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Introduction Resection of musculoskeletal tumors and reconstruction with tumor endoprostheses often results in blood loss requiring transfusion of blood products. We assessed the blood-saving potential of using monopolar tungsten needle electrodes and polytetrafluoroethylene (PTFE)-coated spatula electrodes (intervention) compared with conventional dissection with sharp instruments and coagulation with uncoated steel electrodes (control). Methods We retrospectively analyzed data of 132 patients (79 interventions, 53 controls) undergoing surgery by one single experienced surgeon in our tertiary referral center between 2012 and 2021. Results Intraoperative blood loss in the intervention group was reduced by 29% [median (IQR): 700 (400–1200) vs 500 (200–700) ml; p = 0.0043]. Postoperative wound drainage decreased by 41% [median (IQR): 1230 (668–2041) vs 730 (450–1354) ml; p = 0.0080]. Additionally, patients in need of PRBCs during surgery declined from 43% to 15% (23/53 vs 12/79; p = 0.0005), while the transfusion rate after surgery did not change notably. The number of patients in need of revision surgery due to wound healing disorders was low in both groups (control group: 4/53 vs intervention group: 4/79). Only one patient in the control group and two patients in the intervention group underwent revision surgery due to hemorrhage. Baseline characteristics were similar between groups (sex, Charlson Comorbidity score, tumor entity). Conclusion Dissection with tungsten needle electrodes and PTFE-coated spatula electrodes appears an effective surgical blood-saving measure without increased risk of wound healing disorders. Level of evidence III, retrospective comparative study. Clinical trial registration. The study was registered at ClinicalTrials.gov. Identifier: NCT05164809.

To investigate whether (1 → 3)-β-d-Glucan (BDG)-guidance shortens time to antifungal therapy and thereby reduces mortality of sepsis patients with high risk of invasive Candida infection (ICI).Multicenter, randomized, controlled trial carried out between September 2016 and September 2019 in 18 intensive care units enrolling adult sepsis patients at high risk for ICI. Patients in the control group received targeted antifungal therapy driven by culture results. In addition to targeted therapy, patients in the BDG group received antifungals if at least one of two consecutive BDG samples taken during the first two study days was ≥ 80 pg/mL. Empirical antifungal therapy was discouraged in both groups. The primary endpoint was 28-day-mortality.339 patients were enrolled. ICI was diagnosed in 48 patients (14.2%) within the first 96 h after enrollment. In the BDG-group, 48.8% (84/172) patients received antifungals during the first 96 h after enrollment and 6% (10/167) patients in the control group. Death until day 28 occurred in 58 of 172 patients (33.7%) in the BDG group and 51 of 167 patients (30.5%) in the control group (relative risk 1.10; 95% confidence interval, 0.80-1.51; p = 0.53). Median time to antifungal therapy was 1.1 [interquartile range (IQR) 1.0-2.2] days in the BDG group and 4.4 (IQR 2.0-9.1, p 0.01) days in the control group.Serum BDG guided antifungal treatment did not improve 28-day mortality among sepsis patients with risk factors for but unexpected low rate of IC. This study cannot comment on the potential benefit of BDG-guidance in a more selected at-risk population.

Background Acute 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. Methods We 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 (Placebo). 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. Results Of 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 PaO2/FiO2 ratio did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than Placebo (p = 0.17). Secondary analysis showed that the 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. Conclusions The primary result of our study was negative. Our data suggest that inhaled prostacyclin might be beneficial treatment in patients with COVID-19 induced ARDS. Trial registration: The study was approved by the Institutional Review Board of the Research Ethics Committee of the University of Tübingen (899/2018AMG1) and the corresponding ethical review boards of all participating centers. The trial was also approved by the Federal Institute for Drugs and Medical Devices (BfArM, EudraCT No. 2016003168-37) and registered at clinicaltrials.gov (NCT03111212) on April 6th 2017.

Rationale Health-related quality of life after surviving acute respiratory distress syndrome has come into focus in recent years, especially during the coronavirus disease 2019 pandemic. Objectives A total of 144 patients with acute respiratory distress syndrome caused by COVID-19 or of other origin were recruited in a randomized multicenter trial. Methods Clinical data during intensive care treatment and data up to 180 days after study inclusion were collected. Changes in the Sequential Organ Failure Assessment score were used to quantify disease severity. Disability was assessed using the Barthel index on days 1, 28, 90, and 180. Measurements Mortality rate and morbidity after 180 days were compared between patients with and without COVID-19. Independent risk factors associated with high disability were identified using a binary logistic regression. Main results The SOFA score at day 5 was an independent risk factor for high disability in both groups, and score dynamic within the first 5 days significantly impacted disability in the non-COVID group. Mortality after 180 days and impairment measured by the Barthel index did not differ between patients with and without COVID-19. Conclusions Resolution of organ dysfunction within the first 5 days significantly impacts long-term morbidity. Acute respiratory distress syndrome caused by COVID-19 was not associated with increased mortality or morbidity.

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.

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.

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.

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.

