thomas H. Marwick, Debasish Banerjee, Carlo Briguori, Tara I. Chang, Chien-Liang Chen, Christopher R. deFilippi, Xiaoqiang Ding, Charles J. Ferro, Jagbir Gill, Mario Gössl, Nicole M. Isbel, Hideki Ishii, Meg J. Jardine, Philip A. Kalra, Günther Laufer, Krista L. Lentine, Kevin Lobdell, Charmaine E. Lok, Gérard M. London, Jolanta Małyszko, Patrick B. Mark, Mohamed Marwan, Yuxin Nie, Patrick S. Parfrey, Roberto Pecoits-Filho, Helen Pilmore, Wajeh Y. Qunibi, Paolo Raggi, Marcello Rattazzi, Patrick Rossignol, Josiah Ruturi, Charumathi Sabanayagam, Catherine M. Shanahan, Gautam R. Shroff, Rukshana Shroff, Angela C. Webster, Daniel E. Weiner, Simon Winther, Alexander C. Wiseman, Anthony Yip, and Alexander Zarbock
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Psychological intervention ,CAD ,State of the art review ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Revascularization ,medicine.disease ,female genital diseases and pregnancy complications ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,cardiovascular diseases ,030212 general & internal medicine ,Cardiology and Cardiovascular Medicine ,business ,Intensive care medicine ,Prospective cohort study ,Very high risk ,Kidney disease - Abstract
Highlights •CKD is associated with very high risk of CAD. CAD management is complicated in CKD patients, due to comorbid conditions and potential side effects during interventions. •There are few trials related to CAD with focus on CKD patients, particularly in those with advanced CKD. •Additional prospective studies focusing on diagnosis, prevention, and treatment of CAD are needed in CKD.
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- 2019
32. Inhaled Prostacyclin Improves Oxygenation in Patients with COVID-19-induced Acute Respiratory Distress Syndrome
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Helene A. Haeberle, Stefanie Calov, Peter Martus, Lina Maria Serna Higuita, Michael Koeppen, Almuth Goll, Alexander Zarbock, Melanie Meersch, Raphael Weiss, Martin Mehrländer, Gernot Marx, Christian Putensen, Bernhard Nieswandt, Valbona Mirakaj, and Peter Rosenberger
- Subjects
ARDS ,Coronavirus disease 2019 (COVID-19) ,Oxygenation index ,business.industry ,Prostacyclin ,Oxygenation ,medicine.disease ,Anesthesia ,Multicenter trial ,medicine ,In patient ,Adverse effect ,business ,medicine.drug - Abstract
SummaryBackgroundAcute Respiratory Distress Syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS.MethodsWe performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride. The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events.FindingsOf 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n=73) or sodium chloride (n=77). Data from 144 patients were analyzed. The baseline oxygenation index did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than NaCl (p=0·17). Oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p=0·04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups.InterpretationAlthough the primary result of our study was negative, our data suggest that inhaled prostacyclin might be a more beneficial treatment than standard care for patients with ARDS.
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- 2021
33. Control of Neutrophil activation through Semaphorin 7A-Plexin C1 is essential for immune defense during pulmonary sepsis
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Michael Koeppen, Alexander Zarbock, Kristian C. Ngamsri, Maximilian Bamberg, Peter Rosenberger, Helene A. Haeberle, David Köhler, Harry Magunia, Ka-Lin Heck-Swain, Tiago Granja, Marius Keller, Bernhard Nieswand, Franziska M. Konrad, Anika Fuhr, Philip Burkhardt, Tamam Bakchoul, and Linyan Tang
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ARDS ,Lung ,Innate immune system ,biology ,business.industry ,Plexin ,medicine.disease ,Sepsis ,medicine.anatomical_structure ,Interstitial space ,Semaphorin ,Immunology ,biology.protein ,Medicine ,Platelet activation ,business - Abstract
Pulmonary defense mechanisms are critical for host integrity during the early phase of pneumonia and sepsis. These processes are fundamentally dependent on the activation of neutrophils during the early phase of the innate immune response. Recent work has shown that semaphorin 7A (Sema7A) holds significant impact on platelet activation, yet its role in neutrophil migration and function is not well known. We report here that Sema7A binds to neutrophil PlexinC1, increasing integrins and L-selectin on the neutrophil surface. Sema7A-induced neutrophil activation also prompted neutrophil chemotaxis in vitro and the formation of platelet-neutrophil complexes in vivo. We also observed altered adhesion and transmigration of neutrophils in Sema7A-/- animals in the lung. Sema7A-/- animals also showed altered crawling properties of neutrophils. This resulted in increased number of neutrophils in the interstitial space of Sema7A-/- animals but reduced numbers of neutrophils in the alveolar space during pneumonia-induced pulmonary sepsis. This was associated with significantly worse outcome of Sema7A-/- animals in a model of Klebsiella pneumoniae. Furthermore, we were able to show a correlation between serum levels of Sema7A in patients with ARDS and oxygenation levels. Thus, we show here that Sema7A has an immunomodulatory effect though which might influence patient outcome during pulmonary sepsis.SummarySema7A controls pulmonary immune defense
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- 2021
