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Blood clot formation, a crucial process in hemostasis and thrombosis, has garnered substantial attention for its implications in various medical conditions. Microscopic examination of blood clots provides vital insights into their composition and structure, aiding in the understanding of clot pathophysiology and the development of targeted therapeutic strategies. This study explores the use of topological data analysis (TDA) to assess plasma clot characteristics microscopically, focusing on the identification of the elements components, holes and Wasserstein distances. This approach should enable researchers to objectively classify fibrin networks based on their topologic architecture. We tested this mathematical characterization approach on plasma clots formed in static conditions from porcine and human citrated plasma samples, where the effect of dilution and direct thrombin inhibition was explored. Confocal microscopy images showing fluorescence labeled fibrin networks were analyzed. Both treatments resulted in visual differences in plasma clot architecture, which could be quantified using TDA. Significant differences between baseline and diluted samples, as well as blood anticoagulated with argatroban, were detected mathematically. Therefore, TDA could be indicative of clots with compromised stability, providing a valuable tool for thrombosis risk assessment. In conclusion, microscopic examination of plasma clots, coupled with Topological Data Analysis, offers a promising avenue for comprehensive characterization of clot microstructure. This method could contribute to a deeper understanding of clot pathophysiology and thereby refine our ability to assess clot characteristics., (© 2024. The Author(s).)

Body mass index (BMI) is seen as a predictor of cardiovascular disease (CVD) in lipedema patients. A valid predictor of CVD is increased aortic stiffness (IAS), and previous research described IAS in lipedema. However, it is not known if this applies to all patients. In this cross-sectional single-center cohort study, peripheral pulse wave velocity (PWV) as a non-invasive indicator of aortic stiffness was measured in 41 patients with lipedema, irrespective of stage and without pre-existing cardiovascular conditions or a history of smoking and a maximum body mass index (BMI) of 35 kg/m 2 . Automatically electrocardiogram-triggered oscillometric sensor technology by the Gesenius-Keller method was used. Regardless of the stage of lipedema disease, there was no significant difference in PWV compared to published standard values adjusted to age and blood pressure. BMI alone is not a predictor of cardiovascular risk in lipedema patients. Measuring other anthropometric factors, such as the waist-hip ratio or waist-height ratio, should be included, and the existing cardiovascular risk factors, comorbidities, and adipose tissue distribution for accurate risk stratification should be taken into account. Automated sensor technology recording the PWV represents a valid and reliable method for health monitoring and early detection of cardiovascular risks.

The photoplethysmogram (PPG) signal is widely measured by clinical and consumer devices, and it is emerging as a potential tool for assessing vascular age. The shape and timing of the PPG pulse wave are both influenced by normal vascular aging, changes in arterial stiffness and blood pressure, and atherosclerosis. This review summarizes research into assessing vascular age from the PPG. Three categories of approaches are described: 1 ) those which use a single PPG signal (based on pulse wave analysis), 2 ) those which use multiple PPG signals (such as pulse transit time measurement), and 3 ) those which use PPG and other signals (such as pulse arrival time measurement). Evidence is then presented on the performance, repeatability and reproducibility, and clinical utility of PPG-derived parameters of vascular age. Finally, the review outlines key directions for future research to realize the full potential of photoplethysmography for assessing vascular age.

New Findings: What is the central question of this study? First, we validated easy-to-use oscillometric left ventricular ejection time (LVET) against echocardiographic LVET. Second, we investigated progression of left ventricular ejection time index (LVETI), pre-ejection period index (PEPI), total electromechanical systole index (QS2I) and PEP/LVET ratio during 60 days of head-down tilt (HDT). What is the main finding and its importance? The LVET osci and LVET echo showed good agreement in effect direction. Hence, LVET osci might be useful to evaluate cardiovascular responses during space flight. Moreover, the approach might be useful for individual follow-up of patients with altered ejection times. Furthermore, significant effects of 60 days of HDT were captured by measurements of LVETI, PEPI, QS2I and PEP/LVET ratio., Abstract: Systolic time intervals that are easy to detect might be used as parameters reflecting cardiovascular deconditioning. We compared left ventricular ejection time (LVET) measured via ultrasound Doppler on the left ventricular outflow tract with oscillometrically measured LVET, measured at the brachialis. Furthermore, we assessed the progression of the left ventricular ejection time index (LVETI), the pre-ejection period index (PEPI), the Weissler index (PEP/LVET) and the total electromechanical systole index (QS2I) during prolonged strict head-down tilt (HDT) bed rest, including 16 male and eight female subjects. Simultaneous oscillometric and echocardiographic LVET measurements showed significant correlation (r = 0.53 with P = 0.0084 before bed rest and r = 0.73 with P < 0.05 on the last day of bed rest). The shortening of LVET during HDT bed rest measured with both approaches was highly concordant in their effect direction, with a concordance rate of 0.96. Our results also demonstrated a significant decrease of LVETI (P < 0.0001) and QS2I (P = 0.0992) and a prolongation of PEPI (P = 0.0049) and PEP/LVET (P = 0.0003) during HDT bed rest over 60 days. Four days after bed rest, LVETI recovered completely to its baseline value. Owing to the relationship between shortening of LVETI and heart failure progression, the easy-to-use oscillometric method might not only be a useful way to evaluate the cardiovascular system during space flights, but could also be of high value in a clinical setting., (© 2021 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Extracorporeal membrane oxygenation (ECMO) is a specialised life support modality for patients with refractory cardiac or respiratory failure. Multiple studies strived to evaluate the benefits of ECMO support, but its efficacy remains controversial with still inconsistent and sparse information. Methods: This retrospective analysis included patients with ECMO support, admitted between January 2010 and December 2019 at a tertiary university ECMO referral centre in Austria. The primary endpoint of the study was overall all-cause three-month mortality with risk factors and predictors of mortality. Secondary endpoints covered the analysis of demographic and clinical characteristics of patients needing ECMO, including incidence and type of adverse events during support. Results: In total, 358 patients fulfilled inclusion criteria and received ECMO support due to cardiogenic shock (258, 72%), respiratory failure (88, 25%) or hypothermia (12, 3%). In total, 41% (145) of patients died within the first three months, with the median time to death of 9 (1−87) days. The multivariate analysis identified hypothermia (HR 3.8, p < 0.001), the Simplified Acute Physiology Score III (HR 1.0, p < 0.001), ECMO initiation on weekends (HR 1.6, p = 0.016) and haemorrhage during ECMO support (HR 1.7, p = 0.001) as factors with higher risk for mortality. Finally, the most frequent adverse event was haemorrhage (160, 45%) followed by thrombosis. Conclusions: ECMO is an invasive advanced support system with a high risk of complications. Nevertheless, well-selected patients can be successfully rescued from life-threatening conditions by prolonging the therapeutic window to either solve the underlying problem or install a long-term assist device. Hypothermia, disease severity, initiation on weekends and haemorrhage during ECMO support increase the risk for mortality. In the case of decision making in a setting of limited (ICU) resources, the reported risk factors for mortality may be contemplable, especially when judging a possible ECMO support termination.

