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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

PLOS ONE 17(1), e0262110 (2022). doi:10.1371/journal.pone.0262110, Published by PLOS, San Francisco, California, US

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 &lt, 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.

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 &ldquo, Reversal of Trauma-induced Coagulopathy using First-line Coagulation Factor Concentrates or Fresh-Frozen Plasma&rdquo, 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 &times, 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.

BackgroundSepsis 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.MethodsA 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.ResultsThe 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).ConclusionsThis 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.

Background: Trauma-induced coagulopathy (TIC) substantially contributes to mortality in bleeding trauma patients. We evaluated the feasibility and efficacy of pre-hospital administration of fibrinogen concentrate to trauma patients bleeding or presumed to bleed. (FC; Clottafact®, LFB France). Methods: A prospective, randomised, placebo-controlled, double-blinded trial was conducted in Austria, Germany and the Czech Republic. Adult trauma patients aged ≥18 years with major bleeding and a need for volume therapy were eligible for enrolment. Patients were randomised to treatment with FC or placebo. The target FC dose of 50 mg/kg bodyweight or an equivalent amount of placebo was administered at the scene or during transportation to the study centre. The primary endpoint was blood clot stability as reflected by maximum clot firmness in the functional FIBTEM assay (FibMCF). The trial was registered with ClinicalTrials.gov, number NCT01475344 (FIinTIC-Trial). Findings: Between 2011 and 2015, 67 patients were enrolled, of whom 14 were excluded due to predefined exclusion criteria or missing data. Thus, the primary analysis included 53 patients, of whom 28 received FC group and 25 received placebo. Median FibMCF decreased in the placebo group between baseline (before administration of study treatment) and admission to the emergency department, from 12.5 (interquartile range: 10.5-14) mm to 11 (9.5-13) mm, p=0.0226, but increased in the FC group from 13 (11-15) mm to 15 (13.5-17) mm, p=0.0062. The median between-group difference in the change in FibMCF was 5 (3-7) mm, p 200 mg/dl, throughout all observation time points. Interpretation: Early FC administration is feasible in the complex and time-sensitive environment of pre-hospital trauma care; it protects against early fibrinogen depletion and promotes rapid blood clot initiation and clot stability. Trial Registration Number: The trial was registered with ClinicalTrials.gov, number NCT01475344 (FIinTIC-Trial). Funding: The study was funded by LFB Biomedicaments (France), the US Army/Department of Defense (Coalition Warfare Grant) and the Austrian Ministry of Sports and Defence; the study medication and an unrestricted grant were provided by LFB Biomedicaments. In addition, the study was sponsored by the Medical University of Innsbruck (Austria). Declaration of Interest: BS has received travel grants, honoraria for speaking or participation at meetings from CSL Behring, BBraun and Biotest. BZ has received speaker fees from CSL Behring. 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. HS has received honoraria for participation in advisory board meetings for Bayer Healthcare, Bohringer Ingelheim and Tem International, and has received study grants from CSL Behring. 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. MM has received fees for lectures, advisory board services, travel and research support from Astra Zeneca, Bayer, Biotest, CSL Behring, IL-Werfen and LFB Biomedicaments. HS has received honoraria for participation in advisory board meetings for Bayer Healthcare, Bohringer Ingelheim and Tem International, and has received study grants from CSL Behring. PI received non-financial (technical) support from TEM International GmbH during conduction of the study; personal fees from Baxter GmbH, CSL Behring GmbH, Fresenius Kabi GmbH Austria, Bayer Austria GmbH, LFB, and non-financial support from TEM International, outside the submitted work. WJM is employee of the US Army, Department of Defense, one of the funding organisations. BT, EO, HH, HT, MT, MK, WV, IZ, CaroN, ChriN and UM declare no conflict of interest. Ethical Approval: The study protocol was approved by the Medical Ethics Committee at each participating centre as well as by the national authorities of each participating country.

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. Electronic supplementary material The online version of this article (10.1186/s13613-018-0457-8) contains supplementary material, which is available to authorized users.

Trauma is one of the leading causes of mortality in the world, accounting for millions of deaths per year. One of the most frequent causes of death in trauma patients is hemorrhage. The presence of a coagulopathy in trauma patients more than doubles the expected mortality. Coagulation management is a key aspect of care for bleeding trauma patients and has been investigated in many studies. However, it is unclear whether a particular approach to coagulation management is associated with a reduction in mortality. Treatment may be guided (e.g., viscoelastic test-guided administration of coagulation factor concentrates) or nonguided (e.g., treatment with a fixed ratio of plasma:red blood cells). This review aimed to assess the published literature regarding coagulation management technique and mortality rate. From the 41 articles obtained in the literature search, there appeared to be a trend toward lower mortality in studies utilizing a guided approach, despite a higher injury severity score in these patients. There were many methodological variations across studies including coagulation management approaches, inclusion criteria, time and type of measurements, use of early fast coagulation monitoring and damage control surgery principles, additional products to those under study, and potential regional differences. It is essential that controlled trials are performed to ascertain optimal transfusion approaches in trauma patients.

