Publications by authors named "Alexander Zarbock"

250 Publications

Neutrophils in acute inflammation - current concepts and translational implications.

Blood 2021 Oct 8. Epub 2021 Oct 8.

University of Muenster, Muenster, Germany.

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, one 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 not only capturing, rolling, adhesion, crawling and transmigration but furthermore 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. 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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http://dx.doi.org/10.1182/blood.2021012295DOI Listing
October 2021

Platelet Inhibition by Low-Dose Acetylsalicylic Acid Reduces Neuroinflammation in an Animal Model of Multiple Sclerosis.

Int J Mol Sci 2021 Sep 14;22(18). Epub 2021 Sep 14.

Department of Neurology, University Hospital Düsseldorf, 40225 Düsseldorf, Germany.

Aside from the established immune-mediated etiology of multiple sclerosis (MS), compelling evidence implicates platelets as important players in disease pathogenesis. Specifically, numerous studies have highlighted that activated platelets promote the central nervous system (CNS)-directed adaptive immune response early in the disease course. Platelets, therefore, present a novel opportunity for modulating the neuroinflammatory process that characterizes MS. We hypothesized that the well-known antiplatelet agent acetylsalicylic acid (ASA) could inhibit neuroinflammation by affecting platelets if applied at low-dose and investigated its effect during experimental autoimmune encephalomyelitis (EAE) as a model to study MS. We found that oral administration of low-dose ASA alleviates symptoms of EAE accompanied by reduced inflammatory infiltrates and less extensive demyelination. Remarkably, the percentage of CNS-infiltrated CD4 T cells, the major drivers of neuroinflammation, was decreased to 40.98 ± 3.28% in ASA-treated mice compared to 56.11 ± 1.46% in control animals at the disease maximum as revealed by flow cytometry. More interestingly, plasma levels of thromboxane A were decreased, while concentrations of platelet factor 4 and glycoprotein VI were not affected by low-dose ASA treatment. Overall, we demonstrate that low-dose ASA could ameliorate the platelet-dependent neuroinflammatory response in vivo, thus indicating a potential treatment approach for MS.
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http://dx.doi.org/10.3390/ijms22189915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465626PMC
September 2021

Reticulocyte and Erythrocyte Hemoglobin Parameters for Iron Deficiency and Anemia Diagnostics in Patient Blood Management. A Narrative Review.

J Clin Med 2021 Sep 19;10(18). Epub 2021 Sep 19.

Department of Anaesthesiology, Inselspital, Bern University Hospital, University of Bern, 3012 Bern, Switzerland.

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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http://dx.doi.org/10.3390/jcm10184250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470754PMC
September 2021

Perioperative renal protection.

Curr Opin Crit Care 2021 Sep 15. Epub 2021 Sep 15.

Department of Anesthesiology, Intensive Care and Pain Medicine, University of Muenster, Muenster, Germany.

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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http://dx.doi.org/10.1097/MCC.0000000000000881DOI Listing
September 2021

The Journey Begins: Personalized Acute Kidney Injury Therapy.

Crit Care Med 2021 10;49(10):1822-1825

Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany.

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http://dx.doi.org/10.1097/CCM.0000000000005100DOI Listing
October 2021

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.

Scand J Trauma Resusc Emerg Med 2021 Sep 8;29(1):131. Epub 2021 Sep 8.

Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany.

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 < 0.05; relative risk 2.01; 95%CI 1.08, 3.89). No statistical significant differences in the psychological processing could be shown for gender, age, relationship to the patient, current employment in the health sector, location of cardiac arrest or number of additional bystanders.

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.
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http://dx.doi.org/10.1186/s13049-021-00945-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425096PMC
September 2021

Protocol for a prospective, international cohort study on the Management and Outcomes of Perioperative Care among European Diabetic Patients (MOPED).

BMJ Open 2021 09 6;11(9):e044394. Epub 2021 Sep 6.

Universität Münster, Münster, UK.

