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Perfluorocarbons are oxygen-carrying, dense liquids initially intended for the use in partial or total liquid ventilation in patients with severe acute respiratory distress syndrome (ARDS), but did not show beneficial effects in clinical studies. However, perfluorocarbons may be used for lung lavage in severe alveolar proteinosis. In ARDS, oxygenation may be so severely compromised that the use of non-oxygenated perfluorocarbons may not be possible. We report of a case of severe non-resolving ARDS treated with extracorporeal membrane oxygenation (ECMO) to secure oxygenation, using perfluorocarbon in a single instillation to aid the clearance of debris and proteinacous edema.

Purpose This executive summary of a national living guideline aims to provide rapid evidence based recommendations on the role of drug interventions in the treatment of hospitalized patients with COVID-19. Methods The guideline makes use of a systematic assessment and decision process using an evidence to decision framework (GRADE) as recommended standard WHO (2021). Recommendations are consented by an interdisciplinary panel. Evidence analysis and interpretation is supported by the CEOsys project providing extensive literature searches and living (meta-) analyses. For this executive summary, selected key recommendations on drug therapy are presented including the quality of the evidence and rationale for the level of recommendation. Results The guideline contains 11 key recommendations for COVID-19 drug therapy, eight of which are based on systematic review and/or meta-analysis, while three recommendations represent consensus expert opinion. Based on current evidence, the panel makes strong recommendations for corticosteroids (WHO scale 5–9) and prophylactic anticoagulation (all hospitalized patients with COVID-19) as standard of care. Intensified anticoagulation may be considered for patients with additional risk factors for venous thromboembolisms (VTE) and a low bleeding risk. The IL-6 antagonist tocilizumab may be added in case of high supplemental oxygen requirement and progressive disease (WHO scale 5–6). Treatment with nMABs may be considered for selected inpatients with an early SARS-CoV-2 infection that are not hospitalized for COVID-19. Convalescent plasma, azithromycin, ivermectin or vitamin D3 should not be used in COVID-19 routine care. Conclusion For COVID-19 drug therapy, there are several options that are sufficiently supported by evidence. The living guidance will be updated as new evidence emerges.

Children have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and a substantially lower risk for developing severe coronavirus disease 2019 compared with adults. However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n = 18) and age-matched SARS-CoV-2-positive (n = 24) children and corresponding samples from adults (n = 44), covering an age range of 4 weeks to 77 years. Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than in adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A)+ cytotoxic T cells and a CD8+ T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults. Single-cell sequencing reveals pre-activated immunity as important for milder COVID-19 symptoms in children.

Introduction Adequate staffing in the intensive care units (ICUs) is the most important factor to provide optimal care and ensure favorable outcomes in critically ill patients. Recently, the need for ICU beds has reached unprecedented levels and the management and treatment of critically ill patients has been in focus. The aim of the study was to assess the targeted and actual nurse-to-patient (NPR) and physician-to-patient ratios (PPR) regarding patients with and without COVID-19. Methods We conducted a nationwide online survey assessing the standard of care in German ICUs treating patients with COVID-19. We asked questions regarding targeted PPR and NPR and their implementation in daily clinical practice to heads of German ICU departments. Results We received 244 responses of which 171 were eligible for final analysis. Targeted median PPR ratio was 8 [interquartile range (IQR) = 4] and targeted NPR was 2 (IQR = 1). For COVID-19 patients, the median targeted PPR was 6 (IQR = 2) and the median targeted NPR was 2 (IQR = 0). Targeted PPRs were rarely met by 15.2% and never met by 3.5% of responding institutions. Targeted NPRs were rarely met in 32.2% and never in 5.3% of responding institutions. Conclusion In contrast to PPR, targeted NPRs were largely unattainable in German ICUs. Our results raise concern in view of studies linking worse outcomes in critically ill patients to suboptimal NPRs. This warrants further health policy efforts regarding optimal staffing in the ICU.

