Sibylle Kozek-Langenecker

Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM®)-guided administration of fibrinogen concentrate and prothrombin complex concentrate

IntroductionThe appropriate strategy for trauma-induced coagulopathy management is under debate. We report the treatment of major trauma using mainly coagulation factor concentrates.MethodsThis retrospective analysis included trauma patients who received ≥ 5 units of red blood cell concentrate within 24 hours. Coagulation management was guided by thromboelastometry (ROTEM®). Fibrinogen concentrate was given as first-line haemostatic therapy when maximum clot firmness (MCF) measured by FibTEM (fibrin-based test) was <10 mm. Prothrombin complex concentrate (PCC) was given in case of recent coumarin intake or clotting time measured by extrinsic activation test (EXTEM) >1.5 times normal. Lack of improvement in EXTEM MCF after fibrinogen concentrate administration was an indication for platelet concentrate. The observed mortality was compared with the mortality predicted by the trauma injury severity score (TRISS) and by the revised injury severity classification (RISC) score.ResultsOf 131 patients included, 128 received fibrinogen concentrate as first-line therapy, 98 additionally received PCC, while 3 patients with recent coumarin intake received only PCC. Twelve patients received FFP and 29 received platelet concentrate. The observed mortality was 24.4%, lower than the TRISS mortality of 33.7% (P = 0.032) and the RISC mortality of 28.7% (P > 0.05). After excluding 17 patients with traumatic brain injury, the difference in mortality was 14% observed versus 27.8% predicted by TRISS (P = 0.0018) and 24.3% predicted by RISC (P = 0.014).ConclusionsROTEM®-guided haemostatic therapy, with fibrinogen concentrate as first-line haemostatic therapy and additional PCC, was goal-directed and fast. A favourable survival rate was observed. Prospective, randomized trials to investigate this therapeutic alternative further appear warranted.

Chronic pelvic pain treated with gabapentin and amitriptyline: A randomized controlled pilot study

SummaryBACKGROUND: The aim of this study was to compare the efficacy and side effects of gabapentin, amitriptyline, and their combination in women with chronic pelvic pain. METHODS: In this open-label, prospective, randomized trial, 56 women with chronic pelvic pain were investigated with a two-year follow-up at the Vienna Medical University Hospital. If pain intensity assessed by a visual analog scale (VAS) was 5 or more (0, no pain; 10, maximal pain), despite analgesic therapy using the nonopioid drug metamizol together with weak opioids, patients were randomized to receive gabapentin (n = 20), amitriptyline (n = 20), or a combination of both drugs (n = 16). Doses of gabapentin and amitriptyline were increased to maximum daily doses of 3600xa0mg and 150xa0mg, respectively, until sufficient pain relief or the occurrence of side effects. VAS and side effects were evaluated before treatment and at 1, 3, 6, 12 and 24 months afterwards. RESULTS: All patients experienced significant pain relief during the observation period. However, after 6, 12 and 24 months, pain relief was significantly better in patients receiving gabapentin either alone or in combination with amitriptyline than in patients receiving monotherapy with amitriptyline (gabapentin: 0 months, 7.7 ± 1.5; 6 months, 1.6 ± 0.9; 12 months, 1.5 ± 0.9; 24 months, 1.9 ± 0.9; amitriptyline: 0 months, 7.3 ± 1.5; 6 months, 2.2 ± 1.6; 12 months, 2.2 ± 1.6; 24 months; 3.4 ± 0.9; amitriptyline-gabapentin: 0 months, 7.6 ± 0.8; 6 months, 1.3 ± 0.9; 12 months, 1.7 ± 1.0; 24 months, 2.3 ± 0.9). Side effects were lower in the gabapentin group than in the two other groups, the difference reaching statistical significance after three months (P < 0.05). CONCLUSION: Gabapentin alone or in combination with amitriptyline is better than amitriptyline alone in the treatment of female chronic pelvic pain.ZusammenfassungEINLEITUNG: Gegenstand der Studie war der Vergleich der Wirksamkeit und Verträglichkeit von Gabapentin bzw. Amitriptylin allein mit der Kombination der beiden Medikamente bei chronischen Unterbauchschmerzen (chronic pelvic pain, CPP). METHODEN: 56 weibliche Patientinnen mit chronischen Unterbauschmerzen wurden bei der prospektiven, randomisierten Open-label-Studie mit einem 2-jährigem Follow-up an der Schmerzambulanz der Universitätsklinik Wien, Österreich, eingeschlossen. Wenn die Schmerzintensität trotz analgetischer Therapie mit dem Nichtopioid Metamizol und einem schwachen Opioid gemessen auf der visuellen Analogskala (VAS) bei 5 oder darüber lag (0, kein Schmerz; 10, schlimmster vorstellbarer Schmerz), wurden die Patientinnen randomisiert einem der drei Behandlungsarme zugeteilt (Gabapentin, n = 20; Amitriptylin, n = 20, oder beides, n = 16). Die Medikamentengaben von Gabapentin bzw. Amitriptylin wurden auf eine tägliche Dosis von 3600xa0mg bzw. 150xa0mg gesteigert, bis eine suffiziente Schmerzerleichterung erreicht war oder unerwünschte Nebenwirkungen auftraten. VAS-Werte wurde vor Beginn der Behandlung und 1, 3, 6, 12 und 24xa0Monate danach erhoben. ERGEBNISSE: Alle Patientinnen erfuhren während des Beobachtungszeitraumes eine signifikante Schmerzreduktion. Dennoch war die Schmerzreduktion bei Patientinnen, die Gabapentin allein oder in Kombination mit Amitriptylin erhalten hatten, signifikant höher als unter Monotherapie mit Amitriptylin (Gabapentin: 0, 7,7 ± 1,5; 6, 1,6 ± 0,9; 12, 1,5 ± 0,9; 24, 1,9 ± 0,9; Amitriptylin: 0, 7,3 ± 1,5; 6, 2,2 ± 1,6; 12, 2,2 ± 1,6; 24, 3,4 ± 0,9; Amitriptylin-Gabapentin: 0, 7,6 ± 0,8; 6, 1,3 ± 0,9; 12, 1,7 ± 1,0; 24, 2,3 ± 0,9). Unerwünschte Nebenwirkungen traten signifikant seltener in der Gabapentin-Gruppe auf als in den beiden anderen Gruppen (P < 0,05). KONKLUSION: Diese Ergebnisse legen nahe, dass die Pharmakotherapie mit dem Antikonvulsivum Gabapentin die Behandlung von chronischen Unterbauchschmerzen bei ambulanten Patientinnen verbessert.

