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Background: Excess cardiovascular (CV) morbidity and mortality has been observed in patients with COVID-19. Both interleukin-32 (IL-32) and interleukin-34 (IL-34) have been hypothesized to contribute to CV involvement in COVID-19. Methods: This prospective, observational study of patients with laboratory-confirmed COVID-19 infection was conducted from 6 June to 22 December 2020 in a tertiary care hospital in Vienna, Austria. IL-32 and IL-34 levels on admission were collected and tested for their association with CV disease and short-term mortality in patients with COVID-19. CV disease was defined by the presence of coronary artery disease, heart failure, stroke or atrial fibrillation and patients were stratified by CV disease burden. Results: A total of 245 eligible patients with COVID-19 were included, of whom 37 (15.1%) reached the primary endpoint of 28-day mortality. Of the total sample, 161 had no CV disease (65.7%), 69 had one or two CV diseases (28.2%) and 15 patients had ≥three CV diseases (6.1%). Median levels of IL-32 and IL-34 at admission were comparable across the three groups of CV disease burden. IL-32 and IL-34 failed to predict mortality upon both univariable and multivariable Cox regression analysis. The two CV disease groups, however, had a significantly higher risk of mortality within 28 days (one or two CV diseases: crude HR 4.085 (95% CI, 1.913–8.725), p < 0.001 and ≥three CV diseases: crude HR 13.173 (95% CI, 5.425–31.985), p < 0.001). This association persisted for those with ≥three CV diseases after adjustment for age, gender and CV risk factors (adjusted HR 3.942 (95% CI, 1.288–12.068), p = 0.016). Conclusion: In our study population of hospitalized patients with COVID-19, IL-32 and IL-34 did not show any associations with CV disease or 28-day mortality in the context of COVID-19. Patients with multiple CV diseases, however, had a significantly increased risk of short-term mortality.

Background COVID-19 has been associated with a high prevalence of myocardial injury and increased cardiovascular morbidity. Copeptin, a marker of vasopressin release, has been previously established as a risk marker in both infectious and cardiovascular disease. Methods This prospective, observational study of patients with laboratory-confirmed COVID-19 infection was conducted from June 6th to November 26th, 2020 in a tertiary care hospital. Copeptin and high-sensitive cardiac troponin I (hs-cTnI) levels on admission were collected and tested for their association with the primary composite endpoint of ICU admission or 28-day mortality. Results A total of 213 eligible patients with COVID-19 were included of whom 55 (25.8%) reached the primary endpoint. Median levels of copeptin and hs-cTnI at admission were significantly higher in patients with an adverse outcome (Copeptin 29.6 pmol/L, [IQR, 16.2–77.8] vs 17.2 pmol/L [IQR, 7.4–41.0] and hs-cTnI 22.8 ng/L [IQR, 11.5–97.5] vs 10.2 ng/L [5.5–23.1], P

An accurate point-of-care test for detecting effective anticoagulation by direct oral anticoagulants (DOACs) in emergencies is an unmet need. We investigated the accuracy of a urinary qualitative strip test (DOAC Dipstick) to detect relevant DOAC exposure in patients who presented to an emergency department. In this prospective single-center cohort-type cross-sectional study, adults on DOAC treatment were enrolled. We assessed clinical sensitivity and specificity of DOAC Dipstick factor Xa and thrombin inhibitor pads to detect DOAC plasma levels ≥30 ng/mL using urine samples as the testing matrix. Liquid chromatography coupled with tandem-mass spectrometry was used as the reference standard method for plasma and urine measurement of DOAC concentrations. Of 293 patients enrolled, 265 patients were included in the analysis, of whom 92 were treated with rivaroxaban, 65 with apixaban, 77 with edoxaban, and 31 with dabigatran. The clinical sensitivity and specificity of the dipstick on urine samples to detect ≥30 ng/mL dabigatran plasma levels were 100% (95% confidence interval [CI]: 87–100%) and 98% (95% CI: 95–99%), respectively. The sensitivity and specificity of the dipstick to detect ≥30 ng/mL factor Xa inhibitor plasma levels were 97% (95% CI: 94–99%) and 69% (95% CI: 56–79%), respectively. The DOAC Dipstick sensitively identified effective thrombin and factor Xa inhibition in a real-world cohort of patients presenting at an emergency department. Therefore, the dipstick might provide a valuable test to detect relevant DOAC exposure in emergencies, although further studies will be needed to confirm these findings.

Background Dyspnea is a common and often debilitating symptom with a complex diagnostic work-up. Purpose To evaluate the benefits, harms, and diagnostic test accuracy of point-of-care ultrasonography (POCUS) in patients with acute dyspnea. (PROSPERO: CRD42019126419). Data sources Searches of multiple electronic databases without language limitations (January 2004 to August 2020) and reference lists of pertinent articles and reviews. Study selection Five randomized controlled trials (RCTs) and 44 prospective cohort-type studies in patients with acute dyspnea evaluated POCUS as a diagnostic tool to determine the underlying cause of dyspnea. Two investigators independently screened the literature for inclusion. Data extraction Data abstraction by a single investigator was confirmed by a second investigator; 2 investigators independently rated risk of bias and determined certainty of evidence. Data synthesis Point-of-care ultrasonography, when added to a standard diagnostic pathway, led to statistically significantly more correct diagnoses in patients with dyspnea than the standard diagnostic pathway alone. In-hospital mortality and length of hospital stay did not differ significantly between patients who did or did not receive POCUS in addition to standard diagnostic tests. Finally, POCUS consistently improved the sensitivities of standard diagnostic pathways to detect congestive heart failure, pneumonia, pulmonary embolism, pleural effusion, or pneumothorax; specificities increased in most but not all studies. Limitations Most studies assessed diagnostic test accuracy, which has limited utility for clinical decision making. Studies rarely reported on the proportion of indeterminate sonography results, and no evidence is available on adverse health outcomes of false-positive or false-negative POCUS results. Conclusion Point-of-care ultrasonography can improve the correctness of diagnosis in patients with acute dyspnea. Primary funding source American College of Physicians.

BACKGROUND The optimal management of patients presenting to the Emergency Department with hemodynamically stable symptomatic atrial fibrillation remains unclear. We aimed to develop and validate an easy-to-use score to predict the individual probability of spontaneous conversion to sinus rhythm in these patients METHODS: This retrospective cohort study analyzed 2426 cases of first-detected or recurrent hemodynamically stable non-permanent symptomatic atrial fibrillation documented between January 2011 and January 2019 in an Austrian academic Emergency Department atrial fibrillation registry. Multivariable analysis was used to develop and validate a prediction score for spontaneous conversion to sinus rhythm during Emergency Department visit. Clinical usefulness of the score was assessed using decision curve analysis RESULTS: 1420 cases were included in the derivation cohort (68years, 57-76; 43% female), 1006 cases were included in the validation cohort (69years, 58-76; 47% female). Six variables independently predicted spontaneous conversion. These included: duration of atrial fibrillation symptoms ( 125bpm), potassium replacement at K+ level ≤3.9mmol/l, NT-proBNP (

The present document describes the possible applications of contrast-enhanced ultrasound (CEUS) in emergency examinations. Guidelines on contrast medium ultrasound in acute and emergency care and intensive care medicine have not yet been published. Evidence-based CEUS guidelines were first provided by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) and the World Federation for Ultrasound in Medicine and Biology (WFUMB). The presented recommendations describe the possible applications and protocols of CEUS in acute care.Das hier vorgestellte Dokument beschreibt die Anwendungsmöglichkeiten des Kontrastmittelultraschalls („contrast enhanced ultrasound“, CEUS) bei notfallmäßig indizierten Untersuchungen. Leitlinien zur Kontrastmittelsonographie in der klinischen Akut- und Notfallmedizin sowie Intensivmedizin wurden bisher nicht veröffentlicht. Auf die evidenzbasierten Empfehlungen und Leitlinien der European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) und World Federation for Ultrasound in Medicine and Biology (WFUMB) wird verwiesen. Die hier vorgestellten Empfehlungen beschreiben die Anwendungsmöglichkeiten und Protokolle von CEUS in der Akutmedizin.