In COVID-19, hypertension and cardiovascular diseases have emerged as major risk factors for critical disease progression. Concurrently, the impact of the main anti-hypertensive therapies, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), on COVID-19 severity is controversially discussed. By combining clinical data, single-cell sequencing data of airway samples andin vitroexperiments, we assessed the cellular and pathophysiological changes in COVID-19 driven by cardiovascular disease and its treatment options. Anti-hypertensive ACEi or ARB therapy, was not associated with an altered expression of SARS-CoV-2 entry receptorACE2in nasopharyngeal epithelial cells and thus presumably does not change susceptibility for SARS-CoV-2 infection. However, we observed a more critical progress in COVID-19 patients with hypertension associated with a distinct inflammatory predisposition of immune cells. While ACEi treatment was associated with dampened COVID-19-related hyperinflammation and intrinsic anti-viral responses, under ARB treatment enhanced epithelial-immune cell interactions were observed. Macrophages and neutrophils of COVID-19 patients with hypertension and cardiovascular comorbidities, in particular under ARB treatment, exhibited higher expression ofCCL3, CCL4, and its receptorCCR1, which associated with critical COVID-19 progression. Overall, these results provide a potential explanation for the adverse COVID-19 course in patients with cardiovascular disease, i.e. an augmented immune response in critical cells for the disease course, and might suggest a beneficial effect of clinical ACEi treatment in hypertensive COVID-19 patients.

To investigate the immune response and mechanisms associated with severe coronavirus disease 2019 (COVID-19), we performed single-cell RNA sequencing on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from five healthy controls. We identified airway epithelial cell types and states vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In patients with COVID-19, epithelial cells showed an average three-fold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells. Compared to moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand–receptor expression profiles, and activated immune cells, including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF. The transcriptional differences in critical cases compared to moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure. Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19.

The clinical course of COVID-19 is highly variable, however, underlying host factors and determinants of severe disease are still unknown. Based on single-cell transcriptomes of nasopharyngeal and bronchial samples from clinically well-characterized patients presenting with moderate and critical severities, we reveal the different types and states of airway epithelial cells that are vulnerable for SARS-CoV-2 infection. In COVID-19 patients, we observed a two- to threefold increase of cells expressing the SARS-CoV-2 entry receptorACE2within the airway epithelial cell compartment.ACE2is upregulated in epithelial cells through Interferon signals by immune cells suggesting that the viral defense system may increase the number of potentially susceptible cells in the respiratory epithelium. Infected epithelial cells recruit and activate immune cells by chemokine signaling. Recruited T lymphocytes and inflammatory macrophages were hyperactivated and showed a strong interaction with epithelial cells. In critical patients, increased expression ofCCL2, CCL3, CCL5, CXCL9, CXCL10, IL8, IL1BandTNFin macrophages was identified as a likely cause of a hyperinflammatory lung pathology. Moreover, we observed exacerbated epithelial cell death, likely leading to lung injury and respiratory failure in fatal cases. Our study provides novel insights into the pathophysiology of COVID-19 and suggests an immunomodulatory therapy along the CCL2, CCL3/CCR1 axis as promising option to prevent and treat critical course of COVID-19.

Introduction Hemoglobin-based oxygen carriers (HBOC) have been developed as an alternative to blood transfusions . Their nitric-oxide-scavenging properties HBOC also induce vasoconstriction . In acute lung injury , an excess of nitric oxide results in a general vasodilation , reducing oxygenation by impairing the hypoxic pulmonary vasoconstriction . Inhaled nitric oxide (iNO) is used to correct the ventilation perfusion mismatch . We hypothesized that the additional use of HBOC might increase this effect. In a rodent model of ARDS we evaluated the combined effect of HBOC and iNO on vascular tone and gas exchange. Methods ARDS was induced in anaesthetized Wistar rats by saline lavage and aggressive ventilation. Two groups received either hydroxyethylstarch 10% (HES; n = 10) or the HBOC hemoglobin glutamer-200 (HBOC-200; n = 10) via a central venous infusion . Additionally, both groups received iNO. Monitoring of the right ventricular pressure (RVP) and mean arterial pressure (MAP) was performed with microtip transducers. Arterial oxygenation was measured via arterial blood gas analyses. Results Application of HBOC-200 led to a significant increase of MAP and RVP when compared to baseline and to the HES group. This effect was reversed by iNO. The application of HBOC and iNO had no effect on the arterial oxygenation over time. No difference in arterial oxygenation was found between the groups. Conclusion Application of HBOC led to an increase of systemic and pulmonary vascular resistance in this animal model of ARDS. The increase in RVP was reversed by iNO. Pulmonary vasoconstriction by hemoglobin glutamer-200 in combination with iNO did not improve arterial oxygenation in ARDS.