Introduction: Diabetes is common (about 20 million patients in Europe) and patients with diabetes have more surgical interventions than the general population. There are plausible pathophysiological and clinical mechanisms suggesting that patients with diabetes are at an increased risk of postoperative complications. When postoperative complications occur in the general population, they increase major adverse events and subsequently increase 1-year mortality. This is likely to be worse in patients with diabetes. There is variation in practice guidelines in different countries in the perioperative management of patients with diabetes undergoing major surgery and whether this may affect postoperative outcome has not been investigated on a large scale. Neither is it known whether different strata of preoperative glycaemic control affects outcome.

Methods And Analysis: A prospective, observational, international, multicentre cohort study, recruiting 5000 patients with diabetes undergoing elective or emergency surgery in at least n=50 centres. Inclusion criteria are any patient with diabetes undergoing surgery under any substantive anaesthetic technique. Exclusion criteria are not being a confirmed diabetic patient and patients with diabetes undergoing procedures under monitored sedation or local anaesthetic infiltration only. Follow-up duration is 30 days after surgery. Primary outcome is days at home at 30 days. Secondary outcomes are Comprehensive Complications Index, Quality of Recovery (QoR-15) score on Day 1 postoperatively, 30-day mortality, length of hospital stay and incidence of specific major adverse events (Myocardial Infarction (MI), Myocardial Injury after Non-cardiac Surgery (MINS), Acute Kidney Injury (AKI), Postoperative Pulmonary Complications (PPC), Cerebrovascular Accident (CVA), Pulmonary Embolism (PE), DVT, surgical site infection, postoperative pulmonary infection). Tertiary outcomes include time to resumption of normal diabetes therapy, incidence of diabetic ketoacidosis or hypoglycaemia, incidence and duration of use of intravenous insulin infusion therapy and change in diabetic management at 30 days.

Ethics And Dissemination: This study will adhere to the principles of the Declaration of Helsinki (amendment 2013) by the World Medical Association and the ICH-Good Clinical Practice (GCP) Guidelines E6(R2). Specific national and local regulatory authority requirements will be followed as applicable. Ethical approval has been granted by the Institutional Review Board of the Mater Misericordiae University Hospital, Dublin, Ireland (Reference: 1/378/2167). As enrolment for this study is ongoing, ethical approval from additional centres is being added continuously. The main results of Management and Outcomes of Perioperative Care among European Diabetic Patients and its substudies will be published in peer-reviewed international medical journals and presented at Euroanaesthesia congress and other international and national meetings.

Trial Registration Number: NCT04511312.
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http://dx.doi.org/10.1136/bmjopen-2020-044394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422310PMC
September 2021

Diagnosis of Cardiac Surgery-Associated Acute Kidney Injury.

J Clin Med 2021 Aug 19;10(16). Epub 2021 Aug 19.

Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, A1, 48149 Münster, Germany.

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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http://dx.doi.org/10.3390/jcm10163664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397056PMC
August 2021

A Fragile Balance: Does Neutrophil Extracellular Trap Formation Drive Pulmonary Disease Progression?

Cells 2021 07 29;10(8). Epub 2021 Jul 29.

Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, 48149 Muester, Germany.

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.
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http://dx.doi.org/10.3390/cells10081932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394734PMC
July 2021

SKAP2 as a new regulator of oligodendroglial migration and myelin sheath formation.

Glia 2021 Nov 29;69(11):2699-2716. Epub 2021 Jul 29.

Institute of Neuropathology, University Hospital Muenster, Muenster, Germany.

Oligodendroglial progenitor cells (OPCs) are highly proliferative and migratory 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 central nervous system. 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 remodeling 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.
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http://dx.doi.org/10.1002/glia.24066DOI Listing
November 2021

Acute kidney injury.

Nat Rev Dis Primers 2021 07 15;7(1):52. Epub 2021 Jul 15.

Division of Nephrology, Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany.