Background The incidence of acute kidney injury (AKI) has increased over the last decades. Renal replacement therapy (RRT) is increasingly being used. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines define AKI by serum creatinine (SCr) elevation and decrease in urinary output (UO) and suggest prevention strategies and recommendations on the management of RRT. Treatment options are limited and RRT remains the gold standard as supportive treatment but implies a substantial escalation of treatment. With respect to the indications and management of RRT, there are only a few evidence-based recommendations. Objective This review summarizes the clinical relevance of AKI and presents the most important aspects on the indications and implementation of RRT. Material and methods The available evidence is summarized based on the current literature. Results Implementation of the KDIGO bundles to prevent AKI in high-risk patients reduces the incidence of AKI. In the absence of absolute indications, the evidence-based recommendations on when to initiate RRT are limited and controversial. Intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT) procedures can be considered as complementary therapeutic strategies. The CRRT is recommended in hemodynamically unstable patients. Regional citrate anticoagulation is the recommended anticoagulation in CRRT. The optimal effluent dose is effectively 20-25 ml/kg body weight and hour. Spontaneous diuresis is a best predictor of successful cessation of RRT. Conclusion Risk identification and prevention of AKI are essential. In the absence of absolute indications, initiation and accomplishment of RRT should be patient-adapted and carried out in the clinical context. Newly developed biomarkers could be helpful in the future for a better estimation of the prognosis and for a more precise definition of therapeutic strategies of RRT.

Cadmium (Cd2+) is a toxic and non-essential divalent metal ion in eukaryotic cells. Cells can only be targeted by Cd2+ if it hijacks physiological high-affinity entry pathways, which transport essential divalent metal ions in a process termed “ionic and molecular mimicry”. Hence, “free” Cd2+ ions and Cd2+ complexed with small organic molecules are transported across cellular membranes via ion channels, carriers and ATP hydrolyzing pumps, whereas receptor-mediated endocytosis (RME) internalizes Cd2+-protein complexes. Only Cd2+ transport pathways validated by stringent methodology, namely electrophysiology, 109Cd2+ tracer studies, inductively coupled plasma mass spectrometry, atomic absorption spectroscopy, Cd2+-sensitive fluorescent dyes, or specific ligand binding and internalization assays for RME are reviewed whereas indirect correlative studies are excluded. At toxicologically relevant concentrations in the submicromolar range, Cd2+ permeates voltage-dependent Ca2+ channels (“T-type” CaV3.1, CatSper), transient receptor potential (TRP) channels (TRPA1, TRPV5/6, TRPML1), solute carriers (SLCs) (DMT1/SLC11A2, ZIP8/SLC39A8, ZIP14/SLC39A14), amino acid/cystine transporters (SLC7A9/SLC3A1, SLC7A9/SLC7A13), and Cd2+-protein complexes are endocytosed by the lipocalin-2/NGAL receptor SLC22A17. Cd2+ transport via the mitochondrial Ca2+ uniporter, ATPases ABCC1/2/5 and transferrin receptor 1 is likely but requires further evidence. Cd2+ flux occurs through the influx carrier OCT2/SLC22A2, efflux MATE proteins SLC47A1/A2, the efflux ATPase ABCB1, and RME of Cd2+-metallothionein by the receptor megalin (low density lipoprotein receptor-related protein 2, LRP2):cubilin albeit at high concentrations thus questioning their relevance in Cd2+ loading. Which Cd2+-protein complexes are internalized by megalin:cubilin in vivo still needs to be determined. A stringent conservative and reductionist approach is mandatory to verify relevance of transport pathways for Cd2+ toxicity and to overcome dissemination of unsubstantiated conjectures.

Background Regional citrate anticoagulation (RCA) in continuous renal replacement therapy can effectively anticoagulate dialysis circuits without having adverse effects on systemic heparin application. In particular, in continuous renal replacement therapy RCA is well established and represents a safe procedure with longer filter lifetimes and fewer bleeding complications. Objectives To provide guidance on the indications, advantages and disadvantages, and use of RCA, current recommendations from the renal section of the DGIIN (Deutschen Gesellschaft fur Internistische Intensivmedizin und Notfallmedizin), OGIAIN (Osterreichischen Gesellschaft fur Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutschen Interdisziplinaren Vereinigung fur Intensiv- und Notfallmedizin) are stated. Materials and methods The recommendations in this paper are based on the current KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, other published guidelines and protocols as well as the expert knowledge and clinical experience of the authors. Results The use of commercially available machines with coupled pumps and integrated safety features, effective personal training and standardized protocols for clinical usage (SOP) is particularly important for the safe clinical use of RCA in renal replacement therapy. Contrary to previous recommendations, even liver failure or shock with lactic acidosis may no longer be an absolute contra-indication for RCA. However, these particular patients have to be carefully monitored for signs of citrate accumulation.

