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Deep metabolomic, proteomic and immunologic phenotyping of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients have matched a wide diversity of clinical symptoms with potential biomarkers for coronavirus disease 2019 (COVID-19). Within here, several studies described the role of metabolites, lipoproteins and inflammation markers during infection and in recovered patients. In fact, after SARS-CoV-2 viral infection almost 20-30% of patients experience persistent symptoms even after 12 weeks of recovery which has been defined as long-term COVID-19 syndrome (LTCS). Emerging evidence revealed that a dysregulated immune system and persisting inflammation could be one of the key drivers of LTCS. However, how these small biomolecules such as metabolites, lipoprotein, cytokines and chemokines altogether govern pathophysiology is largely underexplored. Thus, a clear understanding how these parameters into an integrated fashion could predict the disease course may help to stratify LTCS patients from acute COVID-19 or recovered specimen and would help to elucidate a potential mechanistic role of these biomolecules during the disease course. Here, we report an integrated analysis of blood serum and plasma by in vitro diagnostics research NMR spectroscopy and flow cytometry-based cytokine quantification in a total of 125 individuals (healthy controls (HC; n=73), recovered (n=12), acute (n=7) and LTCS (n=33)). We identified that in LTCS patients lactate and pyruvate were significantly different from either healthy controls or acute COVID-19 patients. Further correlational analysis of cytokines and metabolites indicated that creatine, glutamine, and high-density lipoprotein (HDL) phospholipids were distributed differentially amongst patients or individuals. Of note, triglycerides and several lipoproteins (apolipoproteins Apo-A1 and A2) in LTCS patients demonstrate COVID-19-like alterations compared to HC. Interestingly, LTCS and acute COVID-19 samples were distinguished mostly by their creatinine, phenylalanine, succinate, 3-hydroxybutyrate (3-HB) and glucose concentrations, illustrating an imbalanced energy metabolism. Most of the cytokines and chemokines were present at low levels in LTCS patients compared with HC except IL-18 chemokine, which tended to be higher in LTCS patients and correlated positively with several amino acids (creatine, histidine, leucine, and valine), metabolites (lactate and 3-HB) and lipoproteins. The identification of these persisting plasma metabolites, lipoprotein and inflammation alterations will help to better stratify LTCS patients from other diseases and could help to predict ongoing severity of LTCS patients.Graphical abstractLayman summary & significance of the researchAlmost 20-30% of individuals infected with the SARS-CoV-2 virus regardless of hospitalization status experience long-term COVID-19 syndrome (LTCS). It is devasting for millions of individuals worldwide and hardly anything is known about why some people experience these symptoms even after 3 to 12 months after the acute phase. In this, we attempted to understand whether dysregulated metabolism and inflammation could be contributing factors to the ongoing symptoms in LTCS patients. Total blood triglycerides and the Cory cycle metabolites (lactate and pyruvate) were significantly higher, lipoproteins (Apo-A1 and A2) were drastically lower in LTCS patients compared to healthy controls. Correlation analysis revealed that either age or gender are positively correlated with several metabolites (citrate, glutamate, 3-hydroxybutyrate, glucose) and lipoproteins (Apo-A1, HDL Apo-A1, LDL triglycerides) in LTCS patients. Several cytokines and chemokines were also positively correlated with metabolites and lipoproteins thus, dysregulation in metabolism and inflammation could be a potential contributory factor for LTCS symptoms.

Extracorporeal circulation (ECC) is frequently used in intensive care patients with impaired lung or cardiac function. Despite being a life-saving therapeutic option, ECC is associated with increased risk for both bleeding and thrombosis. The management of bleeding and thromboembolic events in ECC patients is still challenging partly due to the lack of information on the pathophysiological changes in hemostasis and platelet function during the procedure. Using a combination of an ex vivo model for shear stress and a sensitive and easy-to-use laboratory method, we analyzed platelet responsiveness during ECC. After shear stress simulation in an ex vivo closed-loop ECC model, we found a significantly decreased response of α-granules after activation with adenosine diphosphate and thrombin receptor activating peptide (TRAP-6) and CD63 expression after activation with TRAP-6. Mepacrine uptake was also significantly reduced in the ex vivo shear stress model.In the same line, platelets from patients under ECC with venovenous systems and venoarterial systems showed impaired CD62P degranulation after stimulation with ADP and TRAP-6 compared with healthy control on day 1, 6, and 10 after implantation of ECC. However, no correlation between platelet degranulation and the occurrence of bleeding or thromboembolic events was observed.The used whole blood flow cytometry with immediate fixation after drawing introduces a sensitive and easy-to-use method to determine platelet activation status and our data confirm that increased shear stress conditions under ECC can cause impaired degranulation of platelet.