Acute kidney injury (AKI) is defined by a sudden loss of excretory kidney function. AKI is part of a range of conditions summarized as acute kidney diseases and disorders (AKD), in which slow deterioration of kidney function or persistent kidney dysfunction is associated with an irreversible loss of kidney cells and nephrons, which can lead to chronic kidney disease (CKD). New biomarkers to identify injury before function loss await clinical implementation. AKI and AKD are a global concern. In low-income and middle-income countries, infections and hypovolaemic shock are the predominant causes of AKI. In high-income countries, AKI mostly occurs in elderly patients who are in hospital, and is related to sepsis, drugs or invasive procedures. Infection and trauma-related AKI and AKD are frequent in all regions. The large spectrum of AKI implies diverse pathophysiological mechanisms. AKI management in critical care settings is challenging, including appropriate volume control, nephrotoxic drug management, and the timing and type of kidney support. Fluid and electrolyte management are essential. As AKI can be lethal, kidney replacement therapy is frequently required. AKI has a poor prognosis in critically ill patients. Long-term consequences of AKI and AKD include CKD and cardiovascular morbidity. Thus, prevention and early detection of AKI are essential.
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http://dx.doi.org/10.1038/s41572-021-00284-zDOI Listing
July 2021

[Present practise patterns of renal replacement therapy in German intensive care medicine].

Med Klin Intensivmed Notfmed 2021 Jun 30. Epub 2021 Jun 30.

Klinik für Anästhesiologie, Universitätsklinikum Düsseldorf, Düsseldorf, Deutschland.

About 50% of all critically ill patients develop acute kidney injury (AKI) and approximately 15% receive renal replacement therapy (RRT). Although RRT is frequently used in intensive care units in Germany, it is currently unknown which RRT procedures are available, which qualification the involved staff has, which anticoagulation strategies are used and how RRT doses are prescribed. To investigate quality and structural characteristics of the performance of RRT in intensive care units throughout Germany, the German Interdisciplinary Society of Intensivists (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin [DIVI]) performed an inquiry among their members. A total of 897 members participated in the survey in which practical aspects were queried. In 69.1% of the cases, RRT was performed in hospitals with more than 400 beds and in 74.5% in university hospitals or other primary care hospitals. Furthermore, 93.3% of clinics are equipped with continuous and 75.8% with intermittent renal replacement devices. In 91.9%, indication for initiation of RRT was performed by trained physicians specialized in intensive care medicine or nephrologists. Intermittent as well as continuous modalities are both present in three-quarters of cases, which allows for individualized therapy. However, the documentation of dialysis dose needs to be improved.
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http://dx.doi.org/10.1007/s00063-021-00835-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243065PMC
June 2021

Diabetes With Multiple Autoimmune and Inflammatory Conditions Linked to an Activating SKAP2 Mutation.

Diabetes Care 2021 08 25;44(8):1816-1825. Epub 2021 Jun 25.

Department of Laboratory Medicine, University of California, San Francisco, San Francisco, San Francisco, CA

Objective: Multiple genome-wide association studies have identified a strong genetic linkage between the locus and type 1 diabetes (T1D), but how this leads to disease remains obscure. Here, we characterized the functional consequence of a novel 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 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 variants in autoimmune T1D.
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http://dx.doi.org/10.2337/dc20-2317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385470PMC
August 2021

[Intensive care for pregnant patients : A detailed excursus in four steps].

Anaesthesist 2021 07 18;70(7):618-620. Epub 2021 Jun 18.

Klinik für Anaesthesiologie, Klinikum der Universität München, Campus Großhadern, Marchioninistr. 15, 81377, München, Deutschland.

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http://dx.doi.org/10.1007/s00101-021-01006-6DOI Listing
July 2021

Patients with COVID-19: in the dark-NETs of neutrophils.

Cell Death Differ 2021 May 24. Epub 2021 May 24.

First Department of Internal Medicine, Department of Medicine, University Hospital of Alexandroupolis, and Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis, Greece.

SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.
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http://dx.doi.org/10.1038/s41418-021-00805-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142290PMC
May 2021

Platelets orchestrate the resolution of pulmonary inflammation in mice by T reg cell repositioning and macrophage education.

