[Principles of the pharmacology of local anesthetics]. / Grundlagen der Pharmakologie von Lokalanästhetika.

The development of local anesthetics revolutionized the performance of painful interventions. Local anesthetics have an effect on voltage-gated sodium channels in nerve fibers and modulate the conduction of impulses. With respect to the chemical structure, local anesthetics can be divided into amide and ester types. The structural differences of local anesthetics have an influence on the duration of action, the degradation pathways and specific side effects. Severe adverse events include cardiotoxicity and neurotoxicity. In addition to basic measures, such as the monitoring and securing of vital parameters, lipid infusion represents a treatment option in cases of intoxication. The recent developments of local anesthetics are particularly concerned with the reduction of toxicity and prolonging the duration of action.

Monitoring of Argatroban in Critically Ill Patients: A Prospective Study Comparing Activated Partial Thromboplastin Time, Point-of-Care Viscoelastic Testing with Ecarin Clotting Time and Diluted Thrombin Time to Mass Spectrometry.

BACKGROUND: The direct thrombin inhibitor argatroban is indicated for the treatment of heparin-induced thrombocytopenia II, but it is also used off-label to treat critically ill patients presenting with heparin resistance, severe antithrombin deficiency, or hypercoagulability. Direct drug monitoring is not routinely available, and argatroban dosing is mainly based on global coagulation assays such as activated partial thromboplastin time (PTT) or diluted thrombin time (TT), both of which have limitations in patients with hypercoagulability. METHODS: Blood samples were obtained from critically ill patients treated with argatroban. Activated PTT and diluted TT were measured with a STA R Max3 analyzer (STAGO Deutschland GmbH, Germany) using an argatroban-calibrated kit. Ecarin clotting time was measured using a point-of-care viscoelastic test device. Liquid chromatography with tandem mass spectrometry was performed using a reversed-phase column, a solvent gradient, and an API4000 mass spectrometer with electrospray. Correlation was described using Pearson correlation coefficient r and Bayesian multilevel regression to estimate relationships between outcomes and covariates. RESULTS: From June 2021 to March 2022, 205 blood samples from 22 patients were analyzed, allowing for 195 activated PTT-liquid chromatography with tandem mass spectrometry comparisons, 153 ecarin clotting time-liquid chromatography with tandem mass spectrometry comparison, and 105 diluted TT-liquid chromatography with tandem mass spectrometry comparisons. Compared to liquid chromatography with tandem mass spectrometry, performance of argatroban quantification was best for diluted TT (r = 0.91), followed by ecarin clotting time (r = 0.58) and activated PTT (r = 0.48). Regression analysis revealed that patients with sepsis were more prone to argatroban overdosing (coefficient, 4.194; 95% credible interval, 2.220 to 6.792). CONCLUSIONS: Although activated PTT monitoring of argatroban is the most commonly used test, in critically ill patients, diluted TT provides more precise measurements. Alternately, point-of-care viscoelastic ecarin clotting time also provides guidance for argatroban dosing to identify overdosing if available. The data also suggested that patients with sepsis are at greater risk for argatroban overdosing.

[Principles of the pharmacology of local anesthetics]. / Grundlagen der Pharmakologie von Lokalanästhetika.

The development of local anesthetics revolutionized the performance of painful interventions. Local anesthetics have an effect on voltage-gated sodium channels in nerve fibers and modulate the conduction of impulses. With respect to the chemical structure, local anesthetics can be divided into amide and ester types. The structural differences of local anesthetics have an influence on the duration of action, the degradation pathways and specific side effects. Severe adverse events include cardiotoxicity and neurotoxicity. In addition to basic measures, such as the monitoring and securing of vital parameters, lipid infusion represents a treatment option in cases of intoxication. The recent developments of local anesthetics are particularly concerned with the reduction of toxicity and prolonging the duration of action.

Hemostatic disorders associated with extracorporeal membrane oxygenation.

