Pulmonary Embolism in Patients with COVID-19

Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) and the resulting syndrome, COVID-19, have been associated with inflammation and a prothrombotic state, with increases in fibrin, fibrinogen, fibrin degradation products and D-dimers. In some studies, elevations in these markers have been associated with worse clinical outcomes. Several studies have demonstrated a high prevalence of venous thromboembolism (VTE), and pulmonary embolism (PE), particularly in patients admitted to the intensive care unit (ICU), even in those receiving prophylactic anticoagulation. The high rate of thrombosis in COVID-19 is driven by at least two interrelated processes: a hypercoagulable state responsible for large-vessel thrombosis and thromboembolism and direct vascular and endothelial injury responsible for in situ microvascular thrombosis. The presence of PE and pulmonary thrombosis may explain why hypoxemia is out of proportion to impairment in lung compliance in some patients with COVID-19 pneumonia. Diagnosing PE in patients with COVID-19 pneumonia may be challenging, because the two pathologies share many signs and symptoms. It has been demonstrated that the administration of prophylactic anticoagulation within 24 h of admission in patients with COVID-19 was associated with decreased mortality when compared with no prophylactic anticoagulation. Given the antithrombotic, anti-inflammatory and possibly antiviral properties of heparins, it has been hypothesized that anticoagulation with heparin administered at doses higher than conventionally used for venous thromboprophylaxis may improve outcomes. In non-critically ill patients hospitalized with COVID-19, therapeutic-dose anticoagulants with heparin (most commonly, low-molecular-weight heparin) increased the probability of survival until hospital discharge with a reduced need for ICU-level organ support at 21 days as compared with usual-care thromboprophylaxis. In Critically ill patients with confirmed COVID-19, therapeutic-dose anticoagulation did not increase the probability of survival to hospital discharge or the number of days free of cardiovascular o respiratory organ support and had a 95% probability of being inferior to usual-care pharmacologic thromboprophylaxis. Currently, randomized trials evaluating the use of tissue plasminogen activator and Tenecteplase in patients with COVID-19 ARDS are underway.

Microdosing as a Potential Tool to Enhance Clinical Development of Novel Antibiotics: A Tissue and Plasma PK Feasibility Study with Ciprofloxacin

Background and Objective In microdose studies, drug pharmacokinetics is measured in humans after administration of subtherapeutic doses. While previous microdose studies focused primarily on plasma pharmacokinetics, we set out to evaluate the feasibility of microdosing for a pharmacokinetic assessment in subcutaneous tissue and epithelial lining fluid. Methods Healthy subjects received a single intravenous bolus injection of a microdose of [14C]ciprofloxacin (1.1 µg, 7 kBq) with (cohort A, n = 9) or without (cohort B, n = 9) a prior intravenous infusion of a therapeutic dose of unlabeled ciprofloxacin (400 mg). Microdialysis and bronchoalveolar lavage were applied for determination of subcutaneous and intrapulmonary drug concentrations. Microdose [14C]ciprofloxacin was quantified by accelerator mass spectrometry and therapeutic-dose ciprofloxacin by liquid chromatography–tandem mass spectrometry. Results The pharmacokinetics of therapeutic-dose ciprofloxacin (cohort A) in plasma, subcutaneous tissue, and epithelial lining fluid was in accordance with previous data. In plasma and subcutaneous tissue, the dose-adjusted area under the concentration–time curve of microdose ciprofloxacin was similar in cohorts A and B and within an 0.8-fold to 1.1-fold range of the area under the concentration–time curve of therapeutic-dose ciprofloxacin. Penetration of microdose ciprofloxacin into subcutaneous tissue was similar in cohorts A and B and comparable to that of therapeutic-dose ciprofloxacin with subcutaneous tissue-to-plasma area under the concentration–time curve ratios of 0.44, 0.44, and 0.38, respectively. Penetration of microdose ciprofloxacin into epithelial lining fluid was highly variable and failed to predict the epithelial lining fluid penetration of therapeutic-dose ciprofloxacin. Conclusions Our study confirms the feasibility of microdosing for pharmacokinetic measurements in plasma and subcutaneous tissue. Microdosing combined with microdialysis is a potentially useful tool in clinical antimicrobial drug development, but its applicability for the assessment of pulmonary pharmacokinetics with bronchoalveolar lavage requires further studies. Clinical Trial Registration ClinicalTrials.gov NCT03177720 (registered 6 June, 2017).