J Exp Med 2021 07 20;218(7). Epub 2021 May 20.

Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany.

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.
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http://dx.doi.org/10.1084/jem.20201353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142284PMC
July 2021

Postoperative acute kidney injury in adult non-cardiac surgery: joint consensus report of the Acute Disease Quality Initiative and PeriOperative Quality Initiative.

Nat Rev Nephrol 2021 09 11;17(9):605-618. Epub 2021 May 11.

Center for Critical Care Nephrology, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research.
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http://dx.doi.org/10.1038/s41581-021-00418-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367817PMC
September 2021

Restrictive fluid management versus usual care in acute kidney injury (REVERSE-AKI): a pilot randomized controlled feasibility trial.

Intensive Care Med 2021 06 7;47(6):665-673. Epub 2021 May 7.

Department of Intensive Care, Austin Hospital, Melbourne, Australia.

Purpose: We compared a restrictive fluid management strategy to usual care among critically ill patients with acute kidney injury (AKI) who had received initial fluid resuscitation.

Methods: This multicenter feasibility trial randomized 100 AKI patients 1:1 in seven ICUs in Europe and Australia. Restrictive fluid management included targeting negative or neutral daily fluid balance by minimizing fluid input and/or enhancing urine output with diuretics administered at the discretion of the clinician. Fluid boluses were administered as clinically indicated. The primary endpoint was cumulative fluid balance 72 h from randomization.

Results: Mean (SD) cumulative fluid balance at 72 h from randomization was - 1080 mL (2003 mL) in the restrictive fluid management arm and 61 mL (3131 mL) in the usual care arm, mean difference (95% CI) - 1148 mL (- 2200 to - 96) mL, P = 0.033. Median [IQR] duration of AKI was 2 [1-3] and 3 [2-7] days, respectively (median difference - 1.0 [- 3.0 to 0.0], P = 0.071). Altogether, 6 out of 46 (13%) patients in the restrictive fluid management arm and 15 out of 50 (30%) in the usual care arm received renal replacement therapy (RR 0.42; 95% CI 0.16-0.91), P = 0.043. Cumulative fluid balance at 24 h and 7 days was lower in the restrictive fluid management arm. The dose of diuretics was not different between the groups. Adverse events occurred more frequently in the usual care arm.

Conclusions: In critically ill patients with AKI, a restrictive fluid management regimen resulted in lower cumulative fluid balance and less adverse events compared to usual care. Larger trials of this intervention are justified.
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http://dx.doi.org/10.1007/s00134-021-06401-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195764PMC
June 2021

How new biomarkers aid the anesthetist to detect and prevent perioperative acute kidney injury.

Curr Opin Anaesthesiol 2021 Jun;34(3):364-372

Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Germany.

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.
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http://dx.doi.org/10.1097/ACO.0000000000000980DOI Listing
June 2021

In Response.

Anesth Analg 2021 05;132(5):e83-e84

Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany,

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http://dx.doi.org/10.1213/ANE.0000000000005473DOI Listing
May 2021

Comparison of C-C motif chemokine ligand 14 with other biomarkers for adverse kidney events after cardiac surgery.

J Thorac Cardiovasc Surg 2021 Mar 10. Epub 2021 Mar 10.

Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Muenster, Muenster, Germany. Electronic address:

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 < .001).

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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http://dx.doi.org/10.1016/j.jtcvs.2021.03.016DOI Listing
March 2021

Acute Kidney Injury in Cardiac Surgery.

Crit Care Clin 2021 Apr 13;37(2):267-278. Epub 2021 Feb 13.