Background ROTEM®/TEG® (rotational thromboelastometry) assays appear to be useful for the treatment of bleeding trauma patients. However, data on the prevalence and impact of abnormal ROTEM® assays are scarce. Methods This is a prospective cohort study of blunt trauma patients (Injury Severity Score ≥15 or Glasgow Coma Score ≤14) admitted to Innsbruck Medical University Hospital between July 2005 and July 2008. Standard coagulation tests, antithrombin (AT), prothrombin fragments (F1+2), thrombin–antithrombin complex (TAT), and ROTEM® assays were measured after admission. Data on 334 patients remained for final analysis. Results ROTEM® parameters correlated with standard coagulation tests (all Spearman r>0.5), and significant differences in mortality were detected for defined ROTEM® thresholds [FIBTEM 7 mm (21% vs 9%, P=0.006), EXTEM MCF (maximum clot firmness) 45 mm (25.4% vs 9.4%, P=0.001)]. EXTEM MCF was independently associated with early mortality [odds ratio (OR) 0.94, 95% confidence interval (CI) 0.9–0.99] and MCF FIBTEM with need for red blood cell transfusion (OR 0.92, 95% CI 0.87–0.98). In polytrauma patients with or without head injury (n=274), the prevalence of low fibrinogen concentrations, impaired fibrin polymerization, and reduced clot firmness was 26%, 30%, and 22%, respectively, and thus higher than the prolonged international normalized ratio (14%). Hyperfibrinolysis increased fatality rates and occurred as frequently in isolated brain injury (n=60) as in polytrauma (n=274) (5%, 95% CI 1.04–13.92 vs 7.3%, 95% CI 4.52–11.05). All patients showed elevated F1+2 and TAT and low AT levels, indicating increased thrombin formation. Conclusions Our data enlarge the body of evidence showing that ROTEM® assays are useful in trauma patients. Treatment concepts should focus on maintaining fibrin polymerization and treating hyperfibrinolysis.

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.

Perioperative coagulopathy impacts on patient outcome by influencing final blood loss and transfusion requirements. The recognition of pre-existing disturbances and the basic understanding of the principles of and dynamic changes of haemostasis during surgery are pre-conditions for safe patient management. The newly developed cellular model of coagulation facilitates the understanding of coagulation, thereby underscoring the importance of the tissue factor-bearing cell and the activated platelet. Amount of blood loss as well as amount and type of fluids used are the main factors involved in the development ofdilutional coagulopathy, which is the most frequently observed cause of coagulopathy in the otherwise healthy surgical patient. Recent data from studies using viscoelastic coagulation studies confirm the central role of fibrinogen in stable clot formation and provide essential knowledge about its changes during blood loss and fluid administration. Besides early decrease in clot firmness during mild-to-moderate dilution, profound dilution results in a critical decrease in thrombin generation as well as a reduction in numbers and function of platelets. Although our knowledge of perioperative coagulopathy has dramatically increased over the past few years, several questions such as critical thresholds for fibrinogen, platelets, impact of FXIII and TAFI remain unanswered and need to be investigated further.

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.

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).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.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.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.

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.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.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.

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.

This case series presents three patients with sepsis/septic shock in whom standard coagulation tests (interna- tional normalized ratio, activated partial thromboplastin time, fibrinogen, antithrombin, thrombocytes) and ROTEM ® thromboelastometry (InTEM, ExTEM, FibTEM) were simultaneously performed. Although all patients showed signifi- cantly prolonged plasmatic coagulation times with a putatively increased risk of bleeding, ROTEM ® thromboelastometry revealed normal clotting times and even signs of hypercoagulability. Therefore, no coagulation active therapy was per- formed in any patient, not even before invasive procedures or major surgical interventions. No bleeding occurred in any study patient during surgery or the subsequent stay on the intensive care unit. These observations suggest that some criti- cally ill patients with sepsis and abnormal standard coagulation tests may in fact have hypercoagulability. ROTEM ® thromboelastometry can add important information in these patients and enable that blood products are used targeted and only for substitution of relevant deficencies. Future studies are necessary to validate these preliminary findings.

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.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.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.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.