Safety and Efficacy of Intermediate- and Therapeutic-Dose Anticoagulation for Hospitalised Patients with COVID-19: A Systematic Review and Meta-Analysis

Background: COVID-19 patients are at high thrombotic risk. The safety and efficacy of different anticoagulation regimens in COVID-19 patients remain unclear. Methods: We searched for randomised controlled trials (RCTs) comparing intermediate- or therapeutic-dose anticoagulation to standard thromboprophylaxis in hospitalised patients with COVID-19 irrespective of disease severity. To assess efficacy and safety, we meta-analysed data for all-cause mortality, clinical status, thrombotic event or death, and major bleedings. Results: Eight RCTs, including 5580 patients, were identified, with two comparing intermediate- and six therapeutic-dose anticoagulation to standard thromboprophylaxis. Intermediate-dose anticoagulation may have little or no effect on any thrombotic event or death (RR 1.03, 95% CI 0.86–1.24), but may increase major bleedings (RR 1.48, 95% CI 0.53–4.15) in moderate to severe COVID-19 patients. Therapeutic-dose anticoagulation may decrease any thrombotic event or death in patients with moderate COVID-19 (RR 0.64, 95% CI 0.38–1.07), but may have little or no effect in patients with severe disease (RR 0.98, 95% CI 0.86–1.12). The risk of major bleedings may increase independent of disease severity (RR 1.78, 95% CI 1.15–2.74). Conclusions: Certainty of evidence is still low. Moderately affected COVID-19 patients may benefit from therapeutic-dose anticoagulation, but the risk for bleeding is increased.

Intravitreal moxifloxacin in acute post-phacoemulsification endophthalmitis: a case report

Background: Vancomycin and ceftazidime are commonly used intravitreal antibiotics to treat acute post-phacoemulsification endophthalmitis. However, they are not commercially available in appropriate therapeutic dose for intravitreal injection. Moxifloxacin is a broad-spectrum antibiotic that is commercially available in appropriate therapeutic dose for intravitreal injection, thus providing a rationale for its use in acute post-phacoemulsification endophthalmitis.Case presentation: A 46-year-old female presented with blurred vision, redness, and pain in the right eye 5 days after phacoemulsification. Visual acuity was hand movement and conjunctival and circumcorneal injection, corneal oedema, anterior chamber reaction, and vitreous opacities were observed. The patient was treated with intravitreal moxifloxacin 500 μg/0.1 ml, vitrectomy, and topical and oral antibiotics. Visual acuity improved to 6/15 and follow-up at 5 weeks did not reveal any signs of intraocular inflammation.Conclusion: Intravitreal moxifloxacin is an alternative in the treatment of acute post-phacoemulsification endophthalmitis.

FARMACOCINÉTICA Y BIODISPONIBILIDAD ABSOLUTA DE MARBOFLOXACINA EN BÚFALOS (Bubalus bubalis)

The aim of this study was to evaluate the pharmacokinetic behaviour and the absolute bioavailability of marbofloxacin (MFX) in adult water buffaloes and to estimate the pharmacokinetic parameters for calculating the therapeutic dose in this animal species. Six adult buffaloes (3 males and 3 females) where treated by intravenous (IV) and subcutaneous (SC) route with a 10% experimental MFX injectable formulation at the dose of 2 mg/kg. After administration blood samples were drawn at pre-established times and MFX plasma concentrations where determined by microbiologic method. The pharmacokinetic analysis was made by compartmental analysis. After IV administration MFX presented a clearance of 198.4 ± 21.0 mL.kg.h and a half-life of elimination of 7.64 ± 3.29 h. After SC administration marbofloxacin presented a half-life of elimination of 8.5 ± 2.42 h, reaching it maximum plasma concentration (1.67 ± 0.516 μg/mL) at 1.69 ± 0.231 h, with a bioavailability of 80.8 ± 11.2 %. The estimated values of clearance and bioavailability will be employed in further studies for calculating the therapeutic dose of MFX in water buffaloes.

Management of hemostasis in a patient with liver cirrhosis in the perioperative period.