Meditation as a form of body–mind interaction for primary and secondary prevention in cardiovascular disease has been discussed critically in the past. However, data that aimed to link this intervention to a reduction of various aspects of cardiovascular disease, rendering it a potential part of a cost-effective treatment approach in patients at risk, remain scarce and inconclusive. This article aims to provide an overview of currently available evidence in the literature and the potential impact of meditation on cardiovascular health. However, the data highlighted in this article cannot render with certainty directly reproducible effects of meditation on patients’ cardiovascular disease profiles. Meditation may be suggested only as an additional link in the chain of primary and secondary prevention until future research provides sufficient data on this topic.

Hypoxic liver injury (HLI) is a frequent and life-threatening complication in critically ill patients that occurs in up to ten percent of critically ill patients. However, there is a lack of data on HLI following cardiac arrest and its clinical implications on outcome. Aim of this study was to investigate incidence, outcome and functional outcome of patients with HLI after in-hospital cardiac arrest (IHCA) and out-of-hospital cardiac arrest (OHCA).We conducted an analysis of a cardiac arrest registry data over a 7-year period. All patients with non-traumatic OHCA and IHCA with return of spontaneous circulation (ROSC) treated at the emergency department of a tertiary care hospital were included in the study. HLI was defined according to established criteria. Predictors of HLI, occurrence, clinical and neurological outcome were assessed using multivariable regression.Out of 1068 patients after IHCA and OHCA with ROSC, 219 (21%) patients developed HLI. Rate of HLI did not differ significantly in IHCA and OHCA patients. Multivariate regression analysis identified time-to-ROSC [OR 1.18, 95% CI (1.01-1.38); p 0.05], presence of cardiac failure [OR 2.57, 95% CI (1.65-4.01); p 0.001] and Charlson comorbidity index [OR 0.83, 95% CI (0.72-0.95); p 0.01] as independent predictors for occurrence of HLI. Good functional outcome was significantly lower in patients suffering from HLI after 28-days (35% vs. 48%, p 0.001) and 1-year (34% vs. 44%, p 0.001). Occurrence of HLI was associated with unfavourable neurological outcome [OR 1.74, 95% CI (1.16-2.61); p 0.01] in multivariate regression analysis.New onset of HLI is a frequent finding after IHCA and OHCA. HLI is associated with increased mortality, unfavourable neurological and overall outcome.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) is currently finally determined in laboratory settings by real-time reverse-transcription polymerase-chain-reaction (rt-PCR). However, simple testing with immediately available results are crucial to gain control over COVID-19. The aim was to evaluate such a point-of-care antigen rapid test (AG-rt) device in its performance compared to laboratory-based rt-PCR testing in COVID-19 suspected, symptomatic patients.MethodsFor this prospective study, two specimens each of 541 symptomatic female (54.7%) and male (45.3%) patients aged between 18 and 95 years tested at five emergency departments (ED, n=296) and four primary healthcare centres (PHC, n=245), were compared, using AG-rt (positive/negative/invalid) and rt-PCR (positive/negative and cycle threshold, Ct) to diagnose SARS-CoV-2. Diagnostic accuracy, sensitivity, specificity, positive predictive values (PPV), negative predictive value (NPV), and likelihood ratios (LR+/-) of the AG-rt were assessed.ResultsDifferences between ED and PHC were detected regarding gender, age, symptoms, disease prevalence, and diagnostic performance. Overall, 174 (32.2%) were tested positive on AG-rt and 213 (39.4%) on rt-PCR. AG correctly classified 91.7% of all rt-PCR positive cases with a sensitivity of 80.3%, specificity of 99.1%, PPV of 98.3, NPV of 88.6%, LR(+) of 87.8, and LR(-) of 0.20. The highest sensitivities and specificities of AG-rt were detected in PHC (sensitivity: 84.4%, specificity: 100.0%), when using Ct of 30 as cut-off (sensitivity: 92.5%, specificity: 97.8%), and when symptom onset was within the first three days (sensitivity: 82.9%, specificity: 99.6%).ConclusionsThe highest sensitivity was detected with a high viral load. Our findings suggest that AG-rt are comparable to rt-PCR to diagnose SARS-CoV-2 in COVID-19 suspected symptomatic patients presenting both at emergency departments and primary health care centres.SUMMARYThe rapid SARS-Cov-2 antigen test (SARS-CoV-2 Rapid Antigen Test (Roche Diagnostics), was compared in symptomatic patients with PCR testing both in emergency departments and primary health care centres. It showed an overall sensitivity of 80.3% and specificity of 99.1%; these were higher with lower PCR cycle threshold numbers and with a shorter onset of symptoms.

Standard blood laboratory parameters may have diagnostic potential, if polymerase-chain-reaction (PCR) tests are not available on time. We evaluated standard blood laboratory parameters of 655 COVID-19 patients suspected to be infected with SARS-CoV-2, who underwent PCR testing in one of five hospitals in Vienna, Austria. We compared laboratory parameters, clinical characteristics, and outcomes between positive and negative PCR-tested patients and evaluated the ability of those parameters to distinguish between groups. Of the 590 patients (20–100 years, 276 females and 314 males), 208 were PCR-positive. Positive compared to negative PCR-tested patients had significantly lower levels of leukocytes, neutrophils, basophils, eosinophils, lymphocytes, neutrophil-to-lymphocyte ratio, monocytes, and thrombocytes; while significantly higher levels were detected with erythrocytes, hemoglobin, hematocrit, C-reactive-protein, ferritin, activated-partial-thromboplastin-time, alanine-aminotransferase, aspartate-aminotransferase, lipase, creatine-kinase, and lactate-dehydrogenase. From all blood parameters, eosinophils, ferritin, leukocytes, and erythrocytes showed the highest ability to distinguish between COVID-19 positive and negative patients (area-under-curve, AUC: 72.3–79.4%). The AUC of our model was 0.915 (95% confidence intervals, 0.876–0.955). Leukopenia, eosinopenia, elevated erythrocytes, and hemoglobin were among the strongest markers regarding accuracy, sensitivity, specificity, positive and negative predictive value, positive and negative likelihood ratio, and post-test probabilities. Our findings suggest that especially leukopenia, eosinopenia, and elevated hemoglobin are helpful to distinguish between COVID-19 positive and negative tested patients.

