Gisela Scharbert

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.

Ultrasound-guided Lumbar Facet Nerve Block A Sonoanatomic Study of a New Methodologic Approach

Background: Lumbar facet nerve (medial branch) block for pain relief in facet syndrome is currently performed under fluoroscopic or computed tomography scan guidance. In this three-part study, the authors developed a new ultrasound-guided methodology, described the necessary landmarks and views, assessed ultrasound-derived distances, and tested the clinical feasibility. Methods: (1) A paravertebral cross-axis view and long-axis view were defined under high-resolution ultrasound (15 MHz). Three needles were guided to the target point at L3–L5 in a fresh, nonembalmed cadaver under ultrasound (2–6 MHz) and were subsequently traced by means of dissection. (2) The lumbar regions of 20 volunteers (9 women, 11 men; median age, 36 yr [23–67 yr]; median body mass index, 23 kg/m2 [19–36 kg/m2]) were studied with ultrasound (3.5 MHz) to assess visibility of landmarks and relevant distances at L3–L5 in a total of 240 views. (3) Twenty-eight ultrasound-guided blocks were performed in five patients (two women, three men; median age, 51 yr [31–68 yr]) and controlled under fluoroscopy. Results: In the cadaver, needle positions were correct as revealed by dissection at all three levels. In the volunteers, ultrasound landmarks were delineated as good in 19 and of sufficient quality in one (body mass index, 36 kg/m2). Skin-target distances increased from L3 to L5, reaching statistical significance (*, **P < 0.05) between these levels on both sides: L3r, 45 ± 6 mm*; L4r, 48 ± 7 mm; L5r, 50 ± 6 mm*; L3l, 44 ± 5 mm**; L4l, 47 ± 6 mm; L5l, 50 ± 6 mm**. In patients, 25 of 28 ultrasound-guided needles were placed accurately, with the remaining three closer than 5 mm to the radiologically defined target point. Conclusion: Ultrasound guidance seems to be a promising new technique with clinical relevance and the potential to increase practicability while avoiding radiation in lumbar facet nerve block.

The Short- and Long-Term Benefit in Chronic Low Back Pain Through Adjuvant Electrical Versus Manual Auricular Acupuncture

Acupuncture is an established adjuvant analgesic modality for the treatment of chronic pain. Electrical stimulation of acupuncture points is considered to increase acupuncture analgesia. In this prospective, randomized, double-blind, controlled study we tested the hypothesis that auricular electroacupuncture (EA) relieves pain more effectively than conventional manual auricular acupuncture (CO) in chronic low back pain patients with insufficient pain relief (visual analogue scale [VAS] ≥5) treated with standardized analgesic therapy. Disposable acupuncture needles were inserted in the auricular acupuncture points 29, 40, and 55 of the dominant side and connected to a newly developed battery-powered miniaturized stimulator worn behind the ear. Patients were randomized into group EA (n = 31) with continuous low-frequency auricular EA (1 Hz biphasic constant current of 2 mA) and group CO (n = 30) without electrical stimulation (sham-electroacupuncture). Treatment was performed once weekly for 6 wk, and in each group needles were withdrawn 48 h after insertion. During the study period and a 3-mo follow-up, patients were asked to complete the McGill questionnaire. Psychological well being, activity level, quality of sleep, and pain intensity were assessed by means of VAS; moreover, analgesic drug consumption was documented. Pain relief was significantly better in group EA during the study and the follow-up period as compared with group CO. Similarly, psychological well-being, activity, and sleep were significantly improved in group EA versus group CO, the consumption of analgesic rescue medication was less, and more patients returned to full-time employment. Neuropathic pain in particular improved in patients treated with EA. There were no adverse side effects. These results are the first to demonstrate that continuous EA stimulation of auricular acupuncture points improves the treatment of chronic low back pain in an outpatient population.

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.

The effects of test temperature and storage temperature on platelet aggregation: a whole blood in vitro study.

We systematically evaluated the effects of test temperature and storage temperature on platelet aggregation using flow cytometry and impedance aggregometry. Aliquots of citrated whole blood from 27 healthy adult male volunteers were stored at 37°C and 22°C. Aliquots were subjected to impedance aggregometry in response to collagen, adenosine diphosphate, ristocetin, and arachidonic acid performed at 22°C, 34°C, 37°C, and 40°C. The expression of activated fibrinogen receptor was determined on adenosine diphosphate-activated platelets at 22°C and 37°C by whole blood flow cytometry using PAC-1 for fluorescent staining. Aggregation induced by collagen, ristocetin, and arachidonic acid was not significantly different at the test temperatures of 34°C and 37°C but was significantly impaired at 22°C. In contrast, adenosine diphosphate-induced aggregation was significantly increased at both 34°C and 22°C. Hyperthermia exclusively impaired collagen-induced aggregation. Storage temperature of 22°C exclusively enhanced adenosine diphosphate- and collagen-induced aggregation compared with storage at 37°C. The binding of PAC-1 was enhanced at test temperatures below 37°C. Prewarming the antibody above 22°C significantly decreased binding. Our results suggest that mild hypothermic test conditions have no relevant effect, whereas profound hypothermia induces defects in adhesion, thromboxane generation, and activation. The pathomechanism for the increased response to adenosine diphosphate at mild and profound hypothermia remains unclear. Storage temperature considerably affects the aggregation response to the agonists adenosine diphosphate and collagen but not to arachidonic acid and ristocetin. Flow cytometry using the temperature-labile antibody PAC-1 fails to assess temperature effects on platelet aggregability.

