Facial appearance associates with longitudinal multi-organ failure: an ICU cohort study.

BACKGROUND: Facial appearance, whether consciously or subconsciously assessed, may affect clinical assessment and treatment strategies in the Intensive Care Unit (ICU). Nevertheless, the association between objective clinical measurement of facial appearance and multi-organ failure is currently unknown. The objective of this study was to examine whether facial appearance at admission is associated with longitudinal evaluation of multi-organ failure. METHODS: This was a sub-study of the Simple Intensive Care Studies-II, a prospective observational cohort study. All adult patients acutely admitted to the ICU between March 26, 2019, and July 10, 2019, were included. Facial appearance was assessed within three hours of ICU admission using predefined pictograms. The SOFA score was serially measured each day for the first seven days after ICU admission. The association between the extent of eye-opening and facial skin colour with longitudinal Sequential Organ Failure Assessment (SOFA) scores was investigated using generalized estimation equations. RESULTS: SOFA scores were measured in 228 patients. Facial appearance scored by the extent of eye-opening was associated with a higher SOFA score at admission and follow-up (unadjusted 0.7 points per step (95%CI 0.5 to 0.9)). There was no association between facial skin colour and a worse SOFA score over time. However, patients with half-open or closed eyes along with flushed skin had a lower SOFA score than patients with a pale or normal facial skin colour (P-interaction < 0.1). CONCLUSIONS: The scoring of patients' facial cues, primarily the extent of eye-opening and facial colour, provided valuable insights into the disease state and progression of the disease of critically ill patients. The utilization of advanced monitoring techniques that incorporate facial appearance holds promise for enhancing future intensive care support.

Deep embedded clustering generalisability and adaptation for integrating mixed datatypes: two critical care cohorts.

We validated a Deep Embedded Clustering (DEC) model and its adaptation for integrating mixed datatypes (in this study, numerical and categorical variables). Deep Embedded Clustering (DEC) is a promising technique capable of managing extensive sets of variables and non-linear relationships. Nevertheless, DEC cannot adequately handle mixed datatypes. Therefore, we adapted DEC by replacing the autoencoder with an X-shaped variational autoencoder (XVAE) and optimising hyperparameters for cluster stability. We call this model "X-DEC". We compared DEC and X-DEC by reproducing a previous study that used DEC to identify clusters in a population of intensive care patients. We assessed internal validity based on cluster stability on the development dataset. Since generalisability of clustering models has insufficiently been validated on external populations, we assessed external validity by investigating cluster generalisability onto an external validation dataset. We concluded that both DEC and X-DEC resulted in clinically recognisable and generalisable clusters, but X-DEC produced much more stable clusters.

Bilateral Femoral Cannulation Is Associated With Reduced Severe Limb Ischemia-Related Complications Compared With Unilateral Femoral Cannulation in Adult Peripheral Venoarterial Extracorporeal Membrane Oxygenation: Results From the Extracorporeal Life Support Registry.

OBJECTIVES: Peripheral venoarterial extracorporeal membrane oxygenation (ECMO) with femoral access is obtained through unilateral or bilateral groin cannulation. Whether one cannulation strategy is associated with a lower risk for limb ischemia remains unknown. We aim to assess if one strategy is preferable. DESIGN: A retrospective cohort study based on the Extracorporeal Life Support Organization registry. SETTING: ECMO centers worldwide included in the Extracorporeal Life Support Organization registry. PATIENTS: All adult patients (≥ 18 yr) who received peripheral venoarterial ECMO with femoral access and were included from 2014 to 2020. INTERVENTIONS: Unilateral or bilateral femoral cannulation. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the occurrence of limb ischemia defined as a composite endpoint including the need for a distal perfusion cannula (DPC) after 6 hours from implantation, compartment syndrome/fasciotomy, amputation, revascularization, and thrombectomy. Secondary endpoints included bleeding at the peripheral cannulation site, need for vessel repair, vessel repair after decannulation, and in-hospital death. Propensity score matching was performed to account for confounders. Overall, 19,093 patients underwent peripheral venoarterial ECMO through unilateral ( n = 11,965) or bilateral ( n = 7,128) femoral cannulation. Limb ischemia requiring any intervention was not different between both groups (bilateral vs unilateral: odds ratio [OR], 0.92; 95% CI, 0.82-1.02). However, there was a lower rate of compartment syndrome/fasciotomy in the bilateral group (bilateral vs unilateral: OR, 0.80; 95% CI, 0.66-0.97). Bilateral cannulation was also associated with lower odds of cannulation site bleeding (bilateral vs unilateral: OR, 0.87; 95% CI, 0.76-0.99), vessel repair (bilateral vs unilateral: OR, 0.55; 95% CI, 0.38-0.79), and in-hospital mortality (bilateral vs unilateral: OR, 0.85; 95% CI, 0.81-0.91) compared with unilateral cannulation. These findings were unchanged after propensity matching. CONCLUSIONS: This study showed no risk reduction for overall limb ischemia-related events requiring DPC after 6 hours when comparing bilateral to unilateral femoral cannulation in peripheral venoarterial ECMO. However, bilateral cannulation was associated with a reduced risk for compartment syndrome/fasciotomy, lower rates of bleeding and vessel repair during ECMO, and lower in-hospital mortality.