The concept of intensive care units (ICU) has existed for almost 70 years, with outstanding development progress in the last decades. Multidisciplinary care of critically ill patients has become an integral part of every modern health care system, ensuing improved care and reduced mortality. Early recognition of severe medical and surgical illnesses, advanced prehospital care and organized immediate care in trauma centres led to a rise of ICU patients. Due to the underlying disease and its need for complex mechanical support for monitoring and treatment, it is often necessary to facilitate bed-side diagnostics. Immediate diagnostics are essential for a successful treatment of life threatening conditions, early recognition of complications and good quality of care. Management of ICU patients is incomprehensible without continuous and sophisticated monitoring, bedside ultrasonography, diverse radiologic diagnostics, blood gas analysis, coagulation and blood management, laboratory and other point-of-care (POC) diagnostic modalities. Moreover, in the time of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, particular attention is given to the POC diagnostic techniques due to additional concerns related to the risk of infection transmission, patient and healthcare workers safety and potential adverse events due to patient relocation. This review summarizes the most actual information on possible diagnostic modalities in critical care, with a special focus on the importance of point-of-care approach in the laboratory monitoring and imaging procedures.

Tigecycline is a novel glycylcycline broad-spectrum antibiotic offering good coverage for critically ill patients experiencing complicated infections. A known side effect is a coagulation disorder with distinct hypofibrinogenemia. To date, the information on possible risk factors and outcomes is sparse. Therefore, the aim of this study is to examine the time course of fibrinogen level changes during tigecycline therapy in critically ill patients. Moreover, we sought to identify risk factors for coagulopathy and to report on clinically important outcomes. We retrospectively reviewed all intensive care patients admitted to our General and Surgical Intensive Care Unit receiving tigecycline between 2010 and 2018. A total of 130 patients were stratified into two groups based on the extent of fibrinogen decrease. Patients with a greater fibrinogen decrease received a higher dose, a longer treatment and more dose changes of tigecycline, respectively. In regard to the underlying pathology, these patients showed higher inflammation markers as well as a slightly reduced liver synthesis capacity. We, therefore, conclude that such a fibrinogen decrease may be based upon further impairment of liver synthesis during severe inflammatory states. To decrease the risk of bleeding, cautious monitoring of coagulation in critically ill patients treated with high-dose tigecycline is warranted.

Hyperphosphataemia can originate from tissue ischaemia and damage and may be associated with injury severity in polytrauma patients. In this retrospective, single-centre study, 166 polytrauma patients (injury severity score (ISS) ≥ 16) primarily requiring intensive care unit (ICU) treatment were analysed within a five-year timeframe. ICU-admission phosphate levels defined a hyperphosphataemic (>1.45 mmol/L; n = 56) opposed to a non-hyperphosphataemic group ( n = 110). In the hyperphosphataemic group, injury severity was increased (ISS median and IQR: 38 (30-44) vs. 26 (22-34); p < 0.001), as were signs of shock (lactate, resuscitation requirements), tissue damage (ASAT, ALAT, creatinine) and lastly in-hospital mortality (35.7% vs. 5.5%; p < 0.001). Hyperphosphataemia at ICU admission was shown to be a risk factor for mortality (1.46-2.10 mmol/L: odds ratio (OR) 3.96 (95% confidence interval (CI) 1.03-15.16); p = 0.045; >2.10 mmol/L: OR 12.81 (CI 3.45-47.48); p < 0.001) and admission phosphate levels alone performed as good as injury severity score (ISS) in predicting in-hospital mortality (area under the ROC curve: 0.811 vs. 0.770; p = 0.389). Hyperphosphataemia at ICU admission is related to tissue damage and shock and indicates injury severity and subsequent mortality in polytrauma patients. Admission phosphate levels represent an easily feasible yet strong predictor for in-hospital mortality.