34. Why the renin–angiotensin–aldosterone system (RAAS) in critically ill patients can no longer be ignored
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Rinaldo Bellomo, Lakhmir S. Chawla, and Alexander Zarbock
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2019-20 coronavirus outbreak ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,RC86-88.9 ,business.industry ,Critically ill ,Critical Illness ,Research ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,MEDLINE ,Angiotensin-Converting Enzyme Inhibitors ,Medical emergencies. Critical care. Intensive care. First aid ,Biomarker ,Critical Care and Intensive Care Medicine ,Major adverse kidney events ,Acute kidney injury ,Renin-Angiotensin System ,Renin ,Renin–angiotensin system ,Renin angiotensin system ,Commentary ,Humans ,Medicine ,business ,Intensive care medicine - Abstract
Background Preliminary studies have suggested that the renin-angiotensin system is activated in critical illness and associated with mortality and kidney outcomes. We sought to assess in a larger, multicenter study the relationship between serum renin and Major Adverse Kidney Events (MAKE) in intensive care unit (ICU) patients. Methods Prospective, multicenter study at two institutions of patients with and without acute kidney injury (AKI). Blood samples were collected for renin measurement a median of 2 days into the index ICU admission and 5–7 days later. The primary outcome was MAKE at hospital discharge, a composite of mortality, kidney replacement therapy, or reduced estimated glomerular filtration rate to ≤ 75% of baseline. Results Patients in the highest renin tertile were more severely ill overall, including more AKI, vasopressor-dependence, and severity of illness. MAKE were significantly greater in the highest renin tertile compared to the first and second tertiles. In multivariable logistic regression, this initial measurement of renin remained significantly associated with both MAKE as well as the individual component of mortality. The association of renin with MAKE in survivors was not statistically significant. Renin measurements at the second time point were also higher in patients with MAKE. The trajectory of the renin measurements between time 1 and 2 was distinct when comparing death versus survival, but not when comparing MAKE versus those without. Conclusions In a broad cohort of critically ill patients, serum renin measured early in the ICU admission is associated with MAKE at discharge, particularly mortality. Supplementary Information The online version contains supplementary material available at 10.1186/s13054-021-03725-z.
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- 2021
35. Resolving immune cells with patrolling behaviour by magnetic resonance time-lapse single cell tracking
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Anne Helfen, Moritz Wildgruber, Mirjam Gerwing, Alexander Zarbock, Ina Fredrich, Walter Heindel, Enrica Wilken, Max Masthoff, Cornelius Faber, Silke Niemann, Helena Block, Christian Schwarz, Lydia Wachsmuth, Lisa Zondler, Asli Havlas, and Felix Noah Freppon
- Subjects
Medicine (General) ,time-lapse MRI ,Inflammation ,Stimulus (physiology) ,Time-Lapse Imaging ,General Biochemistry, Genetics and Molecular Biology ,Monocytes ,immune response ,Mice ,Immune system ,R5-920 ,Cell Movement ,Medicine ,Animals ,Biomass ,Innate immune system ,medicine.diagnostic_test ,business.industry ,Monocyte ,Patrolling ,iron oxide nanoparticles ,Magnetic resonance imaging ,General Medicine ,single cell tracking ,Magnetic Resonance Imaging ,Disease Models, Animal ,medicine.anatomical_structure ,patrolling monocytes ,Cell Tracking ,Immune System ,Immunology ,Female ,Cell tracking ,medicine.symptom ,Single-Cell Analysis ,business ,Research Article - Abstract
Background: Immune cells show distinct motion patterns that change upon inflammatory stimuli. Monocytes patrol the vasculature to screen for pathogens, thereby exerting an early task of innate immunity. Here, we aimed to non-invasively analyse single patrolling monocyte behaviour upon inflammatory stimuli. Methods: We used time-lapse Magnetic Resonance Imaging (MRI) of the murine brain to dynamically track single patrolling monocytes within the circulation distant to the actual site of inflammation in different inflammatory conditions, ranging from a subcutaneous pellet model to severe peritonitis and bacteraemia. Findings: Single patrolling immune cells with a velocity of
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- 2021
36. The Journey Begins: Personalized Acute Kidney Injury Therapy
- Author
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Alexander Zarbock
- Subjects
medicine.medical_specialty ,business.industry ,Acute kidney injury ,Clinical Investigations ,biomarkers ,Critical Care and Intensive Care Medicine ,medicine.disease ,Kidney ,sepsis ,acute kidney injury ,randomized controlled trial ,medicine ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Humans ,insulin-like growth factor-binding protein 7 ,Intensive care medicine ,business ,tissue inhibitor of metalloproteinases-2 - Abstract