Rotational thromboelastometry as a biomarker for mortality - The Maastricht Intensive Care COVID cohort.

BACKGROUND: Patients with severe coronavirus disease 2019 (COVID-19) present with persisting hypercoagulability, hypofibrinolysis and prolonged clot initiation as measured with viscoelastic assays. The objective of this study was to investigate the trajectories of traditional assays of hemostasis, routine and tissue plasminogen activator (tPA) rotational thromboelastometry (ROTEM) in COVID-19 patients and to study their association with mortality. METHODS: Patients enrolled within the Maastricht Intensive Care COVID (MaastrICCht) cohort were included. Traditional assays of hemostasis (prothrombin time; PT, fibrinogen and D-dimer) were measured daily and ROTEM EXTEM, FIBTEM and tPA assays were performed weekly. Trajectories of these biomarkers were analyzed over time for survivors and non-survivors using linear mixed-effects models. Additional Fine and Gray competing risk survival analysis was performed for the first available measurement after intubation. RESULTS: Of the 138 included patients, 57 (41 %) died in the intensive care unit (ICU). Over 450, 400 and 1900 individual measurements were available for analysis of routine, tPA ROTEM and traditional assays of hemostasis, respectively, with a median [IQR] follow-up of 15 [8-24] days. Non-survivors on average had prolonged CT (clotting time) and increased fibrinogen compared to survivors. MCF (maximum clot firmness), LOT (lysis onset time), LT (lysis time) and PT measurements increased more over time in non-survivors compared to survivors. Associations persisted after adjustment for demographics and disease severity. EXTEM and FIBTEM CT at intubation were associated with increased 45-day ICU mortality. CONCLUSIONS: ROTEM measurements demonstrate a further increase of hypercoagulability and (hypo)fibrinolysis parameters in non-survivors throughout ICU admission. Furthermore, prolonged CT at intubation was associated with higher 45-day ICU mortality.

Higher levels of circulating desphospho-uncarboxylated matrix Gla protein over time are associated with worse survival: the prospective Maastricht Intensive Care COVID cohort.

BACKGROUND: Extra-hepatic vitamin K-status, measured by dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP), maintains vascular health, with high levels reflecting poor vitamin K status. The occurrence of extra-hepatic vitamin K deficiency throughout the disease of COVID-19 and possible associations with pulmonary embolism (PE), and mortality in intensive care unit (ICU) patients has not been studied. The aim of this study was to investigated the association between dp-ucMGP, at endotracheal intubation (ETI) and both ICU and six months mortality. Furthermore, we studied the associations between serially measured dp-ucMGP and both PE and mortality. METHODS: We included 112 ICU patients with confirmed COVID-19. Over the course of 4 weeks after ETI, dp-ucMGP was measured serially. All patients underwent computed tomography pulmonary angiography (CTPA) to rule out PE. Results were adjusted for patient characteristics, disease severity scores, inflammation, renal function, history of coumarin use, and coronary artery calcification (CAC) scores. RESULTS: Per 100 pmol/L dp-ucMGP, at ETI, the odds ratio (OR) was 1.056 (95% CI: 0.977 to 1.141, p = 0.172) for ICU mortality and 1.059 (95% CI: 0.976 to 1.059, p = 0.170) for six months mortality. After adjustments for age, gender, and APACHE II score, the mean difference in plasma dp-ucMGP over time of ICU admission was 167 pmol/L (95% CI: 4 to 332, p = 0.047). After additional adjustments for c-reactive protein, creatinine, and history of coumarin use, the difference was 199 pmol/L (95% CI: 50 to 346, p = 0.010). After additional adjustment for CAC score the difference was 213 pmol/L (95% CI: 3 to 422, p = 0.051) higher in ICU non-survivors compared to the ICU survivors. The regression slope, indicating changes over time, did not differ. Moreover, dp-ucMGP was not associated with PE. CONCLUSION: ICU mortality in COVID-19 patients was associated with higher dp-ucMGP levels over 4 weeks, independent of age, gender, and APACHE II score, and not explained by inflammation, renal function, history of coumarin use, and CAC score. No association with PE was observed. At ETI, higher levels of dp-ucMGP were associated with higher OR for both ICU and six month mortality in crude and adjusted modes, although not statistically significantly.