Background Intensive care patients with renal failure or insufficiency comprise a heterogeneous group of subjects with widely differing metabolic patterns and nutritional requirements. They include subjects with various stages of acute kidney injury (AKI), acute-on-chronic renal failure (A-CKD), without/with renal replacement therapy (RRT), chronic kidney disease (CKD), and subjects on regular hemodialysis or peritoneal dialysis therapy (HD/PD). Goals Development of recommendations by the renal section of DGIIN (Deutsche Gesellschaft fur Internistische Intensivmedizin und Notfallmedizin), OGIAIN (Osterreichische Gesellschaft fur Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutsche Interdisziplinare Vereinigung fur Intensiv- und Notfallmedizin) for the metabolic management and the planning, indication, implementation, and monitoring of nutrition therapy in this heterogeneous group of patients. Materials and methods The recommendations are based on recent evidence and current recommendations of DGEM (Deutsche Gesellschaft fur Ernahrungsmedizin), ASPEN (American Society for Parenteral and Enteral Nutrition) and ESPEN (European Society for Clinical Nutrition and Metabolism) and also the KDGIO (Kidney Disease: Improving Global Outcomes) clinical practice guidelines for AKI and the expert knowledge and clinical experience of the authors. Results Nutrition support in these patient groups is not fundamentally different from that in other disease states but must consider the multiple variations in metabolism and nutrient requirements. Nutrition therapy must be adapted to the stage of disease and especially, in those patients on RRT. Nutritional needs can differ widely between patients but also in the same patient during the course of the disease. Conclusions Thus, the patient with renal failure requires an individualized approach in nutrition support and because of the altered metabolism of many nutrients and intolerances for electrolytes and fluids, the nutrition support in patients with renal insufficiency requires close clinical and laboratory monitoring.

Background Acute kidney injury (AKI) has both high mortality and morbidity. Objectives To prevent the occurrence of AKI, current recommendations from the renal section of the DGIIN (Deutschen Gesellschaft fur Internistische Intensivmedizin und Notfallmedizin), OGIAIN (Osterreichischen Gesellschaft fur Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutschen Interdisziplinaren Vereinigung fur Intensiv- und Notfallmedizin) are stated. Materials and methods The recommendations stated in this paper are based on the current Kidney Disease Improving Global Outcomes (KDIGO) guidelines, the published statements of the "Working Group on Prevention, AKI section of the European Society of Intensive Care Medicine" and the expert knowledge and clinical experience of the authors. Results Currently there are no approved clinically effective drugs for the prevention of AKI. Therefore the mainstay of prevention is the optimization of renal perfusion by improving the mean arterial pressure (>65 mm Hg, higher target may be considered in hypertensive patients). This can be done by vasopressors, preferably norepinephrine and achieving or maintaining euvolemia. Hyperhydration that can lead to AKI itself should be avoided. In patients with maintained diuresis this can be done by diuretics that are per se no preventive drug for AKI. Radiocontrast enhanced imaging should not be withheld from patients at risk for AKI; if indicated, however, the contrast media should be limited to the smallest possible volume.

Background Many anti-infective drugs require dose adjustments in critically ill patients with acute kidney injury (AKI) and renal replacement therapy, in order to achieve adequate therapeutic drug concentrations. Objectives The fundamental pharmacokinetic and pharmacodynamic principles of drug dose adjustment are presented. Recommendations on anti-infective drug dosage in intensive care are provided. Materials and methods We established dose recommendations of selected anti-infective drugs based on information in the summary of product characteristics, published studies and recommendations, pharmacokinetic and pharmacodynamic considerations, and the experience and expert opinion of the authors. Results Out of a total of 37 anti-infective drugs (31 antibiotics, 2 antivirals, 4 antifungals) 8 can be administered independent of renal function. For 29 anti-infective drugs, a specific recommendation on drug dosage could be made in case of intermittent hemodialysis and for 24 anti-infective drugs in case of continuous hemo(dia)filtration. Conclusions Recommendations on dosing of important anti-infective drugs in critically ill patients with AKI and renal replacement therapy are provided.

Background Acute kidney injury (AKI) is a common complication in intensive care unit (ICU) patients. The incidence of AKI in ICU patients exceeds 50% and the associated morbidity and mortality rates increase with severity of AKI. In addition, long-term consequences of AKI are underestimated and several studies show impaired long-term outcome after AKI. In about 5-25% of ICU patients with AKI renal replacement therapy (RRT) is required. Objectives To assist in indication, timing, modality and application of renal replacement therapy of adult patients, current recommendations from the renal sections of the DGIIN (Deutschen Gesellschaft fur Internistische Intensivmedizin und Notfallmedizin), OGIAIN (Osterreichischen Gesellschaft fur Internistische und Allgemeine Intensivmedizin und Notfallmedizin) and DIVI (Deutschen Interdisziplinaren Vereinigung fur Intensiv- und Notfallmedizin) are stated. Materials and methods The recommendations stated in this paper are based on the current KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, recommendations from the 17th Acute Disease Quality Initiative (ADQI) Consensus Group, the French Intensive Care Society (SRLF) with the French Society of Anesthesia Intensive Care (SFAR) and the expert knowledge and clinical experience of the authors. Results Today, different treatment modalities for RRT are available. Although continuous RRT and intermittent dialysis therapy as well as continuous dialysis therapy have comparable outcomes, differences exist with respect to practical application as well as health-economic aspects. Individualized risk stratification might be helpful to choose the right time to start and the right treatment modality for patients.