Department of Anesthesiology, Intensive Care, and Pain Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, A1, Münster 48149, Germany. Electronic address:

Acute kidney injury (AKI) occurs frequently after cardiac surgery and is associated with high morbidity and mortality. Although the number of cardiac surgical procedures is constantly growing worldwide, incidence of cardiac surgery-associated AKI is still around 40% and has a significant impact on global health care costs. Numerous trials attempted to identify strategies to prevent AKI and attenuate its detrimental consequences. Effective options remained elusive. Current evidence supports a multimodal risk-stratification approach with biomarker-guided management of high-risk patients, perioperative administration of dexmedetomidine, and implementation of a care bundle as recommended by the Kidney Disease: Improving Global Outcomes group.
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http://dx.doi.org/10.1016/j.ccc.2020.11.009DOI Listing
April 2021

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.

Anesth Analg 2021 08;133(2):292-302

From the Department of Anesthesiology, Intensive Care Medicine and Pain Medicine, University Hospital Münster, Münster, Germany.

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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http://dx.doi.org/10.1213/ANE.0000000000005458DOI Listing
August 2021

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.

J Cardiothorac Vasc Anesth 2021 Jul 6;35(7):2043-2051. Epub 2021 Feb 6.

University of Alberta, Edmonton, AB, Canada.

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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http://dx.doi.org/10.1053/j.jvca.2021.02.004DOI Listing
July 2021

Kindlin-3: at the right place at the right time.

Blood 2021 01;137(1):1-2

University Hospital Münster.

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http://dx.doi.org/10.1182/blood.2020008359DOI Listing
January 2021

MCAM/CD146 Signaling PLCγ1 Leads to Activation of β-Integrins in Memory T-Cells Resulting in Increased Brain Infiltration.

Front Immunol 2020 14;11:599936. Epub 2020 Dec 14.

Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Münster, Germany.

Multiple sclerosis is a chronic auto-inflammatory disease of the central nervous system affecting patients worldwide. Neuroinflammation in multiple sclerosis is mainly driven by peripheral immune cells which invade the central nervous system and cause neurodegenerative inflammation. To enter the target tissue, immune cells have to overcome the endothelium and transmigrate into the tissue. Numerous molecules mediate this process and, as they determine the tissue invasiveness of immune cells, display great therapeutic potential. Melanoma cell adhesion molecule (MCAM) is a membrane-anchored glycoprotein expressed by a subset of T-cells and MCAM+ T-cells have been shown to contribute to neuroinflammation in multiple sclerosis. The role of the MCAM molecule for brain invasion, however, remained largely unknown. In order to investigate the role of the MCAM molecule on T-cells, we used different and assays, including flow chambers, biochemistry and microscopy experiments of the mouse brain. We demonstrate that MCAM directly mediates adhesion and that the engagement of MCAM induces intracellular signaling leading to β1-integrin activation on human T-cells. Furthermore, we show that MCAM engagement triggers the phosphorylation of PLCγ1 which is required for integrin activation and thus amplification of the cellular adhesive potential. To confirm the physiological relevance of our findings , we demonstrate that MCAM plays an important role in T-cell recruitment into the mouse brain. In conclusion, our data demonstrate that MCAM expressed on T-cells acts as an adhesion molecule and a signaling receptor that may trigger β1-integrin activation PLCγ1 upon engagement.
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http://dx.doi.org/10.3389/fimmu.2020.599936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767877PMC
June 2021

Kinetic Changes of Plasma Renin Concentrations Predict Acute Kidney Injury in Cardiac Surgery Patients.

Am J Respir Crit Care Med 2021 05;203(9):1119-1126

Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Muenster, Muenster, Germany.