Background Mid‐regional pro‐atrial natriuretic peptide (MR‐proANP) is a strong prognostic marker in several inflammatory, respiratory and cardiovascular conditions, but has not been studied in COVID‐19 yet. Methods This prospective, observational study of patients with COVID‐19 infection was conducted from 6 June to 26 November 2020 in different wards of a tertiary hospital. MR‐proANP, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and high‐sensitive cardiac troponin I levels on admission were collected and tested for their association with disease severity and 28‐day mortality. Results A total of 213 eligible patients with COVID‐19 were included in the final analyses of whom 13.2% (n = 28) died within 28 days. Median levels of MR‐proANP at admission were significantly higher in nonsurvivors (307 pmol/L IQR, [161 ‐ 532] vs 75 pmol/L [IQR, 43 ‐ 153], P

BackgroundCoronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is current pandemic disease. Acute polymerase-chain-reaction is the gold standard test for this disease, is not available everywhere. Standard blood laboratory parameters may have diagnostic potential.MethodsWe evaluated standard blood laboratory parameters of 655 COVID-19 patients suspected to be infected with SARS-CoV-2, who underwent PCR testing in one of five hospitals in Vienna, Austria. Additionally, clinical characteristics and 28-day outcome were obtained from medical records. We compared standard blood laboratory parameters, clinical characteristics, and outcomes between positive and negative PCR-tested patients and evaluated the ability of those parameters to distinguish between groups.ResultsOf the 590 study patients including 276 females and 314 males, aged between 20 and 100 years, 208 were tested positive by means of PCR. Patients with positive compared to negative PCR-tests had significantly lower levels of leukocytes, basophils, eosinophils, monocytes, and thrombocytes; while significantly higher levels were detected with hemoglobin, C-reactive-protein (CRP), neutrophil-to-lymphocyte ratio (NLR), activated-partial-thromboplastin-time (aPTT), creatine-kinase (CK), lactate-dehydrogenase (LDH), alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), and lipase. Our multivariate model correctly classified 83.9% of cases with a sensitivity of 78.4%, specificity of 87.3%, positive predictive value of 79.5%, and negative predictive value of 86.6%. Decreasing leucocytes and eosinophils and increasing hemoglobin and CRP were significantly associated with an increased likelihood of being COVID-19 positive tested.ConclusionsOur findings suggest that especially leucocytes, eosinophils, hemoglobin, and CRP are helpful to distinguish between COVID-19 positive and negative tested patients and that a certain blood pattern is able to predict PCR-results.SummaryDecreasing leucocytes and eosinophils and increasing hemoglobin and CRP were significantly associated with an increased likelihood of being COVID-19 positive tested. Each single parameter showed either a high sensitivity (leucocytes, eosinophils, CRP, monocytes, thrombocytes) or specificity (NLR, CK, ALT, lipase), or a sensitivity and specificity around 60% (Hb, LDH, AST).

Postoperative atrial fibrillation (POAF) is one of the most frequent complications after cardiothoracic surgery and a predictor for postoperative mortality and prolonged ICU-stay. Current guidelines suggest the multi-channel inhibitor Vernakalant as a treatment option for rhythm control. However, rare cases of severe hypotension and cardiogenic shock following drug administration have been reported. To elucidate the impact of Vernakalant on hemodynamics, we included ten ICU patients developing POAF after elective cardiac surgery, all of them awake and breathing spontaneously, in this prospective trial. Patients received the recommended dosage of Vernakalant and were clinically observed and monitored (heart rate, invasive blood pressure, pulse oximetry, central venous pressure) in 1-minute-intervals for 20 minutes before- and 120 minutes after the first dose of Vernakalant. The median time from the end of surgery until occurrence of POAF amounted up to 52.8 [45.9–77.4] hours, it took 3.5 [1.2–10.1] hours from occurrence of POAF until the first application of Vernakalant. All patients received catecholamine support with epinephrine that was held steady and not dynamic throughout the observational phase. We noted stable hemodynamic conditions, with a trend towards a reduction in heart rate throughout the 120 minutes after drug administration. In 7 patients (70%), conversion to sustained sinus rhythm (SR) occurred within 8.0 minutes [6.0–9.0]. No serious adverse events (SAEs) were noted during the observation period. In this prospective trial in ICU-patients showing POAF after cardiac surgery, intravenous Vernakalant did not induce clinically relevant negative effects on patients’ hemodynamics but resulted in conversion to sustained SR after a median of 8.0 minutes in 7 out of ten patients.

ObjectivesTo assess the predictive value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitive troponin T (hs-TnT) serum levels for mid-term mortality in patients presenting with symptomatic atrial fibrillation (AF) to an emergency department.MethodsNon-interventional cohort/follow-up study, including consecutive patients presenting to a tertiary care university emergency department due to symptomatic AF between 2012 and 2016. Multivariable Cox proportional hazard regression models were used to estimate the mortality rates and hazards per 100 patient-years (pry) for NT-proBNP and hs-TnT serum levels in quintiles.Results2574 episodes of 1754 patients (age 68 (IQR 58–75) years, female gender 1199 (44%), CHA2DS2-VASc 3 (IQR 1–4)) were recorded. Following the exclusion of incomplete datasets, 1780 episodes were available for analysis. 162 patients deceased during the mid-term follow-up (median 23 (IQR 4–38) months); the mortality rate was 4.72/100 pry. Hazard for death increased with every quintile of NT-proBNP by 1.53 (HR; 95% CI 1.27 to 1.83; pConclusionElevated NT-proBNP and hs-TnT levels are independently associated with increased mid-term mortality in patients presenting to an emergency department due to symptomatic AF.Trial registration numberNCT03272620; Results.

Objectives Recent data suggest that early increased fibrinolysis may be associated with unfavorable prognosis in cardiac arrest. The current study aimed to assess whether there is an optimal fibrinolysis cutoff value as determined by thrombelastometry at hospital admission to predict poor outcome in a cohort of adult patients with out-of-hospital cardiac arrest. Design Prospective observational cohort study. Setting Emergency department of a 2.100-bed tertiary care facility in Vienna, Austria, Europe. Patients Patients with out-of-hospital cardiac arrest of presumed cardiac origin, subjected to targeted temperature management, who had achieved return of spontaneous circulation at admission were analyzed. Interventions None. Measurements and main results Fibrinolysis was assessed by thrombelastometry at the bedside immediately after hospital admission and is given as maximum lysis (%). The outcome measure was the optimal cutoff for maximum lysis at hospital admission to predict poor outcome (a composite of Cerebral Performance Category 3-5 or death) at day 30, assessed by receiver operating characteristic curve analysis. Seventy-eight patients (61% male, median 59 yr) were included in the study from March 2014 to March 2017. Forty-two patients (54%) had a poor 30-day outcome including 23 nonsurvivors (30%). The maximum lysis cutoff at admission predicting poor 30-day outcome with 100% specificity (95% CI, 90-100%) was greater than or equal to 20%. Tissue-type plasminogen activator antigen levels were likewise elevated in patients with poor neurologic outcome or death 52 ng/mL (interquartile range, 26-79 ng/mL) versus 29 ng/mL (interquartile range, 17-49 ng/mL; p = 0.036). Conclusions Increased fibrinolysis at admission assessed by thrombelastometry specifically predicts poor outcome in cardiac arrest with presumed cardiac etiology.