Background: Cardiovascular risk may be increased in astronauts after long term space flights based on biomarkers indicating premature vascular aging. We tested the hypothesis that 60 days of strict 6° head down tilt bed rest (HDTBR), an established space analog, promotes vascular stiffening and that artificial gravity training ameliorates the response., Methods: We studied 24 healthy participants (8 women, 24-55 years, BMI = 24.3 ± 2.1 kg/m 2 ) before and at the end of 60 days HDTBR. 16 subjects were assigned to daily artificial gravity. We applied echocardiography to measure stroke volume and isovolumetric contraction time (ICT), calculated aortic compliance (stroke volume/aortic pulse pressure), and assessed aortic distensibility by MRI. Furthermore, we measured brachial-femoral pulse wave velocity ( bf PWV) and pulse wave arrival times (PAT) in different vascular beds by blood pressure cuffs and photoplethysmography. We corrected PAT for ICT (cPAT)., Results: In the pooled sample, diastolic blood pressure (+8 ± 7 mmHg, p < 0.001), heart rate (+7 ± 9 bpm, p = 0.002) and ICT (+8 ± 13 ms, p = 0.036) increased during HDTBR. Stroke volume decreased by 14 ± 15 ml ( p = 0.001). bf PWV, aortic compliance, aortic distensibility and all cPAT remained unchanged. Aortic area tended to increase ( p = 0.05). None of the parameters showed significant interaction between HDTBR and artificial gravity training., Conclusion: 60 days HDTBR, while producing cardiovascular deconditioning and cephalad fluid shifts akin to weightlessness, did not worsen vascular stiffness. Artificial gravity training did not modulate the response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Möstl, Orter, Hoffmann, Bachler, Hametner, Wassertheurer, Rabineau, Mulder, Johannes, Jordan and Tank.)

Antithrombin (AT) is a natural anticoagulant that interacts with activated proteases of the coagulation system and with heparan sulfate proteoglycans (HSPG) on the surface of cells. The protein, which is synthesized in the liver, is also essential to confer the effects of therapeutic heparin. However, AT levels drop in systemic inflammatory diseases. The reason for this decline is consumption by the coagulation system but also by immunological processes. Aside from the primarily known anticoagulant effects, AT elicits distinct anti-inflammatory signaling responses. It binds to structures of the glycocalyx (syndecan-4) and further modulates the inflammatory response of endothelial cells and leukocytes by interacting with surface receptors. Additionally, AT exerts direct antimicrobial effects: depending on AT glycosylation it can bind to and perforate bacterial cell walls. Peptide fragments derived from proteolytic degradation of AT exert antibacterial properties. Despite these promising characteristics, therapeutic supplementation in inflammatory conditions has not proven to be effective in randomized control trials. Nevertheless, new insights provided by subgroup analyses and retrospective trials suggest that a recommendation be made to identify the patient population that would benefit most from AT substitution. Recent experiment findings place the role of various AT isoforms in the spotlight. This review provides an overview of new insights into a supposedly well-known molecule.

Background: Critically ill coronavirus disease 2019 (COVID-19) patients present with a hypercoagulable state with high rates of macrovascular and microvascular thrombosis, for which hypofibrinolysis might be an important contributing factor., Methods: We retrospectively analysed 20 critically ill COVID-19 patients at Innsbruck Medical University Hospital whose coagulation function was tested with ClotPro® and compared with that of 60 healthy individuals at Augsburg University Clinic. ClotPro is a viscoelastic whole blood coagulation testing device. It includes the TPA test, which uses tissue factor (TF)-activated whole blood with added recombinant tissue-derived plasminogen activator (r-tPA) to induce fibrinolysis. For this purpose, the lysis time (LT) is measured as the time from when maximum clot firmness (MCF) is reached until MCF falls by 50%. We compared COVID-19 patients with prolonged LT in the TPA test and those with normal LT., Results: Critically ill COVID-19 patients showed hypercoagulability in ClotPro assays. MCF was higher in the EX test (TF-activated assay), IN test (ellagic acid-activated assay), and FIB test (functional fibrinogen assay) with decreased maximum lysis (ML) in the EX test (hypofibrinolysis) and highly prolonged TPA test LT (decreased fibrinolytic response), as compared with healthy persons. COVID-19 patients with decreased fibrinolytic response showed higher fibrinogen levels, higher thrombocyte count, higher C-reactive protein levels, and decreased ML in the EX test and IN test., Conclusion: Critically ill COVID-19 patients have impaired fibrinolysis. This hypofibrinolytic state could be at least partially dependent on a decreased fibrinolytic response., Competing Interests: Declarations of interest MB has received research funding and travel grants from LFB Biomedicaments, Baxter GmbH, CSL Behring GmbH, Mitsubishi Tanabe and non-financial support from TEM International outside the submitted work. MJ reported receiving grants from Baxter; grants and personal fees from Fresenius Kabi; and speaking, consulting honoraria, or both from Sphingotec, CLS-Behring, Fresenius and Astute Medical outside the submitted work. CT reports grants and personal fees from BrainLab, grants and personal fees from DePuySynthes, grants and personal fees from Intrinsic Therapeutics, grants from TETEC AG, personal fees from Aesculap, grants and personal fees from Signus Medizintechnik, grants and personal fees from Medtronic, grants and personal fees from Icotec AG, grants and personal fees from Edge Therapeutics, grants from BIT-Pharma, outside the submitted work. DF has received study funding, honoraria for consultancy and board activity from Astra Zeneca, AOP orphan, Baxter, Bayer, BBraun, Biotest, CSL Behring, Delta Select, Dade Behring, Edwards, Fresenius, Glaxo, Haemoscope, Hemogem, Lilly, LFB, Mitsubishi Pharma, NovoNordisk, Octapharm, Pfizer, Tem-Innovation outside the submitted work. The other authors declare no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Septic shock is a major burden to healthcare with mortality rates remaining high. Blood purification techniques aim to reduce cytokine levels and resultant organ failure. Regarding septic shock, hemoadsorption via CytoSorb seems promising, but the main effects on organ failure and mortality remain unclear. In this retrospective single-center study, septic shock patients receiving CytoSorb in addition to renal replacement therapy (n = 42) were analyzed and compared to matched controls (n = 42). A generalized propensity-score and Mahalanobis distance matching method ('genetic' matching) was applied. Baseline comparability was high. Differences were merely present in higher initial Sequential Organ Failure Assessment (SOFA) scores (median and interquartile range: 13.0 (12.0-14.75) vs. 12.0 (9.0-14.0)) and requirements of norepinephrine equivalents (0.54 (0.25-0.81) vs. 0.25 (0.05-0.54) µg/kg/min) in the CytoSorb group. While remaining fairly constant in the controls, the catecholamines decreased to 0.26 (0.11-0.40) µg/kg/min within 24 h after initiation of CytoSorb therapy. In-hospital mortality was significantly lower in the CytoSorb group (35.7% vs. 61.9%; p = 0.015). Risk factors for mortality within the CytoSorb group were high lactate levels and low thrombocyte counts prior to initiation. Hereby, a cut-off value of 7.5 mmol/L lactate predicted mortality with high specificity (88.9%). Thus, high lactate levels may indicate absent benefits when confronted with septic shock patients considered eligible for CytoSorb therapy.

