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Background: Recent data suggest that vacation may improve cardiovascular health, an effect possibly moderated by altitude. The aim of the present study was to study the effect of a 3-week vacation at moderate and low altitude on perceived health in individuals with increased cardiovascular risk.Methods: Seventy-two overweight males, both occupationally active and retired (mean age=56.6 +/- 7.2 years), with signs of metabolic syndrome were randomly assigned to identical sojourns at either moderate (1,700 m) or low (300 m) altitude and engaged in four 3- to 4-h heart-rate-controlled hiking tours per week. Perceived health was measured 2 weeks before vacation, at the beginning and end of vacation, and 7 weeks after vacation.Results: Fitness, recreational ability, positive and negative mood and social activities improved during vacation, independent of altitude and occupational status, although the day-to-day improvement in quality of sleep was delayed at moderate altitude. During the follow-up examinations, improvements in all reported aspects of health except for social activities were maintained. In comparison to retired individuals, active individuals showed a greater long-term improvement in social activities.Conclusion: Vacation positively affects perceived health independent of altitude or occupational status in generally inactive overweight males. [ABSTRACT FROM AUTHOR]

Background: More than 1.5 billion passengers travel by aircraft every year. Leg edema, as a sign of venous stasis, is a well-known problem among passengers during and after long-haul flights. Until now, no studies have been done on the development of leg edema and fluid shifts under real flight conditions. The aim of our study was to evaluate edema formation in the leg and to investigate possible fluid shifts to the interstitial space under real flight conditions.Methods: Twenty participants, 10 without risk and 10 with moderate risk for venous thrombosis, were selected. They flew from Vienna to Washington, flight time 9 h, and returned 2 days later. Investigations were done 48 h before the flight, between the fifth and eighth flight hour on board to Washington and back to Vienna, immediately after arrival in Vienna, and 1 and 3 days after arrival. Plethysmographic measurements were carried out using an optoelectronic scanner system (Perometer). Thickness of the skin was measured at the forehead and in front of the tibia.Results: There were no differences in all measurements between both groups. The volume of the leg increased from 8242 +/- 1420 mL to 8496 +/- 1474 mL after the flight (p <.001). Volume accumulation was distributed to the lower leg as well as to the thigh. Skin thickness in front of the tibia increased significantly during the flight (p <.05), and remained elevated 1 day after arrival.Conclusion: We have demonstrated that long-haul flights induce significant fluid accumulation in the lower extremity, involving the lower leg and thigh. This increase in tissue thickness was maintained for some days after the flights. [ABSTRACT FROM AUTHOR]

Prolonged physical exercise is associated with multiple changes in the immune status indicating an acute phase response and an activation of the immune system. Eccentric muscle activation (e.g. downhill running) induces micro-trauma of skeletal muscles thus inducing an inflammatory response. At present there are no data to which extent the immune system is activated after a downhill marathon run and if there arc any correlations between immune activation and markers for muscle damage or functional impairment of leg muscles. As model for severe eccentric exercise we selected the Tyrolean Speed Marathon (42 km downhill run, 795 m vertical difference). 13 volunteers (12 male, 1 female; mean running time 224 min [range 193 - 266 min.]) finished the run. Blood from antecubital veins was collected 3-4 days before (T1 ), 3-4 hrs before (T2) and immediately after the marathon (T3) as well as on the morning after the run (T4). We measured serum neopterin concentrations, white blood cell count. C-reactive protein (CRP), creatine kinase (CK), myoglobin (Mb), cardiac troponin I (cTnl) and troponin Τ (cTnT). Moreover, isokinetic muscle tests were performed. Following significant changes were found (before vs. after the run): increase in neopterin, CRP, total leukocyte count, CK. Mb, cTnl, cTnT, whereas isokinetic dynamometry showed a reduction in peak hamstring torque of both thighs after the marathon. There were no significant correlations (Spearman's rank correlation coefficient) between the observed changes in neopterin and CRP, CK, Mb. cTnT, cTnl or between neopterin concentrations and parameters of isokinetic muscle tests. We could demonstrate that a 42 km downhill marathon is associated a) with an activation of the cellular immune system, as evidenced by the increase in serum-neopterin. b) pronounced micro-skeletal muscle damage with high serum creatine kinase and myoglobin, and c) eccentric hamstring fatigue. The absolute changes in neopterin were moderate and similar to other types of exercise (flat course and bicycle marathon, mountain hiking).

Prolonged physical exercise is associated with several immunological changes, e.g. increase in proinflammatory cytokines, changes in the white blood count etc. Great discrepancies exist with regard to the exercise- induced influence on serum immunoglobulin and neopterin values. One explanation could be the shifts in plasma volume (PV) during and after exercise which might influence plasma concentrations of these parameters. Therefore we investigated the consequences of a marathon race in a homogenous group of experienced runners on plasma volume shifts, serum Immunglobulin and neopterin concentrations. Plasma values with and without correction for plasma volume shifts were compared. PV was significantly diminished after the race (-8.4%) followed by a rise 34h after finish (+8.5%). Serum immunoglobulin IgG, IgA and IgM were increased within the first hours postmarathon and normalized in the recovery period. When chages in PV were considered, only IgA rose significantly. Serum neopterin remained unchanged after the marathon independently whether corrected for PV changes or not. We conclude that the increase in immunoglobulins in our study was mainly the consequence of plasma volume changes. Since neopterin was unchanged we have at least in our study no evidence for exercise-induced activation of the cellular immune system.