Background: The COVID-19 pandemic reached Germany in spring 2020. No proven treatment for SARS-CoV-2 was available at that time, especially for severe COVID-19-induced ARDS. We determined whether the infusion of mesenchymal stromal cells (MSCs) would help to improve pulmonary function and overall outcome in patients with severe COVID-19 ARDS. We offered MSC infusion as an extended indication to all critically ill COVID-19 patients with a Horovitz index Result: Four out of 5 MSC-treated patients compared to 50% of control patients (9 out of 18) received ECMO support (80%). The MSC group showed a higher Murray score on admission than control patients, reflecting more severe pulmonary compromise (3.5 ± 0.2 versus 2.8 ± 0.3). MSC infusion was safe and well tolerated. The MSC group had a significantly higher Horovitz score on discharge than the control group. Compared to controls, patients with MSC treatment showed a significantly lower Murray score upon discharge than controls. In the MSC group, 4 out of 5 patients (80%) survived to discharge and exhibited good pulmonary function, whereas only 8 out of 18 patients (45%) in the control group survived to discharge. Conclusion: MSC infusion is a safe treatment for COVID-19 ARDS that improves pulmonary function and overall outcome in this patient population.

Background Accumulating evidence indicates toward an association between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and procoagulatory state in blood. Thromboelastographic investigations are useful point-of-care devices to assess coagulation and fibrinolysis.Objectives We investigated the hypothesis that the procoagulatory state in COVID-19 patients is associated with impaired fibrinolysis system.Methods Altogether, 29 COVID-19 patients admitted to normal wards or to the intensive care unit (ICU) were included in this descriptive study. Whole blood samples were investigated by thromboelastography to assess coagulation and fibrinolysis. Additionally, standard routine coagulation testing and immunoassays for factors of fibrinolysis as plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), plasminogen activity and α2-antiplasmin (A2AP) were performed.Results A significantly increased lysis resistance and a significantly longer time of lysis after adding tissue plasminogen activator were observed in blood samples from ICU COVID-19 patients compared with healthy controls (maximal lysis: 3.25 ± 0.56 vs. 6.20 ± 0.89%, p = 0.0127; lysis time: 365.7 ± 44.6 vs. 193.2 ± 16.3 seconds, p = 0.0014). PAI-1 activity was significantly higher in plasma samples of ICU COVID-19 patients (PAI-1: 4.92 ± 0.91 vs. 1.28 ± 0.33 U/mL, p = 0.001). A positive correlation between the activity of PAI-1 and lysis time of the formed clot (r = 0.70, p = 0.0006) was observed.Conclusion Our data suggest that severe SARS-CoV-2 infection is associated with impaired fibrinolytic activity in blood, where fibrinolytic inhibitors are elevated leading to an increased resistance to clot lysis. Thromboelastography could offer a tool to investigate the contribution of the fibrinolytic status to the procoagulatory condition in COVID-19.

The pathophysiology of COVID-19 associated thrombosis seems to be multifactorial. We hypothesized that COVID-19 is accompanied by procoagulant platelets and platelet apoptosis with subsequent alteration of the coagulation system. We investigated depolarization of mitochondrial inner transmembrane potential (ΔΨm), cytosolic calcium (Ca2+) concentration, and phosphatidylserine (PS) externalization by flow cytometry. Platelets from intensive care unit (ICU) COVID-19 patients (n=21) showed higher ΔΨm depolarization, cytosolic Ca2+ concentration and PS externalization, compared to healthy controls (n=18) and COVID-19 non-ICU patients (n=4). Moreover significant higher cytosolic Ca2+ concentration and PS was observed compared to septic ICU control group (ICU control). In ICU control group (n=5; ICU non-COVID-19) cytosolic Ca2+ concentration and PS externalization was comparable to healthy control, with an increase in ΔΨm depolarization. Sera from ICU COVID-19 patients induced significant increase in apoptosis markers (ΔΨm depolarization, cytosolic Ca2+ concentration and PS externalization) compared to healthy volunteer and septic ICU control. Interestingly, immunoglobulin G (IgG) fractions from COVID-19 patients induced an Fc gamma receptor IIA dependent platelet apoptosis (ΔΨm depolarization, cytosolic Ca2+ concentration and PS externalization). Enhanced PS externalization in platelets from ICU COVID-19 patients was associated with increased sequential organ failure assessment (SOFA) score (r=0.5635) and D-Dimer (r=0.4473). Most importantly, patients with thrombosis had significantly higher PS externalization compared to those without. The strong correlations between procoagulant platelet and apoptosis markers and increased D-Dimer levels as well as the incidence of thrombosis may indicate that antibody-mediated platelet apoptosis potentially contributes to sustained increased thromboembolic risk in ICU COVID-19 patients.