The effect of ex vivo anticoagulants on whole blood platelet aggregation

Pre- and intraoperative platelet function monitoring is increasingly recommended in order to detect risk factors for bleeding and to target coagulation management. The ideal anticoagulant for accurate platelet aggregometry remains controversial. The aim of this experimental trial was to compare platelet aggregability in whole blood stored in citrate, heparin and direct thrombin inhibitors. Whole blood was drawn from 11 healthy adult volunteers who had not taken any medication in the previous 14 days. Blood was stored in trisodium citrate, unfractionated heparin, melagatran, lepirudin and argatroban. Platelet aggregation was performed using the impedance aggregometer Multiplate® (Dynabyte, Munich, Germany) with adenosine diphosphate (ADP), thrombin receptor activating peptide (TRAP), collagen, arachidonic acid and ristocetin as agonists. Samples were analysed immediately after blood sampling (baseline), as well as 30 and 120 min afterwards. At baseline there were no significant differences in aggregability between samples containing direct thrombin inhibitors and heparin. In contrast, aggregation in response to all agonists except for ristocetin was significantly impaired in citrated blood. During storage the response to arachidonic acid and collagen was maintained by direct thrombin inhibitors and heparin, whereas ADP-, TRAP- and ristocetin-induced aggregation varied considerably over time in all ex vivo anticoagulants tested. Pre-analytical procedures should be standardized because storage duration and anticoagulants significantly affect platelet aggregability in whole blood. For point-of-care monitoring with immediate analysis after blood withdrawal all tested direct thrombin inhibitors as well as unfractionated heparin can be used as anticoagulants whereas citrate is not recommended.

Molecular adsorbent recirculating system and hemostasis in patients at high risk of bleeding: an observational study

IntroductionLiver failure is associated with reduced synthesis of clotting factors, consumptive coagulopathy, and platelet dysfunction. The aim of the study was to evaluate the effects of liver support using a molecular adsorbent recirculating system (MARS) on the coagulation system in patients at high risk of bleeding.MethodsWe studied 61 MARS treatments in 33 patients with acute liver failure (n = 15), acute-on-chronic liver failure (n = 8), sepsis (n = 5), liver graft dysfunction (n = 3), and cholestasis (n = 2). Standard coagulation tests, standard thromboelastography (TEG), and heparinase-modified and abciximab-fab-modified TEG were performed immediately before and 30 minutes after commencement of MARS, and after the end of MARS treatment. Prostaglandin I2 was administered extracorporeally to all patients; 17 patients additionally received unfractioned heparin.ResultsThree moderate bleeding complications in three patients, requiring three to four units of packed red blood cells, were observed. All were sufficiently managed without interrupting MARS treatment. Although there was a significant decrease in platelet counts (median, 9 G/l; range, -40 to 145 G/l) and fibrinogen concentration (median, 15 mg/dl; range, -119 to 185 mg/dl) with a consecutive increase in thrombin time, the platelet function, as assessed by abciximab-fab-modified TEG, remained stable. MARS did not enhance fibrinolysis.ConclusionMARS treatment appears to be well tolerated during marked coagulopathy due to liver failure. Although MARS leads to a further decrease in platelet count and fibrinogen concentration, platelet function, measured as the contribution of the platelets to the clot firmness in TEG, remains stable. According to TEG-based results, MARS does not enhance fibrinolysis.