Introduction: Acute kidney injury is a frequent complication in critically ill patients with and without COVID-19. The aim of this study was to evaluate the incidence of, and risk factors for, acute kidney injury and its effect on clinical outcomes of critically ill COVID-19 patients in Tyrol, Austria., Methods: This multicenter prospective registry study included adult patients with a SARS-CoV-2 infection confirmed by polymerase chain reaction, who were treated in one of the 12 dedicated intensive care units during the COVID-19 pandemic from February 2020 until May 2022., Results: In total, 1042 patients were included during the study period. The median age of the overall cohort was 66 years. Of the included patients, 267 (26%) developed acute kidney injury during their intensive care unit stay. In total, 12.3% (n = 126) required renal replacement therapy with a median duration of 9 (IQR 3-18) days. In patients with acute kidney injury the rate of invasive mechanical ventilation was significantly higher with 85% (n = 227) compared to 41% (n = 312) in the no acute kidney injury group (p < 0.001). The most important risk factors for acute kidney injury were invasive mechanical ventilation (OR = 4.19, p < 0.001), vasopressor use (OR = 3.17, p < 0.001) and chronic kidney disease (OR = 2.30, p < 0.001) in a multivariable logistic regression analysis. Hospital and intensive care unit mortality were significantly higher in patients with acute kidney injury compared to patients without acute kidney injury (Hospital mortality: 52.1% vs. 17.2%, p < 0.001, ICU-mortality: 47.2% vs. 14.7%, p < 0.001)., Conclusion: As in non-COVID-19 patients, acute kidney injury is clearly associated with increased mortality in critically ill COVID-19 patients. Among known risk factors, invasive mechanical ventilation has been identified as an independent and strong predictor of acute kidney injury., (© 2023. The Author(s).)

Background: Widely varying mortality rates of critically ill Coronavirus disease 19 (COVID-19) patients in the world highlighted the need for local surveillance of baseline characteristics, treatment strategies and outcome. We compared two periods of the COVID-19 pandemic to identify important differences in characteristics and therapeutic measures and their influence on the outcome of critically ill COVID-19 patients., Methods: This multicenter prospective register study included all patients with a SARS-CoV‑2 infection confirmed by polymerase chain reaction, who were treated in 1 of the 12 intensive care units (ICU) from 8 hospitals in Tyrol, Austria during 2 defined periods (1 February 2020 until 17 July: first wave and 18 July 2020 until 22 February 2021: second wave) of the COVID-19 pandemic., Results: Overall, 508 patients were analyzed. The majority (n = 401) presented during the second wave, where the median age was significantly higher (64 years, IQR 54-74 years vs. 72 years, IQR 62-78 years, p < 0.001). Invasive mechanical ventilation was less frequent during the second period (50.5% vs 67.3%, p = 0.003), as was the use of vasopressors (50.3% vs. 69.2%, p = 0.001) and renal replacement therapy (12.0% vs. 19.6%, p = 0.061), which resulted in shorter ICU length of stay (10 days, IQR 5-18 days vs. 18 days, IQR 5-31 days, p < 0.001). Nonetheless, ICU mortality did not change (28.9% vs. 21.5%, p = 0.159) and hospital mortality even increased (22.4% vs. 33.4%, p = 0.039) in the second period. Age, frailty and the number of comorbidities were significant predictors of hospital mortality in a multivariate logistic regression analysis of the overall cohort., Conclusion: Advanced treatment strategies and learning effects over time resulted in reduced rates of mechanical ventilation and vasopressor use in the second wave associated with shorter ICU length of stay. Despite these improvements, age appears to be a dominant factor for hospital mortality in critically ill COVID-19 patients., (© 2021. The Author(s).)

Background: Bleeding is a common problem in children with congenital heart disease undergoing major cardiac surgery requiring cardiopulmonary bypass (CPB). Little is known about optimal management with blood products., Objective: To investigate clinical outcome and hemostatic effects of fibrinogen concentrate (FC) in combination with prothrombin complex concentrate (PCC) versus standard treatment with fresh frozen plasma (FFP) in children undergoing cardiac surgery., Methods: For this single-institution cohort study, data on 525 children were analyzed. Propensity score matching in 210 children was applied to reduce the impact of various baseline characteristics., Results: Three children treated with FC/PCC developed surgical site bleeding requiring surgical revision. One child developed central venous line-related thrombosis. Blood loss through chest tube drainage was independent of FC/PCC. Coagulation abnormalities were not present in any of these children. Time to extubation and ICU stay did not differ. In the FC/PCC group, children received (median, Q1, Q3) 52 mg/kg (32, 83) FC and 28IU/kg (13, 44) PCC. Fibrinogen concentration was comparable at baseline. On admission to the ICU, fibrinogen was higher in children receiving FC/PCC, namely, 232 mg/dL (196, 280), than in children receiving FFP (186 mg/dL, 149, 224; P < .001). On discharge from the ICU, values did not differ ((FC/PCC 416 mg/dL (288, 501)), non-FC/PCC 418 mg/dL (272, 585; P = 1.000))., Conclusion: FC/PCC was well tolerated and permitted hemostasis to be maintained, even in the very young. We were not able to detect a signal for inferiority of this treatment. We conclude that FC/PCC can safely replace FFP., (© 2021 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Fibrinogen supplementation is recommended for treatment of severe trauma hemorrhage. However, required dosages and aimed for post-treatment fibrinogen levels remain a matter of discussion. Within the published RETIC study, adult patients suffering trauma-induced coagulopathy were randomly assigned to receive fibrinogen concentrate (FC) as first-line ( n = 50) or crossover rescue ( n = 20) therapy. Depending on bodyweight, a single dose of 3, 4, 5, or 6 g FC was administered and repeated if necessary (FibA10 < 9 mm). The dose-dependent response (changes in plasma fibrinogen and FibA10) was analyzed. Receiver operating characteristics (ROC) analysis regarding the need for massive transfusion and correlation analyses regarding fibrinogen concentrations and polymerization were performed. Median FC single doses amounted to 62.5 (57 to 66.66) mg.kg - 1 . One FC single-dose sufficiently corrected fibrinogen and FibA10 (median fibrinogen 213 mg.dL -1 , median FibA10 11 mm) only in patients with baseline fibrinogen above 100 mg.dL -1 and FibA10 above 5 mm, repeated dosing was required in patients with lower baseline fibrinogen/FibA10. Fibrinogen increased by 83 or 107 mg.dL -1 and FibA10 by 4 or 4.5 mm after single or double dose of FC, respectively. ROC curve analysis revealed post-treatment fibrinogen levels under 204.5 mg.dL - 1 to predict the need for massive transfusion (AUC 0.652; specificity: 0.667; sensitivity: 0.688). Baseline fibrinogen/FibA10 levels should be considered for FC dosing as only sufficiently corrected post-treatment levels limit transfusion requirements., Competing Interests: PI has received personal fees from Baxter GmbH, personal fees from CSL Behring GmbH, personal fees from Fresenius Kabi GmbH Austria, personal fees from Bayer GmbH Austria, personal fees from LFB, non-financial support from TEM International, 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. MM has received personal fees from CSL Behring GmbH, outside the submitted work. The remaining authors have disclosed that they have no potential conflicts of interest.