Blood flow through left ventricular assist devices (LVAD) may induce activation and dysfunction of platelets. Dysfunctional platelets cause coagulation disturbances and form platelet-neutrophil conjugates (PNC), which contribute to inflammatory tissue damage. This prospective observational cohort study investigated patients, who underwent implantation of a LVAD (either HeartMate II (HM II) (n = 7) or HeartMate 3 (HM 3) (n = 6)) and as control patients undergoing coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR) (n = 10). We performed platelet and leukocyte flow cytometry, analysis of platelet activation markers, and platelet aggregometry. Platelet CD42b expression was reduced at baseline and perioperatively in HM II/3 compared to CABG/AVR patients. After surgery the platelet activation marker β-thromboglobulin and platelet microparticles increased in all groups while platelet aggregation decreased. Platelet aggregation was more significantly impaired in LVAD compared to CABG/AVR patients. PNC were higher in HM II compared to HM 3 patients. We conclude that LVAD implantation is associated with platelet dysfunction and proinflammatory platelet-leukocyte binding. These changes are less pronounced in patients treated with the newer generation LVAD HM 3. Future research should identify device-specific LVAD features, which are associated with the least amount of platelet activation to further improve LVAD therapy.

The pandemia of coronavirus disease 2019 (COVID-19) has caused more than 355,000 confirmed deaths worldwide. However, publications on postmortem findings are scarce. We present the pulmonary findings in four cases of fatal COVID-19 with a spectrum of lung pathology reflecting disease course and duration, invasive therapies, and laboratory features. Early disease is characterized by neutrophilic, exudative capillaritis with microthrombosis and high levels of IL-1beta and IL-6. Later stages are associated with diffuse alveolar damage and ongoing intravascular thrombosis in small to medium-sized pulmonary vessels, occasionally with areas of infarction equivalents, accompanied by laboratory features of disseminated intravascular coagulation. In late stages, organizing pneumonia with extensive intra-alveolar proliferation of fibroblasts and marked metaplasia of alveolar epithelium can be observed. Viral RNA is encountered in the lung, with virus particles in endothelial cells and pneumocytes. In many patients, multi-organ failure with severe liver damage sets in finally, possibly as consequence of an early-onset pro-inflammatory cytokine storm and/or thrombotic microangiopathy. Electronic supplementary material The online version of this article (10.1007/s00428-020-02881-x) contains supplementary material, which is available to authorized users.