Evaluation of the Platelet Mapping™ Assay on rotational thromboelastometry ROTEM®

Rotational thromboelastometry ROTEM® is available as point-of-care coagulation monitoring in an increasing number of European operating theatres and emergency rooms. The Platelet Mapping™ Assay has been described as a platelet aggregation assay for thromboelastography TEG®. The aim of this experimental trial was to evaluate feasibility of the Platelet Mapping™ Assay on the ROTEM® test system. Whole blood was drawn from 22 adult volunteers and patients with and without antiplatelet medication. Platelet aggregability was determined in three whole blood assays: the Platelet Mapping™ Assay using both activators arachidonic acid (AA) and adenosine diphosphate (ADP) on TEG®, its adapted version on ROTEM®, and the multiple electrode impedance aggregometer Multiplate®. Percent aggregation inhibition results were plotted in a linear regression analysis and correlation was estimated. Sensitivity and specificity for detecting antiplatelet medication were determined. Overall correlations were statistically significant with an r2 = 0.83 in AA-activated and an r2 = 0.82 in ADP-activated Platelet Mapping™ Assay. AA-activated tests and the Multiplate® analysis identified aspirin-inhibition in 86% and 100%, respectively. ADP-activated tests and the Multiplate® analysis identified clopidogrel-inhibition in 67% and 89%, respectively. Specificity was low both in ROTEM® and TEG®. Differences in frequency distribution between the results obtained in ROTEM® and TEG® were not statistically significant. The Platelet Mapping™ Assay can be performed on the ROTEM®. For the perioperative scenario, however, longer test duration and higher costs have to be considered compared to Multiplate® analyses.

Mild and moderate hypothermia increases platelet aggregation induced by various agonists: a whole blood in vitro study

The mechanisms causing temperature-dependent bleeding, especially in hypothermic patients, warrant clarification. Therefore the aim of this study was to investigate platelet aggregation at the clinically important temperature range of 30–34°C. After obtaining informed consent citrated whole blood was drawn from 12 healthy adult male volunteers, who had not taken any medication in the previous 14 days. After venipuncture blood samples were incubated at 37°C until platelet testing. Platelet aggregation was performed in whole blood using the impedance aggregometer Multiplate® at five different test temperatures between 30°C and 34°C. Aggregation responses at 37°C served as controls. At temperatures of mild and moderate hypothermia (30–34°C), overall platelet aggregation was increased compared to 37°C. Increases were recorded in response to collagen, thrombin receptor activating peptide and ristocetin between 31°C and 34°C and in response to adenosine diphosphate between 30°C and 34°C. Overall platelet aggregation is increased at mild and moderate hypothermia down to 30°C. These results indicate that bleeding complications reported in mildly hypothermic patients are not due to hypothermia-induced platelet inhibition. The pathomechanism of the overall increased platelet aggregation between 30°C and 34°C requires further detailed study.

Simulation of an epidural test dose with intravenous isoproterenol in awake and in halothane-anesthetized children.

Background An epidural test dose containing epinephrine does not reliably produce hemodynamic responses in children under halothane anesthesia. The purpose of this study was to determine hemodynamic responses to intravenous isoproterenol in both awake and halothane‐anesthetized children. Methods After obtaining institutional review board approval and parental informed consent, 72 ASA physical status 1 or 2 children (2.8 +/‐1.7 yr) undergoing elective minor surgery were studied before and during anesthesia with 1.2 minimum alveolar concentration halothane. A bolus containing 0.25 mg/kg bupivacaine and 0.05 micro gram/kg, 0.075 micro gram/kg, or 0.1 micro gram/kg isoproterenol, or bupivacaine and saline was injected via a peripheral arm vein to simulate intravascular injection of an epidural test dose. Results Before induction of anesthesia, all patients showed a positive test response after isoproterenol injection (heart rate increase greater or equal to 20 beats/min). During anesthesia, 79% of patients receiving 0.05 micro gram/kg, 89% of patients receiving 0.075 micro gram/kg, and 100% of patients receiving 0.1 micro gram/kg met the criterion of a positive test response. Among each treatment group, all infants showed a positive test response. Blood pressure did not differ among the groups at any time. Transient benign dysrhythmias occurred in only one patient under halothane anesthesia receiving 0.075 micro gram/kg isoproterenol. Conclusion Isoproterenol at a dose of 0.1 micro gram/kg is a sensitive indicator for intravascular injection of a test dose in children anesthetized with halothane and nitrous oxide. Isoproterenol at a dose of 0.05 micro gram/kg approximates a minimal effective dose in awake children and in infants. After detailed studies on neural toxicity, isoproterenol could be of value as an epidural test agent in children.