In patients with severely compromised gas exchange, interhospital transportation is frequently necessary due to the need to provide access to specialized care. Risks are inherent during transport, so the anticipated benefits of transportation must be weighed against the possible negative outcome during the transport. The use of specialized teams during transportation can help to reduce adverse events. Diligent planning of the transportation, monitoring and medical staff during transport can decrease adverse events and reduce risks. This article defines the group of patients that may benefit from referral. This article discusses the risks associated with the transportation of patients with severely impaired gas exchange and the risks related to different means of transportation. The decisions required before transportation are described as well as the practical approach starting at the transferring hospital until arrival at the admitting hospital.

For patients with acute respiratory insufficiency, mechanical (“invasive”) ventilation is a fundamental therapeutic measure to ensure sufficient gas exchange. Despite decades of strong research efforts, central questions on mechanical ventilation therapy are still answered incompletely. Therefore, many different ventilation modes and settings have been used in daily clinical practice without scientifically sound bases. At the same time, implementation of the few evidence-based therapeutic concepts (e.g., “lung protective ventilation”) into clinical practice is still insufficient. The aim of our guideline project “Mechanical ventilation and extracorporeal gas exchange in acute respiratory insufficiency” was to develop an evidence-based decision aid for treating patients with and on mechanical ventilation. It covers the whole pathway of invasively ventilated patients (including indications of mechanical ventilation, ventilator settings, additional and rescue therapies, and liberation from mechanical ventilation). To assess the quality of scientific evidence and subsequently derive recommendations, we applied the Grading of Recommendations, Assessment, Development and Evaluation method. For the first time, using this globally accepted methodological standard, our guideline contains recommendations on mechanical ventilation therapy not only for acute respiratory distress syndrome patients but also for all types of acute respiratory insufficiency. This review presents the two main chapters of the guideline on choosing the mode of mechanical ventilation and setting its parameters. The guideline group aimed that – by thorough implementation of the recommendations – critical care teams may further improve the quality of care for patients suffering from acute respiratory insufficiency. By identifying relevant gaps of scientific evidence, the guideline group intended to support the development of important research projects.

Fur Patienten mit schwerem akuten Lungenversagen (ARDS) konnte ein signifikanter Uberlebensvorteil bei der Durchfuhrung von Bauchlagerungen gezeigt werden. Auch Patienten, die mit einer extrakorporalen Membranoxygenierung (ECMO) behandelt werden, konnten davon profitieren. Die Lagerung ist jedoch mit einem potenziell erhohten Risiko schwerer lagerungsbedingter Komplikationen vergesellschaftet. In dieser Studie sollen die Machbarkeit und die Sicherheit der intermittierenden Bauchlage fur Patienten mit schwerem ARDS unter laufender ECMO-Therapie untersucht werden. Wir untersuchten retrospektiv alle Patienten, die zwischen Januar 2009 und August 2013 auf der Interdisziplinaren Operativen Intensivstation des Universitatsklinikums Leipzig mit venovenoser (vv)ECMO und Bauchlage behandelt wurden. Basisdaten, Krankenhausletalitat und schwere Zwischenfalle wurden erfasst. Als schwere Zwischenfalle wurden Dislokationen oder Obstruktionen von Atemwegszugangen, ECMO-Kanulen und ein Herz-Kreislauf-Stillstand definiert. Ergebnisse werden als Median (1. Quartile; 3. Quartile) angegeben. Es wurden 26 Patienten mit ECMO-Therapie und Bauchlage behandelt. Ursachen des ARDS waren Pneumonien (n = 20), Aspirationen (n = 2) und in 4 Fallen andere seltenere Grunde. Die 26 Patienten wurden 8 (6;11) Tage mit ECMO behandelt. In dieser Zeit fuhrten wir insgesamt 134 Bauchlagerungen durch. Jeder Patient erfuhr im Mittel 5 (3;7) Lagerungsphasen fur jeweils 12 (8;12) h. Wir konnten keine schweren Zwischenfalle feststellen. Die Krankenhausletalitat betrug 42 %, die Letalitat unter ECMO 35 %. Bei Patienten mit ECMO-Therapie bei schwerem ARDS fanden wir bei der Anwendung von Bauchlage keine schwerwiegenden Zwischenfalle.