Objectives Extracorporeal membrane oxygenation is used to stabilize severe cardiocirculatory and/or respiratory failure. However, extracorporeal membrane oxygenation is associated with a coagulopathy characterized by thromboembolic and hemorrhagic complications. This study aimed to characterize the pathomechanism of the extracorporeal membrane oxygenation-associated coagulopathy and identify options to optimize its monitoring and therapy. Design Prospective observational clinical trial. Setting ICU of a university hospital. Patients Patients treated with venovenous extracorporeal membrane oxygenation (n = 10) due to acute respiratory distress syndrome and patients treated with venoarterial extracorporeal membrane oxygenation (n = 8) due to cardiocirculatory failure. One patient per group (venovenous extracorporeal membrane oxygenation or venoarterial extracorporeal membrane oxygenation) had surgery before extracorporeal membrane oxygenation. Interventions Blood was sampled before, and 1, 24, and 48 hours after extracorporeal membrane oxygenation implantation. Point-of-care tests (thrombelastometry/platelet aggregometry), conventional coagulation tests, whole blood counts, and platelet flow cytometry were performed. Measurements and main results Even before extracorporeal membrane oxygenation, plasmatic coagulation and platelet aggregation were impaired due to systemic inflammation, liver failure, anticoagulants (heparins, phenprocoumon, apixaban), and antiplatelet medication. During extracorporeal membrane oxygenation, hemodilution and contact of blood components with artificial surfaces and shear stress inside extracorporeal membrane oxygenation additionally contributed to coagulation and platelet defects. Fibrinogen levels, fibrin polymerization, platelet activation, and microparticle release were increased in venovenous extracorporeal membrane oxygenation compared to venoarterial extracorporeal membrane oxygenation patients. Point-of-care results were available faster than conventional analyses. Bleeding requiring blood product application occurred in three of 10 venovenous extracorporeal membrane oxygenation patients and in four of eight venoarterial extracorporeal membrane oxygenation patients. No thrombotic events were observed. In-hospital mortality was 30% for venovenous extracorporeal membrane oxygenation and 37.5% for venoarterial extracorporeal membrane oxygenation patients. Conclusions The extracorporeal membrane oxygenation-associated coagulopathy is a multifactorial and quickly developing syndrome. It is characterized by individual changes of coagulation parameters and platelets and is aggravated by anticoagulants. The underlying factors of the extracorporeal membrane oxygenation-associated coagulopathy differ between venovenous extracorporeal membrane oxygenation and venoarterial extracorporeal membrane oxygenation patients and are best diagnosed by a combination of point-of-care and conventional coagulation and platelet analyses. Therapy protocols for treating extracorporeal membrane oxygenation-associated coagulopathy should be further validated in large-scale prospective clinical investigations.

Zusammenfassung Zielsetzung In Krankenhausern ist das Fallmanagement (FM) auf den Krankenhausstationen wesentlicher Erfolgsfaktor fur die Sicherstellung einer hohen Qualitat und Wirtschaftlichkeit der zu erbringenden Gesundheitsdienstleistungen. Die vorliegende Studie untersucht mit welchen Potentialen und Moglichkeiten das FM am Point of Care (POC) optimiert werden kann. Methode Mittels eines strukturierten Interviewinventars wurde eine Soll-Analyse von typischen Mikroprozessen des Fallmanagements auf Krankenhausstationen durchgefuhrt. Dazu wurde eine Felduntersuchung an 24 deutschen bettenfuhrenden Krankenhausabteilungen der Maximalversorgung in Form von strukturierten Interviews mit homogenen Fokusgruppen durchgefuhrt, diese mit Hilfe eines erweiterten Balanced-Scorecard-Ansatzes ausgewertet und die Ergebnisse anschliesend mit den Fokusgruppen reflektiert. Ergebnisse Vor allem die Prozessqualitat und -sicherheit des Fallmanagements sowie die Sicherstellung der leistungsrelevanten Dokumentationen am POC bietet deutliche Optimierungspotentiale. Ein wesentlicher Optimierungsansatz wird dabei in der Reduktion der Fragmentierung der Teilprozesse des klinischen Fallmanagements, verbunden mit der Homogenisierung dieses Tatigkeitsspektrums in einer neuen und interdisziplinar agierenden Berufsgruppe, den klinischen Fallmanagern (KFM), gesehen. Schlussfolgerung Die Homogenisierung der Aktivitaten des Fallmanagements auf Krankenhausstationen durch klinische Fallmanager (KFM) bietet Potentiale und Moglichkeiten den arztlichen und pflegerischen Dienst von diesen Tatigkeiten zu entlasten und gleichzeitig die Qualitat und Wirtschaftlichkeit der Gesundheitsdienstleistungen fur Patienten, Mitarbeiter und sektorenubergreifenden Mitbehandlern zu verbessern.

Sağır, Özlem (Balikesir Author), Introduction More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. Methods and analysis EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. Ethics and dissemination EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369. ©

Thromboembolic events are frequently reported in patients infected with the SARS-CoV-2 virus. However, the exact mechanisms of thromboembolic events remain elusive. In this work, we show that immunoglobulin G (IgG) subclass in patients with COVID-19 trigger the formation of procoagulant PLTs in a Fc-gamma-RIIA (FcγRIIA) dependent pathway leading to increased thrombus formation in vitro. Most importantly, these events were significantly inhibited via FcγRIIA blockade as well as by the elevation of PLTs’ intracellular cyclic-adenosine-monophosphate (cAMP) levels by the clinical used agent Iloprost. The novel findings of FcγRIIA mediated prothrombotic conditions in terms of procoagulant PLTs leading to higher thrombus formation as well as the successful inhibition of these events via Iloprost could be promising for the future treatment of the complex coagulopathy observed in COVID-19 disease.Key points-Fc-gamma-receptor IIA mediated PS externalization on the PLT surface triggers increased thrombus formation-Inductors of cAMP inhibit antibody-mediated thrombus formation and may have potential therapeutic advantage in COVID-19