Applications of rotational thromboelastometry in heparin monitoring in critical COVID-19 disease: Observations in the Maastricht Intensive Care COVID cohort.

Background: Critically ill COVID-19 patients are at risk for venous thromboembolism (VTE). Therefore, they receive thromboprophylaxis and, when appropriate, therapeutic unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). To monitor heparins in COVID-19 disease, whole-blood rotational thromboelastometry (ROTEM) may be a promising alternative to the aPTT and anti-Xa assays. Objective: To evaluate the ROTEM INTEM/HEPTEM ratios in mechanically ventilated COVID-19 patients treated with UFH and therapeutic LMWH. Material and methods: A subcohort of mechanically ventilated COVID-19 patients of the prospective Maastricht Intensive Care Covid (MaastrICCht) cohort was studied. Anti-Xa, aPTT, and ROTEM measurements following treatment with UFH or therapeutic dose of LMWH (nadroparin) were evaluated using uni- and multivariable linear regression analysis and receiver operating characteristics. Results: A total of 98 patients were included, of which 82 were treated with UFH and 16 with therapeutic LMWH. ROTEM-measured INTEM/HEPTEM CT ratio was higher in patients using UFH (1.4 [1.3-1.4]) compared to patients treated with LMWH (1.0 [1.0-1.1], p < 0.001). Both the aPTT and anti-Xa were associated with the CT ratio. However, the ß-regression coefficient (95%CI) was significantly higher in patients on UFH (0.31 (0.001-0.62)) compared to therapeutic LMWH (0.09 (0.05-0.13)) for comparison with the anti-Xa assay. Furthermore, ROC analysis demonstrated an area under the curve for detecting UFH of 0.936(0.849-1.00), 0.851(0.702-1.000), and 0.645(0.465-0.826) for the CT ratio, aPTT, and anti-Xa, respectively. Conclusion: The ROTEM INTEM/HEPTEM CT ratio appears a promising tool to guide anticoagulant therapy in ICU patients with COVID-19 disease, but associations with clinical endpoints are currently lacking.

High-Sensitivity Cardiac Troponin I and T Kinetics Differ following Coronary Bypass Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Cardiac troponin I and T are both used for diagnosing myocardial infarction (MI) after coronary artery bypass grafting (CABG), also known as type 5 MI (MI-5). Different MI-5 definitions have been formulated, using multiples of the 99th percentile upper reference limit (10×, 35×, or 70× URL), with or without supporting evidence. These definitions are arbitrarily chosen based on conventional assays and do not differentiate between troponin I and T. We therefore investigated the kinetics of high-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) following CABG. METHODS: A systematic search was applied to MEDLINE and EMBASE databases including the search terms "coronary artery bypass grafting" AND "high-sensitivity cardiac troponin." Studies reporting hs-cTnI or hs-cTnT on at least 2 different time points were included. Troponin concentrations were extracted and normalized to the assay-specific URL. RESULTS: For hs-cTnI and hs-cTnT, 17 (n = 1661 patients) and 15 studies (n = 2646 patients) were included, respectively. Preoperative hs-cTnI was 6.1× URL (95% confidence intervals: 4.9-7.2) and hs-cTnT 1.2× URL (0.9-1.4). Mean peak was reached 6-8 h postoperatively (126× URL, 99-153 and 45× URL, 29-61, respectively). Subanalysis of hs-cTnI illustrated assay-specific peak heights and kinetics, while subanalysis of surgical strategies revealed 3-fold higher hs-cTnI than hs-cTnT for on-pump CABG and 5-fold for off-pump CABG. CONCLUSION: Postoperative hs-cTnI and hs-cTnT following CABG surpass most current diagnostic cutoff values. hs-cTnI was almost 3-fold higher than hs-cTnT, and appeared to be highly dependent on the assay used and surgical strategy. There is a need for assay-specific hs-cTnI and hs-cTnT cutoff values for accurate, timely identification of MI-5.