Hemostatic disorders are common during extracorporeal membrane oxygenation (ECMO)-therapy. This includes both bleeding and thrombotic complications. Particularly bleeding is often associated with fatal outcome. The early identification of hemorrhagic diathesis and the diagnosis of the underlying pathology are essential. A distinction into device-, disease-, and drug-related disorders appears reasonable. However, both correct diagnosis and therapy can be challenging and sometimes counterintuitive. Since bleeding seems to be more frequent and dangerous compared to thrombosis, the understanding of coagulation disorders and minimizing anticoagulation has been focused in recent years. Due to progress in membrane coating and configuration of modern ECMO circuits it is even possible to perform ECMO without any anticoagulation in well selected cases. It became apparent that routine laboratory tests are likely to miss severe coagulation disorders during ECMO-therapy. Better understanding can also help to individualize anticoagulation in patients and hence preventing complications. Acquired von Willebrand syndrome, platelet dysfunction, waste coagulopathy as well as silent hemolysis should be taken into account when bleeding or thromboembolic complications appear. Recognizing impaired intrinsic fibrinolysis may favour intensified anticoagulation even in patients exhibiting signs of bleeding. Drug monitoring with standard coagulation tests, viscoelastic tests and anti-Xa-levels as wells as screening for disorders of primary hemostasis should be implemented in clinical routine to guide physicians through complex anticoagulative therapy. The patient's coagulative status should be interpreted taking the underlying disease and current therapy into account in order to enable a personalized approach to hemostasis in patients treated with ECMO.

Treatment of Acquired von Willebrand Disease due to Extracorporeal Membrane Oxygenation in a Pediatric COVID-19 Patient with Vonicog Alfa: A Case Report and Literature Review.

Acquired von Willebrand disease (aVWD) is frequently observed in patients with the need for extracorporeal membrane oxygenation (ECMO). aVWD can be treated by plasma-derived concentrates containing factor VIII (FVIII) and/or von Willebrand factor (VWF) and recombinant VWF concentrate as well as adjuvant therapies such as tranexamic acid and desmopressin. However, all of these therapeutic options possibly cause thromboembolism. Therefore, the optimal treatment remains uncertain. This report presents a case of a 16-year-old patient suffering from severe acute respiratory distress syndrome due to coronavirus disease 2019 with the need of ECMO support. Our patient developed aVWD under ECMO therapy characterized by loss of high-molecular-weight multimers (HMWM) and severe bleeding symptoms following endoscopic papillotomy due to sclerosing cholangitis. At the same time standard laboratory parameters showed hypercoagulability with increased fibrinogen level and platelet count. The patient was successfully treated with recombinant VWF concentrate (rVWF; vonicog alfa; Veyvondi) combined with topic tranexamic acid application and cortisone therapy. rVWF concentrate vonicog alfa is characterized by ultra-large multimers and absence of FVIII. Patient could be successfully weaned from ECMO support after 72 days. Multimer analysis 1 week after ECMO decannulation showed an adequate reappearance of HMWM.

The impact of concomitant infective endocarditis in patients with spondylodiscitis and isolated spinal epidural empyema and the diagnostic accuracy of the modified duke criteria.

Background: The co-occurrence of infective endocarditis (IE) and primary spinal infections (PSI) like spondylodiscitis (SD) and isolated spinal epidural empyema (ISEE) has been reported in up to 30% of cases and represents a life-threatening infection that requires multidisciplinary management to be successful. Therefore, we aimed to characterize the clinical phenotypes of PSI patients with concomitant IE and furthermore to assess the accuracy of the modified Duke criteria in this specific population. Methods: We conducted a retrospective cohort study in consecutive SD and ISEE patients treated surgically at our University Spine Center between 2002 and 2022 who have undergone detailed phenotyping comprising demographic, clinical, imaging, laboratory, and microbiologic assessment. Comparisons were performed between PSI patients with IE (PSICIE) and without IE (PSIWIE) to identify essential differences. Results: Methicillin-susceptible Staphylococcus aureus (MSSA) was the most common causative pathogen in PSICIE group (13 patients, 54.2%) and aortic valve IE was the most common type of IE (12 patients, 50%), followed by mitral valve IE (5 patients, 20.8%). Hepatic cirrhosis (p < 0.011; OR: 4.383; 95% CI: 1.405-13.671), septic embolism (p < 0.005; OR: 4.387; 95% CI: 1.555-12.380), and infection with Streptococcus spp. and Enterococcus spp. (p < 0.003; OR: 13.830; 95% CI: 2.454-77.929) were identified as significant independent risk factors for the co-occurrence of IE and PSI in our cohort. The modified Duke criteria demonstrated a sensitivity of 100% and a specificity of 66.7% for the detection of IE in PSI patients. Pathogens were detected more frequently via blood cultures in the PSICIE group than in the PSIWIE group (PSICIE: 23, 95.8% vs. PSIWIE: 88, 62.4%, p < 0.001). Hepatic cirrhosis (PSICIE: 10, 41.7% vs. PSIWIE: 33, 21.6%, p = 0.042), pleural abscess (PSICIE: 9, 37.5% vs. PSIWIE: 25, 16.3%, p = 0.024), sepsis (PSICIE: 20, 83.3% vs. PSIWIE: 67, 43.8%, p < 0.001), septic embolism (PSICIE: 16/23, 69.6% vs. PSIWIE: 37/134, 27. 6%, p < 0.001) and meningism (PSICIE: 8/23, 34.8% vs. PSIWIE: 21/152, 13.8%, p = 0.030) occurred more frequently in PSICIE than in PSIWIE patients. PSICIE patients received longer intravenous antibiotic therapy (PSICIE: 6 [4-7] w vs. PSIWIE: 4 [2.5-6] w, p < 0.001) and prolonged total antibiotic therapy overall (PSICIE: 11 [7.75-12] w vs. PSIWIE: 8 [6-12] w, p = 0.014). PSICIE patients spent more time in the hospital than PSIWIE (PSICIE: 43.5 [33.5-53.5] days vs. PSIWIE: 31 [22-44] days, p = 0.003). Conclusions: We report distinct clinical, radiological, and microbiological phenotypes in PSICIE and PSIWIE patients and further demonstrate the diagnostic accuracy of the modified Duke criteria in patients with PSI and concomitant IE. In the high-risk population of PSI patients, the modified Duke criteria might benefit from amending pleural abscess, meningism, and sepsis as minor criteria and hepatic cirrhosis as major criterion.

