Efficacy of prehospital administration of fibrinogen concentrate in trauma patients bleeding or presumed to bleed (FIinTIC): A multicentre, double-blind, placebo-controlled, randomised pilot study.

BACKGROUND: Trauma-induced coagulopathy (TIC) substantially contributes to mortality in bleeding trauma patients. OBJECTIVE: The aim of the study was to administer fibrinogen concentrate in the prehospital setting to improve blood clot stability in trauma patients bleeding or presumed to bleed. DESIGN: A prospective, randomised, placebo-controlled, double-blinded, international clinical trial. SETTING: This emergency care trial was conducted in 12 Helicopter Emergency Medical Services (HEMS) and Emergency Doctors' vehicles (NEF or NAW) and four trauma centres in Austria, Germany and Czech Republic between 2011 and 2015. PATIENTS: A total of 53 evaluable trauma patients aged at least 18 years with major bleeding and in need of volume therapy were included, of whom 28 received fibrinogen concentrate and 25 received placebo. INTERVENTIONS: Patients were allocated to receive either fibrinogen concentrate or placebo prehospital at the scene or during transportation to the study centre. MAIN OUTCOME MEASURES: Primary outcome was the assessment of clot stability as reflected by maximum clot firmness in the FIBTEM assay (FIBTEM MCF) before and after administration of the study drug. RESULTS: Median FIBTEM MCF decreased in the placebo group between baseline (before administration of study treatment) and admission to the Emergency Department, from a median of 12.5 [IQR 10.5 to 14] mm to 11 [9.5 to 13] mm (P = 0.0226), but increased in the FC Group from 13 [11 to 15] mm to 15 [13.5 to 17] mm (P = 0.0062). The median between-group difference in the change in FIBTEM MCF was 5 [3 to 7] mm (P < 0.0001). Median fibrinogen plasma concentrations in the fibrinogen concentrate Group were kept above the recommended critical threshold of 2.0 g l-1 throughout the observation period. CONCLUSION: Early fibrinogen concentrate administration is feasible in the complex and time-sensitive environment of prehospital trauma care. It protects against early fibrinogen depletion, and promotes rapid blood clot initiation and clot stability. TRIAL REGISTRY NUMBERS: EudraCT: 2010-022923-31 and ClinicalTrials.gov: NCT01475344.

Comparison of arterial versus venous parameters of Rotational thromboelastometry and multiple platelet function analyzer: results of a pilot study.

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.

Clinical review: Prothrombin complex concentrates--evaluation of safety and thrombogenicity.

Prothrombin complex concentrates (PCCs) are used mainly for emergency reversal of vitamin K antagonist therapy. Historically, the major drawback with PCCs has been the risk of thrombotic complications. The aims of the present review are to examine thrombotic complications reported with PCCs, and to compare the safety of PCCs with human fresh frozen plasma. The risk of thrombotic complications may be increased by underlying disease, high or frequent PCC dosing, and poorly balanced PCC constituents. The causes of PCC thrombogenicity remain uncertain but accumulating evidence indicates the importance of factor II (prothrombin). With the inclusion of coagulation inhibitors and other manufacturing improvements, today's PCCs may be considered safer than earlier products. PCCs may be considered preferable to fresh frozen plasma for emergency anticoagulant reversal, and this is reflected in the latest British and American guidelines. Care should be taken to avoid excessive substitution with prothrombin, however, and accurate monitoring of patients' coagulation status may allow thrombotic risk to be reduced. The risk of a thrombotic complication due to treatment with PCCs should be weighed against the need for rapid and effective correction of coagulopathy.

First-Line Administration of Fibrinogen Concentrate in the Bleeding Trauma Patient: Searching for Effective Dosages and Optimal Post-Treatment Levels Limiting Massive Transfusion-Further Results of the RETIC Study.

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.

Intraoperatively salvaged red blood cells contain nearly no functionally active platelets, but exhibit formation of microparticles: results of a pilot study in orthopedic patients.

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.

[Coagulation management in trauma-related massive bleeding. - Recommendations of the Task Force for Coagulation (AGPG) of the Austrian Society of Anesthesiology, Resuscitation and Intensive Care Medicine (OGARI)]. / Gerinnungsmanagement bei traumatisch bedingter Massivblutung - Empfehlungen der Arbeitsgruppe für perioperative Gerinnung der OGARI.