The purpose of this prospective study was to assess the blood-sparing effect, the quality of analgesia, and the incidence of side-effects of a low-dose regime of intrathecal opioids (ITO) when compared with those of a high-dose regime in scoliosis surgery in children.Forty-six children were randomly included into one of the three groups to receive morphine 5 microg kg(-1) plus sufentanil 1 microg kg(-1) [low-dose intrathecal opioid (LITO)], morphine 15 microg kg(-1) plus sufentanil 1 microg kg(-1) [high-dose intrathecal opioid (HITO)] intrathecally, or no intrathecal opioid. Postoperative analgesia was provided by i.v. opioids. Intraoperative blood loss, postoperative quality of analgesia, opioid requirements, and the incidence of side-effects were recorded for 3 days.Intraoperative blood loss was significantly reduced by ITOs [LITO: 41.4 (sd 18.8) ml kg(-1); HITO: 37.5 (6.9) ml kg(-1); control: 76.9 (15.3) ml kg(-1), P0.001], with no difference between the two intrathecal opioid groups. Mean pain scores on the day of surgery were lower in both intrathecal opioid groups (LITO: 2.2 and HITO: 2.1) when compared with the control group (4.1, P0.03) and opioid consumption was significantly decreased [LITO: 304.3 (65.0) microg kg(-1); HITO: 224.1 (51.8) microg kg(-1); control: 667.7 (89.5) microg kg(-1), P0.002]. Side-effects of intrathecally administered opioids were similarly frequent in all groups.Intrathecal administration of opioids significantly reduces blood loss and postoperative opioid demand, thereby showing side-effects comparable with the control group. These effects were already seen with the low-dose regimen and high dose did not further improve efficacy.

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.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.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.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.

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.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.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.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.

Albumin is often cited in textbooks as the gold standard for fluid replacement in paediatrics, but in practice artificial colloids are more frequently used. Although one concern with the use of artificial colloids is their intrinsic action on haemostasis, the available data in children are inconclusive for 6% hydroxyethyl starch 130/0.4 (HES) and no data exist for gelatine solution with respect to coagulation. A total of 42 children (3-15 kg) undergoing surgery and needing colloid replacement were randomly assigned to receive 15 mlxkg(-1) of either albumin 5%, 4% modified gelatine solution or 6% hydroxyethyl starch 130/0.4 solution. Standard coagulation tests and modified thrombelastography (ROTEM) were performed. After colloid administration, routine coagulation test results changed significantly and comparably in all groups, although activated partial thromboplastin time values increased more with gelatine and HES. Coagulation time was unchanged in the children who received albumin or gelatine but other activated modified thrombelastography values were significantly impaired in all groups. After gelatine and after albumin the median clot firmness decreased significantly but remained within the normal range. Following HES, coagulation time increased significantly, and clot formation time, alpha angle, clot firmness, and fibrinogen/fibrin polymerisation were significantly more impaired than for albumin or gelatine, reaching median values below the normal range. From a haemostatic point of view it might be preferable to use gelatine solution as an alternative to albumin; HES showed the greatest effects on the overall coagulation process.

Summary. Objectives: The hypothesis that the administration of fibrinogen concentrate enables restoration of impaired clot formation and increased bleeding in severe thrombocytopenia was tested. Methods: Thirty pigs were anesthetized, instrumented for blood sampling (routine coagulation tests, modified thrombelastography ROTEM®), hemodynamic monitoring and platelet apheresis to a target below 30 × 109 L−1 after splenectomy. Thereafter 10 each of the animals randomly received two apheresis platelet concentrates, 250 mg kg−1 fibrinogen concentrate or normal saline solution. A standardized liver injury was subsequently inflicted to induce uncontrolled hemorrhage. Results: Median (Q1, Q3) clot firmness increased significantly more in thrombocytopenic pigs after fibrinogen administration (42 mm (41, 43) to 60 mm (57, 63)) than following platelet transfusion (40 mm (37, 45) to 52 mm (48, 55), P = 0.0004) or placebo (45 mm (41, 48) to 45 mm (43, 46), P = 0.0002). Median blood loss velocity after liver injury was significantly less with fibrinogen (33 mL min−1, P = 0.005) than with platelets (62 mL min−1, P = 0.037) or saline (84 mL min−1, P = 0.005), and median survival time after liver injury was 55 min in the fibrinogen, 26 min in the platelet (P = 0.035) and 19 min in the saline group (P =

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®) 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.