Serial thrombin generation and exploration of alternative anticoagulants in critically ill COVID-19 patients: Observations from Maastricht Intensive Care COVID Cohort.

Background: COVID-19 associated coagulopathy (CAC) is associated with an increase in thromboembolic events. Current guidelines recommend prophylactic heparins in the management of CAC. However, the efficacy of this strategy in the intensive care population remains uncertain. Objective: We aimed to measure thrombin generation (TG) to assess CAC in intensive care unit (ICU) patients receiving thromboprophylaxis with low molecular weight heparin (LMWH) or unfractionated heparin (UFH). In addition, we performed statistical modeling to link TG parameters to patient characteristics and clinical parameters. Lastly, we studied the potency of different anticoagulants as an alternative to LMWH treatment in ex vivo COVID-19 plasma. Patients/Methods: We included 33 patients with confirmed COVID-19 admitted at the ICU. TG was measured at least twice over the course of 6 weeks after admission. Thrombin generation parameters peak height and endogenous thrombin potential (ETP) were compared to healthy controls. Results were subsequently correlated with a patient characteristics and laboratory measurements. In vitro spiking in TG with rivaroxaban, dabigatran, argatroban and orgaran was performed and compared to LMWH. Results: Anti-Xa levels of all patients remained within the therapeutic range throughout follow-up. At baseline, the mean (SE) endogenous thrombin potential (ETP) was 1,727 (170) nM min and 1,620 (460) nM min for ellagic acid (EA) and tissue factor (TF), respectively. In line with this we found a mean (SE) peak height of 353 (45) nM and 264 (96) nM for EA and TF. Although fluctuating across the weeks of follow-up, TG parameters remained elevated despite thromboprophylaxis. In vitro comparison of LMWHs and direct thrombin inhibitors (e.g., agratroban, dabigatran) revealed a higher efficacy in reducing coagulation potential for direct thrombin inhibition in both ellagic acid (EA) and tissue factor (TF) triggered TG. Conclusion: In a sub-group of mechanically ventilated, critically ill COVID-19 patients, despite apparent adequate anti-coagulation doses evaluated by anti-Xa levels, thrombin generation potential remained high during ICU admission independent of age, sex, body mass index, APACHE II score, cardiovascular disease, and smoking status. These observations could, only partially, be explained by (anti)coagulation and thrombosis, inflammation, and multi-organ failure. Our in vitro data suggested that direct thrombin inhibition compared with LMWH might offer an alternate, more effective anticoagulant strategy in COVID-19.

Serial Assessment of Myocardial Injury Markers in Mechanically Ventilated Patients With SARS-CoV-2 (from the Prospective MaastrICCht Cohort).

Myocardial injury in COVID-19 is associated with in-hospital mortality. However, the development of myocardial injury over time and whether myocardial injury in patients with COVID-19 at the intensive care unit is associated with outcome is unclear. This study prospectively investigates myocardial injury with serial measurements over the full course of intensive care unit admission in mechanically ventilated patients with COVID-19. As part of the prospective Maastricht Intensive Care COVID cohort, predefined myocardial injury markers, including high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and electrocardiographic characteristics were serially collected in mechanically ventilated patients with COVID-19. Linear mixed-effects regression was used to compare survivors with nonsurvivors, adjusting for gender, age, APACHE-II score, daily creatinine concentration, hypertension, diabetes mellitus, and obesity. In 90 patients, 57 (63%) were survivors and 33 (37%) nonsurvivors, and a total of 628 serial electrocardiograms, 1,565 hs-cTnT, and 1,559 NT-proBNP concentrations were assessed. Log-hs-cTnT was lower in survivors compared with nonsurvivors at day 1 (ß -0.93 [-1.37; -0.49], p <0.001) and did not change over time. Log-NT-proBNP did not differ at day 1 between both groups but decreased over time in the survivor group (ß -0.08 [-0.11; -0.04] p <0.001) compared with nonsurvivors. Many electrocardiographic abnormalities were present in the whole population, without significant differences between both groups. In conclusion, baseline hs-cTnT and change in NT-proBNP were strongly associated with mortality. Two-thirds of patients with COVID-19 showed electrocardiographic abnormalities. Our serial assessment suggests that myocardial injury is common in mechanically ventilated patients with COVID-19 and is associated with outcome.