Introduction: On February 25, 2020, the first 2 patients were tested positive for severe acute respiratory syndrome coronavirus‑2 (SARS-CoV-2) in Tyrol, Austria. Rapid measures were taken to ensure adequate intensive care unit (ICU) preparedness for a surge of critically ill coronavirus disease-2019 (COVID-19) patients., Methods: This cohort study included all COVID-19 patients admitted to an ICU with confirmed or strongly suspected COVID-19 in the State of Tyrol, Austria. Patients were recorded in the Tyrolean COVID-19 intensive care registry. Date of final follow-up was July 17, 2020., Results: A total of 106 critically ill patients with COVID-19 were admitted to 1 of 13 ICUs in Tyrol from March 9 to July 17, 2020. Median age was 64 years (interquartile range, IQR 54-74 years) and the majority of patients were male (76 patients, 71.7%). Median simplified acute physiology score III (SAPS III) was 56 points (IQR 49-64 points). The median duration from appearance of first symptoms to ICU admission was 8 days (IQR 5-11 days). Invasive mechanical ventilation was required in 72 patients (67.9%) and 6 patients (5.6%) required extracorporeal membrane oxygenation treatment. Renal replacement therapy was necessary in 21 patients (19.8%). Median ICU length of stay (LOS) was 18 days (IQR 5-31 days), median hospital LOS was 27 days (IQR 13-49 days). The ICU mortality was 21.7% (23 patients), hospital mortality was 22.6%. There was no significant difference in ICU mortality in patients receiving invasive mechanical ventilation and in those not receiving it (18.1% vs. 29.4%, p = 0.284). As of July 17th, 2020, two patients are still hospitalized, one in an ICU, one on a general ward., Conclusion: Critically ill COVID-19 patients in Tyrol showed high severity of disease often requiring complex treatment with increased lengths of ICU and hospital stay. Nevertheless, the mortality was found to be remarkably low, which may be attributed to our adaptive surge response providing sufficient ICU resources.

Although platelets play a central role in haemostasis, the dynamics of platelet counts during haemostatic resuscitation, the response to platelet transfusion, and effects on clinical outcome are poorly described for trauma patients. As a sub-study of the already published randomized controlled RETIC Study "Reversal of Trauma-induced Coagulopathy using First-line Coagulation Factor Concentrates or Fresh-Frozen Plasma" trial, we here analysed whether the type of first-line haemostatic resuscitation influences the frequency of platelet transfusion and determined the effects of platelet transfusion in coagulopathic patients with major trauma. Patients randomly received first-line plasma (FFP) or coagulation factor concentrates (CFC), mainly fibrinogen concentrate. In both groups, platelets were transfused to maintain platelet counts between 50 and 100 × 10 9 /L. Transfusion rates were significantly higher in the FFP (n = 44) vs. CFC (n = 50) group (FFP 47.7% vs. CFC 26%); p = 0.0335. Logistic regression analysis adjusted for the stratification variables injury severity score (ISS) and brain injury confirmed that first-line FFP therapy increases the odds for platelet transfusion (odds ratio (OR) 5.79 (1.89 to 20.62), p = 0.0036) and this effect was larger than a 16-point increase in ISS (OR 4.33 (2.17 to 9.74), p = 0.0001). In conclusion, early fibrinogen supplementation exerted a platelet-saving effect while platelet transfusions did not substantially improve platelet count and might contribute to poor clinical outcome., Competing Interests: P.I. has received personal fees from Baxter GmbH, personal fees from CSL Behring GmbH, personal fees from Fresenius Kabi GmbH Austria, personal fees from Bayer GmbH Austria, personal fees from LFB, and non-financial support from TEM International, outside the submitted work. D.F. 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, and Tem-Innovation, outside the submitted work. M.M. has received personal fees from CSL Behring GmbH, outside the submitted work. The remaining authors have disclosed that they have no potential conflicts of interest.