Background: Scores can assess the severity and course of disease and predict outcome in an objective manner. This information is needed for proper risk assessment and stratification. Furthermore, scoring systems support optimal patient care, resource management and are gaining in importance in terms of artificial intelligence., Objective: This study evaluated and compared the prognostic ability of various common pediatric scoring systems (PRISM, PRISM III, PRISM IV, PIM, PIM2, PIM3, PELOD, PELOD 2) in order to determine which is the most applicable score for pediatric sepsis patients in terms of timing of disease survey and insensitivity to missing data., Methods: We retrospectively examined data from 398 patients under 18 years of age, who were diagnosed with sepsis. Scores were assessed at ICU admission and re-evaluated on the day of peak C-reactive protein. The scores were compared for their ability to predict mortality in this specific patient population and for their impairment due to missing data., Results: PIM (AUC 0.76 (0.68-0.76)), PIM2 (AUC 0.78 (0.72-0.78)) and PIM3 (AUC 0.76 (0.68-0.76)) scores together with PRSIM III (AUC 0.75 (0.68-0.75)) and PELOD 2 (AUC 0.75 (0.66-0.75)) are the most suitable scores for determining patient prognosis at ICU admission. Once sepsis is pronounced, PELOD 2 (AUC 0.84 (0.77-0.91)) and PRISM IV (AUC 0.8 (0.72-0.88)) become significantly better in their performance and count among the best prognostic scores for use at this time together with PRISM III (AUC 0.81 (0.73-0.89)). PELOD 2 is good for monitoring and, like the PIM scores, is also largely insensitive to missing values., Conclusion: Overall, PIM scores show comparatively good performance, are stable as far as timing of the disease survey is concerned, and they are also relatively stable in terms of missing parameters. PELOD 2 is best suitable for monitoring clinical course., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Mirjam Bachler has received personal fees and travel grants from LFB Biomedicaments, Takeda GmbH, CSL Behring GmbH, Mitsubishi Tanabe and non-financial support from TEM International outside the submitted work., (©2020 Niederwanger et al.)

Developing hypernatremia while on intensive care unit (ICU) is a common problem with various undesirable effects. A link to persistent inflammation, immunosuppression and catabolism syndrome (PICS) can be established in two ways. On the one hand, hypernatremia can lead to inflammation and catabolism via hyperosmolar cell stress, and on the other, profound catabolism can lead to hypernatremia via urea-induced osmotic diuresis. In this retrospective single-center study, we examined 115 patients with prolonged ICU stays (≥14 days) and sufficient renal function. Depending on their serum sodium concentrations between ICU day 7 and 21, allocation to a hypernatremic (high) and a nonhypernatremic group (low) took place. Distinct signs of PICS were detectable within the complete cohort. Thirty-three of them (28.7%) suffered from ICU-acquired hypernatremia, which was associated with explicitly higher signs of inflammation and ongoing catabolism as well as a prolonged ICU length of stay. Catabolism was discriminated better by the urea generation rate and the urea-to-creatinine ratio than by serum albumin concentration. An assignable cause for hypernatremia was the urea-induced osmotic diuresis. When dealing with ICU patients requiring prolonged treatment, hypernatremia should at least trigger thoughts on PICS as a contributing factor. In this regard, the urea-to-creatinine ratio is an easily accessible biomarker for catabolism.

Red Bull energy drink is popular among athletes, students and drivers for stimulating effects or enhancing physical performance. In previous work, Red Bull has been shown to exert manifold cardiovascular effects at rest and during exercise. Red Bull with caffeine as the main ingredient increases blood pressure in resting individuals, probably due to an increased release of (nor)-epinephrine. Red Bull has been shown to alter heart rate or leaving it unchanged. Little is known about possible effects of caffeinated energy drinks on pulmonary ventilation/perfusion distribution at sea level or at altitude. Here, we hypothesized a possible alteration of pulmonary blood flow in ambient air and in hypoxia after Red Bull consumption. We subjected eight anesthetized piglets in normoxia (FiO 2 = 0.21) and in hypoxia (FiO 2 = 0.13), respectively, to 10 mL/kg Red Bull ingestion. Another eight animals served as controls receiving an equivalent amount of saline. In addition to cardiovascular data, ventilation/perfusion distribution of the lung was assessed by using the multiple inert gas elimination technique (MIGET). Heart rate increased in normoxic conditions but was not different from controls in acute short-term hypoxia after oral Red Bull ingestion in piglets. For the first time, we demonstrate an increased fraction of pulmonary shunt with unchanged distribution of pulmonary blood flow after Red Bull administration in acute short-term hypoxia. In summary, these findings do not oppose moderate consumption of caffeinated energy drinks even at altitude at rest and during exercise.