Для пациентов с циррозом печени характерны существенные изменения в системе гемостаза. Описан клинический случай ведения пациента с циррозом печени, портальной гипертензией, варикозными венами желудка, оперированного на высоте желудочно-кишечного кровотечения, на фоне выявленных тромбоэмболических осложнений (тромбоэмболия легочной артерии и тромбоз глубоких вен голеней). В предоперационном периоде был установлен кава-фильтр. В первые двое суток послеоперационного периода в качестве антикоагулянта вводили концентрат антитромбина III (АТ-III) по 1000 ЕД в связи с исходным его дефицитом (64%) и для дальнейшего обеспечения эффективности терапии низкомолекулярными гепаринами (НМГ). По мере увеличения уровня тромбоцитов с 66×109/л до 200×109/л в качестве антикоагулянта был назначен парнапарин натрия в лечебной дозе. Эффективность терапии НМГ оценивали с помощью тромбоэластографии (ТЭГ). На 9-е сутки после операции диагностировано развитие гепаринорезистентности на фоне тромбоцитоза более 1 млн, гиперфибриногенемии, высокой активности фактора VIII и вновь выявленного дефицита АТ-III (53%). Клинически гепаринорезистентность проявилась образованием флотирующего тромба в правой бедренной вене. К максимальной лечебной дозе парнапарина (17000 анти- Ха) добавлен антиагрегант клопидогрел (75 мг) и начато введение концентрата АТ-III по 1000 МЕ в течение 3 сут. Преодолена гепаринорезистентность с нормализацией уровня АТ-III (89%), достигнута дезагрегация тромбоцитов. Через 7 сут диагностирован полный лизис флотирующего тромба в правой бедренной вене. В дальнейшем пациент в течение 1 мес амбулаторно находился на терапии парнапарином (17000 анти- Ха активность в сутки) и клопидогрелом (75 мг/сут). По данным компьютерной ангиопульмонографии: полный лизис тромба в легочной артерии, кава-фильтр удален. Заключение. Мониторинг системы гемостаза у пациента с циррозом печени позволил контролировать адекватность проводимой антикоагулянтной терапии и использовать арсенал имеющихся в распоряжении клинициста препаратов. Patients with liver cirrhosis are characterized by significant hemostasis changes. A clinical case is described of patient management with liver cirrhosis, portal hypertension, stomach varicose veins, operated at the height of gastrointestinal bleeding, with revealed thromboembolic complications (pulmonary embolism and deep vein thrombosis of the lower legs). Cava filter was installed in preoperative period. In the first 2 days of the postoperative period, antithrombin III (AT-III) concentrate was administered as an anticoagulant, 1000 units each due to its initial deficiency (64%) and to further ensure the therapy efficacy with low molecular weight heparins (LMWH). By increasing the platelet count from 66×109/L to 200×109/L, a therapeutic dose of parnaparin sodium was prescribed as an anticoagulant. The efficacy of LMWH therapy was assessed by thromboelastography (TEG). On the day 9 after surgery heparin resistance was diagnosed with thrombocytosis (more than 1 million), hyperfibrinogenemia, high activity of VIII factor and re-identified AT-III deficiency (53%). Clinically, heparin resistance was manifested by floating thrombus in the right femoral vein. The antiaggregant clopidogrel (75 mg) was added to the maximum therapeutic dose of parnaparin (17,000 anti- Xa), and the administration of AT-III concentrate (1000 IU) was started for 3 days. Heparin resistance was overcome with normalization of AT-III level (89%), platelet disaggregation was achieved. Complete lysis of floating thrombus in the right femoral vein was diagnosed after 7 days. Later the patient was treated with parnaparin (17,000 anti- Xa activity per day) and clopidogrel (75 mg/day) during 1 month outpatiently. According to computer pulmonary angiography, complete thrombus lysis in the pulmonary artery was revealed, the cava filter was removed. Conclusions. Hemostasis monitoring in patient with liver cirrhosis made it possible to control the adequacy of the anticoagulant therapy and to use the arsenal of drugs available to the clinician.

High versus Standard Intensity of Thromboprophylaxis in Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis

Thromboprophylaxis in hospitalized patients with COVID-19 has been associated with a survival benefit and is strongly recommended. However, the optimal dose of thromboprophylaxis remains unclear. A systematic review and meta-analysis (PubMed/EMBASE) of studies comparing high (intermediate or therapeutic dose) versus standard (prophylactic dose) intensity of thrombo-prophylaxis with regard to outcome of hospitalized patients with COVID-19 was performed. Randomized and non-randomized studies that provided adjusted effect size estimates were included. Meta-analysis of 7 studies comparing intermediate versus prophylactic dose of thromboprophylaxis (2 randomized and 5 observational, n = 2009, weighted age 61 years, males 61%, ICU 53%) revealed a pooled adjusted relative risk (RR) for death at 0.56 (95% confidence intervals (CI) 0.34, 0.92) in favor of the intermediate dose. For the same comparison arms, the pooled RR for venous thromboembolism was 0.84 (95% CI 0.54, 1.31), and for major bleeding events was 1.63 (95% CI 0.79, 3.37). Meta-analysis of 17 studies comparing therapeutic versus prophylactic dose of thromboprophylaxis (2 randomized and 15 observational, n = 7776, weighted age 64 years, males 54%, ICU 21%) revealed a pooled adjusted RR for death at 0.73 (95% CI 0.47, 1.14) for the therapeutic dose. An opposite trend was observed in the unadjusted analysis of 15 observational studies (RR 1.24 (95% CI 0.88, 1.74)). For the same comparison arms, the pooled RR for venous thromboembolism was 1.13 (95% CI 0.52, 2.48), and for major bleeding events 3.32 (95% CI 2.51, 4.40). In conclusion, intermediate compared with standard prophylactic dose of thromboprophylaxis appears to be rather safe and is associated with additional survival benefit, although most data are derived from observational retrospective analyses. Randomized studies are needed to define the optimal thromboprophylaxis in hospitalized patients with COVID-19.