Background Mechanical ventilation is life-saving for patients with acute respiratory insufficiency. In a German prevalence study, 13.6% of patients in intensive care units received mechanical ventilation for more than 12 hours; 20% of these patients received mechanical ventilation as treatment for acute respiratory distress syndrome (ARDS). The new S3 guideline is the first to contain recommendations for the entire process of treatment in these groups of patients (indications, ventilation modes/parameters, ac- companying measures, treatments for refractory impairment of gas exchange, weaning, and follow-up care). Methods This guideline was developed according to the GRADE methods. Pertinent publications were identified by a systematic search of the literature, the quality of the evidence was evaluated, a risk/benefit assessment was conducted, and recommendations were issued by interdisciplinary consensus. Results Mechanical ventilation is recommended as primary treatment for patients with severe ARDS. In other patient groups, non-in- vasive ventilation can lower mortality. If mechanical ventilation is needed, ventilation modes allowing spontaneous breathing seem beneficial (quality of evidence [QoE]: very low). Protective ventilation (high positive end-expiratory pressure, low tidal volume, limited peak pressure) improve the survival of ARDS patients (QoE: high). If a severe impairment of gas exchange is present, prone posi- tioning lessens mortality (QoE: high). Veno-venous extracorporeal membrane oxygenation (vvECMO) has not unequivocally been shown to improve survival. Early mobilization and weaning protocols can shorten the duration of ventilation (QoE: moderate). Conclusion Recommendations for patients undergoing mechanical ventilation include lung-protective ventilation, early sponta- neous breathing and mobilization, weaning protocols, and, for those with severe impairment of gas exchange, prone positioning. It is further recommended that patients with ARDS and refractory impairment of gas exchange should be transferred to an ARDS/ECMO center, where extracorporeal methods should be applied only after application of all other therapeutic options.

Viele Einsatze in der praklinischen Notfallrettung erscheinen den Rettern als „Fehleinsatze“ oder falsche Indikationen im Sinne der Landesrettungsgesetze. Solche Einsatze werden oftmals durch soziale Aspekte getriggert, oder diese stehen gar im Vordergrund des Einsatzes. Mitarbeiter der Rettungsdienste werden mit sozialen Problemen konfrontiert und fuhlen sich in der Folge haufig damit allein gelassen. Der vorliegende Beitrag fordert das Verstandnis der Rettungsdienstmitarbeiter fur die Zusammenhange zwischen gesellschaftlichen Problemen und Gesundheit. Fur haufige soziale Notfalle im Rettungsdienst werden Losungsstrategien angeboten. In dieser Arbeit werden Zusammenhange zwischen soziookonomischem Status und Gesundheit bzw. Krankheit aufgezeigt. Typische Einsatzindikationen, bei denen soziale Aspekte eine grose Rolle spielen, werden dargestellt und Losungsstrategien fur das Vorgehen vorgeschlagen. Diskutiert wird der Umgang mit Fallen von Kindesmisshandlung und hauslicher Gewalt. Drei klassische psychiatrische Problematiken mit haufig sozialer Komponente werden erortert: psychomotorische Erregungszustande, Suizide und alkoholassoziierte Einsatze. Hier wird besonders auf Fremdgefahrdung und aggressive Patienten eingegangen. Gerade bei alteren und chronisch-kranken Patienten spielen neben der Behandlung medizinischer Fragen soziale Probleme eine wichtige Rolle. Die Moglichkeiten des Rettungsteams zur Losung sozialer Probleme sind in aller Regel stark begrenzt. Es ist fur den Notarzt jedoch wichtig, die Strukturen und nichtmedizinischen Ansprechpartner in der eigenen Region zu kennen und zielgerichtet an sie zu verweisen. Dazu gehoren Sozialdienste, Jugendamter; Kriseninterventionsteams oder beispielsweise sozialpsychiatrische Dienste.