This study was conducted to assess whether the combined administration of fibrinogen and prothrombin complex concentrate (PCC) enables the reversal of dilutional coagulopathy resulting from intended blood loss and fluid replacement, and whether this treatment reduces further blood loss and mortality.In 20 anaesthetized pigs, approximately 65% of the estimated blood volume was withdrawn and replaced with the same amount of hydroxyethyl starch (6% HES 130/0.4) to mimic blood loss and to develop a dilutional coagulopathy. Pigs (randomized) received either fibrinogen (200 mg kg(-1)) and PCC (35 IU kg(-1)) (n=10), or placebo (n=10). Thereafter, a standard liver laceration was performed to induce uncontrolled haemorrhage. The subsequent blood loss and survival time were determined as primary outcome variables. Throughout the experiment serial blood samples were obtained to assess the competence of the haemostatic system using standard coagulation tests, modified Thrombelastograph measurements (ROTEM) and electron microscopy clot imaging.As compared with baseline, after haemodilution both groups showed statistically significant impairment of haemostasis as measured with standard coagulation tests and thrombelastography. These parameters significantly improved after administration of the study drugs while aPPT measurements remained unchanged. Blood loss after liver injury was significantly less in the treatment group as compared with placebo: 240 ml (50-830) vs 1800 ml (1500-2500) (P0.0001). All treated animals survived, whereas 80% of the placebo group died (P0.0001).During haemodilution, substitution of fibrinogen and PCC causes an enhancement of coagulation and final clot strength. This reversal of dilutional coagulopathy may reduce blood loss and mortality when large amounts of colloids are needed to maintain normovolaemia during huge blood losses.

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.

Colloids and crystalloids are usually administered as treatment for hypovolemia in severely injured patients. However, dilution of clotting factors and platelets together with impaired fibrinogen polymerization are associated with fluid therapy and may aggravate hemorrhage, thus worsening final outcome of these patients. We investigated, in an in vitro model, whether the addition of fibrinogen to diluted blood samples can reverse dilutional coagulopathy. Blood from 5 healthy male volunteers was diluted by 60% using lactated Ringer's solution, 4% modified gelatin solution, or 6% hydroxyethyl starch 130/0.4, as well as the combination of lactated Ringer's solution with either of the 2 colloid solutions. Thereafter, aliquots of diluted blood samples were incubated with 3 different concentrations of fibrinogen (0.75, 1.5, and 3.0 mg/mL). Measurements were performed by modified thrombelastography (ROTEM; Pentapharm, Munich, Germany). After 60% dilution, clotting times increased, whereas clot firmness and fibrin polymerization decreased significantly. After administration of fibrinogen, clotting times decreased and clot firmness, as well as fibrin polymerization, increased in all diluted blood samples. The effect of in vitro fibrinogen substitution on ROTEM variables was dependent on the fibrinogen dosage and the type of solution used to dilute the blood samples.

SummaryGuidelines of official societies for diagnosis and therapy of intraoperatively occurring hypocoagulability rely mainly on data of patients receiving whole blood transfusions. They recommend -provided that laboratory evaluation shows deficiency (values >1.5 fold normal)- administration of fresh frozen plasma, cryoprecipitate and platelet concentrates (platelet count

Background This study was conducted to determine whether replacement of fibrinogen is useful in reversing dilutional coagulopathy following severe haemorrhage and administration of colloids. Methods In 14 anaesthetized pigs, approximately 65% of the estimated blood volume was withdrawn and replaced with the same amount of gelatin solution to achieve dilutional coagulopathy. Animals were randomized to receive either 250 mg kg−1 fibrinogen (n=7) or normal saline (n=7). A standardized liver injury was then inflicted to induce uncontrolled haemorrhage. Modified thrombelastography and standard coagulation tests were performed at baseline, after blood withdrawal, after dilution, after injection of the study drugs, and on conclusion of the protocol. Further, electron microscopy imaging of the blood clots was performed and blood loss after liver injury was determined. Results Severely impaired haemostasis was observed after haemodilution with gelatin substitution. With administration of fibrinogen, clot firmness and dynamics of clot formation reached baseline values. Median blood loss following liver injury was significantly less (P=0.018) in the fibrinogen-treated animals (1100 ml; 800–1400 ml) than in the placebo group (2010 ml; 1800–2200 ml). Conclusions Replacing 65% of the estimated blood volume with gelatin in swine resulted in dilutional coagulopathy; subsequent fibrinogen administration improved clot formation and reduced blood loss significantly.

The authors report two cases of delayed post-operative anterior spinal artery syndrome (ASAS) following posterior correction with Cotrel Dubousset (CD) instrumentation for adolescent idiopathic scoliosis. Sensory pathways were continuously monitored from skin incision to awakening. In both cases intraoperative SEPs were normal and the wake-up test revealed no neurological deficit. Both patients were presented with incomplete paraplegia (no sensory impairment) three and ten hours after surgery. Without delay, both patients underwent revision surgery, and the CD instrumentation was removed. Immediately after surgery, both patients' motor power in their lower extremities improved rapidly. In cases with delayed ASAS after posterior scoliosis correction, the removal of the instrumentation system was shown to be sufficient to regain full motor recovery caudal to the level of impairment.

