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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.

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.

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.

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

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.

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.

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.

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...

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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

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.

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.

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.

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.

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.