Extreme obesity is a strong predictor for in-hospital mortality and the prevalence of long-COVID in severe COVID-19 patients with acute respiratory distress syndrome.

Acute Respiratory Distress Syndrome (ARDS) is common in COVID-19 patients and is associated with high mortality. The aim of this observational study was to describe patients' characteristics and outcome, identifying potential risk factors for in-hospital mortality and for developing Long-COVID symptoms. This retrospective study included all patients with COVID-19 associated ARDS (cARDS) in the period from March 2020 to March 2021 who were invasively ventilated at the intensive care unit (ICU) of the University Hospital Dresden, Germany. Between October 2021 and December 2021 patients discharged alive (at minimum 6 months after hospital discharge-midterm survival) were contacted and interviewed about persistent symptoms possibly associated with COVID-19 as well as the quality of their lives using the EQ-5D-5L-questionnaire. Long-COVID was defined as the occurrence of one of the symptoms at least 6 months after discharge. Risk factors for mortality were assessed with Cox regression models and risk factors for developing Long-COVID symptoms by using relative risk (RR) regression. 184 Patients were included in this study (male: n = 134 (73%), median age 67 (range 25-92). All patients were diagnosed with ARDS according to the Berlin Definition. 89% of patients (n = 164) had severe ARDS (Horovitz-index < 100 mmHg). In 27% (n = 49) extracorporeal membrane oxygenation was necessary to maintain gas exchange. The median length of in-hospital stay was 19 days (range 1-60). ICU mortality was 51%, hospital mortality 59%. Midterm survival (median 11 months) was 83% (n = 55) and 78% (n = 43) of these patients presented Long-COVID symptoms with fatigue as the most common symptom (70%). Extreme obesity (BMI > 40 kg/m2) was the strongest predictor for in-hospital mortality (hazard ratio: 3.147, confidence interval 1.000-9.897) and for developing Long-COVID symptoms (RR 1.61, confidence interval 1.26-2.06). In-hospital mortality in severe cARDS patients was high, but > 80% of patients discharged alive survived the midterm observation period. Nonetheless, most patients developed Long-COVID symptoms. Extreme obesity with BMI > 40 kg/m2 was identified as independent risk factor for in-hospital mortality and for developing Long-COVID symptoms.Trial registration DRKS-ID DRKS00027856.

Enhancing Anticoagulation Monitoring and Therapy in Patients Undergoing Microvascular Reconstruction in Maxillofacial Surgery: A Prospective Observational Trial.