BACKGROUND: The modalities of tracheostomy for critically ill patients are still controversially discussed. Although the use of percutaneous dilatational tracheostomy (PDT) is generally accepted to be a safe procedure, it is still not considered to be suitable for patients requiring a permanent tracheostomy. METHODS: This was an observational cohort study investigating long-term outcome parameters of PDT. All patients having received a PDT at the interdisciplinary ICU at the University of Leipzig between October 2008 and August 2009 that survived to discharge were asked for consent to participate (n = 103). Baseline data, admitting diagnosis, reasons for tracheostomy, and timing for tracheostomy were recorded. Subjects and medical providers were asked for neurological outcome, adverse events, and personal discomfort related to the tracheostomy. The study period was 2 y from the time of tracheostomy. RESULTS: Seventy-one subjects were finally included in the survey. Data of 8 subjects (11%) were incomplete. Reasons for tracheostomy were the need for long-term ventilation (42%), weaning (31%), and neurological deficits (27%). No severe adverse events were registered. Sixty-five percent of all subjects could finally be decannulated. Two subjects remained with their initial tracheostomy, and in 5 subjects (7%) tracheostomy was modified to a surgical tracheostomy. Thirty-seven percent of subjects died during the 2 y. Twenty-five of the surviving subjects (35%) had only minor or moderate neurological and psychological deficits. Complaints were mostly connected to swallowing and breathing. CONCLUSIONS: Decannulations after PDT are easily done. Complications after PDT requiring a transformation to a surgical tracheostomy are rare. Elective surgical conversions are not necessary.

Recommendations concerning the management of hemoglobin levels and hematocrit in patients on extracorporeal membrane oxygenation (ECMO) still advise maintenance of a normal hematocrit. In contrast, current transfusion guidelines for critically ill patients support restrictive transfusion practice. We report on a series of patients receiving venovenous ECMO (vvECMO) for acute respiratory distress syndrome (ARDS) treated according to the restrictive transfusion regimen recommended for critically ill patients. We retrospectively analyzed 18 patients receiving vvECMO due to severe ARDS. Hemoglobin concentrations were kept between 7 and 9 g/dL with a transfusion trigger at 7 g/dL or when physiological transfusion triggers were apparent. We assessed baseline data, hospital mortality, time on ECMO, hemoglobin levels, hematocrit, quantities of packed red blood cells received, and lactate concentrations and compared survivors and nonsurvivors. The overall mortality of all patients on vvECMO was 38.9%. Mean hemoglobin concentration over all patients and ECMO days was 8.30 ± 0.51 g/dL, and hematocrit was 0.25 ± 0.01, with no difference between survivors and nonsurvivors. Mean numbers of given PRBCs showed a trend towards higher quantities in the group of nonsurvivors, but the difference was not significant (1.97 ± 1.47 vs. 0.96 ± 0.76 units; P = 0.07). Mean lactate clearance from the first to the third day was 45.4 ± 28.3%, with no significant difference between survivors and nonsurvivors (P = 0.19). In our cohort of patients treated with ECMO due to severe ARDS, the application of a restrictive transfusion protocol did not result in an increased mortality. Safety and feasibility of the application of a restrictive transfusion protocol in patients on ECMO must further be evaluated in randomized controlled trials.

A 33-years-old male patient presented with cardiac arrhythmias, acute shock and multiple organ dysfunction after the surgical removal of a massive epidermoid posterior to the brainstem. The patient initially presented with paraesthesia along the right C6 dermatome due to a big tumour at the brain stem. Surgical removal was performed without adverse events and he was transferred to our intensive care unit (ICU) immediately after the operation. Though initially showing a stable postsurgical course he developed cardiac arrhythmias and a state of acute distributive shock with consecutive multi organ failure. Extensive diagnostic measures could not identify a specific cause for this rapid deterioration. However, under carefully monitored symptomatic therapy the patient improved quickly, was extubated 72 h after admission and discharged from the ICU 6 days later. The follow-up did not show any persisting neurological deficits and no evidence of a residual tumour in the MRI-study.

On 16 December 2006, most Eurotransplant countries changed waiting time oriented liver allocation policy to the urgency oriented Model for End-stage Liver Disease (MELD) system. There are limited data on the effects of this policy change within the Eurotransplant community.A total of 154 patients who had undergone deceased donor liver transplantation (LT) were retrospectively analyzed in three time periods: period A (1-year pre-MELD, n = 42) versus period B (1-year post-MELD, n = 52) versus period C (2 years after MELD implementation, n = 60).The median MELD score at the time of LT increased from 16.3 points in period A to 22.4 and 20.4 in periods B and C, respectively (p = 0.007). Waitlist mortality decreased from 18.4% in period A to 10.4% and 9.4% in periods B and C, respectively (p = 0.015). Three-month mortality did not change significantly (10% each for periods A, B and C). One-year survival was 84% for the MELD 6-19 group compared with 81% in the MELD 20-29 group and 74% in the MELD ≥30 group (p = 0.823). Analyzing MELD score and previously described prognostic scores [i.e. survival after liver transplantation (SALT) score and donor-MELD (D-MELD) score] with regard to 1-year survival, only a high risk SALT score was predictive (p = 0.038). In our center, 2 years after implementation of the MELD system, waitlist mortality decreased, while 90-day mortality did not change significantly.Up to now, only the SALT score proved to be of prognostic relevance post-transplant.