The current study aims to evaluate whether prophylactic anticoagulation using argatroban or an increased dose of unfractionated heparin (UFH) is effective in achieving the targeted activated partial thromboplastin time (aPTT) of more than 45 s in critically ill heparin-resistant (HR) patients. Patients were randomized either to continue receiving an increased dose of UFH, or to be treated with argatroban. The endpoints were defined as achieving an aPTT target of more than 45 s at 7 h and 24 h. This clinical trial was registered on clinicaltrials.gov (NCT01734252) and on EudraCT (2012-000487-23). A total of 42 patients, 20 patients in the heparin and 22 in the argatroban group, were included. Of the patients with continued heparin treatment 55% achieved the target aPTT at 7 h, while only 40% of this group maintained the target aPTT after 24 h. Of the argatroban group 59% reached the target aPTT at 7 h, while at 24 h 86% of these patients maintained the targeted aPTT. Treatment success at 7 h did not differ between the groups ( p = 0.1000), whereas at 24 h argatroban showed significantly greater efficacy ( p = 0.0021) than did heparin. Argatroban also worked better in maintaining adequate anticoagulation in the further course of the study. There was no significant difference in the occurrence of bleeding or thromboembolic complications between the treatment groups. In the case of heparin-resistant critically ill patients, argatroban showed greater efficacy than did an increased dose of heparin in achieving adequate anticoagulation at 24 h and in maintaining the targeted aPTT goal throughout the treatment phase., Competing Interests: Mirjam Bachler has received research funding and travel grants from LFB Biomedicaments, Baxter GmbH, CSL Behring GmbH, and Mitsubishi Tanabe, as well as non-financial support from TEM International outside the submitted work. Benedikt Treml has received travel grants from Pfizer. Bettina Schenk has received travel grants, and honoraria for speaking or participation at meetings from CSL Behring, BBraun, and Biotest. Dietmar Fries has received study funding, as well as honoraria for consultancy and board activity from Astra Zeneca, AOP orphan, Baxter, Baer, BBraun, Biotest, CSL Behring, Delta Select, Dae Behring, Edwards, Fresenius, Glaxo, Haemoscope, Hemogem, Lilly, LFB, Mitsubishi Pharma, NovoNordisk, Octapharm, Pfizer, and Tem-Innovation outside the submitted work. The other authors (Tobias Hell, Johannes Bösch, Barbara Friesenecker, Benjamin Treichl, Ingo Lorenz, Daniel Stengg, Stefan Hruby, Bernd Wallner, Elgar Oswald, Mathias Ströhle, Christian Niederwanger, and Christian Irsara) declared no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Tigecycline offers broad anti-bacterial coverage for critically ill patients with complicated infections. A described but less researched side effect is coagulopathy. The aim of this study was to test whether tigecycline interferes with fibrinogen polymerization by peripheral interactions. To study the effect of unmetabolized tigecycline, plasma of healthy volunteers were spiked with increasing concentrations of tigecycline. In a second experimental leg, immortalized human liver cells (HepG2) were treated with the same concentrations to test an inhibitory effect of hepatic tigecycline metabolites. Using standard coagulation tests, only the activated thromboplastin time in humane plasma was prolonged with increasing concentrations of tigecycline. Visualization of the fibrin network using confocal live microscopy demonstrated a qualitative difference in tigecycline treated experiments. Thrombelastometry and standard coagulation tests did not indicate an impairment of coagulation. Although the discrepancy between functional and immunologic fibrinogen levels increased in cell culture assays with tigecycline concentration, fibrinogen levels in spiked plasma samples did not show significant differences determined by functional versus immunologic methods. In our in vitro study, we excluded a direct effect of tigecycline in increasing concentrations on blood coagulation in healthy adults. Furthermore, we demonstrated a rapid loss of mitochondrial activity in hepatic cells with supra-therapeutic tigecycline dosages., Competing Interests: The authors declare no conflict of interest.

Aims: This study aimed to determine the time needed for one or two companion rescuers to access, extricate, and deliver cardiopulmonary resuscitation (CPR) to a fully buried manikin during a simulated avalanche burial scenario. Materials and Methods: In this randomized, single-blinded study, 18 medical students were required to extricate a manikin manually from a simulated avalanche burial of 1 m in depth, either alone or in teams of two. Each participant performed three consecutive tests with the manikin in three different positions in random order. Results: Median time to first manikin contact was 2.5 minutes, median time to airway access 7.2 minutes, and median time to standard position for CPR 10.1 minutes. Overall, the number of rescuers (one compared to two rescuers, 10.5 minutes vs. 9.3 minutes; p  = 0.686) and the burial position of the manikin (10.8 minutes vs. 10.6 minutes vs. 8.8 minutes; p  = 0.428) had no influence on extrication times. Preexisting training (6.1 minutes vs. 11.0 minutes p  = 0.006) and a learning effect obtained during the experiments (12.4 minutes the first test vs. 9.3 in the third test; p  = 0.017) improved all extrication times. Conclusion: It takes an average of 7 minutes after location of a simulated avalanche victim, buried at a depth of 1 m, to free the airway, plus a further 3 minutes to initiate CPR in standard supine position. This is more than two-thirds of the 15 minutes considered necessary for successful companion avalanche rescue. Even minimal training significantly reduced extrication times. These findings emphasize the importance of regular practice in specific extrication techniques that should be part of any training in avalanche companion rescue.