Background: Effective treatment of trauma-induced coagulopathy is important; however, the optimal therapy is still not known. We aimed to compare the efficacy of first-line therapy using fresh frozen plasma (FFP) or coagulation factor concentrates (CFC) for the reversal of trauma-induced coagulopathy, the arising transfusion requirements, and consequently the development of multiple organ failure., Methods: This single-centre, parallel-group, open-label, randomised trial was done at the Level 1 Trauma Center in Innsbruck Medical University Hospital (Innsbruck, Austria). Patients with trauma aged 18-80 years, with an Injury Severity Score (ISS) greater than 15, bleeding signs, and plasmatic coagulopathy identified by abnormal fibrin polymerisation or prolonged coagulation time using rotational thromboelastometry (ROTEM) were eligible. Patients with injuries that were judged incompatible with survival, cardiopulmonary resuscitation on the scene, isolated brain injury, burn injury, avalanche injury, or prehospital coagulation therapy other than tranexamic acid were excluded. We used a computer-generated randomisation list, stratification for brain injury and ISS, and closed opaque envelopes to randomly allocate patients to treatment with FFP (15 mL/kg of bodyweight) or CFC (primarily fibrinogen concentrate [50 mg/kg of bodyweight]). Bleeding management began immediately after randomisation and continued until 24 h after admission to the intensive care unit. The primary clinical endpoint was multiple organ failure in the modified intention-to-treat population (excluding patients who discontinued treatment). Reversal of coagulopathy and need for massive transfusions were important secondary efficacy endpoints that were the reason for deciding the continuation or termination of the trial. This trial is registered with ClinicalTrials.gov, number NCT01545635., Findings: Between March 3, 2012, and Feb 20, 2016, 100 out of 292 screened patients were included and randomly allocated to FFP (n=48) and CFC (n=52). Six patients (four in the FFP group and two in the CFC group) discontinued treatment because of overlooked exclusion criteria or a major protocol deviation with loss of follow-up. 44 patients in the FFP group and 50 patients in the CFC group were included in the final interim analysis. The study was terminated early for futility and safety reasons because of the high proportion of patients in the FFP group who required rescue therapy compared with those in the CFC group (23 [52%] in the FFP group vs two [4%] in the CFC group; odds ratio [OR] 25·34 [95% CI 5·47-240·03], p<0·0001) and increased needed for massive transfusion (13 [30%] in the FFP group vs six [12%] in the CFC group; OR 3·04 [0·95-10·87], p=0·042) in the FFP group. Multiple organ failure occurred in 29 (66%) patients in the FFP group and in 25 (50%) patients in the CFC group (OR 1·92 [95% CI 0·78-4·86], p=0·15)., Interpretation: Our results underline the importance of early and effective fibrinogen supplementation for severe clotting failure in multiple trauma. The available sample size in our study appears sufficient to make some conclusions that first-line CFC is superior to FFP., Funding: None., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: In the operating room and at the ICU, Rotational thromboelastometry (ROTEM) and multiple platelet function analyzer (Multiplate) are frequently performed on arterial blood samples while known reference ranges refer to venous blood only. To evaluate whether there are clinical important differences between parameters measured in arterial and venous blood, we performed a prospective study in patients undergoing orthopedic surgery., Methods: Arterial and venous blood samples were drawn simultaneously after line insertion (T0), intraoperatively (T1), at the end of surgery (T2) and the INTEM, EXTEM and FIBTEM ROTEM assays, as well as the ASPI, ADP and TRAP assays were performed in arterial and venous samples using the ROTEM and the Multiplate device, respectively., Results: After informed consent, 52 patients were enrolled and data of 50 patients remained for final analysis. Venous and arterial measurement results correlated significantly with a coefficient of 0.519-0.977. At the three measurement points only a few statistically significant deviations were detected for some of the ROTEM and Multiplate parameters. The magnitude of differences was small and most likely without clinical relevance. Pathological conditions were detected with similar frequency regardless of the sampling site. Only Multiplate TRAP at T0 indicated low platelet aggregation more frequently in venous than in arterial samples (p = 0.0455); however, values were only narrow below reference range., Conclusion: The observed differences between arterial and venous results were within the range of variability of the methods reported for venous blood. Pathological values that might be clinically relevant could be detected at similar rates regardless of the sampling site.

Background: FFP and coagulation factor concentrates are used to correct trauma-induced coagulopathy (TIC). However, data on coagulation profiles investigating effects of therapy are scarce., Methods: This is an analysis of 144 patients with major blunt trauma ((ISS)≥15), who were enrolled in a prospective cohort study investigating characteristics and treatment of TIC. Patients who received fibrinogen concentrate and/or prothrombin complex concentrate alone (CF Group) were compared with those additionally receiving FFP transfusions (FFP Group)., Results: Sixty-six patients exclusively received CF, while 78 patients additionally received FFP. Overall, patients were comparable regarding age, gender and ISS (CF Group, ISS 37 (29, 50); FFP Group ISS 38 (33, 55), p=0.28). Patients treated with CF alone showed sufficient haemostasis and received significantly fewer units of red blood cells (RBC) and platelets than did those also receiving FFP [(RBC 2(0, 4) U vs. 9 (5, 12) U; platelets 0 (0, 0) U vs. 1 (0, 2) U, p<0.001)]. In addition, fewer patients in the CF Group developed multiorgan failure (MOF) (18.2% vs. 37.2%, p=0.01) or sepsis (16.9% vs. 35.9%, p=0.014) than in the FFP Group. Propensity score-matching (n=28 pairs) used to reduce the impact of treatment selection confirmed that additional FFP administration showed no benefit in restoring haemostasis, but was associated with significantly higher transfusion rates for RBC and platelets., Conclusion: The use of CF alone effectively corrected coagulopathy in patients with severe blunt trauma and concomitantly decreased exposure to allogeneic transfusion, which may translate into improved outcome., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Previous data show improved clot formation after retransfusion of salvaged red blood cells (RBCs). This study was conducted to explore whether such RBCs contain clinically relevant numbers of active residual platelets (PLTs) or exhibit formation of microparticles (MPs)., Study Design and Methods: Thirteen patients undergoing major orthopedic surgery were included in the study, and arterial blood samples from patients and samples from the retransfusion bag were analyzed with various PLT function tests and flow cytometry., Results: With commercial blood cell counters, the numbers of PLTs in the RBC unit were reduced to approximately 25% compared to patients' blood. In contrast, results from flow cytometry showed an 11- to 945-fold reduction in median counts referring to total PLTs and free PLTs. Interestingly, smaller quantities of PLT-derived MPs were found in samples from the retransfusion bag than in patients' arterial blood. Conversely, RBC- and white blood cell-derived MP counts were increased in the retransfusion bag compared to the patient. Rotational thrombelastometry and the Impact-R system (DiaMed) showed a pronounced impairment of PLT ability with regard to adhesion, aggregation, and clot formation. With the use of confocal microscopy, only a few free thrombocytes were detectable among the huge numbers of RBCs., Conclusion: Only few free and thus active PLTs are detectable in processed RBCs. It seems very unlikely that these few PLTs can improve clot strength. Nevertheless, the impact of the detected MPs on thrombin generation needs to be clarified in further studies.