Even nowadays and at specialized centers, one of the leading causes of death is exsanguination. Trauma-induced coagulopathy (TIC) occuring with massive blood loss primarily results from loss of coagualtion factors and platelets and is aggravated by hemodilution. In addition, hyperfibrinolysis, hypothermia, acidosis and hypocalcaemia also contribute to the development of severe haemostatic derangement. During the past few years new insights into the pathophysiology of TIC and the widespread use of viscoelastic coagulation monitoring provoked the development of alternative treatment concepts. As for the previously recommended standard therapy using fresh frozen plasma and platelet concentrates also for alternative strategies no data from large prospective randomized studies are available until now, however, the evidence is growing favoring the use of coagulation factor concentrates guided by viscoelastic measurements.

Dynamics of Platelet Counts in Major Trauma: The Impact of Haemostatic Resuscitation and Effects of Platelet Transfusion-A Sub-Study of the Randomized Controlled RETIC Trial.

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 × 109 /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.

Detection of protamine and heparin after termination of cardiopulmonary bypass by thrombelastometry (ROTEM): results of a pilot study.

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.

An assessment of cardiopulmonary bypass-induced changes in platelet function using whole blood and classical light transmission aggregometry: the results of a pilot study.

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.

Time for changing coagulation management in trauma-related massive bleeding.

PURPOSE OF REVIEW: New insights into the pathophysiology of trauma-induced coagulopathy, the increasing availability of point-of-care devices and awareness of side effects of intravenous fluids and traditional fresh frozen plasma therapy has encouraged new concepts for managing massive blood loss. RECENT FINDINGS: Trauma-induced coagulopathy primarily results from blood loss, hypovolemia-induced activation of the protein C system and consequent increase of the fibrinolytic potential, whereas hemodilution, localized consumption of clotting factors and platelets, hypothermia, acidosis, anemia and hypocalcemia further decrease the hemostatic potential. The widespread use of viscoelastic devices highlighted the importance of the contribution of fibrinogen to clot firmness, a precondition for cessation of bleeding. The evidence is growing that targeted therapy using coagulation factor concentrates guided by viscoelastic measurements enables effective correction of severe coagulopathy. SUMMARY: During massive blood loss, viscoelastic measurements should guide aggressive treatment of deficiency or hyperfibrinolysis or both. In addition, the impact of contributing factors should be considered and as far as possible corrected. New data underscore the importance of avoiding hypoperfusion, and the use of coagulation factor concentrates should enable more effective correction of coagulopathy.

Response patterns of routinely measured inflammatory and coagulatory parameters in sepsis.

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.

Fibrinogen in craniosynostosis surgery.

BACKGROUND: During craniosynostosis repair, massive blood loss, consumption and dilution of clotting factors often result in coagulopathy, for which cryoprecipitate, fresh frozen plasma (FFP), and platelets are recommended for treatment. However, cryoprecipitate is not available in most European countries, and the efficacy of FFP in correcting fibrinogen deficiency is limited. We report our experience with human fibrinogen concentrate (Hemocomplettan) used to improve impaired fibrinogen polymerization in children. METHODS: Results of routine coagulation tests, thrombelastometry (ROTEM), transfusion requirements, administration of fibrinogen concentrate, and data on the postoperative course of nine consecutive children undergoing major craniofacial surgery were retrospectively collected from anesthesia protocols, medical charts, laboratory and ROTEM databases. RESULTS: The nine children aged 12 (8, 22) mo (median [25th, 75th percentile]), weighing 9.5 (9, 10) kg had a calculated blood loss of 80 (49, 92)% of calculated blood volume during the surgery lasting 6.4 (4.5, 7.2) h. Impaired fibrinogen polymerization detected by ROTEM was the main problem underlying dilutional coagulopathy. In all cases, sufficient hemostasis was achieved without adverse effects by administering (if necessary), repeated doses of fibrinogen concentrates (each single dose 30 mg/kg) without FFP or platelet transfusions. All children were successfully weaned from mechanical ventilation within a few hours and were able to be discharged early from the Intensive Care Unit. CONCLUSIONS: Administration of fibrinogen concentrate effectively improves fibrinogen polymerization and total clot strength, which were the main underlying problems of dilutional coagulopathy in children undergoing craniosynostosis surgery.