More efficacious anticoagulant and antiplatelet agents have been introduced in vascular medicine and in the prevention of perioperative venous thromboembolisms. Patient management should be guided by familiarity with thepharmacology of coagulation-altering drugs and by consensus statements. The present paper reviews recommendations from the Austrian Task Force for Perioperative Coagulation which are based on thorough evaluation of the available pharmacological information and case reports. The consensus statement focuses on neuraxial and peripheral techniques and is designed to encourage safe and quality patient care.

Resuscitation of patients in hemorrhagic shock remains one of the most challenging aspects of trauma care. We showed in experimental studies that vasopressin, but not fluid resuscitation, enabled short-term and long-term survival in a porcine model of uncontrolled hemorrhagic shock after penetrating liver trauma. In this case report, we present two cases with temporarily successful cardiopulmonary resuscitation (CPR) using vasopressin and catecholamines in uncontrolled hemorrhagic shock with subsequent cardiac arrest that was refractory to catecholamines and fluid replacement. In a third patient, an infusion of vasopressin was started before cardiac arrest occurred; in this case, we were able to stabilize blood pressure thus allowing further therapy. The patient underwent multiple surgical procedures, developed multi-organ failure, but was finally discharged from the critical care unit without neurological damage.

Hemorrhage after traumatic injury results in coagulopathy which only worsens the situation. This coagulopathy is caused by depletion and dilution of clotting factors and platelets, increased fibrinolytic activity, hypothermia, metabolic changes and anemia. The effect of synthetic colloids used for compensating the blood loss, further aggravates the situation through their specific action on the hemostatic system. Bedside coagulation monitoring permits relevant impairment of the coagulation system to be detected very early and the efficacy of the hemostatic therapy to be controlled directly. Administration of fresh frozen plasma (FFP), platelet concentrates and antifibrinolytic agents is essential for restoring the impaired coagulation system in trauma patients. Clotting factor concentrates should be administered if coagulopathy is based on diagnosed depletion of clotting factors, if FFP is not available and if transfusion of FFP is insufficient to treat the coagulopathy. Recombined FVIIa is frequently employed during severe bleeding which could not be treated by conventional methods but the results of on-going clinical trials are not yet available.

Effective treatment of severe or uncontrolled bleeding is a challenge for physicians in the operating room and intensive care unit. However, even aggressive conventional therapy may ultimately fail in some patients. Administration of recombinant activated factor VII (rFVIIa) may be the only remaining therapeutic option to stop life-threatening coagulopathic bleeding. We here describe the clinical course of 5 patients exhibiting severe continuous bleeding that could not be stopped by surgical intervention and appropriate hemostatic management but resolved after a mean dose of 90 microg/kg of rFVIIa (range, 90-120 microg/kg). Four of the five patients recovered completely, and one patient died after developing sepsis in multiorgan failure. In all patients, bleeding from wound surfaces stopped within minutes of the administration of rFVIIa. Coagulation measurements improved, and transfusion requirements declined considerably. No adverse effects associated with rFVIIa were observed.

Recent changes in quality of transfusion supply, transfusion triggers as well as fluid therapy promote the development of dilutional coagulopathy. Nevertheless, up to now guidelines generally assume presence of hypocoagulability when more than one individual circulating blood volume is lost. This might be true for some patients under some conditions but is not necessarily true for every patient. Routine coagulation tests are insufficient in predicting increased bleeding and, moreover, available after an unacceptable time delay. Therefore the occurrence of diffuse microvascular bleeding is often used as clinical sign to start hemostatic therapy. However, such severe derangement of hemostasis might lead to the development of secondary tissue damage and frequently is unresponsive to conventional treatment. Coagulopathy occurring during extensive surgery or after polytrauma can be detected and treated early when using the ROTEM® monitoring. Recent data showing a direct beneficial effect of hemostatic therapy on blood loss and final outcome are scarce. However, evidence exists that the amount of blood loss, presence of coagulopathy and number of transfusions needed are associated with poor outcome in bleeding patients. Although manifold articles have been published already using thrombelastography for various indications (medline research "thrombelastography", 2022 articles), further data are needed to confirm the clinical experience that this technique is an excellent tool for safe patient management.