Background: Sepsis is characterized by a pro-inflammatory and pro-coagulatory shift which can induce life-threatening complications. Close monitoring and risk stratification of sepsis patients is crucial for proper treatment and consequently patient outcome. Therefore, this study focuses on the response patterns of inflammatory and coagulatory parameters used in clinical routines to estimate the course of sepsis., Methods: A total of 1,110 patients diagnosed with sepsis were retrospectively analyzed to identify response patterns for risk stratification of routine parameters measured at the peak level of C-reactive protein. Cluster analysis was used and the differences in the patient characteristics and 28-day survival were assessed. Cox proportional hazards regression model for survival stratified by the clusters was performed., Results: The analyses revealed the parameters to have five distinct response patterns. These clusters reflect the etiology as well as the course of sepsis associated with different mortalities. Here, impairment of the liver plays a crucial role in the ability to appropriately respond to sepsis. Of the routinely measured parameters, C-reactive protein and antithrombin seem to be unspecific for stratification of septic patients. Adjusted for the individual clusters, survival was associated with an increase in fibrinogen ( p  = 0.0042), platelets ( p  = 0.0003) and PT ( p  = 0.001) as well as a decrease in leukocytes ( p  = 0.034)., Conclusions: This study reveals that patients have distinct response patterns of inflammatory and coagulatory parameters depending on disease etiology. These patterns are associated with different mortalities although the patients have similar levels of C-reactive protein. Independently of the type of response, good coagulatory capacity seems to be crucial for patient survival., Competing Interests: The authors state that they have no competing interests with regard to this study. Mirjam Bachler has received personal fees from LFB Biomedicaments, Baxter GmbH, CSL Behring GmbH, Mitsubishi Tanabe and non-financial support from TEM International outside the submitted work. Petra Innerhofer has received personal fees from Baxter GmbH, CSL Behring GmbH, Fresenius Kabi GmbH Austria, Bayer GmbH Austria and LFB and non-financial support from TEM International, outside the submitted work. Dietmar Fries has received study funding, honoraria for consultancy and board activity from Astra Zeneca, AOP orphan, Baxter, Baer, BBraun, Biotest, CSL Behring, Delta Select, Dae Behring, Edwards, Fresenius, Glaxo, Haemoscope, Hemogem, Lilly, LFB, Mitsubishi Pharma, NovoNordisk, Octapharm, Pfizer, Tem-Innovation outside the submitted work.

Background: Sepsis is associated with a deflection of inflammatory and coagulative parameters, since some clotting factors are known to be involved in the host's defense against infection and inflammation. These parameters could play a crucial role in the course of sepsis and be used as prognostic markers in critically ill children., Methods: A total of 250 critically ill pediatric patients diagnosed with sepsis were retrospectively analyzed to identify routinely measured predictors for in-hospital mortality at the peak level of C-reactive protein. Those parameters entered multivariate logistic regression analysis as well as a decision tree for survival., Results: Multivariate logistic regression analysis revealed fibrinogen, platelets and activated partial thromboplastin time (aPTT) at the peak level of C-reactive protein to be predictors for survival (p = 0.03, p = 0.01 and p = 0.02, respectively). An increase in fibrinogen and platelets is linked to survival, whereas an aPTT prolongation is associated with higher mortality; adjusted odds ratios (95% CI) for an increase of 100 mg/dl in fibrinogen are 1.35 (1.04-1.82) per 50 G/l platelets 1.94 (1.3-3.29) and 0.83 (0.69-0.96) for an aPTT prolongation of 10 s. Decision tree analysis shows that a fibrinogen level below 192 mg/dl (90.9% vs. 13% mortality) is most distinctive in non-survivors., Conclusions: High levels of fibrinogen and platelets as well as a non-overshooting aPTT are associated with a higher survival rate in pediatric patients with diagnosed sepsis. In particular, hypofibrinogenemia is distinctive for a high mortality rate in septic critically ill children.

Background: Sepsis remains a major problem in intensive care medicine. It is often accompanied by coagulopathies, leading to thrombotic occlusion of small vessels with subsequent organ damage and even fatal multi-organ failure. Prediction of the clinical course and outcome-especially in the heterogeneous group of pediatric patients-is difficult. Antithrombin, as an endogenous anticoagulant enzyme with anti-inflammatory properties, plays a central role in controling coagulation and infections. We investigated the relationship between antithrombin levels and organ failure as well as mortality in pediatric patients with sepsis., Methods: Data from 164 patients under the age of 18, diagnosed with sepsis, were retrospectively reviewed. Antithrombin levels were recorded three days before to three days after peak C-reactive protein to correlate antithrombin levels with inflammatory activity. Using the concept of developmental haemostasis, patients were divided into groups <1 yr and ≥1 yr of age., Results: In both age groups, survivors had significantly higher levels of antithrombin than did deceased patients. An optimal threshold level for antithrombin was calculated by ROC analysis for survival: 41.5% (<1 yr) and 67.5% (≥1 yr). The mortality rate above this level was 3.3% (<1 yr) and 9.5% (≥1 yr), and below this level 41.7% (<1 yr) and 32.2% (≥1 yr); OR 18.8 (1.74 to 1005.02), p  = 0.0047, and OR 4.46 (1.54 to 14.89), p  = 0.003. In children <1 yr with antithrombin levels <41.5% the rate of respiratory failure (66.7%) was significantly higher than in patients with antithrombin levels above this threshold level (23.3%), OR 6.23 (1.23 to 37.81), p  = 0.0132. In children ≥1 yr, both liver failure (20.3% vs 1.6%, OR 15.55 (2.16 to 685.01), p  = 0.0008) and a dysfunctional intestinal tract (16.9% vs 4.8%, OR 4.04 (0.97 to 24.08), p  = 0.0395) occurred more frequently above the antithrombin threshold level of 67.5%., Conclusion: In pediatric septic patients, significantly increased mortality and levels of organ failure were found below an age-dependent antithrombin threshold level. Antithrombin could be useful as a prognostic marker for survival and occurrence of organ failure in pediatric sepsis., Competing Interests: The authors state that they have no competing interests in regard to this study. Mirjam Bachler has received personal fees from LFB Biomedicaments, Baxter GmbH, CSL Behring GmbH, Mitsubishi Tanabe and non-financial support from TEM International outside the submitted work.