Meta-Analysis Evaluating High-Sensitivity Cardiac Troponin T Kinetics after Coronary Artery Bypass Grafting in Relation to the Current Definitions of Myocardial Infarction.

Various definitions of myocardial infarction type 5 after coronary artery bypass grafting (CABG) have been proposed (myocardial infarction [MI-5], also known as peri-procedural MI), using different biomarkers and different and arbitrary cut-off values. This meta-analysis aims to determine the expected release of high-sensitivity cardiac troponin T (hs-cTnT) after CABG in general and after uncomplicated surgery and off-pump CABG in particular. A systematic search was applied to 3 databases. Studies on CABG as a single intervention and reporting on postoperative hs-cTnT concentrations on at least 2 different time points were included. All data on hs-cTnT concentrations were extracted, and mean concentrations at various points in time were stratified. Eventually, 15 studies were included, encompassing 2,646 patients. Preoperative hs-cTnT was 17 ng/L (95% confidence interval [CI] 13 to 20 ng/L). Hs-cTnT peaked at 6 to 8 hours postoperatively (628 ng/L, 95% CI 400 to 856 ng/L; 45x upper reference limit [URL]) and was still increased after 48 hours. In addition, peak hs-cTnT concentration was 614 ng/L (95% CI 282 to 947 ng/L) in patients with a definite uncomplicated postoperative course (i.e., without MI). For patients after off-pump CABG compared to on-pump CABG, the mean peak hs-cTnT concentration was 186 ng/L (95% CI 172 to 200 ng/L, 13 × URL) versus 629 ng/L (95% CI 529 to 726 ng/L, 45 × URL), respectively. In conclusion, postoperative hs-cTnT concentrations surpass most of the currently defined cut-off values for MI-5, even in perceived uncomplicated surgery, suggesting thorough reassessment. Hs-cTnT release differences following on-pump CABG versus off-pump CABG were observed, implying the need for different cut-off values for different surgical strategies.

Hemostasis and fibrinolysis in COVID-19 survivors 6 months after intensive care unit discharge.

BACKGROUND: The prothrombotic phenotype has been extensively described in patients with acute coronavirus disease 2019 (COVID-19). However, potential long-term hemostatic abnormalities are unknown. OBJECTIVE: To evaluate the changes in routine hemostasis laboratory parameters and tissue-type plasminogen activator (tPA) rotational thromboelastometry (ROTEM) 6 months after COVID-19 intensive care unit (ICU) discharge in patients with and without venous thromboembolism (VTE) during admission. METHODS: Patients with COVID-19 of the Maastricht Intensive Care COVID cohort with tPA ROTEM measurement at ICU and 6-month follow-up were included. TPA ROTEM is a whole blood viscoelastic assay that illustrates both clot development and fibrinolysis due to simultaneous addition of tissue factor and tPA. Analyzed ROTEM parameters include clotting time, maximum clot firmness (MCF), lysis onset time (LOT), and lysis time (LT). RESULTS: Twenty-two patients with COVID-19 were included and showed extensive hemostatic abnormalities before ICU discharge. TPA ROTEM MCF (75 mm [interquartile range, 68-78]-59 mm [49-63]; P ≤ .001), LOT (3690 seconds [2963-4418]-1786 seconds [1465-2650]; P ≤ .001), and LT (7200 seconds [6144-7200]-3138 seconds [2591-4389]; P ≤ .001) normalized 6 months after ICU discharge. Of note, eight and four patients still had elevated fibrinogen and D-dimer concentrations at follow-up, respectively. In general, no difference in median hemostasis parameters at 6-month follow-up was observed between patients with (n=14) and without (n=8) VTE, although fibrinogen appeared to be lower in the VTE group (VTE-, 4.3 g/L [3.7-4.7] vs VTE+, 3.4 g/L [3.2-4.2]; P = .05). CONCLUSIONS: Six months after COVID-19 ICU discharge, no persisting hypercoagulable or hypofibrinolytic profile was detected by tPA ROTEM. Nevertheless, increased D-dimer and fibrinogen concentrations persist up to 6 months in some patients, warranting further exploration of the role of hemostasis in long-term morbidity after hospital discharge.

Evolution of NETosis markers and DAMPs have prognostic value in critically ill COVID-19 patients.