Supplemental Digital Content is available in the text., OBJECTIVES: To describe study design considerations and to simulate a trial of biomarker-guided sepsis management aimed to reduce acute kidney injury (acute kidney injury). Tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7, urinary biomarkers of cell-cycle arrest, and indicators of kidney stress can detect acute kidney injury before clinical manifestations. We sought to determine the event rates for acute kidney injury as a function of serial measurements of urinary (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) in patients at risk of sepsis-associated acute kidney injury, so that an escalating series of kidney-sparing sepsis bundles based on international guidelines could be applied. DESIGN: We described the study protocol of “Limiting acute kidney injury Progression In Sepsis,” a phase 4, multicenter, adaptive, randomized controlled trial. We performed simulations to estimate the rates for the trial’s primary endpoint using patient-level data from two previous studies (Sapphire and Protocolized Care for Early Septic Shock). SETTING: Academic and community ICUs. PATIENTS: Critically ill patients with sepsis or septic shock, without evidence of stage 2/3 acute kidney injury at enrollment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Our primary endpoint is progression of two or more stages of acute kidney injury, death, or dialysis within 72 hours after enrollment. In the Sapphire simulation, 45 of 203 patients (22%) with sepsis met the endpoint. In Protocolized Care for Early Septic Shock, 144 of 607 patients (24%) with septic shock met the endpoint. In both simulations, (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) patterns, suggested by Limiting acute kidney injury Progression In Sepsis protocol, stratified the risk for the endpoint from 6% (three negative tests) to 41% (for patients eligible for the highest level of kidney-sparing sepsis bundle) in Sapphire, and 14% (two negative tests) to 46% (for the highest level of kidney-sparing sepsis bundle) in Protocolized Care for Early Septic Shock. CONCLUSIONS: Findings of our Limiting acute kidney injury Progression In Sepsis trial simulation confirmed that (tissue inhibitor of metalloproteinases-2)•(insulin-like growth factor-binding protein 7) could identify patients with different rates of progression to moderate/severe acute kidney injury, death, or dialysis in 72 hours. The Limiting acute kidney injury Progression In Sepsis protocol algorithm is therefore feasible in terms of identifying suitably high-risk individuals for kidney-sparing sepsis bundle.
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- 2021
37. Urinary [TIMP-2]·[IGFBP7]-guided implementation of the KDIGO bundle to prevent acute kidney injury: a meta-analysis
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Jan Rossaint, Rui Shi, Alexander Zarbock, Hong-Tao Tie, and Zhenhan Li
- Subjects
medicine.medical_specialty ,Tissue Inhibitor of Metalloproteinase-2 ,IGFBP7 ,business.industry ,Urinary system ,Urology ,Acute kidney injury ,Acute Kidney Injury ,medicine.disease ,law.invention ,Anesthesiology and Pain Medicine ,Randomized controlled trial ,law ,Meta-analysis ,Practice Guidelines as Topic ,medicine ,Biomarker (medicine) ,Humans ,business ,Biomarkers ,Randomized Controlled Trials as Topic - Published
- 2021
38. One out of three bystanders of out-of-hospital cardiac arrests shows signs of pathological psychological processing weeks after the incident - results from structured telephone interviews
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Peter Brinkrolf, Alexander Zarbock, Camilla Metelmann, Andreas Bohn, Mina Baumgarten, Klaus Hahnenkamp, Bibiana Metelmann, and Carolin Scharte
- Subjects
Adult ,Resuscitation ,medicine.medical_specialty ,Coping (psychology) ,Psychological distress ,Critical Care and Intensive Care Medicine ,Surveys and Questionnaires ,Psychological trauma ,Medicine ,Humans ,Psychiatry ,Pathological ,Original Research ,Out of hospital ,Out-of-hospital cardiac arrest ,RC86-88.9 ,business.industry ,Bystander CPR ,Medical emergencies. Critical care. Intensive care. First aid ,medicine.disease ,Witnessed cardiac arrest ,Cardiopulmonary Resuscitation ,Telephone ,Out-of-hospital CPR ,Telephone interview ,Relative risk ,Emergency Medicine ,Emotional adjustment ,business - Abstract
Background Witnessing an out-of-hospital cardiac arrest (OHCA) is a traumatic experience. This study analyses bystanders` psychological processing of OHCA. We examined the potential impact of bystanders performing resuscitation and the influence of the relationship between bystander and patient (stranger vs. family/friend of the patient) on the psychological processing. Methods A telephone interview survey with bystanders, who witnessed an OHCA of an adult patient was performed weeks after the event between December 2014 and April 2016. The semi-standardized questionnaire contained a question regarding the paramount emotion at the time of the interview. In a post-hoc analysis statements given in response were rated by independent researchers into the categories “signs of pathological psychological processing”, “physiological psychological processing” and “no signs of psychological distress due to the OHCA”. Results In this analysis 89 telephone interviews were included. In 27 cases (30.3%) signs of pathological psychological processing could be detected. Bystanders performing resuscitation had a higher rate of “no signs of psychological distress after witnessing OHCA” compared to those not resuscitating (54.7% vs. 26.7%, p Conclusions One out of three bystanders of OHCA suffers signs of pathological psychological processing. This was independent of bystander´s age, gender and relationship to the patient. Performing resuscitation seems to help coping with witnessing OHCA.