Background: Direct oral anticoagulants (DOACs) pose a great challenge for physicians in life-threatening bleeding events. The aim of this study was to test the efficacy of reversing the DOAC rivaroxaban using four-factor PCC (prothrombin complex concentrate), a non-specific reversing agent., Methods: Patients with life-threatening bleeding events during rivaroxaban treatment were included and administered 25 U kg -1 of PCC. Blood samples were collected immediately prior to as well as after PCC treatment at predefined time intervals. The primary endpoint was defined as the difference in thrombin generation (TG) parameters ETP (endogenous thrombin potential) and C max (peak thrombin generation) prior to and ten minutes subsequent to PCC treatment., Results: Thirteen patients, of whom the majority suffered from intra-cranial haemorrhage (ICH) or subdural haemorrhage (SDH), were included and administered PCC. The results show that the ETP (TG) significantly ( p  = 0.001) improved by 68% and C max (TG) by 54% (p = 0.001) during PCC treatment. In addition, the Quick value (prothrombin time: Quick PT ) significantly improved by 28% and the activated partial thromboplastin time (aPTT) was decreased by 7% ten minutes after PCC administration. C max was reduced at baseline, but not ETP, aPTT or Quick PT . Lag time until initiation (TG, t lag ), thromboelastometry clotting time (CT EXTEM ) and time to peak (TG, t max ) correlated best with measured rivaroxaban levels and were out of normal ranges at baseline, but did not improve after PCC administration. In 77% of the patients bleeding (ICH/SDH-progression) ceased following PCC administration. During the study three participants passed away due to other complications not related to PCC treatment. The possibility of thrombosis formation was also evaluated seven days after administering PCC and no thromboses were found., Conclusions: This study shows that use of PCC improved ETP, C max, Quick PT and aPTT. However, of these parameters, only C max was reduced at the defined baseline. It can be concluded that CT EXTEM, t lag and t max correlated best with the measured rivaroxaban levels. The study drug was found to be safe. Nonetheless, additional studies specifically targeting assessment of clinical endpoints should be performed to further confirm these findings., Clinical Trial Registration: EudraCT trial No. 2013-004484-31., Competing Interests: This study was approved by the Human Subjects Review Board of the Medical University of Innsbruck, Austria (Ref.: UN2013–0048), as well as by the national competent authority (Bundesamt für Sicherheit im Gesundheitswesen, BASG, Vienna, Austria, Ref.: LCM-718199) and registered with EudraCT (Ref.: 2013–004484-31). Written informed consent was obtained from all study participants. Patients, who for medical reasons (unconscious, shock, sedated, etc.) were not able to give their consent to participate in this clinical trial, were enrolled based on the principle of deferred consent according to § 43a (1), Austrian Medicinal Products Law (“Österreichisches Arzneimittelgesetz”). The study was performed in compliance with the Declaration of Helsinki guidelines regarding ethical principles for medical research involving human subjects and followed Good Clinical Practice as defined by the International Conference on Harmonization (ICH-GCP).Not applicable.D. Fries has received study funding, honoraria for consultancy and board activity from Astra Zeneca, AOP orphan, Baxter, Baer, BBraun, Biotest, CSL Behring, Delta Select, Dae Behring, Edwards, Fresenius, Glaxo, Haemoscope, Hemogem, Lilly, LFB, Mitsubishi Pharma, NovoNordisk, Octapharm, Pfizer, Tem-Innovation. R. Beer received speaker’s honoraria from Boehringer Ingelheim RCV Gmbh & Co KG. All other authors declare that they have no conflicts of interest.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background and Aim : Although fibrinogen has been established as a key player in the process of coagulation, many questions about the role of fibrinogen under specific conditions remain. Confocal microscopic assessment of clot formation, and in particular the role that fibrinogen plays in this process, is commonly investigated using pre-labeled fibrinogen. This has a number of drawbacks, primarily that it is impossible to stain fibrin networks after their formation. The aim of the present study is to present an alternative for conveniently post-staining fibrin in a wide range of models/situations, in real time and with high resolution. Methods : We combined a peptide known to bind fibrin and linked it to fluorescein isothiocyanate (FITC), creating the FITC-Fibrin-Binding Peptide (FFBP). We subsequently tested its fibrin-binding capability in vitro under static conditions, as well as under simulated flow, using real-time live confocal microscopy. Results : Fibrin stained with FFBP overlaps with fibrin stained with fibrinogen pre-labeled with Alexa Fluor 647 following coagulation induction. In contrast to pre-labeled fibrinogen, FFBP also stains already formed fibrin networks. By combining FFBP with real-time live confocal microscopy even the visualization of single fibrin fibers is possible. Conclusions : These data indicate that FFBP is a valid and valuable tool for real-time live confocal assessment of clot formation. Relevance for patients: Our findings present a valuable alternative for the visualization of fibrin even after its formation, and we believe this approach will be particularly valuable for future investigations of important, but previously overlooked, aspects of clot formation., Competing Interests: C. Solomon was an employee of CSL Behring at the time of writing and previously received speaker honoraria and re-search support from Tem International and CSL Behring and travel support from Haemoscope Ltd (former manufacturer of TEG®). D. Fries has received honoraria for consulting, lecture fees and sponsoring for academic studies from the following companies: Astra Zeneca, AOP Orphan, Baxter, Bayer, B. Braun, Biotest, CSL Behring, Delta Select, Dade Behring, Edwards, Fresenius, Glaxo, Haemoscope, Hemogem, Lilly, LFB, Mitsubishi Pharma, NovoNordisk, Octapharm, Pfizer, Tem-Innovation. M. Hermann, N. Weiss, B. Schenk and M. Bachler have no conflicts of interest to disclose.