To explore whether intravenous administration of routinely used crystalloid or colloid solutions differently affects the coagulation system, we investigated orthopaedic patients. Since crystalloid solutions might cause hypercoagulability, we here present our results on molecular markers of coagulation and fibrinolysis. Patients undergoing knee replacement surgery randomly received isovolemic amounts of lactated Ringer's solution, 6% hydroxyethyl starch 200/0.5 or 4% modified gelatine. Arterial blood samples for determination of specific molecular markers of activated coagulation (thrombin/antithrombin complex, D-dimer, prothrombin fragment F1 + 2), fibrinolysis (plasmin/alpha 2-antiplasmin complex, tissue plasminogen activator, plasminogen activator inhibitor-1), and concentrations of coagulation factor XIII were obtained at baseline, before tourniquet release, at the end of surgery and 2 h after operation. During the observation period, thrombin/antithrombin complex increased from 4.8 to 54.7 microg/l, D-dimer increased from 0.3 to 6.0 mg/ml, prothrombin fragment F1 + 2 increased from 1.7 to 5.9 nmol/l, tissue plasminogen activator decreased from 7.3 to 6.7 ng/ml, plasminogen activator inhibitor-1 increased from 68.4 to 71.0 ng/ml, plasmin/alpha 2-antiplasmin complex increased from 281.5 to 884 microg/l and factor XIII decreased from 89.0 to 58.5%. All parameters changed significantly but without any detectable difference in the response profile between the groups receiving different intravenous fluids. During knee replacement surgery a pronounced activation of the coagulation/fibrinolytic system was observed, regardless of whether patients received crystalloid or colloid fluids. Thus, these results cannot confirm the hypothesis that crystalloid fluids per se cause hypercoagulability in vivo.

Quantitative changes of hemostasis during hemodilution remain unclear. With the increasing popularity of artificial blood substitutes (ABS), which solely provide oxygen-transport capacity, this issue becomes even more complex. We developed a mathematical model to quantitatively analyze hemostasis during hemodilution and validated it by recalculating patient data. We calculated and compared maximal allowable blood losses (MABL) related to minimal acceptable hematocrit, platelet concentration, and plasma fibrinogen concentration. MABL is the maximal blood loss that can be tolerated without any additional blood products. The variable with the smallest MABL thus limits hemodilution foremost. Hemodilution included isovolemic replacement of blood loss with colloid or acute normovolemic hemodilution (ANH) followed by isovolemic replacement of blood loss with colloid and ABS. We also related our findings to preoperative patient data (n = 204). The decline in platelet concentrations rarely (2% of all patients) limits hemodilution. By contrast, critical plasma fibrinogen (or =100 mg/dL) concentrations can often (or =20% of all patients) limit hemodilution if their initial concentrations are within the lower normal range (300 mg/dL). These findings become more frequent if ANH is combined with ABS. Under those circumstances ANH blood products are solely required for stabilization of hemostasis, thereby defeating the original purpose of combining ANH with ABS.The causes of quantitative changes of hemostasis during hemodilution, as well as their clinical effect and relevance, remain unclear. Using a validated, realistic mathematical model, we demonstrate that hemostasis, especially plasma fibrinogen, can limit the extent of hemodilution. This phenomenon is particularly prominent when acute normovolemic hemodilution is combined with artificial blood substitutes.

Background. We describe the development and comparison of a psychometric questionnaire on patient satisfaction with anaesthesia care among six hospitals. Methods. We used a rigorous protocol: generation of items, construction of the pilot questionnaire, pilot study, statistical analysis (construct validity, factor analysis, reliability analysis), compilation of the final questionnaire, main study, repeated analysis of construct validity and reliability. We compared the mean total problem score and the scores for the dimensions: ‘Information/Involvement in decision‐making', and ‘Continuity of personal care by anaesthetist'. The influence of potential confounding variables was tested (multiple linear regression). Results. The average problem score from all hospitals was 18.6%. Most problems are mentioned in the dimensions ‘Information/Involvement in decision‐making' (mean problem score: 30.9%) and ‘Continuity of personal care by anaesthetist' (mean problem score: 32.2%). The overall assessment of the quality of anaesthesia care was good to excellent in 98.7% of cases. The most important dimension was ‘Information/Involvement in decision‐making'. The mean total problem score was significantly lower for two hospitals than the total mean for all hospitals (significantly higher at two hospitals) (P

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.