- Published
- 2021
39. Reticulocyte and Erythrocyte Hemoglobin Parameters for Iron Deficiency and Anemia Diagnostics in Patient Blood Management. A Narrative Review
- Author
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Norbert Ostendorf, Alexander Zarbock, Mathias Zimmermann, Olaf Hagemann, Dietrich Doll, Christian Hoenemann, and Markus M. Luedi
- Subjects
medicine.medical_specialty ,Blood management ,Anemia ,reticulocyte hemoglobin (Ret He) ,610 Medicine & health ,Review ,anemia of inflammation (ACD, anemia of chronic decease) ,iron deficiency ,hemic and lymphatic diseases ,Medicine ,Vitamin B12 ,Hematinic ,Intensive care medicine ,patient blood management ,business.industry ,General Medicine ,Iron deficiency ,medicine.disease ,anemia ,Erythropoietin ,Erythropoiesis ,Hemoglobin ,hospital acquired anemia ,business ,610 Medizin und Gesundheit ,medicine.drug - Abstract
Anemia, iron deficiency and other hematinic deficiencies are a major cause of perioperative transfusion needs and are associated with increased morbidity and mortality. Anemia can be caused either by decreased production of hemoglobin or red blood cells or by increased consumption and blood loss. Decreased production can involve anything from erythropoietin or vitamin B12 insufficiency to absolute or functional lack of iron. Thus, to achieve the goal of patient blood management, anemia must be addressed by addressing its causes. The traditional parameters to diagnose anemia, despite offering elaborate options, are not ideally suited to giving a simple overview of the causes of anemia, e.g., iron status for erythropoiesis, especially during the acute phase of inflammation, acute blood loss or iron deficiency. Reticulocyte hemoglobin can thus help to uncover the cause of the anemia and to identify the main factors inhibiting erythropoiesis. Regardless of the cause of anemia, reticulocyte hemoglobin can also quickly track the success of therapy and, together with the regular full blood count it is measured alongside, help in clearing the patient for surgery.
- Published
- 2021
40. Diagnosis of Cardiac Surgery-Associated Acute Kidney Injury
- Author
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Alexander Zarbock and Christina Massoth
- Subjects
medicine.medical_specialty ,business.industry ,urogenital system ,Acute kidney injury ,biomarkers ,General Medicine ,Review ,medicine.disease ,Cardiac surgery ,law.invention ,Clinical Practice ,acute kidney injury ,law ,medicine ,Cardiopulmonary bypass ,Medicine ,Intensive care medicine ,business ,cardiopulmonary bypass ,cardiac surgery ,Kidney disease - Abstract
Acute kidney injury after cardiac surgery is characterized by specific patterns of damage and recovery that are important to consider for management and outcome. The Kidney Disease: Improving Global Outcomes (KDIGO) classification covers only part of the conceptual framework and is thus insufficient for a comprehensive diagnosis. This review highlights the strengths and limitations of the recent criteria and provides an overview of biomarkers of cardiac surgery-associated acute kidney injury (CSA-AKI). The evolving understanding of CSA-AKI as a time-sensitive condition has increased the demand to enhance the diagnostic criteria and translate biomarkers into clinical practice.