The acute respiratory distress syndrome (ARDS) is characterized by a maldistribution of pulmonary blood flow towards non-ventilated atelectatic lung areas being the main reason for intrapulmonary right-to-left shunt with the consequence of severe arterial hypoxemia. The application of inhaled nitric oxide (iNO) is a therapeutic option to selectively influence pulmonary blood flow in order to improve arterial oxygenation and to decrease pulmonary artery pressure without relevant systemic side effects. Although randomized controlled trials demonstrated no survival benefit in patient populations covering the entire severity range of acute lung injury, iNO represents a feasible rescue treatment for ARDS patients with severe refractory hypoxemia and is, therefore, an important option for ARDS therapy in specialized centers.

With most of the immunosuppressive protocols consisting of calcineurin inhibitors (CI), nephrotoxicity has become a major long-term complication often compromising outcome. In a single-center retrospective study, we reviewed 1173 liver transplantations to identify variables indicative for the occurrence of chronic renal dysfunction (CRD) (defined as ≥1 episode of serum creatinine increase ≥1.8 mg/dL ≥2 wk). Chronic renal dysfunction was found in 137 (11.7%) of all transplants [82 (7%) early (after 3–12 months), 55 (4.7%) late-onset (>12 months)]. Compared to 5-/10-yr survival rates in non-CRD transplants (84/74%) survival was significantly decreased in early (66/46%), but unchanged in late-onset CRD (98/86%). Rates of alcoholic cirrhosis and prior renal dysfunction were significantly increased in patients with CRD. In a multivariate logistic regression analysis, only cyclosporine A (CyA) as immunosuppression remained an independent risk factor. No correlations to age, gender, rejection/retransplantation or diabetes were found. Surprisingly, renal function (creatinine) showed no difference between patients on CI monotherapy (FK/CyA) compared to those who had mycophenolate mofetil (MMF) added. In liver transplantation, early onset CRD significantly compromises survival. CyA-based immunosuppression appears to have a stronger impact than FK. The fact that patients with long-term severe chronic renal dysfunction failed to improve under MMF rescue therapy emphasizes the importance of new diagnostic strategies to earlier identify at-risk patients.

The treatment of acute lung injury is one of the most challenging tasks in intensive care medicine. Conventional therapeutic options cover lung protective mechanical ventilation with low tidal volumes and adequate PEEP, restrictive fluid management, prone positioning, and early recruitment maneuvers. These options should be used in parallel and should be accompanied by a suitable anti-infective therapy. In cases of refractory hypoxemia, inhaled nitric oxide offers in most patients a successful rescue option. In specialized centers the application of ECMO remains as a final ultima ratio.

In major trauma patients, multiple organ failure (MOF) is considered a leading cause of death. Acute lung injury is deemed a "pacemaker" of MOF. The purpose of this study was to determine if incidence of organ failure and mortality in multiple trauma patients can be reduced by implementation of lung-protective strategies.All critically ill multiple trauma patients admitted to the ICU of a major trauma center in Berlin, Germany from January 1999 to December 2002 were analyzed retrospectively. Patients were ventilated pressure controlled with low tidal volumes and adequate PEEP.n=287 patients were included. The most frequent injuries were traumatic brain injury (TBI-68%), chest trauma (68%), and lung contusions (55%). Injury severity score (ISS) was 32+/-19 (mean+/-standard deviation), polytraumaschluessel (PTS) 34+/-19, and APACHE II 14+/-7. During their ICU-stay 16 patients died, 9 (56%) from TBI. Single-organ-failure occurred in n=69 patients (24%, mortality 5%), two-organ-failure in n=22 (8%, mortality 14%), and MOF in n=9 (3%, mortality 13%); one patient died from MOF 14 days after trauma. The number of days on mechanical ventilation increased depending on the number of organs failed (R=0.618, p0.001). Seven patients (2%) fulfilled ARDS criteria for longer than 24h despite optimized ventilatory settings, one died of irreversible shock. Patients with MOF had a significantly increased ICU-LOS (35+/-15 days) compared to patients without organ failure (11+/-11 days; p0.001).The low incidence of MOF in our series of trauma patients suggests that MOF may be prevented in some patients by implementation of lung-protective strategies. The improved outcome was associated with an increased ICU-LOS.