Background: In this study, we explored whether antiplatelet medications impair whole blood impedance aggregometry after cardiac surgery and cardiopulmonary bypass (CPB) compared with classical light transmission aggregometry (LTA)., Methods: Multiplate (M) assays measuring changes in electrical resistance as aggregation units over time, and LTA assays (% aggregation) induced by collagen (COL), adenosine diphosphate (ADP), or arachidonic acid were performed simultaneously using arterial blood samples obtained before induction of anesthesia, 15 min and 3 h after neutralization of heparin in 70 consecutive patients scheduled for elective coronary artery bypass grafting. Patients in Group A (n = 48) discontinued intake of antiplatelet drugs for at least 7 days and served as controls, patients in Group B (n = 11) received aspirin 100 mg/d and those in Group C (n = 11) aspirin 100 mg/d and clopidogrel 75 mg/d (dual antiplatelet therapy) until the day before surgery., Results: In patients without antiplatelet therapy, 15 min and 3 h after protamine a significant decrease in platelet aggregation was observed with all three agonists and both aggregation methods. In patients receiving aspirin alone, LTA-COL, LTA-ADP and M-ADP changed significantly over time, and ADP assays of both aggregation methods showed a significant decrease in platelet aggregation 15 min after protamine in patients receiving dual antiplatelet therapy. When calculating the areas under the receiver-operating characteristic curves for discrimination of antiplatelet agents, LTA-COL was able to discriminate between controls and patients receiving aspirin or dual antiplatelet therapy 15 min and 3 h after CPB and the M-ADP assay was able to discriminate between controls and patients receiving dual antiplatelet therapy 3 h after protamine., Conclusion: Whole blood and classical LTA performed with all commonly used agonists enable detection of CPB-induced changes in platelet aggregation in patients not taking antiplatelet medication, whereas in patients receiving antiplatelet therapy, ADP-induced antiplatelet assays are preferable for detecting CPB-induced impairment of platelet aggregation.

Background: Our goal of this study was to determine whether protamine's effects on coagulation can be detected and differentiated from those of heparin when using thrombelastometry (ROTEM)., Methods: To reverse the effects of heparin after cardiopulmonary bypass (CPB), 22 consecutive patients undergoing aortocoronary bypass graft surgery were included. According to clinical routine, all patients received a first dose of protamine calculated from the total amount of heparin given; additional protamine (70 U/kg) was administered to patients with activated clotting time (ACT) above baseline and clinical signs of diffuse bleeding. Simultaneously, routine ACT measurements, ROTEM assays (heparin-sensitive INTEM, and heparinase-containing HEPTEM test) and standard coagulation tests were performed, and the activity of coagulation factors as well as antifactor Xa activity measured., Results: Administration of additional protamine (n = 16) resulted in a statistically significant increase in coagulation times on the intrinsically activated test (INTEM-CT), namely from (mean [+/-SD]) 219.8 (+/-19.1) s to 241.1 (+/-21.7) s (P < 0.001), and on the heparinase-containing test (HEPTEM-CT), namely from 210.2 (+/-19.9) s to 226.8 (+/-21.8) s (P < 0.001). These changes were not observed in patients receiving a single protamine dose (n = 6). The INTEM-CT:HEPTEM-CT ratio correctly identified 56 of the 58 samples as not containing residual heparin and correctly detected residual heparin in 3 of the only 6 samples showing elevated antifactor Xa values after CPB., Conclusion: Our preliminary data show that at termination of CPB administration of additional protamine results in a brief prolongation of coagulation times on the INTEM and HEPTEM test and that ROTEM might be useful in excluding residual heparin in cases showing prolonged ACT.

Modified rotation thrombelastometry (ROTEM) is widely used in near-patient assessment of hemostasis, but data on functional consequences initiated by acute endotoxinemia are rare. To test the hypothesis that the ROTEM technique allows detection of endotoxinemia-induced changes in hemostasis, we conducted a pilot study on pigs. Fifteen healthy pigs were anesthetized and instrumented for invasive hemodynamic monitoring. Several coagulation tests and the ROTEM assay were performed at baseline and 60 min after administration of a bolus of 200 microg of Escherichia coli lipopolysaccharide followed by a continuous infusion of 0.1 microg/kg per min. After induction of acute endotoxinemia, clot formation time increased (P = 0.001), and alpha angle (P = 0.001) and maximum clot firmness decreased significantly (P = 0.001) in intrinsically and extrinsically activated ROTEM assays. Moreover, fibrinogen/fibrin polymerization showed significantly lower values during endotoxinemia (P = 0.001), and coagulation time shortened for the intrinsically activated assay (P = 0.017). Simultaneously, a significant decrease in platelet count (P = 0.001), fibrinogen (P = 0.001), antithrombin and protein C (P = 0.001) was registered, whereas results of standard coagulation tests and D-dimers showed no significant changes although thrombin-antithrombin complex increased (P = 0.001). Wilcoxon Z score analysis showed that changes in ROTEM variables were comparable to changes in antithrombin, protein C, platelet count, white blood cells and fibrinogen concentrations. The ROTEM assays were able to reflect endotoxinemia-dependent changes in the hemostatic system in pigs early by showing not only activation but also signs of consumption, whereas results of routine coagulation tests remained unchanged.