- Published
- 2021
41. A Fragile Balance: Does Neutrophil Extracellular Trap Formation Drive Pulmonary Disease Progression?
- Author
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Helena Block and Alexander Zarbock
- Subjects
0301 basic medicine ,Extracellular Traps ,community-acquired pneumonia ,QH301-705.5 ,Neutrophils ,neutrophil extracellular traps ,Inflammation ,Disease ,Review ,chronic obstructive pulmonary disease ,cystic fibrosis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Humans ,Biology (General) ,Lung ,biology ,business.industry ,COVID-19 ,General Medicine ,Neutrophil extracellular traps ,Pneumonia ,030104 developmental biology ,medicine.anatomical_structure ,inflammation ,030220 oncology & carcinogenesis ,Neutrophil elastase ,Myeloperoxidase ,Immunology ,biology.protein ,Disease Progression ,medicine.symptom ,business ,influenza - Abstract
Neutrophils act as the first line of defense during infection and inflammation. Once activated, they are able to fulfil numerous tasks to fight inflammatory insults while keeping a balanced immune response. Besides well-known functions, such as phagocytosis and degranulation, neutrophils are also able to release “neutrophil extracellular traps” (NETs). In response to most stimuli, the neutrophils release decondensed chromatin in a NADPH oxidase-dependent manner decorated with histones and granule proteins, such as neutrophil elastase, myeloperoxidase, and cathelicidins. Although primarily supposed to prevent microbial dissemination and fight infections, there is increasing evidence that an overwhelming NET response correlates with poor outcome in many diseases. Lung-related diseases especially, such as bacterial pneumonia, cystic fibrosis, chronic obstructive pulmonary disease, aspergillosis, influenza, and COVID-19, are often affected by massive NET formation. Highly vascularized areas as in the lung are susceptible to immunothrombotic events promoted by chromatin fibers. Keeping this fragile equilibrium seems to be the key for an appropriate immune response. Therapies targeting dysregulated NET formation might positively influence many disease progressions. This review highlights recent findings on the pathophysiological influence of NET formation in different bacterial, viral, and non-infectious lung diseases and summarizes medical treatment strategies.
- Published
- 2021
42. Diabetes With Multiple Autoimmune and Inflammatory Conditions Linked to an Activating SKAP2 Mutation
- Author
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Michael S. German, Lauren Spector, Niklas Rutsch, Wesley Dixon, Chester E. Chamberlain, Wint Lwin, Karline Saintus, Mark S. Anderson, Louis H. Philipson, Lisa R. Letourneau-Freiberg, Alexander Zarbock, Clifford A. Lowell, and Juehu Wang
- Subjects
Proband ,Adult ,Chemokine ,Myeloid ,Endocrinology, Diabetes and Metabolism ,Genome-wide association study ,medicine.disease_cause ,Autoimmune Disease ,Medical and Health Sciences ,Immune tolerance ,Autoimmune Diseases ,Endocrinology & Metabolism ,Young Adult ,Immune system ,Emerging Technologies: Data Systems and Devices ,Diabetes Mellitus ,Genetics ,Internal Medicine ,medicine ,2.1 Biological and endogenous factors ,Humans ,Aetiology ,Metabolic and endocrine ,Pediatric ,Advanced and Specialized Nursing ,Mutation ,biology ,business.industry ,Prevention ,Inflammatory and immune system ,Diabetes ,Human Genome ,Intracellular Signaling Peptides and Proteins ,Phenotype ,medicine.anatomical_structure ,Diabetes Mellitus, Type 1 ,Immunology ,biology.protein ,business ,Type 1 ,Genome-Wide Association Study - Abstract
OBJECTIVE Multiple genome-wide association studies have identified a strong genetic linkage between the SKAP2 locus and type 1 diabetes (T1D), but how this leads to disease remains obscure. Here, we characterized the functional consequence of a novel SKAP2 coding mutation in a patient with T1D to gain further insight into how this impacts immune tolerance. RESEARCH DESIGN AND METHODS We identified a 24-year-old individual with T1D and other autoimmune and inflammatory conditions. The proband and first-degree relatives were recruited for whole-exome sequencing. Functional studies of the protein variant were performed using a cell line and primary myeloid immune cells collected from family members. RESULTS Sequencing identified a de novo SKAP2 variant (c.457G>A, p.Gly153Arg) in the proband. Assays using monocyte-derived macrophages from the individual revealed enhanced activity of integrin pathways and a migratory phenotype in the absence of chemokine stimulation, consistent with SKAP2 p.Gly153Arg being constitutively active. The p.Gly153Arg variant, located in the well-conserved lipid-binding loop, induced similar phenotypes when expressed in a human macrophage cell line. SKAP2 p.Gly153Arg is a gain-of-function, pathogenic mutation that disrupts myeloid immune cell function, likely resulting in a break in immune tolerance and T1D. CONCLUSIONS SKAP2 plays a key role in myeloid cell activation and migration. This particular mutation in a patient with T1D and multiple autoimmune conditions implicates a role for activating SKAP2 variants in autoimmune T1D.