Background A prospective observational study was conducted in two clinical cohorts of patients to compare the effect of enoxaparin and rivaroxaban on rotational thromboelastometry (ROTEM), coagulation activation markers and thrombin generation. Methods A total of 188 consecutive patients scheduled for major orthopedic surgery receiving 40-mg enoxaparin subcutaneously or 10-mg rivaroxaban orally were evaluated. Blood samples were taken before induction of anesthesia and on day 4 after surgery [postoperative day 4 (pod 4)]. The extrinsically (EXTEM) and the intrinsically (INTEM) activated ROTEM assay, antithrombin, prothrombin fragments (F1 + 2), thrombin-antithrombin complex (TAT) and D-dimers were measured, and the thrombodynamic ratio (TDR) was calculated. Thrombin generation was determined using calibrated automated thrombography. To compare the groups, changes (Δ) in baseline versus pod 4 were calculated. Results EXTEM clotting time (CT) increased more with rivaroxaban than with enoxaparin; values above the reference range were observed (median ΔEXTEM-CT 15 vs. 5 s, P ≤ 0.0001). The increase in INTEM-CT (values remained within the normal ranges) was slight with enoxaparin and significant with rivaroxaban; ΔINTEM-CT was comparable. EXTEM-TDR, unchanged with rivaroxaban, increased significantly with enoxaparin, whereas ΔINTEM-TDR was comparable. ΔAT, ΔF1 + 2 and ΔTAT were significantly lower in the rivaroxaban group. Endogenous thrombin potential (ETP), unchanged with rivaroxaban, decreased significantly with enoxaparin; the maximal rising slope (mean velocity rate index) decreased more with rivaroxaban. Conclusion Data show that prolonged CT in the extrinsic ROTEM and thrombin generation assays reflecting initiation and propagation of thrombin may be useful for detecting treatment with rivaroxaban. The significance of observed differences in markers of coagulation needs to be investigated further.

To explore whether polymorphonuclear leukocytes (PMNL) are activated to the priming threshold through intraoperative blood salvage, and are thus able to induce endothelial damage, we investigated chemotactic response (n = 20) and respiratory burst (RB; n = 20) of PMNL without (basal respiratory burst, bPMNL-RB) and after in vitro stimulation with formyl-Met-Leu-Phe (fMLP-RB) and phorbol myristate acetate (PMA-RB). Blood was processed with a continuous autotransfusion device (CATS). Heparin (Heparin group) and sodium citrate (Citrate group) were used alternately as an anticoagulant for each half of the chemotaxis and RB studies. Comparison of measurements from the processed autologous erythrocyte concentrates (paEC) to pre- and intraoperative arterial blood samples showed no statistically significant difference for any test of PMNL functional responses in an orthopedic patient population. Analysis of intraindividual changes demonstrated a significantly increased bPMNL-RB (both groups, P = 0.0032; Heparin group, P = 0.0098), fMLP-RB (both groups, P = 0.0484; Citrate group, P = 0.0371), and PMA-RB (Citrate group, P = 0.002) in the paEC compared with intraoperative arterial samples, whereas the chemotactic response did not change. Nevertheless, median values of all RB measurements in the paEC were within the range of pre- and intraoperative values, indicating that PMNLs contained in the paEC are neither impaired nor activated to the priming threshold. The results confirm the clinical experience that intraoperative blood salvage is safe to use during major orthopedic surgery and questions the beneficial effect of special leukocyte-removing filters.

BACKGROUND: To estimate the impact of RBC preparations on the status of postoperative immune activation, the soluble cytokine receptors of TNFα (sTNF-R) and IL-2 (sIL-2R), as well as neopterin and cell-mediated lympholysis (CML), were measured. STUDY DESIGN AND METHODS: Patients undergoing strictly standardized anesthesiologic management for elective orthopedic surgery were enrolled in a prospective study. The perioperative course (Days 0, 3, 7, and 10) of sTNF-R, sIL-2R, neopterin, and CML was compared after random assignment to allogeneic buffy coat-reduced (Group 2, n = 8) or WBC-reduced (Group 3, n = 11) RBC transfusion regimen. Recipients of autologous buffy coat-reduced RBC transfusions (Group 1, n = 15) served as controls. Patients receiving intraoperatively and postoperatively salvaged blood only (n = 10) were separately analyzed as Group 4. RESULTS: In Group 1, a short-lasting increase in soluble cytokine receptors, a diminished cytolytic response (Day 0 vs. Day 7: sTNF-R, p = 0.0001; sIL-2R, p = 0.0004; CML, p = 0.0238), and an elevation of neopterin (Day 0 vs. Day 3: p = 0.0064) were observed. In contrast, in allogeneically transfused patients, sTNF-R (Group 2, p = 0.0469: Group 3, p = 0.0039), sIL-2R (Group 3, p = 0.002) and neopterin (Group 3, p = 0.0164) increased further from baseline to Day 10 (Day 0 vs. Day 10), and this increase was accompanied by a diminished cytolytic response (Day 0 vs. Day 10: Group 2, p = 0.05; Group 3, p = 0.0076). Patients in Group 4 showed a short-lasting increase in sIL-2R (Day 0 vs. Day 3: p = 0.0078), neopterin (Day 0 vs. Day 3: p = 0.0156) and sTNF-R (Day 0 vs. Day 7: p = 0.0781). CONCLUSION: Allogeneic transfusions seem to prolong the postoperative status of immune activation, even when WBC-filtered RBCs are used for the transfusion regimen.