Background Outcome is generally poor in out of hospital cardiac arrests (OHCA) with initial non-shockable rhythms. Termination of resuscitation rules facilitate early prognostication at the scene to cease resuscitation attempts in futile situations and to proceed advanced life support in promising conditions. As pulseless electrical activity (PEA) is present as first rhythm in every 4th OHCA we were interested if the initial electrical frequency in PEA predicts survival. Methods All patients >18 years of age with non-traumatic OHCA and PEA as first rhythm between August 2013 and August 2015 from the Vienna Cardiac Arrest Registry were included in this retrospective observational study. Defibrillator and epidemiological data from the emergency medical system as survival data were processed considering the initial electrical activity in PEA and 30 days survival. Results Out of 2149 OHCA patients, a total of 504 PEA patients were eligible for analyses. These patients were stratified into 4 groups according the initial electrical frequency in PEA: 10–24/min, 25–39/min, 40–59/min, >60/min. Compared to a frequency >60/min all other subgroups were associated with higher mortality especially those with an initial electrical frequency 10–24 (adjusted OR 0.56 (0.39–0.79) p = .001 for each category chance). QRS duration in PEA did not influence outcome. Patients in the >60/min group showed a 30-days-survival rate of 22% and a good neurological outcome in 15% of all patients – comparable to shockable cardiac arrest rhythms. Conclusion Regardless of other resuscitation factors, higher initial electrical frequency in PEA is associated with increased odds of survival and good neurological outcome.

Background Organ failure increases mortality in patients with liver cirrhosis. Data about resuscitated cardiac arrest patients with liver cirrhosis are missing. This study aims to assess aetiology, survival and functional outcome in patients after successful cardiopulmonary resuscitation (CPR) with and without liver cirrhosis. Methods Analysis of prospectively collected cardiac arrest registry data of consecutively hospital-admitted patients following successful CPR was performed. Patient’s characteristics, admission diagnosis, severity of disease, course of disease, short- and long-term mortality as well as functional outcome were assessed and compared between patients with and without cirrhosis. Results Out of 1068 patients with successful CPR, 47 (4%) had liver cirrhosis. Acute-on-chronic liver failure (ACLF) was present in 33 (70%) of these patients on admission, and four patients developed ACLF during follow-up. Mortality at 1 year was more than threefold increased in patients with liver cirrhosis (OR 3.25; 95% CI 1.33–7.96). Liver cirrhosis was associated with impaired neurological outcome (OR for a favourable cerebral performance category: 0.13; 95% CI 0.04–0.36). None of the patients with Child–Turcotte–Pugh (CTP) C cirrhosis survived 28 days with good neurological outcome. Overall nine (19%) patients with cirrhosis survived 28 days with good neurological outcome. All patients with ACLF grade 3 died within 28 days. Conclusion Cardiac arrest survivors with cirrhosis have worse outcome than those without. Although one quarter of patients with liver cirrhosis survived longer than 28 days after successful CPR, patients with CTP C as well as advanced ACLF did not survive 28 days with good neurological outcome. Electronic supplementary material The online version of this article (doi:10.1186/s13613-017-0322-1) contains supplementary material, which is available to authorized users.

The neutrophil lymphocyte ratio(NLR) is a marker of systemic inflammation. We hypothesized that admission NLR is related to mortality and that epinephrine application during resuscitation influences NLR in patients after successful resuscitation from out of hospital cardiac arrest (OHCA).This retrospective cohort study is based on a registry including all OHCA patients who had a presumed cardiac cause of cardiac arrest and achieved sustained ROSC prior to admission between 2005 and 2014. Patients were categorized into three groups according to the calculated NLR at admission (NLR6, ≥6, and 'abnormal differential' indicating no differential blood cell count on patients report due to exceedance of machine predefined parameter limits). The primary outcome measure was long-term mortality after OHCA. Cox proportional hazards models were used for multivariable analysis.Out of 2273 OHCA patients during the study period a total of 1188(52%) patients were eligible for analysis, of those 274(23%) were female and mean age was 64 (25-75 IQR:52-72). Compared to a NLR6 (n=442), adjusted hazard ratio for long-term mortality was significantly higher in patients with a NLR≥6 (n=447; 1.52 (95%CI 1.03-2.24)) and in patients with abnormal differential (n=299; 3.16 (95%CI 2.02-4.97)). Epinephrine application during resuscitation did not explain the effect of NLR on mortality.In this large retrospective cohort study of altogether1000 OHCA patients, hospital admission NLR6 compared to abnormal differential or NLR≥6 was associated with mortality independently from epinephrine application.

Essentials Reversal of anticoagulant effects of dabigatran may occur despite application of idarucizumab. Monitoring of dabigatran level after antidote application is crucial to detect rebound. Repeated doses of idarucizumab may be necessary in cases of massive dabigatran accumulation. Combination of antidote application and renal replacement therapy may offer additional benefit. Summary Idarucizumab is a monoclonal antibody fragment designed for reversing the anticoagulant effects of dabigatran. Administration is recommended as two intravenous boluses of 2.5 g within 15 min of each other or as a single 5 g bolus. However, in certain situations a second dose of the drug could be necessary. We report the case of a 77-year-old man, treated with dabigatran for paroxysmal atrial fibrillation. He presented at our department with acute renal failure, concomitant massive dabigatran accumulation and subsequent acute gastrointestinal bleeding. Fifty minutes after the administration of idarucizumab, the dabigatran plasma concentration decreased from a peak of 1630 ng ml-1 to a level below the detection limit of 30 ng ml-1 and bleeding stopped. Eight hours after administration, the dabigatran plasma level started to increase up to 1560 ng ml-1 (96% of the maximum value obtained), accompanied by a further drop in hemoglobin. Concomitant hemodialysis and hemofiltration led to a continuous decrease in dabigatran plasma levels. However, sepsis and multiorgan failure ensued, which led to death. With this case report we raise the question of whether massive dabigatran accumulation requires repeated doses of idarucizumab, or alternatively, if the combination of antidote with hemodialysis/renal replacement therapy is advisable in order to remove circulating levels of dabigatran.

Transition from cangrelor to oral P2Y12 inhibitors after PCI carries the risk of platelet function recovery and acute stent thrombosis. Whether the recommended transition regimen is appropriate for hypothermic cardiac arrest survivors is unknown. We assessed the rate of high platelet reactivity (HPR) after transition from cangrelor to ticagrelor in hypothermic cardiac arrest survivors. Adult survivors of out-of-hospital cardiac arrest with ST-segment elevation myocardial infarction (STEMI), who were treated for hypothermia (33 °C ± 1) and received intravenous cangrelor during PCI and subsequent oral loading with 180mg ticagrelor were enrolled in this prospective observational cohort study. Platelet function was assessed using whole blood aggregometry. HPR was defined as AUC > 46U. The primary endpoint was the rate of HPR (%) at predefined time points during the first 24 h after cangrelor cessation. Poisson regression was used to estimate the relationship between the overlap time of cangrelor and ticagrelor co-administration and the number of subsequent HPR episodes, expressed as incidence rate ratio (IRR) with 95% confidence interval (95%CI). Between December 2017 and October 2019 16 patients (81% male, 58 years) were enrolled. On average, ticagrelor was administered 39 min (IQR 5−50) before the end of cangrelor infusion. The rate of HPR was highest 90 min after cangrelor cessation and was present in 44% (7/16) of patients. The number of HPR episodes increased significantly with decreasing overlap time of cangrelor and ticagrelor co-administration (IRR 1.03, 95%CI 1.01−1.05; p = 0.005). In this selected cohort of hypothermic cardiac arrest survivors who received cangrelor during PCI, ticagrelor loading within the recommended time frame before cangrelor cessation resulted in a substantial amount of patients with HPR.