- Published
- 2021
43. Thrombopoietin levels in sepsis and septic shock - a meta-analysis
- Author
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C Liu, A Zarbock, and A Margraf
- Subjects
Sepsis ,medicine.medical_specialty ,Septic shock ,business.industry ,Meta-analysis ,Internal medicine ,medicine ,medicine.disease ,business ,Gastroenterology ,Thrombopoietin - Published
- 2021
44. Platelets orchestrate the resolution of pulmonary inflammation in mice by T reg cell repositioning and macrophage education
- Author
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Sven G. Meuth, Alexander Zarbock, Sina Mersmann, Jan Rossaint, Tobias Tekath, Andrés Hidalgo, Katharina Thomas, Oliver Soehnlein, Jesmond Dalli, Andreas Margraf, Jennifer Skupski, and Charlotte Camille Jouvene
- Subjects
0301 basic medicine ,Chemistry ,Immunology ,Cell ,chemical and pharmacologic phenomena ,Inflammation ,030204 cardiovascular system & hematology ,Cell biology ,Transcriptome ,03 medical and health sciences ,Interleukin 10 ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Immune system ,medicine ,Immunology and Allergy ,Macrophage ,Platelet ,Platelet activation ,medicine.symptom - Abstract
Beyond hemostasis, platelets actively participate in immune cell recruitment and host defense, yet their potential in the resolution of inflammatory processes remains unknown. Here, we demonstrate that platelets are recruited into the lung together with neutrophils during the onset of inflammation and alongside regulatory T (T reg) cells during the resolution phase. This partnering dichotomy is regulated by differential adhesion molecule expression during resolution. Mechanistically, intravascular platelets form aggregates with T reg cells, a prerequisite for their recruitment into the lung. This interaction relies on platelet activation by sCD40L and platelet P-selectin binding to PSGL-1 on T reg cells. Physical platelet–T reg cell interactions are necessary to modulate the transcriptome and instruct T reg cells to release the anti-inflammatory mediators IL-10 and TGFβ. Notably, the presence of platelet–T reg cell aggregates in the lung was also required for macrophage transcriptional reprogramming, polarization toward an anti-inflammatory phenotype, and effective resolution of pulmonary inflammation. Thus, platelets partner with successive immune cell subsets to orchestrate both the initiation and resolution of inflammation.
- Published
- 2021
45. How new biomarkers aid the anesthetist to detect and prevent perioperative acute kidney injury
- Author
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Alexander Zarbock and Khaschayar Saadat-Gilani
- Subjects
medicine.medical_specialty ,Psychological intervention ,MEDLINE ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,03 medical and health sciences ,0302 clinical medicine ,Intravascular volume status ,Medicine ,Humans ,030212 general & internal medicine ,Intensive care medicine ,Perioperative management ,business.industry ,Acute kidney injury ,Perioperative ,Guideline ,Acute Kidney Injury ,medicine.disease ,female genital diseases and pregnancy complications ,Anesthesiology and Pain Medicine ,Creatinine ,Anesthetists ,business ,Biomarkers ,Kidney disease - Abstract
Purpose of review Acute kidney injury (AKI) is underestimated but common in the perioperative setting. Although the association of this syndrome with an increased morbidity and mortality has been well established, little progress has been made in the diagnosis or prevention of AKI in recent years. This is partly due to the late detection of AKI by conventional criteria based of functional biomarkers, serum creatinine, and urine output. In addition, conceptually AKI is now recognized as being part of a continuum, in which preventive intervention is time critical. This review will summarize the current best available evidence and explain why timely perioperative management does have impact on the development of AKI and overall outcomes for patients. Recent findings Damage biomarkers can reliably identify AKI earlier than conventional functional biomarkers, facilitating more timely preventive intervention. Although the interventions published in the Kidney Disease: Improving Global Outcomes guideline are all important, the most relevant preventive options perioperatively include maintenance of adequate volume status and perfusion pressure, and the focus on balanced crystalloid solutions as maintenance fluid. Summary AKI is a time critical syndrome that requires timely detection and damage biomarkers can help to adjust the perioperative management to prevent further injury.