BACKGROUND: In reconstructive surgery, loss of a microvascular free flap due to perfusion disorders, especially thrombosis, is a serious complication. In recent years, viscoelastic testing (VET) has become increasingly important in point-of-care (POC) anticoagulation monitoring. This paper describes a protocol for enhanced anticoagulation monitoring during maxillofacial flap surgery. OBJECTIVE: The aim of the study will be to evaluate, in a controlled setting, the predictive value of POC devices for the type of flap perfusion disorders due to thrombosis or bleeding. VET, Platelet monitoring (PM) and standard laboratory tests (SLT) are comparatively examined. METHODS/DESIGN: This study is an investigator-initiated prospective trial in 100 patients undergoing maxillofacial surgery. Patients who undergo reconstructive surgery using microvascular-free flaps will be consecutively enrolled in the study. All patients provide blood samples for VET, PM and SLT at defined time points. The primary outcome is defined as free flap loss during the hospital stay. Statistical analyses will be performed using t-tests, including the Bonferroni adjustment for multiple comparisons. DISCUSSION: This study will help clarify whether VET can improve individualized patient care in reconstruction surgery. A better understanding of coagulation in relation to flap perfusion disorders may allow real-time adaption of antithrombotic strategies and potentially prevent flap complications.

Predictive ability of viscoelastic testing using ClotPro® for short-term outcome in patients with severe Covid-19 ARDS with or without ECMO therapy: a retrospective study.

BACKGROUND: SARS-CoV-2 infections are suspected to trigger the coagulation system through various pathways leading to a high incidence of thromboembolic complications, hypercoagulation and impaired fibrinolytic capacity were previously identified as potentially mechanisms. A reliable diagnostic tool for detecting both is still under discussion. This retrospective study is aimed to examine the prognostic relevance of early viscoelastic testing compared to conventional laboratory tests in COVID-19 patients with acute respiratory distress syndrome (ARDS). METHODS: All mechanically ventilated patients with COVID-19 related ARDS treated in our intensive care unit (ICU) between January and March 2021 were included in this study. Viscoelastic testing (VET) was performed using the ClotPro® system after admission to our ICU. Prevalence of thromboembolic events was observed by standardized screening for venous and pulmonary thromboembolism using complete compression ultrasound and thoracic computed tomography pulmonary angiography at ICU admission, respectively. We examined associations between the severity of ARDS at admission to our ICU, in-hospital mortality and the incidence of thromboembolic events comparing conventional laboratory analysis and VET. ECMO related coagulopathy was investigated in a subgroup analysis. The data were analyzed using the Mann-Whitney U test. RESULTS: Of 55 patients enrolled in this study, 22 patients required treatment with ECMO. Thromboembolic complications occurred in 51% of all patients. Overall hospital mortality was 55%. In patients with thromboembolic complications, signs of reduced fibrinolytic capacity could be detected in the TPA assay with prolonged lysis time, median 460 s (IQR 350-560) vs 359 s (IQR 287-521, p = 0.073). Patients with moderate to severe ARDS at admission to our ICU showed increased maximum clot firmness as a sign of hypercoagulation in the EX-test (70 vs 67 mm, p < 0.05), FIB-test (35 vs 24 mm, p < 0.05) and TPA-test (52 vs 36 mm, p < 0.05) as well as higher values of inflammatory markers (CRP, PCT and IL6). ECMO patients suffered more frequently from bleeding complications (32% vs 15%). CONCLUSION: Although, the predictive value for thromboembolic complications or mortality seems limited, point-of-care viscoelastic coagulation testing might be useful in detecting hypercoagulable states and impaired fibrinolysis in critically ill COVID-19 ARDS patients and could be helpful in identifying patients with a potentially very severe course of the disease.

Point-of-Care Assessment of Direct Oral Anticoagulation in Acute Ischemic Stroke: Protocol for a Prospective Observational Diagnostic Accuracy Study.

BACKGROUND: Treatment of ischemic stroke with recombinant tissue plasminogen activator for intravenous thrombolysis (IVT) must be delivered within a narrow time window after symptom onset. This effective hyperacute treatment can be administered after ruling out active anticoagulation with direct oral anticoagulants (DOACs). Whenever this is impractical, e.g., due to aphasia, plasmatic DOAC levels are measured with a consequent delay in the IVT decision-making process ranging from 30 to 60 minutes of time. This study will test the hypothesis that hyperacute point-of-care assessment of clotting time in the patient's whole blood has sufficient diagnostic accuracy to determine immediately whether stroke patients are pretreated with DOAC. METHODS AND DESIGN: This will be a prospective single-center diagnostic accuracy study in 1,850 consecutive acute ischemic stroke patients at a tertiary stroke center in Saxony, Germany. Presence of active anticoagulation with DOAC will be determined by point-of-care quantification of clotting time via whole blood viscoelastic testing (ClotPro) using Russell venom viper and ecarin assay compared with high-performance liquid chromatography-tandem mass spectrometry as the reference standard. DISCUSSION: Viscoelastic point-of-care assessment of clotting time in whole blood might improve swift delivery of time-sensitive hyperacute treatment with IVT in stroke patients.