The renin-angiotensin-aldosterone system is a major pathway in regulating blood pressure, glomerular filtration, and fluid homeostasis. During inflammatory diseases, generation of angiotensin II might be disturbed, leading to increased renin concentrations. Cardiac surgery and the use of cardiopulmonary bypass both induce inflammatory response and cardiovascular instability, which can contribute to acute kidney injury (AKI). To investigate whether renin concentrations are associated with hypotension and AKI. This is a single-center, prospective, observational study among patients undergoing cardiac surgery. The primary endpoint was the occurrence of AKI within 72 hours after cardiac surgery. A total of 197 patients were available for the primary analysis. The median renin serum concentration was 40.2 μU/ml (quartile 1 [Q1]-Q3, 9.3-144.4) at baseline and 51.3 μU/ml (Q1-Q3, 19.1-167.0) 4 hours after cardiac surgery, whereas the difference between postoperation and preoperation concentrations (Δ-renin) was 3.7 μU/ml (Q1-Q3, -22.7 to 50.9). Patients with an elevated Δ-renin developed an AKI significantly more often (43% vs. 12.2%;  < 0.001). High Δ-renin after cardiac surgery was associated with a significantly lower mean arterial pressure, longer time on vasopressors, and longer length of ICU and hospital stay. The area under the curve (AUC) of Δ-renin for the prediction of AKI (AUC, 0.817; 95% confidence interval, 0.747-0.887) was significantly greater compared with the AUC of the postoperative renin concentrations (AUC, 0.702; 95% CI, 0.610-0.793;  = 0.007). Elevated renin concentrations were associated with cardiovascular instability and increased AKI after cardiac surgery. Elevated renin concentrations could be used to identify high-risk patients for cardiovascular instability and AKI who would benefit from timely intervention that could improve their outcomes.
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http://dx.doi.org/10.1164/rccm.202005-2050OCDOI Listing
May 2021

Randomized controlled multicentre study of albumin replacement therapy in septic shock (ARISS): protocol for a randomized controlled trial.

Trials 2020 Dec 7;21(1):1002. Epub 2020 Dec 7.

Department of Anesthesiology, University Medical Center Göttingen, Göttingen, Germany.

Background: Albumin is a key regulator of fluid distribution within the extracellular space and has several properties beyond its oncotic activity. The accumulating evidence suggests that supplementation of albumin may provide survival advantages only when the insult is severe as in patients with septic shock.

Methods/design: The randomized controlled multicentre study of albumin replacement therapy in septic shock (ARISS) investigates whether the replacement with albumin and the maintenance of its serum levels of at least 30 g/l for 28 days improve survival in patients with septic shock compared to resuscitation and volume maintenance without albumin. Adult patients (≥ 18 years) with septic shock are randomly assigned within a maximum of 24 h after the onset of septic shock after obtaining informed consents to treatment or control groups. Patients assigned to the treatment group receive a 60-g loading dose of human albumin 20% over 2-3 h. Serum albumin levels are maintained at least at 30 g/l in the ICU for a maximum of 28 days following randomization using 40-80 g human albumin 20% infusion. The control group is treated according to the usual practice with crystalloids as the first choice for the resuscitation and maintenance phase of septic shock. The primary endpoint is 90 days mortality and secondary endpoints include 28-day, 60-day, ICU, and in-hospital mortality, organ dysfunction/failure, total amount of fluid administration and total fluid balance in the ICU, and lengths of ICU and hospital stay. In total, 1412 patients need to be analysed, 706 per group. For the sample size estimation, a 15% reduction in 90-day mortality is assumed, i.e. an absolute reduction of 7.5% points to 42.5% (relative risk 1.18). Assuming a dropout rate of 15%, a total of 1662 patients need to be allocated.

Discussion: The results of the clinical trial may influence the treatment of patients with septic shock. The expected improvement in patient survival may result in a reduction in the resources currently used in the treatment of these patients and in the socioeconomic burden of this disease.

Trial Registration: ClinicalTrials.gov NCT03869385 . Registration on 18 July 2019. Protocol version: Final 3.0.
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http://dx.doi.org/10.1186/s13063-020-04921-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720035PMC
December 2020

Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19.

Nat Rev Immunol 2021 01 19;21(1):49-64. Epub 2020 Nov 19.

David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA.

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.
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http://dx.doi.org/10.1038/s41577-020-00470-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675406PMC
January 2021

Systemic Inflammatory Response Syndrome After Surgery: Mechanisms and Protection.

Anesth Analg 2020 12;131(6):1693-1707

From the Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany.

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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http://dx.doi.org/10.1213/ANE.0000000000005175DOI Listing
December 2020
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