Background: To explore whether disturbed fibrin polymerization is the main problem underlying dilutional coagulopathy and can be reversed by fibrinogen administration, we conducted a prospective study using modified thrombelastography (ROTEM)., Methods: Sixty-six orthopedic patients randomly received modified gelatin solution, hydroxyethyl starch 130/0.4, or exclusively Ringer lactate solution. ROTEM analysis was performed, concentrations of coagulation factors and markers of thrombin generation were measured. Fibrinogen concentrate (Hemocomplettan) was administered (30 mg/kg) when thrombelastographically measured fibrinogen polymerization was critically decreased., Results: The alpha angle, clot firmness, and fibrinogen polymerization (median [min to max]) significantly decreased in the patients receiving hydroxyethyl starch (area under the curve minus baseline (-5 [-9 to -2]), followed by gelatin solution (-3 [-8 to 0]), with the least reductions seen for Ringer lactate solution (-2 [- 4 to 1]) (colloids versus Ringer lactate P < 0.0001). Thirteen patients in the colloid groups but none in the Ringer lactate group needed fibrinogen concentrate to maintain borderline clot firmness. Activity of FVII, FVIII, FIX, and von Willebrand ristocetin activity decreased significantly with colloids. Thrombelastographically measured coagulation time, molecular markers of thrombin generation, and activity of all other coagulation factors were comparable in all groups., Conclusion: Disturbance of fibrinogen/fibrin polymerization is the primary problem triggering dilutional coagulopathy during major orthopedic surgery. The magnitude of clot firmness reduction is determined by the type of fluid used, with hydroxyethyl starch showing the most pronounced effects. These undesirable effects of intravascular volume therapy can be reversed by increasing fibrinogen concentration by administering fibrinogen concentrate, even during continuing blood loss and intravascular volume replacement.

Introduction: Long-distance traveling in a sitting position may be associated with an increased incidence for venous thromboembolism. As major contributing factors immobility and compression of leg veins are discussed. At present no studies have been performed measuring the time course of lower limb blood flow, leg volume and leg tissue thickness during a long-haul flight., Materials and Methods: We measured limb volumes (plethysmographic method), lower leg tissue thickness and lower limb venous hemodynamics before, during and after 10 h sitting in modern aircraft chairs under normobaric hypoxia in healthy volunteers (n=12)., Results: Lower leg volume was already significantly increased after 4 h sitting (+109 ml) reaching its maximum after 10 h (+145 ml). These changes were accompanied by an increased body weight, total body water, extracellular water and tissue thickness of the tibia. No significant changes were measured for leg vessel cross-section diameters and maximal flow velocities in superficial femoral veins. After 10 h sitting core temperature, overall surface temperature and skin temperatures in front of the tibia were significantly increased. All parameters returned to baseline one day after sitting., Conclusions: Prolonged sitting in modern aircraft seats is associated with a remarkable fluid accumulation in the lower legs which mainly occurred during the first hours. These fluid shifts were independent of lower limb venous hemodynamics and vessel cross-sectional diameters.

Introduction: Long-haul flights are associated with an increased incidence for venous thromboembolic events. At present, markers of coagulation and fibrinolysis were only analyzed from arm veins after long distance travel. Respective data from leg veins are missing., Materials and Methods: Here, we measured these parameters in healthy volunteers (n=12) before and after 10 h sitting in modern aircraft chairs under normobaric hypoxia (corresponding to 2400 m altitude). Blood was collected from arm and leg veins before, immediately after and 1 day after sitting in the hypoxic chamber., Results: We did not find any evidence for a significant intravasal thrombin and fibrin formation and a changed fibrinolytic activity, neither in arm nor in leg vein blood. TAT, PAP, and PAI-1 remained unchanged, and the increases of F1+2 in arm veins and of d-dimer in leg veins were within the upper reference limits. Moreover, there was no evidence of activation of coagulation as measured by thrombelastography (ROTEM(R)) and the new Thrombin Dynamic Test at both locations. There was no evidence of arm or leg hemoconcentration., Conclusions: In healthy volunteers, prolonged sitting in ergonomically superior aircraft seats does not induce significant changes in blood coagulation and fibrinolysis in venous blood of arm or leg. Since this study was performed under moderate hypoxia, reduction in oxygen pressure seems not to be a crucial factor for venous thrombosis at long-haul flights.

Background: The influence of moderate altitude on the cardiovascular system in patients with metabolic syndrome has not been investigated sufficiently, yet. The aim of this study was to assess the effect of acute and mid-term exposure to moderate altitude (1,700 m) on endothelial function in patients with metabolic syndrome., Methods: Flow-mediated (FMD) and nitroglycerin-mediated vasodilation (NMD) were assessed in 18 patients with coronary risk factors on 5 occasions: (1) at location A (576 m), (2) on the first day at moderate altitude (location B, 1,700 m), (3) after 3 weeks at moderate altitude, (4) and (5) again at location A (6 and 16 weeks after the stay at moderate altitude, respectively). In addition, markers of lipid metabolism, serum erythropoietin and endothelin were measured., Results: FMD on the first day at moderate altitude was similar compared to baseline FMD at location A (7.0 +/- 3.3 vs. 7.4 +/- 4.6%; NS). A 3-week stay at moderate altitude was associated with a significant reduction in FMD (7.4 +/- 4.6 vs. 3.8 +/- 2.5%; p < 0.05) despite a decrease in baseline diameter (4.5 +/- 0.3 vs. 4.3 +/- 0.4 mm; p < 0.05). Six weeks after returning to location A, FMD was still reduced compared to baseline (4.3 +/- 2.8%; p < 0.05) and after further 16 weeks, FMD returned to baseline values (5.5 +/- 3.5%). However, metabolic parameters improved significantly. In contrast, NMD and endothelin levels remained unchanged., Conclusion: In patients with metabolic syndrome, a sojourn of 3 weeks at moderate altitude leads to a prolonged, but reversible impairment of FMD. The discrepancy to improvement of other cardiovascular and metabolic parameters requires further investigation.