Objective: Sudden unexplained death in epilepsy (SUDEP) during inpatient electroencephalography (EEG) monitoring has been a rare but potentially preventable event, with associated cardiopulmonary markers. To date, no systematic evaluation of alarm settings for a continuous pulse oximeter (SpO 2 ) has been performed. In addition, evaluation of the interrelationship between the ictal and interictal states for cardiopulmonary measures has not been reported., Methods: Patients with epilepsy were monitored using video-EEG, SpO 2 , and electrocardiography (ECG). Alarm thresholds were tested systematically, balancing the number of false alarms with true seizure detections. Additional cardiopulmonary patterns were explored using automated ECG analysis software., Results: One hundred ninety-three seizures (32 generalized) were evaluated from 45 patients (7,104 h recorded). Alarm thresholds of 80-86% SpO 2 detected 63-73% of all generalized convulsions and 20-28% of all focal seizures (81-94% of generalized and 25-36% of focal seizures when considering only evaluable data). These same thresholds resulted in 25-146 min between false alarms. The sequential probability of ictal SpO 2 revealed a potential common seizure termination pathway of desaturation. A statistical model of corrected QT intervals (QTc), heart rate (HR), and SpO 2 revealed close cardiopulmonary coupling ictally. Joint probability maps of QTc and SpO 2 demonstrated that many patients had baseline dysfunction in either cardiac, pulmonary, or both domains, and that ictally there was dissociation-some patients exhibited further dysfunction in one or both domains., Significance: Optimal selection of continuous pulse oximetry thresholds involves a tradeoff between seizure detection accuracy and false alarm frequency. Alarming at 86% for patients that tend to have fewer false alarms and at 80% for those who have more, would likely result in a reasonable tradeoff. The cardiopulmonary findings may lead to SUDEP biomarkers and early seizure termination therapies., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Background and Objectives: There is a lack of evidence concerning associations between novel parameters of arterial stiffness as cardiovascular risk markers and traditional structural and functional vascular biomarkers in a population-based Caucasian cohort. We examined these associations in the second follow-up of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA 3)., Methods: Arterial stiffness was measured oscillometrically by pulse wave analysis to derive the cardio-ankle vascular index (CAVI), brachial-ankle (baPWV) and aortic pulse wave velocity (aPWV), and amplitude of the forward and backward wave. Carotid ultrasonography was used to measure carotid intima-media thickness (cIMT) and carotid lumen diameter (LD), and to derive a distensibility coefficient (DC). We used multivariable linear regression models adjusted for several potential confounders for 2,733 people aged 50-81 years., Results: CAVI, aPWV and the amplitude of the forward and backward wave were significant predictors of cIMT (p < 0.001). All parameters were significantly associated with LD (p < 0.001), with aPWV and the amplitude of the forward wave explaining the highest proportion of variance (2%). Only CAVI and baPWV were significant predictors of DC (p < 0.001), explaining more than 0.3% of the DC variance., Conclusion: We demonstrated that novel non-invasive oscillometric arterial stiffness parameters are differentially associated with specific established structural and functional local stiffness parameters. Longitudinal studies are needed to follow-up on these cross-sectional findings and to evaluate their relevance for clinical phenotypes., Competing Interests: SW is the inventor (not holder) of a patent that is partly used in the ARCSolver method utilized in this work. The remaining authors declare no conflict of interest. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Background: Heart rate variability is the variation of the time interval between consecutive heartbeats. Entropy is a commonly used tool to describe the regularity of data sets. Entropy functions are defined using multiple parameters, the selection of which is controversial and depends on the intended purpose. This study describes the results of tests conducted to support parameter selection, towards the goal of enabling further biomarker discovery., Methods: This study deals with approximate, sample, fuzzy, and fuzzy measure entropies. All data were obtained from PhysioNet, a free-access, on-line archive of physiological signals, and represent various medical conditions. Five tests were defined and conducted to examine the influence of: varying the threshold value r (as multiples of the sample standard deviation σ, or the entropy-maximizing rChon), the data length N, the weighting factors n for fuzzy and fuzzy measure entropies, and the thresholds rF and rL for fuzzy measure entropy. The results were tested for normality using Lilliefors' composite goodness-of-fit test. Consequently, the p-value was calculated with either a two sample t-test or a Wilcoxon rank sum test., Results: The first test shows a cross-over of entropy values with regard to a change of r. Thus, a clear statement that a higher entropy corresponds to a high irregularity is not possible, but is rather an indicator of differences in regularity. N should be at least 200 data points for r = 0.2 σ and should even exceed a length of 1000 for r = rChon. The results for the weighting parameters n for the fuzzy membership function show different behavior when coupled with different r values, therefore the weighting parameters have been chosen independently for the different threshold values. The tests concerning rF and rL showed that there is no optimal choice, but r = rF = rL is reasonable with r = rChon or r = 0.2σ., Conclusions: Some of the tests showed a dependency of the test significance on the data at hand. Nevertheless, as the medical conditions are unknown beforehand, compromises had to be made. Optimal parameter combinations are suggested for the methods considered. Yet, due to the high number of potential parameter combinations, further investigations of entropy for heart rate variability data will be necessary.

European eels (Anguilla anguilla) undertake spawning migrations of more than 5000 km from continental Europe and North Africa to frontal zones in the Sargasso Sea. Subsequently, the larval offspring are advected by large-scale eastward ocean currents towards continental waters. However, the Sargasso Sea is oligotrophic, with generally low plankton biomass, and the feeding biology of eel larvae has so far remained a mystery, hampering understanding of this peculiar life history. DNA barcoding of gut contents of 61 genetically identified A. anguilla larvae caught in the Sargasso Sea showed that even the smallest larvae feed on a striking variety of plankton organisms, and that gelatinous zooplankton is of fundamental dietary importance. Hence, the specific plankton composition seems essential for eel larval feeding and growth, suggesting a linkage between eel survival and regional plankton productivity. These novel insights into the prey of Atlantic eels may furthermore facilitate eel larval rearing in aquaculture, which ultimately may replace the unsustainable use of wild-caught glass eels.