The exact contribution of neutrophils to post-resuscitative brain damage is unknown. We aimed to investigate whether neutrophil extracellular trap (NET) formation in the early phase after return of spontaneous circulation (ROSC) may be associated with poor 30 day neurologic function in cardiac arrest survivors. This study prospectively included adult (≥18 years) out-of-hospital cardiac arrest (OHCA) survivors with cardiac origin, who were subjected to targeted temperature management. Plasma levels of specific (citrullinated histone H3, H3Cit) and putative (cell-free DNA (cfDNA) and nucleosomes) biomarkers of NET formation were assessed at 0 and 12 h after admission. The primary outcome was neurologic function on day 30 after admission, which was assessed using the five-point cerebral performance category (CPC) score, classifying patients into good (CPC 1–2) or poor (CPC 3–5) neurologic function. The main variable of interest was the effect of H3Cit level quintiles at 12 h on 30 day neurologic function, assessed by logistic regression. The first quintile was used as a baseline reference. Results are given as crude odds ratio (OR) with 95% confidence interval (95% CI). Sixty-two patients (79% male, median age: 57 years) were enrolled. The odds of poor neurologic function increased linearly, with 0 h levels of cfNDA (crude OR 1.8, 95% CI: 1.2–2.7, p = 0.007) and nucleosomes (crude OR 1.7, 95% CI: 1.0–2.2, p = 0.049), as well as with 12 h levels of cfDNA (crude OR 1.6, 95% CI: 1.1–2.4, p = 0.024), nucleosomes (crude OR 1.7, 95% CI: 1.1–2.5, p = 0.020), and H3Cit (crude OR 1.6, 95% CI: 1.1–2.3, p = 0.029). Patients in the fourth (7.9, 95% CI: 1.1–56, p = 0.039) and fifth (9.0, 95% CI: 1.3–63, p = 0.027) H3Cit quintile had significantly higher odds of poor 30 day neurologic function compared to patients in the first quintile. Increased plasma levels of H3Cit, 12 h after admission, are associated with poor 30 day neurologic function in adult OHCA survivors, which may suggest a contribution of NET formation to post-resuscitative brain damage and therefore provide a therapeutic target in the future.

Aims: Rapid restoration of sinus rhythm is an integral part of the management of recent-onset atrial fibrillation. We aimed to assess safety and efficacy of vernakalant, a multi-channel blocking agent, in combination with external electrical cardioversion. Methods: This prospective cohort study comprised 230 patients (female 35%; median age 50 IQR 42–55) with recent-onset AF presenting to a university tertiary care center during a 6-year period. Management included intravenous vernakalant followed by electrical cardioversion in case of pharmacological failure. Results: Within 11 min (IQR 8–29), sinus rhythm could be restored by sole pharmacological management in 167 patients (73%). A left ventricular function lower than 55% (OR 3.51 (1.45–8.52)) and prior atrial fibrillation episodes being classified as persistent (OR 2.33 (1.13–4.80)) were significant predictors for non-response to vernakalant. Electrical cardioversion was successful in all patients but one within 196 min (IQR 149–300) of administration of first dosage of vernakalant. No serious adverse events could be observed. 3 patients needed further in-patient care. Conclusion: Management of recent-onset atrial fibrillation consisting of intravenous vernakalant followed by electrical cardioversion in case of failure appears safe and efficacious. Achieving a rapid conversion, this approach could potentially save resources and costs. Keywords: Vernakalant, Recent-onset atrial fibrillation, Cardioversion

Cardiac arrest (CA) is still associated with high mortality and morbidity. Data on the changes in management and outcomes over a long period of time are limited. Using data from a single emergency department (ED), we assessed changes over two decades.In this single-center observational study, we prospectively included 4133 patients receiving cardiopulmonary resuscitation and being admitted to the ED of a tertiary care hospital between January 1992 and December 2012.There was a significant improvement in both 6-month survival rates (+10.8%; p 0.001) and favorable neurological outcome (+4.7%; p 0.001). While the number of witnessed CA cases decreased (-4.7%; p 0.001) the proportion of patients receiving bystander basic life support increased (+8.3%; p 0.001). The proportion of patients with initially shockable ECG rhythms remained unchanged, but cardiovascular causes of CA decreased (-9.6%; p 0.001). Interestingly, the time from CA until ED admission increased (+0.1 hours; p = 0.024). The use of percutaneous coronary intervention and therapeutic hypothermia were significantly associated with survival.Outcomes of patients with CA treated at a specialized ED have improved significantly within the last 20 years. Improvements in every link in the chain of survival were noted.

BackgroundSeveral studies have shown that statins have beneficial effects in COPD regarding lung function decline, rates and severity of exacerbation, hospitalisation and need for mechanical ventilation.MethodsWe performed a randomised double-blind placebo-controlled single-centre trial of simvastatin at a daily dose of 40 mg versus placebo in patients with Global Initiative for Chronic Obstructive Lung Disease criteria grades 2–4 at a tertiary care pulmonology department in Austria. Scheduled treatment duration was 12 months and the main outcome parameter was time to first exacerbation.ResultsOverall, 209 patients were enrolled. In the 105 patients taking simvastatin, time to first exacerbation was significantly longer compared to the 104 patients taking placebo: median 341 versus 140 days (log-rank test pversus 147 (59%) (p=0.003). The annualised exacerbation rate was 1.45 events per patient-year in the simvastatin group and 1.9 events per patient-year in the placebo group (incidence rate ratio 0.77, 95% CI 0.60–0.99). We found no effect on quality of life, lung function, 6-min walk test and high-sensitivity C-reactive protein. More patients dropped out in the simvastatin group compared to the placebo group (39 versus 29).ConclusionIn our single-centre RCT, simvastatin at a dose of 40 mg daily significantly prolonged time to first COPD exacerbation and reduced exacerbation rate.

Platelets play an important role in the activation of coagulation. P2Y12 receptor inhibition may be beneficial in inflammatory states. Prasugrel, a potent irreversible inhibitor of P2Y12 receptor-induced platelet activation may reduce activation of coagulation in a human LPS (lipopolysaccharide) model. A double-blind, randomized, crossover trial with a minimum washout period of 6 weeks was performed. Sixteen subjects were randomly assigned to a treatment group that received prasugrel or placebo 2 h before infusion of a bolus of LPS (2 ng/kg of body weight), whereas four subjects were assigned to a control group receiving prasugrel or placebo without LPS. hcDNA (histone-complexed DNA), coagulation and platelet-specific parameters were measured by enzyme immunoassay. Leucocyte aggregate formation was analysed by flow cytometry, and thromboelastometry was performed. LPS infusion markedly activated coagulation. However, prasugrel did not reduce changes in prothrombin fragments 1 and 2 (F1+2), thrombin–antithrombin complexes, microparticle-associated tissue factor, CD40 ligand, P-selectin, platelet–leucocyte aggregation, hcDNA levels or the coagulation profile measured by thromboelastometry. hcDNA plasma levels increased approximately 6-fold after LPS infusion in both treatment groups, but not in the control groups. Potent irreversible P2Y12 inhibition by prasugrel does not affect LPS-induced coagulation activation. The 6-fold increased hcDNA plasma levels after infusion of LPS indicates the formation of neutrophil extracellular traps during sterile inflammation.