Neopterin is a sensitive marker for diseases involving increased activity of the cellular immune system in humans. Many studies, however, provide evidence for neopterin not only as a marker, but also for its characteristic effects. Recently, we were able to demonstrate a considerable influence of exogenous neopterin at a concentration of 100 mumol/l on cardiac performance in the Langendorff model of isolated perfused rat hearts. The present study was designed to investigate its possible mechanism. During co-infusion of neopterin at a concentration of 100 mumol/l with the unspecific nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine monoacetate, the nitric oxide donor PAPA NONOate, the free radical scavenger N-acetylcysteine, or the pro-inflammatory cytokine tumor necrosis factor-alpha the effects on cardiac contractility parameters and coronary vascular resistance were studied in 67 male Sprague-Dawley rats. The temperature-controlled and pressure-constant Langendorff apparatus was used with retrograde perfusion of the aorta and a Krebs-Henseleit buffer. Neither the unspecific nitric oxide synthase inhibitor nor the nitric oxide donor excludes nitric oxide from playing a mechanistic role in our perfusion studies. Tumor necrosis factor-alpha was without any synergistic or antagonistic effects when co-treated with neopterin. N-acetylcysteine was most effective in abolishing neopterin-dependent effects on cardiac function. The negative effects of neopterin on cardiac performance might be due to an enhancement of oxidative stress by neopterin that can be attenuated by the antioxidant N-acetylcysteine. Neopterin has to be considered a pathogenic factor in the development of cardiac dysfunction in chronic disease states with high neopterin levels secondary to activation of the immune system.

Moderate altitude hypoxia (1500 to 2500 m) is known to stimulate erythropoiesis and to improve oxygen transport to tissue by a reduction of Hb-O(2) affinity. Whether this adaptation also occurs in tourists with metabolic syndrome has not yet been investigated sufficiently. Thus, we performed a prospective field study to measure erythropoietic parameters and oxygen transport properties in 24 male volunteers with metabolic syndrome during a 3- week holiday program at 1700 m consisting of four guided, individually adapted hiking tours per week. The following examinations were performed: baseline investigations at 500 m (T1); examinations at moderate altitude on day 1 (T2), day 4 (T3), day 9 (T4), and day 19 (T5); and postaltitude tests (T6) 7 to 10 days after return. On day 1 and day 19, a walk on a standardized hiking test route with oxygen saturation (SpO(2)) measure points was performed. Hemoglobin, packed cell volume, and red cell count showed changes over time, with higher values at T5 as compared to baseline. Reticulocyte count and erythropoietin (EPO) were increased at T2 and increased further until T5. EPO declined toward prealtitude values. P50-value (blood PO(2) at 50% hemoglobin oxygen saturation at actual pH) increased during the altitude sojourn (maximum increase at T5 by +0.40 kPa). At T5 all volunteers had a higher SpO(2) before, during, and at the end of the test route compared to T1. During adaptation to moderate altitude, persons with metabolic syndrome exhibit an increase in EPO and a rightward shift of the oxygen dissociation curve that is similar to healthy subjects.

Long-distance travel in a cramped position by aircraft or by bus and car has been suggested to be associated with an increased risk for thromboembolic events. Recently, we demonstrated moderate activation of coagulation after a long-haul flight. At present the single contributing factors (i.e. hypoxia and low humidity on board an aircraft and prolonged sitting in an aircraft, car or bus inducing venous stasis) have not yet been investigated. Therefore we measured markers of coagulation and fibrinolysis as well as functional parameters of coagulation using activated thrombelastography in 19 healthy volunteers before, during and after a real 10-h bus journey. In addition, changes in leg volume were measured. Thrombelastography revealed moderate activation of coagulation in all travelers, which was accompanied by a significant increase in prothrombin fragment F1 + 2. Thrombin-antithrombin III complexes and D-dimer remained unchanged, and tissue-type plasminogen activator and plasminogen-activator inhibitor 1 decreased after travel. After the travel we found a significant increase in leg volume that was exclusively distributed in the calf. We conclude that beside long-haul flights also long-distance bus travel induces a certain activation of the coagulation system. Thus, it is questionable whether hypoxia is the crucial risk factor for thromboembolic events after long-haul flights., (Copyright 2004 Lippincott Williams and Wilkins)

It was hypothesized that subjects with metabolic syndrome (hypertension, obesity, hyperlipidemia, diabetes mellitus): (1) develop measurable peripheral edema at moderate altitude and (2) might show differences on erythropoiesis, iron status and vascular endothelial growth factor (VEGF) in comparison to healthy subjects during and after a long-term stay (3-week exposure) at moderate altitude (congruent with 1700 m). Twenty-two male subjects with metabolic syndrome were selected. Baseline investigations (t1) were performed in Innsbruck (500 m). All participants were transferred by bus to 1700 m (Alps) and remained there for 3 weeks with examinations on day 1 (after the first night at altitude, t2), day 4 (t3), day 9 (t4) and day 19 (t5). After returning to Innsbruck, post-altitude examinations were conducted after 7-10 days (t6) and 6-7 weeks (t7), respectively. Body mass was decreased from t1 to t7 (P<0.01). Total body water was decreased at t2 (P<0.01), returned to control level (t3, t4), and was found elevated at t7 (P<0.01). Lean body mass did not change, but body fat decreased during the study (P<0.01). Tissue thickness at the forehead decreased during and after altitude exposure (P<0.01), whereas tissue thickness at the tibia did not alter. Erythropoietin (EPO) was elevated as early as t2 and remained increased until t5. Reticulocyte count was increased at t3 and remained above pre-altitude values. VEGF levels were unchanged. After a 3-week exposure to moderate altitude, patients with metabolic syndrome had reduced their body mass, mainly because of a reduction in body fat. The moderate altitude was found to stimulate erythropoiesis in these patients but this was not sufficient to increase serum VEGF concentration.