The in vitro effects of fibrinogen concentrate, factor XIII and fresh frozen plasma on impaired clot formation after 60% dilution.

BACKGROUND: Previous investigations have shown that increasing fibrinogen concentration improves dilution-dependent impairment of clot formation. We conducted an in vitro study to explore whether substitution with fibrin-stabilizing factor XIII (FXIII) combined with fibrinogen promotes further improvement of clot formation, and whether fibrinogen administration as concentrate or fresh frozen plasma (FFP) results in comparable effects. METHODS: Blood from six healthy donors was diluted by 60% using lactated Ringer's solution. Aliquots of diluted blood samples were incubated with two different doses of fibrinogen concentrate, FXIII concentrate, the combination of both, or with two different doses of FFP. Using thrombelastometry (ROTEM) blood samples were analyzed at baseline (undiluted), after dilution and after supplementation. Variables were analyzed for changes from baseline, and effects of fibrinogen concentrate alone or combined with FXIII were compared with effects observed with corresponding FFP doses. RESULTS: After 60% in vitro dilution of blood all ROTEM parameters and global coagulation tests changed significantly. Among the substitutes tested FXIII alone had no effect, the combination with fibrinogen improved coagulation time, alpha angle and fibrinogen/fibrin polymerization significantly more than did small-dose fibrinogen alone. After substituting fibrinogen, median values of all ROTEM variables were within the normal range, thereby showing dose dependency but also significant differences (P = 0.027) from corresponding FFP doses (EXTEM MCF FFP small dose [38 (35, 40.3) mm)], which enabled only coagulation time to be shortened to baseline levels. CONCLUSIONS: Supplementation of fibrinogen restored all ROTEM parameters after dilution. This effect was partially enhanced by adding FXIII and was significantly stronger than for FFP substitution.

Point-of-care whole blood impedance aggregometry versus classical light transmission aggregometry for detecting aspirin and clopidogrel: the results of a pilot study.

BACKGROUND: We determined whether whole blood impedance aggregometry using the Multiplate detects the effects of antiplatelet drugs as reliably as does classical light transmission aggregometry (LTA) or the platelet function analyzer PFA-100(R). METHODS: Multiplate (M) assays, measuring changes in electrical resistance as aggregation units over time (AU*min), and LTA assays induced by collagen (COL), adenosine diphosphate (ADP) or arachidonic acid (AA) and PFA-100 testing, using epinephrine (PFA100-EPI) or ADP (PFA100-ADP) cartridges, were performed simultaneously using arterial blood samples obtained before induction of anesthesia in 70 consecutive patients scheduled for elective coronary artery bypass grafting. Patients in group A (n = 48) 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 until the day before surgery. RESULTS: In controls the median (1st, 3rd quartiles) change in impedance AU*min for M-COL (374 [231-469]) was significantly greater than in patients receiving aspirin (164 [86-211], P = 0.0009) or receiving aspirin and clopidogrel (118 [101-244], P = 0.004). M-ADP values in controls were 258 (158-389), in patients receiving aspirin 261 (159-393), and in patients receiving aspirin and clopidogrel 88 (48-231, P = 0.054). M-AA values were significantly lower in patients receiving aspirin alone (45 [28-60], P = 0.0004) or aspirin and clopidogrel (44 [26-221], P = 0.008) than in controls (200 [86-345]). The areas under the receiver operating characteristic curves indicating the ability to discriminate patients taking aspirin from those not taking aspirin were comparable for COL and AA assays using whole blood impedance aggregometry or classical LTA (M-COL 0.84 [P = 0.001], LTA-COL 0.85 [P = < .001], M-AA 0.84 [P = < .001] and LTA-AA 0.87 [P = < .001]), but only 0.74 for PFA-100-EPI (P = 0.03). Similarly, for discrimination of patients not taking antiplatelet drugs from patients taking clopidogrel and aspirin the areas under the receiver operating characteristic curve were also comparable for both aggregometry methods M-COL 0.77 (P = 0.006), LTA-COL 0.78 (P = 0.004), M-ADP 0.74 (P = 0.015), LTA-ADP 0.73 (P = 0.018). CONCLUSION: Results achieved with the bedside Multiplate assays were not different than those obtained with classical aggregometry for detecting the effects of aspirin and clopidogrel in preoperative patients scheduled for elective cardiac surgery.