Background In elder patients after out‐of‐hospital cardiac arrest, diminished neurologic function as well as reduced neuronal plasticity may cause a low response to targeted temperature management (TTM). Therefore, we investigated the association between TTM (32‐34°C) and neurologic outcome in cardiac arrest survivors with respect to age. Material and Methods This retrospective cohort study included patients 18 years of age or older suffering a witnessed out‐of‐hospital cardiac arrest with presumed cardiac cause, which remained comatose after return of spontaneous circulation. Patients were a priori split by age into four groups (75 years (n = 280)). Subsequently, within these groups, patients receiving TTM were compared to those not treated with TTM. Results Out of 1885 patients, 921 received TTM for 24 hours. TTM was significantly associated with good neurologic outcome in patients 75 years: OR 1.44 (95% CI 0.79‐2.34)). Conclusion In our cohort, it seems that TTM might not be able to achieve the same benefit for neurologic outcome in all age groups. Although the results of this study should be interpreted with caution, TTM was associated with improved neurologic outcome only in younger individuals, patients with 65 years of age or older did not benefit from this treatment.

Background: Prostate-specific antigen (PSA) is used as an outcome measure for relapsed disease in prostate cancer. Nonetheless, there are considerable concerns about its indiscriminate use as a surrogate endpoint for cell growth or survival. We hypothesized that treatment with a luteinizing hormone releasing hormone (LHRH) analog would decrease PSA levels even in the absence of malignant disease. Methods: We determined testosterone and PSA levels in 30 healthy volunteers after a single intramuscular injection of a LHRH depot formulation. Testosterone and PSA levels were quantified by radioimmunoassay and electrochemi-luminescence immunoassay, respectively. Results: After an initial flare-up during the first 3 days testosterone decreased reaching castration levels in 18 of the 30 young men (60%). After the nadir on day 28, testosterone levels increased to normal again. Changes in PSA paralleled those of testosterone. Castration reduced PSA levels by 29% (95% CI 19%–39%) compared to baseline (p Conclusions: LHRH superagonists decrease PSA levels by testosterone deprivation. Conferring these findings to tumor patients, decreases in PSA after treatment with LHRH analogs might not only reflect disease regression but also a direct testosterone mediated effect on PSA. Thus, PSA levels should be cautiously interpreted when patients receive hormonal therapy.

SummaryGranulocyte colony-stimulating factor (G-CSF) stimulates the bone marrow to produce granulocytes and stem cells and is widely used to accelerate neutrophil recovery after chemotherapy. Interestingly, specific G-CSF receptors have been demonstrated not only on myeloid cells, but also on platelets. Data on the effects of G-CSF on platelet function are limited and partly conflicting. The objective of this study was to determine the effect of G-CSF on platelet aggregation and in vivo platelet activation. Seventy-eight, healthy volunteers were enrolled into this randomised, placebo-controlled trial. Subjects received 5 μg/kg methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF, filgrastim) or placebo subcutaneously for four days. We determined platelet aggregation with a whole blood impedance aggregometer with various, clinically relevant platelet agonists (adenosine diphosphate [ADP], collagen, arachidonic acid [AA], ristocetin and thrombin receptor activating peptide 6 [TRAP]). Filgrastim injection significantly enhanced ADP (+40%), collagen (+60%) and AA (+75%) -induced platelet aggregation (all p

Granulocyte colony-stimulating factor (G-CSF) has been associated with the induction of a hypercoagulable state in patients as well as peripheral blood stem donors. Interestingly, sparse data exist on the kinetics of platelet and coagulation activation in response to G-CSF and it is unknown if G-CSF augments shear-dependent platelet function. These two issues are addressed in the current trial. Thirty-six healthy volunteers were enrolled into this study. All subjects received a single-dose of 5 microg/kg filgrastim intravenously. The effects of recombinant G-CSF on platelet and coagulation function were assessed by the platelet function analyzer PFA-100 (collagen/epinephrine (CEPI-CT), collagen/ADP (CADP-CT) closure times), von Willebrand factor activity (vWF : RiCO) ELISA, tissue factor (TF)-mRNA expression on circulating leukocytes and rotation thrombelastography (ROTEM). G-CSF time-dependently enhanced shear dependent platelet function measured by the PFA-100: CEPI-CT declined by 48% and CADP-CT by 31% with nadir values after 24 h (p0.001 as compared to baseline) and returned to near-baseline values after 72 hours. In accordance, VWF : RiCO increased by 59% after 24 h (p0.001) and returned to baseline 48 h later. TF-mRNA peaked after 4 hours (6 fold increase p0.001) and reached near-baseline values after 24 hours. Nadir closure times were seen after 24 hours (-15%; p0.001). Single-dose administration of 5 microg/kg G-CSF significantly enhances shear-dependent platelet function and strongly induces leukocyte TF-mRNA, which translates into shortened clotting times ex vivo.

Monocyte chemoattractant protein-1 (MCP-1, CCL-2) binds to the Duffy antigen (DARC) on red blood cells, which act as a sink for several chemokines including MCP-1. In this study it is hypothesized that DARC may alter the pharmacokinetics of infused recombinant human MCP-1 (rhMCP-1). The primary aim of this first in man trial is to compare the pharmacokinetics of rhMCP-1 in Duffy positive and negative individuals. A randomized, double-blinded, placebo-controlled dose escalation trial was conducted on 36 healthy volunteers. Subjects received infusions of 0.02–2.0 μg/kg rhMCP-1 or placebo for one hour. RhMCP-1 displayed linear pharmacokinetics. Duffy negative individuals reached maximal plasma levels significantly earlier, but overall plasma concentration profiles were not altered. rhMCP-1 markedly increased monocyte counts, and estimated EC50 values were 10-fold higher in Duffy positive than in Duffy negative subjects. Increased monocyte counts were associated with decreased surface expression of intercellular adhesion molecule 1 (ICAM-1, CD54). In contrast, neither CCR-2 or CD11b expression, nor markers of platelet or endothelial activation, inflammation and coagulation were altered. RhMCP-1 is a highly selective chemoattractant for monocytes in humans. The Duffy antigen only minimally alters the pharmacokinetics of rhMCP-1 for doses up to 2 μg/kg.

Aim of the study: Application of mild hypothermia (32–33 ◦C) has been shown to improve neurological outcome in patients with cardiac arrest. However, hypothermia affects hemostasis, and even mild hypothermia is associated with bleeding and increased transfusion requirements in surgery patients. On the other hand, crystalloid hemodilution has been shown to induce a hypercoagulable state. The study aim was to elucidate in which way the induction of mild therapeutic hypothermia by a bolus infusion of cold crystalloids affects the coagulation system of patients with cardiac arrest. Methods: This was a prospective pilot study in 18 patients with cardiac arrest and return of spontaneous circulation (ROSC). Mild hypothermia was initiated by a bolus infusion of cold 0.9% saline fluid (4 ◦C; 30 ml/kg/30 min) and maintained for 24 h. At 0 h (before hypothermia), 1, 6 and 24 h we assessed coagulation parameters (PT, APPT), platelet count and performed thrombelastography (ROTEM) after in vitro addition of heparinase. Results: A total amount of 2528 (±528) ml of 0.9% saline fluid was given. Hematocrit (p < 0.01) and platelet count (−27%; p < 0.05) declined, whereas APTT increased (2.7-fold; p < 0.01) during the observation period. All ROTEM parameters besides clotting time (CT) after 1 h (−20%; p < 0.05) did not significantly change. Conclusion: Mild hypothermia only slightly prolonged clotting time as measured by rotation thrombelastography. Therefore, therapeutic hypothermia initiated by cold crystalloid fluids has only minor overall effects on coagulation in patients with cardiac arrest.