Human In Silico Trials for Parametric Computational Fluid Dynamics Investigation of Cerebrospinal Fluid Drug Delivery: Impact of Injection Location, Injection Protocol, and Physiology

BackgroundIntrathecal drug delivery has a significant role in pain management and CNS disease therapeutics. A fluid-physics based tool to assist clinicians in choosing specific drug doses to the spine or brain may help improve treatment schedules. MethodsThis study applied computational fluid dynamics (CFD) and in vitro model verification to assess intrathecal drug delivery in an anatomically realistic model of the human CSF system. Key parameters analyzed included the role of a) injection location including lumbar puncture (LP), cisterna magna (CM) and intracerebroventricular (ICV), b) LP injection rate, injection volume, and flush volume, c) physiologic factors including cardiac-induced and deep respiration-induced CSF stroke volume increase. Simulations were conducted for 3-hours post-injection and used to quantify spatial-temporal tracer concentration, regional area under the curve (AUC), time to maximum concentration (T max ), and maximum concentration (C max ), for each case. ResultsCM and ICV increased AUC to brain regions by ~2 logs compared to all other simulations. A 3X increase in bolus volume and addition of a 5 mL flush both increased intracranial AUC to the brain up to 2X compared to a baseline 5 mL LP injection. In contrast, a 5X increase in bolus rate (25 mL/min) did not improve tracer exposure to the brain. An increase in cardiac and respiratory CSF movement improved tracer spread to the brain, basal cistern, and cerebellum up to ~2 logs compared to the baseline LP injection. ConclusionThe computational modeling approach provides ability to conduct in silico trials representative of CSF injection protocols. Taken together, the findings indicate a strong potential for delivery protocols to be optimized to reach a target region(s) of the spine and/or brain with a needed therapeutic dose. Parametric modification of bolus rate/volume and flush volume was found to have impact on tracer distribution; albeit to a smaller degree than injection location, with CM and ICV injections resulting in greater therapeutic dose to brain regions compared to LP. CSF stroke volume and frequency both played an important role and may potentially have a greater impact than the modest changes in LP injection protocols analyzed such as bolus rate, volume, and flush.

Prediction of 131i Therapeutic Dose and Prognosis in Hyperthyroidism Patients Using Mechanical Learning Model

ObjectiveMultiple mechanical learning models were used to predict the therapeutic dose of 131I radionuclide in patients with hyperthyroidism, and to compare the calculation results of each prediction model to obtain the optimal model for dose prediction. Meanwhile, the classification model was used to classify the prognosis of the existing clinical hyperthyroidism case data in order to evaluate the administration results and provide reference for the dose given by clinicians.MethodsAccording to the data of hyperthyroidism patients treated with 131I in nuclear medicine department of many hospitals, a prediction model was established based on MATLAB. Firstly, the prediction results of BP neural network, radial basis function (RBF) neural network and support vector machine (SVM) were compared with small sample data, and then the optimal model was selected to predict the drug dose. BP-AdaBoost, SVM and random forest were used to classify the patients after recovery and evaluate whether the dose was accurate.ResultsThe average errors of BP neural network, RBF neural network and SVM models trained with small samples were 6.58%, 17.25% and 14.09% respectively. After comparison, BP neural network was selected to establish the prediction model. The data of 30 cases were randomly selected to verify BP neural network, and average error of the prediction results was 11.99%. Using SVM, BP-AdaBoost and random forest models, 100 groups of case data were selected as the training set and 10 groups as the test set. The classification accuracy were 80%, 90% and 100% respectively. The random forest model with the highest accuracy was selected as the large sample prediction. When 318 groups of cases were trained and 35 groups of cases were used for the test, the classification accuracy was 97.14%.ConclusionThis study compared the prediction effects of various prediction models on 131I therapeutic dose in patients with hyperthyroidism and the accuracy of prognosis classification. BP neural network and random forest achieved the best results respectively. The two models provide reference for clinicians when giving the dose, which has clinical practical significance.