- Published
- 2021
46. L-selectin shedding affects bacterial clearance in the lung: a new regulatory pathway for integrin outside-in signaling
- Author
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Veerle Van Marck, Bernadette Bardel, Alexander Mellmann, Clifford A. Lowell, Anika Cappenberg, Dylan A. McCreedy, Andreas Margraf, Alexander Zarbock, and Katharina Thomas
- Subjects
0301 basic medicine ,Immunology ,Integrin ,Biochemistry ,Phagocytes, Granulocytes, and Myelopoiesis ,Mice ,03 medical and health sciences ,Immune system ,Pneumonia, Bacterial ,Disintegrin ,medicine ,Animals ,L-Selectin ,Lung ,Metalloproteinase ,030102 biochemistry & molecular biology ,biology ,Cell Biology ,Hematology ,Klebsiella Infections ,Cell biology ,Klebsiella pneumoniae ,030104 developmental biology ,medicine.anatomical_structure ,Neutrophil Infiltration ,biology.protein ,L-selectin ,Signal transduction ,Regulatory Pathway - Abstract
Pneumonia induced by Gram-negative bacteria is a common and serious disease associated with high morbidity and mortality. Elimination of bacterial pathogens relies on the recruitment and functions of neutrophils. The adhesion molecule L-selectin has recently been implicated in integrin activation in neutrophils (inside-out signaling). However, the molecular mechanism by which L-selectin participates in host defense against Klebsiella pneumoniae-induced pulmonary inflammation is unknown. We demonstrate that L-selectin-deficient mice are prone to pulmonary infection compared with wild-type controls. Mechanistically, L-selectin cleavage from the neutrophil surface triggered by integrin engagement is involved in neutrophil recruitment into the lung and bacterial clearance. Downstream of integrin ligation, the metalloproteinase A disintegrin and metalloproteinase 17 (ADAM17) sheds L-selectin from the neutrophil surface in an IRhom2-dependent manner. L-selectin cleavage enhances integrin-mediated outside-in signaling, resulting in increased neutrophil effector functions. Thus, we identify a novel regulatory mechanism in neutrophils required for an adequate immune response triggered by integrin engagement during K pneumoniae-induced pulmonary inflammation.
- Published
- 2019
47. Neutrophil Recruitment: From Model Systems to Tissue-Specific Patterns
- Author
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Andreas Margraf, Alexander Zarbock, and Klaus Ley
- Subjects
0301 basic medicine ,Cell signaling ,Chemokine ,Neutrophils ,Immunology ,Integrin ,Cell Communication ,In Vitro Techniques ,Biology ,Models, Biological ,Article ,Sepsis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Homeostasis ,Humans ,Immunology and Allergy ,Cell adhesion molecule ,medicine.disease ,Phenotype ,030104 developmental biology ,Neutrophil Infiltration ,Organ Specificity ,Host-Pathogen Interactions ,Models, Animal ,biology.protein ,Disease Susceptibility ,Neutrophil recruitment ,Biomarkers ,Intravital microscopy ,030215 immunology - Abstract
Neutrophil recruitment is vital for host defense, but also relevant in pathological inflammatory reactions such as sepsis. Model systems have been established to examine different steps of the leukocyte recruitment cascade in vivo and in vitro under inflammatory conditions. Recently, tissue-specific recruitment patterns have come into focus, requiring modification of formerly generalized assumptions. The aim of this review is to summarize existing models of neutrophil recruitment and to point out recent discoveries in organ-specific recruitment patterns. New techniques show that previously-stated assumptions of integrin activation and tissue invasion may need revision. Similarly, neutrophil recruitment to specific organs can rely on different organ properties, adhesion molecules and chemokines. To advance our understanding of neutrophil recruitment, organ-specific intravital microscopy methods are needed.