The aim of the present study was to characterize a murine model of acute respiratory distress syndrome (ARDS) abiding by the Berlin definition of human ARDS and guidelines for animal models of ARDS. To this end, C57BL/6NCrl mice were challenged with lipopolysaccharide (LPS; 15 mg/kg, i.p.) followed 18 h later by injection of oleic acid (OA; 0.12 mL/kg, i.v.). Controls received saline injection at both time points. Haemodynamics were monitored continuously. Arterial blood gas analyses were performed just before and every 30 min after OA challenge. Ninety minutes after OA challenge, the chest of mice was scanned using micro-computed tomography (CT). Cytokine concentrations were measured in plasma samples. Lungs were harvested 90 min after OA challenge for histology, immunohistochemistry, lung weight measurements and tissue cytokine detection. A histological lung injury score was determined. Eighteen hours after LPS challenge, mice exhibited a severe systemic inflammatory response syndrome. Oxygenation declined significantly after OA injections (Pa o2 /Fi o2 283 ± 73 and 256 ± 71 mmHg at 60 and 90 min, respectively; P0.001). Bilateral patchy infiltrates were present on the micro-CT scans. Histology revealed parenchymal damage with accumulation of polymorphonuclear neutrophils, intra-alveolar proteinacous debris and few hyaline membranes. The lung wet : dry ratio indicated damage to the alveolar capillary membrane. Cytokine patterns evidenced a severe local and systemic inflammatory state in plasma and lung tissue. In conclusion, the described two-hit model of ARDS shows a pathological picture of ARDS closely mimicking human ARDS according to the Berlin definition and may facilitate interpretation of prospective experimental results.

From mid-2010 to early 2013 there was a large single-center (Leipzig University Hospital, Germany) outbreak of Klebsiella pneumoniae carbapenemase (KPC) type 2 producing K. pneumoniae (KPC-2-KP) involving a total of 103 patients. The aim of this study was to compare KPC-positive liver transplant recipients (LTR) and KPC-negative controls to determine both the relative risk of infection following colonization with KPC-2-KP and the case fatality rate associated with KPC-2-KP.The study cohort of this retrospective observational study comprised nine patients who had undergone orthotopic liver transplantation (LTx) (median age of 52 years, range 28-73 years) with confirmed evidence of colonization with KPC-2-KP. The data from these nine LTR were matched to 18 LTR (1:2) in whom carbapenem-resistant pathogens were not present and compared for clinical outcomes.Of these nine cases, eight (89 %) progressed to infection due to KPC-2-KP, and five (56 %) were confirmed to have bloodstream infection with KPC-2-KP. Matched-pair analysis of KPC-positive LTR and KPC-negative controls revealed a substantially increased relative risk of 7.0 (95 % confidence interval 1.8-27.1) for fatal infection with KPC-2-producing K. pneumoniae after transplantation with a mortality rate of 78 % (vs. 11 %, p = 0.001).Colonization with KPC-2-KP in LTR leads to high infection rates and excess mortality. Therefore, frequent screening for carbapenem-resistant bacteria in patients on LTx waiting lists appears to be mandatory in an outbreak setting. Patients with evidence of persistent colonization with KPC-producing pathogens should be evaluated with extreme caution for LTx.