Direct thrombin inhibitors: pharmacology and application in intensive care medicine

PurposeAnticoagulation is part of the daily routine of intensive care physicians. As the possibilities of pharmacological anticoagulation are becoming more numerous and diverse, intensive care physicians have to be familiar with indications, contraindications, dosing, and reversal of many different substances. This paper presents an overview of the substance group of direct thrombin inhibitors (DTI) indicated for alternative anticoagulation in intensive care medicine.MethodsThe review is a synopsis of scientific evidence, expert opinion, open forum commentary, and clinical feasibility data.Results and conclusionsDue to their antithrombotic potential without direct activation of platelets, DTI could offer potential advantages over heparins and vitaminxa0K antagonists in critically ill patients, especially regarding heparin-induced thrombocytopenia. Because of multiple organ dysfunction, organ failure, and comedications, simple extrapolation of results of medical to critically ill patients is not permissible. The fine line between thrombosis and bleeding in intensive care patients requires cautious dosing and close drug monitoring. Studies dealing with DTI in the intensive care setting are of utmost clinical interest.

Anaesthesia in patients with drug-eluting stents

Purpose of review The management of patients with recent coronary artery stents presenting for noncardiac surgery has become a major topic of interest and concern for all perioperative caregivers. This review will update recent reports and particularly new guidelines as well as recommendations. Recent findings Based on the available literature all experts recommend avoiding premature discontinuation of antiplatelet drug therapy if possible except for a few surgical procedures. Drug-eluting stents obviously carry more risks than bare-metal stents. Summary Anaesthesiologists may understand the specific problem of drug-eluting stents, the recent debate among cardiologists and the implications for the perioperative scenario.

Less blood loss with tetrastarch

Dear Editor, We read with great interest the recently published systematic review by Hartog et al. [1] on the effect of HES 130 on coagulation. In this review, the authors included 24 studies in which HES 130 was compared to a control fluid (crystalloids or human albumin) for coagulation effect, as determined by viscoelastic point-of-care monitoring. However, studies comparing the coagulation effects to the baseline were excluded for some unexplained reason. In addition, a large number of studies judged by the authors to be irrelevant were also excluded (140 in the first step and 16 in the second step)— again with no explanation for the exclusion. Seventeen of the included studies were in vitro trials with dilutions up to 80 %, but only nine of these (the authors do not mention which ones) showed significant values outside the normal range. In vitro trials are not an adequate approach to determining relevant differences between various fluids in terms of their effect on coagulation for a number of reasons, one of which is the absence of endothelium and compensatory mechanisms, such as buffering, control of pH, and electrolyte environment, as well as metabolic degradation [2]. Furthermore, dose effects were apparent in the in vitro studies included in the review which investigated dilutions above 40 %. The few in vivo studies that were included investigated doses below 40 ml/kg. Therefore, the degree of dilution prepared in the in vitro studies appears to be considerably higher than that achieved in clinical reality. The authors concluded that fluids safer than HES solutions should be chosen for patients with impaired coagulation. However, without referring to clinical outcome parameters this conclusion cannot justified! The primary aim of the physician is to provide the appropriate care to patients with (risk of) bleeding—and not only to correct lab values. Decision-making should be based on safety issues in terms of inert effects of fluids on blood loss, requirements for prohaemostatic drugs and allogeneic blood products, rather than on their isolated effects on lab values. In contrast to information provided in the discussion section of Hartog et al.’s review, a number of random controlled trials are available that demonstrate the safety of tetrastarch compared to gelatins [3], albumin [4, 5], and crystalloids [6]. A pooled analysis based on the single patient data derived from seven RCTs has also demonstrated the superiority of tetrastarch over pentastarch in terms of blood loss and transfusion requirements, and Gandhi et al. [7] found a reduced need for blood products in patients receiving tetrastarch versus hetastarch. The discrepancy between comparable bleeding but more pronounced inhibiting effects of starches on laboratory clot strength compared to other colloidal and crystalloidal solutions remains unclear. The complexity of the haemostatic system with multiple compensatory mechanisms may be responsible.