Introduction: Antithrombin (AT) is well known as an important inhibitor of the coagulation system. An interesting new hypothesis is that antithrombin exerts specific anti-inflammatory effects by stimulating the production of prostacyclin in endothelial cells. Recent studies report beneficial influence on ischemia/reperfusion injury in several organs. These effects are independent of the coagulation system. We investigated the influence of antithrombin on ischemia/reperfusion injury and prostacyclin release in the isolated rat heart. Since the perfusion of the hearts was without blood, the used model essentially describes effects of antithrombin on endothelial cells., Material and Methods: Experiments were performed using the temperature-controlled and pressure-constant Langendorff apparatus. The hearts of 32 male Sprague-Dawley rats were subjected to 20 min of global ischemia followed by 30 min of reperfusion. Antithrombin was administered in three different concentrations (1, 4 and 8 U/ml) 15 min prior to global ischemia. Cardiac contractility parameters and biochemical parameters were measured., Results: Treatment with antithrombin did not increase the release of prostacyclin significantly after ischemia. Antithrombin at a concentration of 8 U/ml led to a significant increase in creatine kinase (CK; p<0.05) and troponin I (p<0.05), whereas measurements of lactate dehydrogenase (LDH) revealed no significant differences between treated and untreated hearts., Conclusion: Our study shows that antithrombin did not reduce ischemia/reperfusion injury in the isolated heart, and prostacyclin is not significantly released following antithrombin treatment. High concentrations of antithrombin, however, might have a negative influence on the reperfused heart. The underlying mechanism remains unclear.

Introduction: Long-haul flights have been suggested to be associated with an increased risk for thromboembolic events. Until now, changes in the coagulation system during an actual flight have not been investigated., Materials and Methods: To explore whether any changes occur in the coagulation system during a real long-haul flight molecular markers for coagulation and fibrinolysis were measured in 20 volunteers (10 subjects with a low and 10 with a moderate risk for venous thromboembolism (VTE)) during and after a return flight from Vienna to Washington. In addition, functional measurements of coagulation were performed using activated thrombelastography., Results: Thrombelastographic measurements revealed activation of coagulation in all passengers, who showed an increased activity of FVII and FVIII as well as suppressed fibrinolysis. There was no evidence of a pronounced thrombin and fibrin formation. We did not find any differences between both groups concerning coagulation changes., Conclusion: Long-haul flights induce a certain activation of the coagulation system. This activated coagulation could be a risk factor for VTE during long-haul flights mainly when other risk factors are present.

Unlabelled: Gelatin solutions are often given in clinical practice once the maximal dose of a median-weight hydroxyethyl starch (HES) has been reached. Colloids are usually combined with lactated Ringer's solution (RL). Whether the combined administration of colloids and/or crystalloids affects blood coagulation is not known. We diluted blood by 20%, 40%, and 60% with RL, gelatin (Gelofusin), 6% HES 130/0.4 (Voluven), and 6% HES 200/0.5 (Iso-Hes), as well as with combinations of these solutions at a ratio of 1:1 (gelatin/RL, 6% HES 130/0.4:RL, 6% HES 200/0.5:RL, 6% HES 130/0.4:gelatin, 6% HES 200/0.5:gelatin). Thereafter, blood was analyzed by using modified thrombelastograph coagulation analysis (ROTEG) and clotting time, clot formation time, and maximal clot firmness were determined. RL had the least effect on hemostasis. Gelatin administered alone impaired the coagulation system significantly less than each median-weight HES administered alone. We conclude that gelatin combined with 6% HES 200/0.5 or 6% HES 130/0.4 decreases hemostasis <6% HES 200/0.5 or 6% HES 130/0.4 administered alone., Implications: The effect of the combined administration of different colloids and/or crystalloids on coagulation is not known. We show that hemostasis is less impaired using a combination of gelatin and median-weight starches than using median-weight starches alone. Furthermore, the combination of lactated Ringer's solution and gelatin decreases the coagulation system to the same extent as the combination of lactated Ringer's solution and 6% hydroxyethyl starch 130/0.4.

Travel-related disorders are a well known problem. In the last years many cases of deep venous thrombosis (DVT) and pulmonary thromboembolism (VTE) were published after several hours lasting journeys by airplane, but also by car, bus and railway. This condition was termed "travel-thrombosis" or "economy class syndrome" for long haul flights. At present the precise incidence for travel-thrombosis is not known. Accepted contributing factors for the development of travel-thrombosis are sitting in a cramped position for several hours, low humidity due to climatisation with the risk for dehydration and increased blood viscosity, reduced fluid intake as well as travellers related risk factors. Whether the special situation in the cabin of an airplane, e.g. mild hypoxia, is an essential contributing factor for DVT and VTE, is controversially discussed. This review will present very recent guidelines of an expert meeting concerning the risk groups for travel-thrombosis (low, moderate and high risk). In addition recommendations for prophylaxis of travel-thrombosis adapted to the different risk groups (leg exercise, adequate fluid intake, compression stockings, low molecular weight heparins) are given.

Granulocyte colony-stimulating factor (G-CSF), a central mediator of the endogenous response to infection and inflammation, is approved for use in the prevention of infection-related complications in patients with nonmyeloid malignancies during antineoplastic therapy associated with high risk of severe neutropenia. Administration of granulocyte colony-stimulating factor results in improvement of host defence paired with anti-inflammatory effects. There is evidence from animal and clinical studies that administration of granulocyte colony-stimulating factor may also be beneficial in non-neutropenic infections. This review focuses mainly on the results of different animal and clinical studies of granulocyte colony stimulating factor used in the treatment of severe infections and sepsis.