Summary. Background: Racial differences in coagulation are poorly understood. While some studies suggest a ‘prothrombotic’ coagulation profile in blacks compared with whites, others report an increased bleeding risk for blacks in various clinical settings. Moreover, preclinical data suggest a link between the Duffy antigen (= DARC, Duffy antigen receptor of chemokines) and coagulation. Objectives: Based on our previous research in Duffy antigen negative Africans, we hypothesized that Africans have an attenuated procoagulant response compared with Caucasians in a model of lipopolysaccharide (LPS)-induced, tissue factor (TF)-triggered coagulation activation. Patients/methods: Healthy male volunteers (16 Duffy-negative Africans, 16 Duffy-positive Caucasians) received 2 ng kg−1 LPS, and outcome parameters were measured using enzyme immunoassays and real-time polymerase chain reaction (RT-PCR, Taqman). Results: LPS increased microparticle (MP)-associated TF procoagulant activity (PCA) less in Africans than Caucasians. Africans had reduced in vivo thrombin formation compared with Caucasians: they generated less thrombin–antithrombin (TAT) complexes (10.4 pg mL−1 vs. 23.0 pg mL−1, P

Objective: Markers of platelet activation are increased in patients undergoing cardiopulmonary resuscitation. Hyperfunctional platelets may contribute to impairment of microcirculatory function and overall poor outcome despite restoration of spontaneous circulation (ROSC). Patients with myocardial infarction have hyperfunctional platelets, which predict the degree of myocardial necrosis. Thus, we hypothesized that platelets may be even more activated in patients whose myocardial infarction leads to cardiac arrest and compared them with patients whose cardiac arrest was due to a noncardiac origin. Design: Prospective observational study. Setting: Emergency department of a tertiary care hospital. Patients: One hundred four patients with witnessed cardiac arrest who achieved ROSC. Interventions: Blood sampling. Measurements and Main Results: We assessed collagen adenosine diphosphate closure time with the platelet function analyzer-100, and measured plasma levels of von Willebrand factor: ristocetin cofactor activity levels by turbidometry. Independent physicians diagnosed the origin of cardiac arrest. The majority of cardiac arrests were caused by myocardial ischemia. Invariably, collagen adenosine diphosphate closure time values (55 seconds; 95% confidence interval: 52-58 seconds) were much shorter in these patients compared with patients with other causes of cardiac arrest (110 seconds; 95% confidence interval: 84-135 seconds, p < 0.001). von Willebrand factor: ristocetin cofactor activity plasma levels were more than three-fold above normal values in both groups. Conclusions: Patients with myocardial ischemia-triggered cardiac arrest had the highest degree of platelet hyperfunction under high shear rates, which was not solely due to increased von Willebrand factor. Future trials are necessary to clarify whether rapid, more aggressive antiplatelet therapy improves outcome after cardiac arrest.

Objective: The aim of this study was to compare the efficacy of Lutrate® 3.75 and 7.5 mg depot to marketed references Lucrin® 3.75 mg and Procrin® 7.5 mg depot. Methods: 20 healthy male volunteers were randomly assigned to receive 1 of 4 active single dose treatments in this double-blind, parallel-group pilot study. Leuprolide acetate and testosterone levels were quantified by radioimmunoassays. Results: The pharmacokinetic profile of leuprolide could be well-described by a 4-step release curve. Leuprolide levels were detectable 14 days longer after injection of the test formulations as compared to the reference products. The total AUC observed with 3.75 and 7.5 mg of the test product were approximately 1.5- and 2.2-fold higher, compared to the reference products, respectively. After the expected testosterone "flare-up" effect, castration was achieved in 4 of 4 subjects with the test formulations, 4 of 5 subjects with Procrin and 2 of 5 subjects with Lucrin. On average, castration lasted more than 1 month with both test formulations compared to 2 weeks with the reference products. Conclusion: Sustained release of leuprolide from this new depot formulation suppressed testosterone levels at least as effectively and for a longer period of time than the reference products.

The Duffy receptor is a promiscuous receptor for chemokines and selectively binds CXC and CC chemokines with high affinity. Preclinical data show that presence of the Duffy receptor on red blood cells may influence plasma levels of proinflammatory cytokines and chemokines and be protective during inflammation. This trial was designed to investigate the influence of the Duffy antigen on human inflammation in vivo.Prospective, analyst-blinded clinical trial.A total of 32 healthy male volunteers: 16 Duffy-positive white subjects and 16 Duffy-negative subjects of African descent.All subjects received an intravenous bolus of 2 ng/kg endotoxin (lipopolysaccharide). Cytokines, chemokines, and their receptors were quantified by enzyme immunoassay, reverse transcriptase-polymerase chain reaction, and flow cytometry.Plasma levels of tumor necrosis factor, interleukin-6, interleukin-10, and whole blood growth-related oncogen-alpha, monocyte chemoattractant protein-1, and interleukin-8 messenger RNA increased similarly in both groups after lipopolysaccharide infusion. Monocyte chemoattractant protein-1 peak plasma levels were roughly two-fold higher in Duffy-positive subjects compared with Duffy-negative subjects (16 ng/mL vs. 7 ng/mL, p.0001). Similarly, growth-related oncogen-alpha levels were 2.5-fold higher in Duffy-positive subjects 2 hrs after lipopolysaccharide infusion (210 pg/mL vs. 85 pg/mL; p.001). Erythrocyte-bound monocyte chemoattractant protein-1, growth-related oncogen-alpha, and interleukin-8 increased 20- to 50-fold in Duffy-positive subjects (p.00001 vs. baseline).The Duffy antigen substantially alters chemokine concentrations in blood, but it does not have a protective effect during human endotoxemia.

BIBT986 is a dual inhibitor of factors Xa and IIa. The aim of this study was to compare with placebo the effect of three doses of BIBT986 on coagulation, platelet activation, and inflammation. This was a prospective, randomized, double-blind, placebo-controlled, parallel-group dose escalation trial in 48 healthy male volunteers. Participants received one of three doses of BIBT986 or placebo intravenously together with a bolus infusion of 2 ng/kg lipopolysaccharide (LPS). BIBT986 dose-dependently changed global coagulation parameters and in vivo markers of thrombin generation and action: BIBT986 doses, which prolonged activated partial thromboplastin time by 100%, completely suppressed the LPS-induced increases in prothrombin fragment, thrombin-antithrombin complexes, and D-dimer, which were 6.1-, 14.5, and 3.5-fold in the placebo group, respectively. BIBT986 did not influence inflammation, fibrinolysis, or platelet activation. Therefore, BIBT986 is a potent anticoagulant in the human endotoxemia model.