Less impairment of hemostasis and reduced blood loss in pigs after resuscitation from hemorrhagic shock using the small-volume concept with hypertonic saline/hydroxyethyl starch as compared to administration of 4% gelatin or 6% hydroxyethyl starch solution.

BACKGROUND: Small-volume resuscitation using hypertonic saline/hydroxyethyl starch 200/0.62 (HS-HES) has been shown to be an effective alternative to the administration of crystalloids or colloids in trauma patients. All i.v. fluids cause dose-related dilutional coagulopathy and show intrinsic effects on the hemostatic system, but only few data refer to functional consequences after small-volume resuscitation. METHODS: Using thrombelastometry (ROTEM), we studied 30 pigs (weighing 35-45 kg) after withdrawal of 60% of blood volume [1484 mL (1369-1624 mL)] and receiving 4 mL/kg HS-HES for compensation of blood loss or 4% gelatin or 6% HES 130/0.4 in a 1:1 ratio to lost blood volume. To compare the ROTEM variables (coagulation time, clot formation time, alpha angle, clot firmness, and fibrinogen polymerization) with bleeding tendency, a hepatic incision was made and blood loss was measured. RESULTS: Median (25th, 75th percentile) fibrinogen polymerization was significantly higher after HS-HES infusion [11 mm (10, 11), P = 0.0034] when compared with administration of 4% gelatin [4.5 mm (3.0, 5.8)] or HES 130/0.4 [3.5 mm (2.3, 4.0)]. Median blood loss after liver incision was 725 mL (900, 375) after HS-HES, 1625 mL (1275, 1950) after 4% gelatin, and 1600 mL (1500, 1800) after 6% HES 130/0.4 (P = 0.004). Hemodynamic stabilization was traceable in all groups but showed differences regarding filling pressures. CONCLUSIONS: Resuscitation from hemorrhagic shock with HS-HES 200/0.62 results in less impairment of clot formation when compared with compensation of blood loss by administering 6% HES 130/0.4 or 4% gelatin.

Inflammatory and coagulatory parameters linked to survival in critically ill children with sepsis.

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.

Endogenous vasopressin and copeptin response in multiple trauma patients.

Endogenous arginine vasopressin (AVP) levels in multiple trauma patients are unknown. Arginine vasopressin is considered to play an important role in severe hemorrhage. In this prospective study, 87 multiple trauma patients (Injury Severity Score >15) and 50 healthy volunteers were enrolled. On admission to the emergency department (ED), demographic, clinical, and laboratory data were documented, and blood was sampled for determination of AVP (radioimmunosassay) and copeptin, a stable fragment of the AVP precursor (immunoluminometric assay). In patients requiring intensive care unit (ICU) therapy, blood and data sampling were repeated at 4, 6, and 24 h after ED admission. Linear logistic and mixed-effects regression analyses were used for statistical analysis. On ED admission, AVP plasma concentrations (43.2 +/- 84.9 pM) were significantly increased when compared with controls (0.92 +/- 0.44 pM, P < 0.001). Plethysmographic oxygen saturation was the only parameter independently associated with AVP (regression coefficient, -0.126; 95% confidence interval, -0.237 to -0.014; P = 0.03). No correlation was observed between AVP and survival (P = 0.62), hemodynamic variables (systolic arterial pressure, P = 0.24; MAP, P = 0.59; diastolic arterial pressure, P = 0.74; central venous pressure, P = 0.36), or brain trauma (P = 0.46). In ICU patients, AVP decreased during the first 24 h (P < 0.001) and was independently associated with heart rate (P = 0.02) and blood glucose (P = 0.009). Copeptin concentrations were correlated with AVP (r2 = 0.718, P < 0.001). In conclusion, AVP was significantly increased in multiple trauma patients and seems to be an integral part of the neuroendocrine response to severe injury. In ICU patients, AVP decreased to moderately elevated levels within 24 h after ED admission.

Changes in blood coagulation of arm and leg veins during a simulated long-haul flight.

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.

Hemostatic changes after crystalloid or colloid fluid administration during major orthopedic surgery: the role of fibrinogen administration.

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.