Hemodynamic conditions with reduced systemic vascular resistance commonly are observed in patients undergoing cardiac surgery and may range from moderate reductions in vascular tone, as a side effect of general anesthetics, to a profound vasodilatory syndrome, often referred to as vasoplegic shock. Therapy with vasopressors is an important pillar in the treatment of these conditions. There is limited guidance on the appropriate choice of vasopressors to restore and optimize systemic vascular tone in patients undergoing cardiac surgery. A panel of experts in the field convened to develop statements and evidence-based recommendations on clinically relevant questions on the use of vasopressors in cardiac surgical patients, using a critical appraisal of the literature following the GRADE system and a modified Delphi process. The authors unanimously and strongly recommend the use of norepinephrine and/or vasopressin for restoration and maintenance of systemic perfusion pressure in cardiac surgical patients; despite that, the authors cannot recommend either of these drugs with respect to the risk of ischemic complications. The authors unanimously and strongly recommend against using dopamine for treating post-cardiac surgery vasoplegic shock and against using methylene blue for purposes other than a rescue therapy. The authors unanimously and weakly recommend that clinicians consider early addition of a second vasopressor (norepinephrine or vasopressin) if adequate vascular tone cannot be restored by a monotherapy with either norepinephrine or vasopressin and to consider using vasopressin as a first-line vasopressor or to add vasopressin to norepinephrine in cardiac surgical patients with pulmonary hypertension or right-sided heart dysfunction.

Background Heparin-induced thrombocytopenia (HIT) is a serious drug induced reaction that may be associated with life threatening complications. Platelet-activating antibodies directed against platelet factor 4 (PF4)/heparin complexes cause the disease. The diagnosis of HIT is challenging, as thrombocytopenia is a frequent finding in intensive care (ICU) patient population, especially during extracorporeal membrane oxygenation. Objective To investigate the performance of a diagnostic algorithm for HIT in ICU patients. Methods ICU patients who developed thrombocytopenia or thrombosis under heparin treatment were included in this study. The pretest probability for HIT was estimated using the 4Ts-score and patient's sera were tested using two rapid immunoassays (RA) LFI-HIT and PaGIA (from Milenia Biotec and DiaMed), and within 72 h using the IgG enzyme immunoassay (EIA) from Hyphen and the heparin induced platelet activation assay (HIPA). Results 392 consecutive ICU patients with suspected HIT were enrolled in this study, of whom 83/392 (21.2%) patients had extracorporeal circulation. Sera from 120/392 (30.6%) and 98/392 (25.0%) patients revealed positive results in RA and IgG EIA, respectively. The HIPA test revealed heparin-dependent platelet activation in a total of 15/392 (3.8%) ICU patients (3 medical and 12 surgical patients). In addition, sera from 7 patients revealed indeterminate HIPA results, of whom 2 patients had a clinical course compatible with HIT. Conclusions Data from our study confirm the high frequency of IgG PF4/heparin antibodies in ICU patients under unfractionated heparin and shows that the combination of 4Ts-score and RA does not reduce the laboratory overinvestigation for HIT in these patients.

In hospitals, case management (CM) on hospital wards is essential for maintaining a high level of quality and efficiency of care. The present study examined how CM at the Point of Care (POC) can be optimized and which potentials exist.The potentials for optimization of typical case management processes performed on hospital wards were analyzed using a structured interview guide. For this purpose, a field study was performed in 24 German hospital departments of tertiary care. Structured interviews were conducted with homogeneous focus groups. The results were evaluated using an extended Balanced Score Card approach and discussed afterwards with the focus groups.Above all, the process quality and safety of case management as well as ensuring the relevant documentation at the POC appears to offer significant potential for optimization. An essential approach to eventually realize the potential for optimization is the reduction of fragmentation of the micro-processes associated with the case management duties on inpatient wards. This homogenization of these activities ideally requires a new and interdisciplinary acting profession, the clinical case managers.The homogenization of the case management activities on hospital wards by clinical case managers has the potential and possibilities to relieve both medical and nursing staff of these activities, while improving the quality and efficiency of care for patients, staff and cross-sectoral healthcare provider at the same time.