Coronavirus disease 19 (COVID-19) presents with disease severities of varying degree. In its most severe form, infection may lead to respiratory failure and multi-organ dysfunction. Here we study the levels and evolution of the damage associated molecular patterns (DAMPS) cell free DNA (cfDNA), extracellular histone H3 (H3) and neutrophil elastase (NE), and the immune modulators GAS6 and AXL in relation to clinical parameters, ICU scoring systems and mortality in patients (n = 100) with severe COVID-19. cfDNA, H3, NE, GAS6 and AXL were increased in COVID-19 patients compared to controls. These measures associated with occurrence of clinical events and intensive care unit acquired weakness (ICUAW). cfDNA and GAS6 decreased in time in patients surviving to 30 days post ICU admission. A decrease of 27.2 ng/mL cfDNA during ICU stay associated with patient survival, whereas levels of GAS6 decreasing more than 4.0 ng/mL associated with survival. The presence of H3 in plasma was a common feature of COVID-19 patients, detected in 38% of the patients at ICU admission. NETosis markers cfDNA, H3 and NE correlated well with parameters of tissue damage and neutrophil counts. Furthermore, cfDNA correlated with lowest p/f ratio and a lowering in cfDNA was observed in patients with ventilator-free days.

Serial markers of coagulation and inflammation and the occurrence of clinical pulmonary thromboembolism in mechanically ventilated patients with SARS-CoV-2 infection; the prospective Maastricht intensive care COVID cohort.

BACKGROUND: The incidence of pulmonary thromboembolism is high in SARS-CoV-2 patients admitted to the Intensive Care. Elevated biomarkers of coagulation (fibrinogen and D-dimer) and inflammation (c-reactive protein (CRP) and ferritin) are associated with poor outcome in SARS-CoV-2. Whether the time-course of fibrinogen, D-dimer, CRP and ferritin is associated with the occurrence of pulmonary thromboembolism in SARS-CoV-2 patients is unknown. We hypothesise that patients on mechanical ventilation with SARS-CoV-2 infection and clinical pulmonary thromboembolism have lower concentrations of fibrinogen and higher D-dimer, CRP, and ferritin concentrations over time compared to patients without a clinical pulmonary thromboembolism. METHODS: In a prospective study, fibrinogen, D-dimer, CRP and ferritin were measured daily. Clinical suspected pulmonary thromboembolism was either confirmed or excluded based on computed tomography pulmonary angiography (CTPA) or by transthoracic ultrasound (TTU) (i.e., right-sided cardiac thrombus). In addition, patients who received therapy with recombinant tissue plasminogen activator were included when clinical instability in suspected pulmonary thromboembolism did not allow CTPA. Serial data were analysed using a mixed-effects linear regression model, and models were adjusted for known risk factors (age, sex, APACHE-II score, body mass index), biomarkers of coagulation and inflammation, and anticoagulants. RESULTS: Thirty-one patients were considered to suffer from pulmonary thromboembolism ((positive CTPA (n = 27), TTU positive (n = 1), therapy with recombinant tissue plasminogen activator (n = 3)), and eight patients with negative CTPA were included. After adjustment for known risk factors and anticoagulants, patients with, compared to those without, clinical pulmonary thromboembolism had lower average fibrinogen concentration of - 0.9 g/L (95% CI: - 1.6 - - 0.1) and lower average ferritin concentration of - 1045 µg/L (95% CI: - 1983 - - 106) over time. D-dimer and CRP average concentration did not significantly differ, 561 µg/L (- 6212-7334) and 27 mg/L (- 32-86) respectively. Ferritin lost statistical significance, both in sensitivity analysis and after adjustment for fibrinogen and D-dimer. CONCLUSION: Lower average concentrations of fibrinogen over time were associated with the presence of clinical pulmonary thromboembolism in patients at the Intensive Care, whereas D-dimer, CRP and ferritin were not. Lower concentrations over time may indicate the consumption of fibrinogen related to thrombus formation in the pulmonary vessels.

Serial EXTEM, FIBTEM, and tPA Rotational Thromboelastometry Observations in the Maastricht Intensive Care COVID Cohort-Persistence of Hypercoagulability and Hypofibrinolysis Despite Anticoagulation.