BACKGROUND: Donor white cells (WBCs) contained in red cell (RBC) transfusions are thought to provoke down-regulation of T-cell-mediated immunity. This study investigated this topic in otherwise healthy patients receiving buffy coat-depleted or WBC-filtered RBCs and undergoing standardized perioperative management. STUDY DESIGN AND METHODS: Patients undergoing elective orthopedic surgery (primary hip and knee replacement surgery) were enrolled in a prospective study. Perioperative changes in T-cell proliferation (stimulation with phytohemagglutinin and mixed lymphocyte culture) and T-cell balance (T-lymphocytes, helper T cells, and suppressor T cells) were compared after random assignment to allogeneic buffy coat-depleted (Group 2, n = 8) or WBC-reduced RBC (Group 3, n = 11) transfusion regimens. Recipients of autologous buffy coat-depleted RBC transfusions (n = 15) served as controls (Group 1). RESULTS: Compared to that in autologous transfusion recipients, alloantigen-induced T-cell proliferation was significantly reduced in recipients of allogeneic WBC-reduced RBCs (Day 3, p = 0.0274). After the transfusion of allogeneic buffy coat-depleted RBCs, a weak trend toward decreased T-cell proliferation was observed (p = 0.0933) and the numbers of CD4+ T cells were also significantly lower (Day 7, p = 0.0389). On Day 10, alloantigen-induced T-cell proliferation remained significantly below baseline after transfusion of WBC-reduced RBCs (p = 0.05), the numbers of CD3+ cells decreased in allogeneic RBC recipients (Group 2, p = 0.078; Group 3, p = 0.05), and those of CD8+ cells decreased significantly after the transfusion of allogeneic buffy coat-depleted RBCs (p = 0.0234) concomitant with an increased CD4:CD8 ratio (p = 0.0391). CONCLUSION: Results of the present study confirm the hypothesis of impaired T-cell-mediated immunity after allogeneic transfusion.

In a prospective randomized study in children, we compared caudal bupivacaine-clonidine with bupivacaine-morphine to evaluate whether clonidine can be used as an alternative to morphine in caudal anaesthesia. Caudal anaesthesia was administered in 36 children undergoing orchidopexy, hernia repair or circumcision, using 1.5 mL kg-1 bupivacaine 0.18% with either 1 microgram kg-1 clonidine (group 1) or 30 micrograms kg-1 morphine (group 2). Haemodynamic and respiratory parameters, anaesthetic requirements, recovery time and pain score were monitored for 24 h. Eleven children in group 1 and nine children in group 2 did not need any supplementary systemic analgesics throughout the 24-h observation period. Mean (+/- SD) duration of analgesia in the remaining patients was 6.3 h (+/- 3.3 h) in group 1 and 7.1 h (+/- 3.4 h) in group 2 (P = 0.43). Recovery time after anaesthesia was significantly longer in group 1 (16.6 +/- 8.8 min) than in group 2 (11.5 +/- 4.7 min) (P < 0.05). We conclude that analgesia provided by 1 microgram kg-1 clonidine added to caudal bupivacaine is comparable with that provided by 30 micrograms kg-1 caudal morphine with bupivacaine. Clonidine at this low dose did not cause respiratory depression.

Background: Normovolemic hemodilution is a well-accepted method for intraoperative blood salvage. However, some controversy exists concerning the possible risk of myocardial fiber injury as a consequence of the reduced oxygen content. Laboratory diagnosis of perioperative myocardial fiber injury is difficult, since biochemical markers are elevated postoperatively due to the surgical trauma. Cardiac troponin I (cTnI) is a new, highly sensitive and specific cardiac marker for the detection of myocardial injury. The aim of our study was to investigate whether normovolemic hemodilution in patients with major orthopedic surgery (13 hemodiluted patients, 15 controls) induces a release of cTnI. Methods: cTnI as a highly specific and sensitive cardiac parameter, as well as total creatine kinase (CK), creatine kinase isoenzyme MB mass (CKMB mass) and myoglobin were measured after induction of anesthesia, after normovolemic hemodilution, prior to retransfusion of blood components, 3 h after surgery, and on the first and third postoperative days. Results: Prior to retransfusion of blood components the hematocrit was decreased to 25.4±1.2% (mean±SEM; range: 18%–34%) in the control group and to 20.2±0.8% (mean±SEM; range: 17%-24%) in the hemodilution group. Total CK, CKMB mass as well as myoglobin concentration increased significantly in both groups, reaching their maxima within the first day of surgery. In contrast, cTnI was below the detection limit of the assay (