Introduction Platelets are main effector cells in haemostasis and also promote inflammation. Platelet-leukocyte complexes are key mediators in a variety of thromboinflammatory disorders and consecutive organ failure. Cell-specific epitopes and activation markers on platelets and leukocytes can be measured using flow cytometry. However, until recently a major restriction has been a paucity in antibody combinations and lack of detection strategies. We aimed to develop a six-colour flow cytometry method which depicts multiple aspects of platelet and leukocyte interactions in human whole blood. Materials and Methods Platelets, including microparticles and aggregates, were detected in flow cytometry using a platelet-specific anti-CD41-FITC antibody and size-defined regions. The morphology of platelet-leukocyte complexes (including granulocyte and monocyte content) were depicted using anti-CD45-PerCP, anti-CD66b-PE-Cy7, and anti-CD14-APC antibodies in a single sample. Expression of platelet and leukocyte activation markers P-selectin and CD11b were detected using anti-CD62P-PE and anti-CD11b-BV421 antibodies, respectively. Results The sensitivity of this assay to detect the effects of various agonists (TRAP-6, ADP, collagen, epinephrine, TNF-α and LPS) is demonstrated. Furthermore, the assay is shown to detect platelet and leukocyte activation induced by extracorporeal circulation in vitro. The suitability of this assay for bedside analysis is demonstrated exemplarily in a patient treated with mechanical circulatory life support. Conclusions Using the concurrent assessment of multiple parameters, this method gives detailed insights into the complexity and dynamics of platelet-leukocyte interactions. This assay carries the potential to increase our understanding of the mechanisms and pathophysiology of platelet-leukocyte interaction in the research laboratory and clinical setting.

Appropriate pain therapy prior to diagnosis in patients with acute abdominal pain remains controversial. Several recent studies have demonstrated that pain therapy does not negatively influence either the diagnosis or subsequent treatment of these patients; however, current practice patterns continue to favour withholding pain medication prior to diagnosis and surgical treatment decision. A systematic review of PubMed, Web-of-Science and The-Cochrane-Library from 1929 to 2011 was carried out using the key words of 'acute', 'abdomen', 'pain', 'emergency' as well as different pain drugs in use, revealed 84 papers. The results of the literature review were incorporated into six sections to describe management of acute abdominal pain: (1) Physiology of Pain; (2) Common Aetiologies of Abdominal Pain; (3) Pre-diagnostic Analgesia; (4) Pain Therapy for Acute Abdominal Pain; (5) Analgesia for Acute Abdominal Pain in Special Patient Populations; and (6) Ethical and Medico-legal Considerations in Current Analgesia Practices. A comprehensive algorithm for analgesia for acute abdominal pain in the general adult population was developed. A review of the literature of common aetiologies and management of acute abdominal pain in the general adult population and special patient populations seen in the emergency room revealed that intravenous administration of paracetamol, dipyrone or piritramide are currently the analgesics of choice in this clinical setting. Combinations of non-opioids and opioids should be administered in patients with moderate, severe or extreme pain, adjusting the treatment on the basis of repeated pain assessment, which improves overall pain management.

Guidelines recommend administering antibiotics within 1 h of sepsis recognition but this recommendation remains untested by randomized trials. This trial was set up to investigate whether survival is improved by reducing the time before initiation of antimicrobial therapy by means of a multifaceted intervention in compliance with guideline recommendations. The MEDUSA study, a prospective multicenter cluster-randomized trial, was conducted from July 2011 to July 2013 in 40 German hospitals. Hospitals were randomly allocated to receive conventional continuous medical education (CME) measures (control group) or multifaceted interventions including local quality improvement teams, educational outreach, audit, feedback, and reminders. We included 4183 patients with severe sepsis or septic shock in an intention-to-treat analysis comparing the multifaceted intervention (n = 2596) with conventional CME (n = 1587). The primary outcome was 28-day mortality. The 28-day mortality was 35.1% (883 of 2596 patients) in the intervention group and 26.7% (403 of 1587 patients; p = 0.01) in the control group. The intervention was not a risk factor for mortality, since this difference was present from the beginning of the study and remained unaffected by the intervention. Median time to antimicrobial therapy was 1.5 h (interquartile range 0.1–4.9 h) in the intervention group and 2.0 h (0.4–5.9 h; p = 0.41) in the control group. The risk of death increased by 2% per hour delay of antimicrobial therapy and 1% per hour delay of source control, independent of group assignment. Delay in antimicrobial therapy and source control was associated with increased mortality but the multifaceted approach was unable to change time to antimicrobial therapy in this setting and did not affect survival.