Garlic at Dietary Doses Does Not Impair Platelet Function

BACKGROUND:In vitro studies suggest that various bioactive constituents of Allium sativum (garlic) inhibit platelet function. The extent, however, to which dietary doses of garlic influence platelet function remains unknown. Therefore, we tested the effect of raw garlic on platelet function using point-of-care monitoring devices sensitive for cyclooxygenase I-inhibition and platelet adhesion. METHODS:Whole blood from 18 healthy volunteers was investigated before and 5 h after ingestion of the study medication consisting of Greek tsatsiki with 4.2 g raw garlic (verum), or Greek tsatsiki without garlic (placebo), in a randomized, crossover, observer-blinded, placebo-controlled study. The potential long-term effects of garlic were investigated in five volunteers after daily ingestion of 4.2 g of raw garlic over 1 wk. Platelet function was assessed with the Platelet Function Analyzer (PFA-100®), impedance aggregometry (Multiplate®), and thrombelastographic Platelet Mapping™. In vitro experiments were performed to prove the sensitivity of the assays to garlic-induced platelet inhibition. RESULTS:Baseline values of platelet function were within normal range in all volunteers. Platelet function was not impaired by single and repeated oral consumption of Greek tsatsiki containing raw garlic in any point-of-care monitoring test used. CONCLUSIONS:Platelet function is not impaired by single and repeated oral consumption of a dietary dose of garlic in healthy volunteers. Dishes containing socially acceptable doses of raw garlic are unlikely to increase the risk of perioperative bleeding. Further studies are warranted to determine the potential additive effects of platelet-inhibiting drugs combined with garlic and other herbs.

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.

Inhibition of Platelet Function by Hydroxyethyl Starch Solutions in Chronic Pain Patients Undergoing Peridural Anesthesia

The use of hydroxyethyl starch (HES) solutions as a fluid replacement before peridural blockade may compromise blood coagulation, thus increasing the risk of neuraxial bleeding. In this prospective, double-blind, placebo-controlled, crossover study, we compared the influence of HES 130 (molecular weight in kilodalton), HES 200, and lactated Ringers solution on platelet function and hemodynamics in chronic low back pain patients scheduled for peridural blockades. Patients received 3 test infusions of 10 mL/kg each administered IV for 30 min. Collagen/epinephrine and collagen/adenosine diphosphate were used as agonists for assessment of platelet function analyzer-closure times. Arterial blood pressure, heart rate, platelet counts, and hemoglobin levels were documented. Platelet function analyzer-closure times remained stable after lactated Ringers solution but were significantly prolonged after HES. The platelet-inhibiting effect of HES 200 was more than that of HES 130. Hemodynamic stability was sufficiently maintained by all test infusions. In contrast to previous observations, a relevant antiplatelet effect of both low and medium molecular weight HES solutions was found in this study in chronic pain patients undergoing peridural anesthesia. Because hemostasiological competence is a prerequisite for safe neuraxial blockade, the decision of HES for intravascular fluid administration before blockade should be critically made.

Measuring the activity of apixaban and rivaroxaban with rotational thrombelastometry.

BACKGROUND Routine drug monitoring is not required for the two novel direct factor Xa inhibitors apixaban and rivaroxaban. Rapidly available test results might be beneficial in case of bleeding or prior to urgent surgery. OBJECTIVES The aim of this study was to evaluate the applicability of the two rotational thrombelastometry (ROTEM®) -modifications Low-tissue factor activated ROTEM® (LowTF-ROTEM®) and Prothrombinase induced clotting time - activated ROTEM® (PiCT®-ROTEM®) for determination of apixaban and rivaroxaban in vitro and ex vivo. METHODS Blood samples from 20 volunteers were spiked with apixaban / rivaroxaban to yield samples with ascending drug concentrations ranging from 50 - 400ng/mL. LowTF - and PiCT® modified ROTEM® tests and determination of the corresponding antifactor Xa activity were performed in duplicate in 280 samples. LowTF-ROTEM® tests were performed in samples from 20 patients on apixaban or rivaroxaban therapy and 20 controls. RESULTS There was a strong correlation between apixaban / rivaroxaban plasma concentrations and the LowTF-ROTEM® parameters Clotting time (CT; spearman correlation coefficient (SCC) 0.81 and 0.81, respectively) and Time to maximum velocity (t,MaxVel; SCC: 0.81 and 0.80, resp.) and a low to moderate correlation for the PiCT®-ROTEM® parameters CT (SCC: 0.38 and 0.59, resp.) and t,MaxVel. (0.51 and 0.69, resp.) in the in vitro experiments. LowTF-ROTEM CT was significantly prolonged in patients on apxiaban or rivaroxaban therapy compared to controls. CONCLUSIONS LowTF-ROTEM® could be a valuable diagnostic tool for rapid determination of the effect of apixaban and rivaroxaban at the point of care.