Background: In kidney transplantation, preservation has a significant influence on organ function. Since previous reports have indicated a benefit of combining histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW) solution, we evaluated the effects of initial flush with low viscosity HTK, followed by storage in UW. Material and Methods: Kidneys from inbred Lewis rats were procured using HTK or UW for initially perfusion and re-flushed after 30 min with either solution. In a third group, after perfusion with HTK, organs were re-flushed with UW. Organs were stored for 16–24 h (4°C). Study parameters were high-energy phosphates, histology, apoptosis, recipient survival and urine excretion of 15-F2t-isoprostanes (oxidative stress marker). Results:Prior to transplantation, tissue ATP/ADP concentrations were: HTK/UW>UW-only >HTK-only. In transplanted kidneys, histological damage was highest after preservation in HTK-only. Twenty-four hours after transplantation (24 h cold ischemia time – CIT), cleaved-PARP was most abundant using UW-only. 16 h of CIT resulted in higher urine concentrations of isoprostanes in the order HTK-only (368 ± 308) > UW-only (157 ± 105) > HTK/UW (67 ± 26), and was lower in HTK/UW after 24 h of CIT (146 ± 38) vs. UW-only (507 ± 33 pg/mg creatinine). Survival (24 h CIT) was significantly reduced, and percentage of initial non-functioning (INF) kidneys highest in HTK-only (2.6 ± 0.3 days, 100%), compared to UW-only (13 ± 4.4 days, 75%) and HTK/UW (18.5 ± 4.6 days, 33%). Conclusions: In long-term preservation, UW is superior over HTK. However, our results indicate that perfusion with HTK prior to storage in UW may improve the results of UW alone which is reflected by better survival, lower rate of INF, higher cellular energy conservation and a decrease of free radicals.

The venous access is essential for adequate delivery of RRT whereas the placement of a large bore catheter has its own risk. According to data of litigation against the NHS in England, cases with central venous (mis)‑cannulation belong to the group of claims with the highest mean cost per closed claim.

In coronavirus disease 2019 (COVID-19), hypertension and cardiovascular diseases are major risk factors for critical disease progression. However, the underlying causes and the effects of the main anti-hypertensive therapies-angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)-remain unclear. Combining clinical data (n = 144) and single-cell sequencing data of airway samples (n = 48) with in vitro experiments, we observed a distinct inflammatory predisposition of immune cells in patients with hypertension that correlated with critical COVID-19 progression. ACEI treatment was associated with dampened COVID-19-related hyperinflammation and with increased cell intrinsic antiviral responses, whereas ARB treatment related to enhanced epithelial-immune cell interactions. Macrophages and neutrophils of patients with hypertension, in particular under ARB treatment, exhibited higher expression of the pro-inflammatory cytokines CCL3 and CCL4 and the chemokine receptor CCR1. Although the limited size of our cohort does not allow us to establish clinical efficacy, our data suggest that the clinical benefits of ACEI treatment in patients with COVID-19 who have hypertension warrant further investigation.

Purpose [1134 C]DASB is currently the most frequently applied highly selective radiotracer for visualisation and quantification of central SERT. Its use, however, is hampered by the short half life of carbon-11, the moderate cortical test retest reliability, and the lack for quantifying endogenous serotonin. Labelling with fluorine-18 allows in principle for longer acquisition times for kinetic analysis in brain tissue and may provide higher sensitivity. The aim of our study was to firstly apply in human the new highly SERT-selective fluorine-18 labelled fluoromethyl analogue of (+)-McN5652 ((+)-[1840 F]FMe-McN5652) and to evaluate its potential for SERT quantification. Methods The PET data of five healthy volunteers (3 male, 2 female, age 39 ± 10 years) coregistered with individual MRI were semi-quantitatively assessed by volume-of-interest analysis using the software package PMOD. Rate constants and distribution volume ratios (DVR) were calculated using a 2-tissue compartment model and arterial input function measurement were corrected for metabolites/plasma data. Standardized uptake region-to-cerebellum ratios as measure of specific radiotracer accumulation were compared with those of a [1146 C]DASB-PET data set of healthy subjects (10 male, 11 female, 38 ± 8 years). Results The 2-tissue compartment model provided adequate fits to the data. Estimates of total distribution volume (VT) demonstrated good identifiability based on coefficient of variation (COV) for the volumes of interest (VOIs) in SERT-rich and also for cortical areas (COV VT < 10%). Compared with [11C]DASB-PET, there was a tendency to lower mean values in (+)-[1851 F]FMe-McN5652 PET, however, the standard deviation was also somewhat lower. Altogether, cerebral (+)-[1853 F]FMe-McN5652 uptake corresponds well with the known SERT distribution also in humans. Conclusion The results showed also that (+)-[1855 F]FMe-McN5652 is suitable for in vivo quantification of SERT with PET. Because of the long half-life of fluorine-18, a widespread application within a satellite concept seems feasible.