Die praoperative Schmerztherapie bei akuten Bauchschmerzen vor erfolgter Diagnostik ist ein haufiger Diskussionspunkt. Inzwischen konnte nachgewiesen werden, dass sie weder die Diagnosestellung noch die resultierende Therapie negativ beeinflusst. Unter Berucksichtigung der jeweiligen Kontraindikationen sind aktuell Paracetamol, Metamizol und Piritramid – jeweils intravenos verabreicht – die Analgetika der Wahl. Bei mittelstarken und starken Schmerzen sollen Nichtopioide und Opioide kombiniert angewendet werden. Therapieanpassungen aufgrund repetitiver Schmerzmessungen verbessern die Analgesie.

Current guidelines and most trials do not consider elevated lactate (Lac) serum concentrations when grading sepsis severity. We therefore assessed the association of different types of circulatory dysfunction regarding presence of hyperlactatemia and need for vasopressor support with clinical presentation and outcome of sepsis.In a secondary analysis of a prospective observational multicenter cohort study, 988 patients with severe sepsis were investigated regarding vasopressor support, Lac levels, and outcome.Twenty-eight-day mortality regarding shock or hyperlactatemia was as follows: hyperlactatemia more than 2.5 mmol/L and septic shock (tissue dysoxic shock): 451 patients with a mortality of 44.8%; hyperlactatemia without vasopressor need (cryptic shock): 72 patients, mortality 35.3%; no hyperlactatemia with vasopressor need (vasoplegic shock): 331 patients, mortality 27.7%; and absence of hyperlactemia or overt shock (severe sepsis): 134 patients, mortality 14.2% (P.001). These groups showed differences in source and origin of infection. The influence of hyperlactatemia on 28-day mortality (P.001) (odds ratio 3.0, 95% confidence interval 2.1-4.1 for Lac4 mmol/L) was independent of vasopressor support (P.001) (odds ratio 2.0, 95% confidence interval 1.3-3.0 for norepinephrine0.1 μg/kg per minute) in logistic regression.Hyperlactatemia increases risk of death independent of vasopressor need resulting in different phenotypes within the classic categories of severe sepsis and septic shock.

To determine whether pro-inflammatory cytokines modulate intercellular adhesion molecule-1 (ICAM-1; CD54) expression on cultured primary human corneal epithelial cells (HCEs), confluent HCEs were treated with various concentrations of interferon-gamma(IFN-gamma), interleukin-1alpha(IL-1alpha), IL-1beta, IL-4, tumor necrosis factor-alpha (TNF-alpha), or combinations over time. ICAM-1 expression was measured by flow cytometry and/or a cell-based ELISA using a monoclonal mouse anti-human CD54 antibody. The apparent MW of ICAM-1 protein was determined by immunoprecipitation of biotinylated HCEs. RT-PCR was used to detect ICAM-1 RNA. The mature cell surface form of HCE ICAM-1 was approximately 110 kDa as determined by immunoprecipitation. IFN-gammaand TNF-alpha induced both dose- and time-dependent increases in ICAM-1 expression. An approximately 20-fold increase in ICAM-1 was seen at 50-100 U IFN-gamma ml-1. ICAM-1 specific mRNA accumulated approximately 4.5-fold after IFN-gammatreatment. TNF-alpha(100 U ml-1) induced a consistent approximately 6.0-fold increase in ICAM-1 expression. When IFN-gammaand TNF-alpha were mixed, at sub-optimal concentrations of each, a synergistic effect on ICAM-1 expression was not detected. Neither IL-4, IL-1alpha nor IL-1beta affected ICAM-1 expression in a consistent fashion. In summary, ICAM-1 was modulated on primary human corneal epithelial cells by the cytokines IFN-gamma and TNF-alpha in a dose- and time-dependent fashion. Cytokine modulation of corneal epithelial cell ICAM-1 during inflammation may contribute to corneal epithelial cell injury by aiding the attachment of inflammatory cells such as eosinophils which express the receptor for ICAM-1, the beta2 integrins (CD11a,b,c/CD18).