Point of care coagulation management in anesthesiology and critical care.

Point of care (POC) devices are increasingly used in the ICU and in anesthesia. Besides POC-devices for blood gas analysis, several devices are available for coagulation measurements. Although basic principles for thromboelastographic measurements are not novel, some promising developments were made during the last decade improving both user-friendliness and measurement reliability. For instance, POC measurements of activated clotting time (ACT) for heparin monitoring is still regarded as standard-of-care in cardiac interventions and surgery. In the field of anesthesia and intensive care medicine, POC-devices for thromboelastographic and platelet aggregation measurements are widely used. Their impact in case of bleeding and patient blood management for cardiothoracic and trauma surgery is well known. Moreover, there are promising concepts for anticoagulation monitoring including new oral anticoagulant drugs. Coagulation POC-devices may also identify patients at specific risk for thromboembolic events quickly. On the other hand, benefits of POC-devices need to be balanced against limitations, which include technical restrictions and operator related errors, mainly affecting reproducibility and interpretation of results. Therefore, it is recommendable to consider results of POC-coagulation testing in comparison to standard laboratory tests (SLT). Nevertheless, in urgent or emergency situations POC results enable fast decision making to optimize patient care.

Noninvasive assessment and quantification of tumor vascularization using [18F]FDG-PET/CT and CE-CT in a tumor model with modifiable angiogenesis-an animal experimental prospective cohort study.

BACKGROUND: This study investigated the noninvasive assessment of tumor vascularization with clinical F-18-fluorodeoxyglucose positron emission tomography/computed tomography and contrast-enhanced computed tomography ([18F]FDG-PET/CT and CE-CT) in experimental human xenograft tumors with modifiable vascularization and compared results to histology. Tumor xenografts with modifiable vascularization were established in 71 athymic nude rats by subcutaneous transplantation of human non-small-cell lung cancer (NSCLC) cells. Four different groups were transplanted with two different tumor cell lines (either A549 or H1299) alone or tumors co-transplanted with rat glomerular endothelial (RGE) cells, the latter to increase vascularization. Tumors were assessed noninvasively by [18F]FDG PET/CT and contrast-enhanced CT (CE-CT) using clinical scanners. This was followed by histological examinations evaluating tumor vasculature (CD-31 and intravascular fluorescent beads). RESULTS: In both tumor lines (A549 and H1299), co-transplantation of RGE cells resulted in faster growth rates [maximal tumor diameter of 20 mm after 22 (± 1.2) as compared to 45 (± 1.8) days, p < 0.001], higher microvessel density (MVD) determined histologically after CD-31 staining [171.4 (± 18.9) as compared to 110.8 (± 11) vessels per mm2, p = 0.002], and higher perfusion as indicated by the number of beads [1.3 (± 0.1) as compared to 1.1 (± 0.04) beads per field of view, p = 0.001]. In [18F]FDG-PET/CT, co-transplanted tumors revealed significantly higher standardized uptake values [SUVmax, 2.8 (± 0.2) as compared to 1.1 (± 0.1), p < 0.001] and larger metabolic active volumes [2.4 (± 0.2) as compared to 0.4 (± 0.2) cm3, p < 0.001] than non-co-transplanted tumors. There were significant correlations for vascularization parameters derived from histology and [18F]FDG PET/CT [beads and SUVmax, r = 0.353, p = 0.005; CD-31 and SUVmax, r = 0.294, p = 0.036] as well as between CE-CT and [18F]FDG PET/CT [contrast enhancement and SUVmax, r = 0.63, p < 0.001; vital CT tumor volume and metabolic PET tumor volume, r = 0.919, p < 0.001]. CONCLUSIONS: In this study, a human xenograft tumor model with modifiable vascularization implementable for imaging, pharmacological, and radiation therapy studies was successfully established. Both [18F]FDG-PET/CT and CE-CT are capable to detect parameters closely connected to the degree of tumor vascularization, thus they can help to evaluate vascularization in tumors noninvasively. [18F]FDG-PET may be considered for characterization of tumors beyond pure glucose metabolism and have much greater contribution to diagnostics in oncology.