Reparixin antagonizes interleukin-8 (IL-8) on the level of signal transduction in vitro. We hypothesized that IL-8 mediates some of the reactions occurring during acute inflammation and specifically that IL-8 may be a mediator of endotoxin induced neutrophilia. We therefore tested the effects of reparixin on humoral and cellular parameters in LPS-induced acute systemic inflammation. The study is a randomized (3:2 active:placebo), double-blind, placebo-controlled parallel group trial. Twenty healthy male volunteers randomly received either reparixin (12) or placebo (8) intravenously. One hour after the start of reparixin/placebo infusion a bolus of 2 ng/kg endotoxin was infused over 1–2 min. Blood samples were obtained over 24 h. Reparixin, being metabolized to ibuprofen, suppressed serum thromboxane B2 levels by 78% compared to baseline and control at 8 h. LPS-induced neutrophilia was not significantly affected by reparixin in human volunteers. Consistently, reparixin did not alter the lymphocyte or monocyte counts and had no effect on LPS-induced systemic inflammation as measured by tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6) release. Regulation of IL-8 receptors CXCR1 and 2 and the degranulation marker CD11b showed the expected kinetics. Reparixin had no effect on thrombin formation as measured by prothrombin fragment (F1+2). In conclusion, our study showed that reparixin was safe but had no impact on endotoxin induced inflammation. In contrast to previous studies with its metabolite ibuprofen, reparixin does not enhance inflammation in this model.

Ethnic neutropenia is common in people of African descent. As interleukin-8 (IL-8) and granulocyte colony stimulating factor (G-CSF) bind to receptors on neutrophils, ethnic differences in neutrophil counts are hypothesized to result in different plasma levels of these cytokines. A prospective study was conducted in 72 healthy young volunteers. Neutrophil counts were 60% higher in Caucasians (P0.00001). Average IL-8 and G-CSF levels were about 50% and 70% higher in African volunteers compared with Caucasian volunteers (P=0.0008 and P=0.00005, respectively). Additionally, oxidative burst capacity in stimulated neutrophils was significantly lower in volunteers of African descent (P=0.03 between both groups). In sum, lower neutrophil counts are associated with higher levels of IL-8 and G-CSF in Africans.

Previous studies suggest worse outcomes after out-of-hospital cardiac arrest (OHCA) at night. We analyzed whether patients admitted after nontraumatic OHCA to a resuscitation center received the same quality post arrest care at day and night and whether quality of care affected clinical outcomes. We analyzed data of OHCA patients with return of spontaneous circulation admitted to the Vienna general hospital emergency department between January 2006 and May 2013. Data reported include admission time (day defined from 8 am to 4 pm based on staffing), time to initiation of hypothermia, and door-to-balloon time in patients with ST-elevation myocardial infarction. Survival and cognitive performance at 12 months were assessed. In this retrospective observational study, 1059 patients (74% males, n = 784) with a mean age of 58 ± 16 years were analyzed. The vast majority was treated with induced hypothermia (77% of day vs. 79% of night admissions, P = 0.32) within 1 hour of admission (median time admission to cooling 27 (confidence interval [CI]: 10–60) vs. 23 (CI: 11–59) minutes day vs. night, P = 0.99). In 298 patients with ST-elevation myocardial infarction, median door-to-balloon time did not differ between day and night admissions (82 minutes, CI: 60 to 142 for day vs. 86 minutes, CI: 50 to 135 for night, P = 0.36). At 12 months, survival was recorded in 238 of 490 day and 275 of 569 night admissions (49% vs. 48%, P = 0.94%), and a good neurologic outcome was recorded in 210 of 490 day and 231 of 569 night admissions (43% vs. 41%, P = 0.46). Patients admitted to our department after OHCA were equally likely to receive timely high-quality postresuscitation care irrespective of time of day. Survival and good neurologic outcome at 12 months did not differ between day and night admissions. Our results may support the concept of specialized post arrest care centers.

Summary. Background: Platelet hyperfunction contributes to acute coronary syndromes (ACS). Thus, we hypothesized that platelet function under high shear stress predicts recurrent ACS during long-term follow-up of ACS patients. Patients and methods: Consecutive ACS patients (n = 208) were prospectively followed-up for an average of 28 months. Platelet function was measured with the platelet function analyzer (PFA-100®; Dade Behring, Marburg, Germany) at baseline for collagen/adenosine diphosphate closure times (CADP-CT) and for collagen/epinephrine closure times (CEPI-CT) after infusion of a uniform dose of 250 mg aspirin. Results: Of the conventional risk factors, only the prevalence of diabetes was higher in ACS patients with re-events. However, use of clopidogrel and use of beta blockers were also slightly lower in patients with re-events (P

Summary. Background: Thrombelastography (TEG) is a whole blood assay to evaluate the viscoelastic properties during blood clot formation and clot lysis. Rotation thrombelastography (e.g. ROTEM®) has overcome some of the limitations of classical TEG and is used as a point-of-care device in several clinical settings of coagulation disorders. Endotoxemia leads to systemic activation of the coagulation system and fibrinolysis in humans. Objectives: We validated whether ROTEM® is sensitive to endotoxin induced, tissue factor-triggered coagulation and fibrinolysis and if its measures correlate with biohumoral markers of coagulation and fibrinolysis. Patients and methods: Twenty healthy male volunteers participated in this randomized placebo-controlled trial. Volunteers received either 2 ng kg−1 National Reference Endotoxin or saline. Results: Endotoxemia significantly shortened ROTEM® clotting time (CT) by 36% (CI 0.26–0.46; P

SummaryThe protein C pathway serves as a modulating system with both anti-inflammatory and anticoagulant properties and is intimately involved in the pathophysiology of inflammation and sepsis. Treatment with recombinant human activated protein C (rhAPC) can reduce the mortality of severe sepsis. We investigated whether an elevation of plasma protein C levels to supranormal levels by infusion of a protein C zymogen concentrate has an effect on coagulation, protein C activation or inflammation in a human endotoxemia model. Eleven healthy male volunteers were enrolled in a double-blind, placebo-controlled two-way cross-over trial. Ten minutes after infusion of 2ng/kg endotoxin each volunteer received either placebo or a plasmaderived protein C zymogen concentrate (Ceprotin®, Baxter) (150 U/kg as a slow bolus infusion followed by 30 U/kg/h continuous infusion until 4 hours after LPS-infusion). Protein C antigen and activity increased 4– to 5-fold after infusion of the concentrate. APC was generated during endotoxin-induced inflammation in the placebo (1.6 fold increase) and the protein C period (4.0-fold increase).The increase of APC levels correlated with the TNF-α and IL-6 release in both periods (r=0.65–0.68; p

Macrophages play a key role in responding to pathogens and initiate an inflammatory response to combat microbe multiplication. Deactivation of macrophages facilitates resolution of the inflammatory response. Deactivated macrophages are characterized by an immunosuppressive phenotype, but the lack of unique markers that can reliably identify these cells explains the poorly defined biological role of this macrophage subset. We identified lipocalin 2 (LCN2) as both a marker of deactivated macrophages and a macrophage deactivator. We show that LCN2 attenuated the early inflammatory response and impaired bacterial clearance, leading to impaired survival of mice suffering from pneumococcal pneumonia. LCN2 induced IL-10 formation by macrophages, skewing macrophage polarization in a STAT3-dependent manner. Pulmonary LCN2 levels were tremendously elevated during bacterial pneumonia in humans, and high LCN2 levels were indicative of a detrimental outcome from pneumonia with Gram-positive bacteria. Our data emphasize the importance of macrophage deactivation for the outcome of pneumococcal infections and highlight the role of LCN2 and IL-10 as determinants of macrophage performance in the respiratory tract.