- Published
- 2019
48. Flow-controlled ventilation during ear, nose and throat surgery
- Author
-
Jonas Weber, Tom Barnes, Steffen Wirth, Ivo Brandes, Stefan Schumann, Johannes Schmidt, Alexander Zarbock, Franziska Günther, and Dietmar Enk
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,law.invention ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,030202 anesthesiology ,law ,Intubation, Intratracheal ,Tidal Volume ,medicine ,Humans ,Intubation ,Prospective Studies ,Expiration ,Tidal volume ,Aged ,Aged, 80 and over ,Mechanical ventilation ,Ventilators, Mechanical ,business.industry ,Ear nose and throat ,Constant flow ,030208 emergency & critical care medicine ,Middle Aged ,Controlled ventilation ,Respiration, Artificial ,Otorhinolaryngologic Surgical Procedures ,Surgery ,Anesthesiology and Pain Medicine ,Ventilation (architecture) ,Female ,business - Abstract
Flow-controlled ventilation (FCV) is a new mechanical ventilation mode that maintains constant flow during inspiration and expiration with standard tidal volumes via cuffed narrow-bore endotracheal tubes. Originating in manually operated 'expiratory ventilation assistance', FCV extends this technique by automatic control of airway flow, monitoring of intratracheal pressure and control of peak inspiratory pressure and end-expiratory pressure. FCV has not yet been described in a clinical study.The aim of this study was to provide an initial assessment of FCV in mechanically ventilated patients undergoing ear, nose and throat surgery and evaluate its potential for future use.An observational study.Two German academic medical centres from 24 November 2017 to 09 January 2018.Consecutive patients (≥ 18 years) scheduled for elective ear, nose and throat surgery. Exclusion criteria were planned laser surgery, intended fibreoptic awake intubation, emergency procedures, increased risk of aspiration, American Society of Anesthesiologists (ASA) physical status more than III and chronic obstructive pulmonary disease classified as GOLD stage more than II.Peri-operative use of FCV provided by a new type of ventilator (Evone) via a narrow-bore endotracheal tube (Tritube).Minute volume, respiratory rate, intratidal tracheal pressure amplitude (Δp) and end-tidal CO2 (PetCO2) were recorded every 5 min. All adverse events were noted. Data are presented as median [IQR].Sixteen patients provided 15 evaluable data sets. A minute volume of 5.0 [4.4 to 6.4] l min and a respiratory rate of 9 [8 to 11] min generated a PetCO2 of 4.9 [4.8 to 5.0] kPa. Δp was 10 [9 to 12] cmH2O. Five adverse events were recorded: a tube obstruction due to airway secretions and four tube dislocations (two attributed to coughing, two not study-related).FCV achieves adequate PetCO2 levels with minute volume and Δp in the normal range. Tritube's high flow resistance may increase the likelihood of tube dislocations if the patient coughs. Although further evaluation is necessary, FCV provides a new option for short-term mechanical ventilation. The successful operation of FCV with narrow-bore tubes contributes to the armamentarium for airway management.DRKS00013312.
- Published
- 2019
49. Nierenersatzverfahren bei akuter Nierenschädigung
- Author
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A Zarbock and M Küllmar
- Subjects
medicine.medical_specialty ,Creatinine ,business.industry ,medicine.medical_treatment ,Incidence (epidemiology) ,Gold standard ,Acute kidney injury ,Context (language use) ,General Medicine ,medicine.disease ,chemistry.chemical_compound ,Anesthesiology and Pain Medicine ,chemistry ,medicine ,Clinical significance ,Renal replacement therapy ,Intensive care medicine ,business ,Kidney disease - Abstract
Background The incidence of acute kidney injury (AKI) has increased over the last decades. Renal replacement therapy (RRT) is increasingly being used. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines define AKI by serum creatinine (SCr) elevation and decrease in urinary output (UO) and suggest prevention strategies and recommendations on the management of RRT. Treatment options are limited and RRT remains the gold standard as supportive treatment but implies a substantial escalation of treatment. With respect to the indications and management of RRT, there are only a few evidence-based recommendations. Objective This review summarizes the clinical relevance of AKI and presents the most important aspects on the indications and implementation of RRT. Material and methods The available evidence is summarized based on the current literature. Results Implementation of the KDIGO bundles to prevent AKI in high-risk patients reduces the incidence of AKI. In the absence of absolute indications, the evidence-based recommendations on when to initiate RRT are limited and controversial. Intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT) procedures can be considered as complementary therapeutic strategies. The CRRT is recommended in hemodynamically unstable patients. Regional citrate anticoagulation is the recommended anticoagulation in CRRT. The optimal effluent dose is effectively 20-25 ml/kg body weight and hour. Spontaneous diuresis is a best predictor of successful cessation of RRT. Conclusion Risk identification and prevention of AKI are essential. In the absence of absolute indications, initiation and accomplishment of RRT should be patient-adapted and carried out in the clinical context. Newly developed biomarkers could be helpful in the future for a better estimation of the prognosis and for a more precise definition of therapeutic strategies of RRT.
- Published
- 2019
50. Nichtkardiale Eingriffe bei Erwachsenen mit angeborenen Herzfehlern
- Author
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Christina Massoth, Manuel Wenk, and Alexander Zarbock
- Subjects
Gynecology ,03 medical and health sciences ,medicine.medical_specialty ,0302 clinical medicine ,Anesthesiology and Pain Medicine ,030202 anesthesiology ,business.industry ,medicine ,030208 emergency & critical care medicine ,General Medicine ,business - Published
- 2019
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