Background: Coronavirus Disease 2019 (COVID-19) patients often present with thromboembolic events. In COVID-19 patients, routine hemostatic assays cannot correctly identify patients at risk for thromboembolic events. Viscoelastic testing with rotational thromboelastometry (ROTEM) might improve the characterization of COVID-19-associated coagulopathy. Objective: To unravel underlying coagulopathy and fibrinolysis over time as measured by serial assessment heparin-independent (FIBTEM and EXTEM) and fibrinolysis illustrating (tissue plasminogen activator; tPA) ROTEM assays. Patients/Methods: Between April 23 and June 12, consecutive adult patients enrolled within the Maastricht Intensive Care COVID (MaastrICCht) cohort were included, and a comprehensive set of clinical, physiological, pharmaceutical, and laboratory variables were collected daily. Twice per week, EXTEM, FIBTEM, and tPA ROTEM were performed. Clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), lysis onset time (LOT), and lysis time (LT) were determined to assess clot development and breakdown and were compared to routine hemostatic assays. Results: In 36 patients, 96 EXTEM/FIBTEM and 87 tPA ROTEM tests were performed during a 6-week follow-up. CT prolongation was present in 54% of EXTEM measurements, which were not matched by prothrombin time (PT) in 37%. Respectively, 81 and 99% of all EXTEM and FIBTEM MCF values were above the reference range, and median MCF remained elevated during follow-up. The ROTEM fibrinolysis parameters remained prolonged with median LOT consequently >49 min and unmeasurable LT in 56% of measurements, suggesting a severe hypofibrinolytic phenotype. Conclusion: ROTEM tests in COVID-19 ICU patients show hypercoagulability and severe hypofibrinolysis persisting over at least 6 weeks.

Suggestions for global coagulation assays for the assessment of COVID-19 associated hypercoagulability.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection is associated with a clear prothrombotic phenotype. Although the exact pathophysiological mechanisms are not yet fully understood, thrombosis is clearly a highly important in the prognosis and outcome of COVID-19. As such, there is a need for diagnostic analysis and quantification of the coagulation potential in these patients, both at diagnosis and follow-up. Global coagulation assays like thrombin generation (TG) and rotational thromboelastometry (ROTEM) might be suitable in estimating COVID-19 associated coagulopathy and thrombosis risk. Therefore, we aimed at validating both assays for samples with high levels of fibrinogen and in the presence of anticoagulant heparins, such as commonly observed for COVID-19 ICU patients. MATERIALS AND METHODS: Calibrated Automated Thrombography (CAT) was optimized to assess plasma thrombin generation in the presence of heparins. The final conditions with either 10 µg/mL Ellagic acid (EA) or PPP Reagent HIGH (high tissue factor; HPPH) were validated according to the EP5 protocol for within-run and between-run variability. Overall variability was well below 10%. To estimate the influences of heparins and high fibrinogen levels, CAT was performed on spiked plasma aliquots from 13 healthy volunteers. Comparable to the CAT method, tPA-ROTEM was used to validate the effect of high fibrinogen and heparins on clotting time, clot firmness and clot lysis parameters. RESULTS: Our adjusted COVID-19 assay showed a heparin dose dependent decrease in peak height and endogenous thrombin potential (ETP) for both EA and HPPH triggered variants. High fibrinogen did not alter the inhibitory effect of either LMWH or UFH, nor did it influence the peak height or ETP in any of the conditions. The tPA-ROTEM showed a significant prolongation in clotting time with the additions of heparin, which normalized with the addition of high fibrinogen. MCF was markedly increased in all hyperfibrinogenemic conditions. A trend towards increased lysis time and, thus, decreased fibrinolysis was observed. CONCLUSION: Thrombin generation and tPA-ROTEM protocols for measurements in the COVID-19 populations were adjusted and validated. The adjusted thrombin generation assay shows good sensitivity for measurements in heparin spiked plasma. High levels of fibrinogen did not alter the assay or the effectiveness of heparins as measured in this assay. t-PA ROTEM was effective in measurement of both high fibrinogen and heparins spiked samples and was sensitive to the expected relevant coagulant changes by these conditions. No clear fibrinolytic effect was observed in different conditions.

Veno-Arterial Extracorporeal Life Support in Heart Transplant and Ventricle Assist Device Centres. Meta-analysis.

AIMS: Because reported mortality on veno-arterial (V-A) extracorporeal life support (ECLS) substantially varies between centres, the aim of the current analysis was to assess the outcomes between units performing heart transplantation and/or implanting ventricular assist device (HTx/VAD) vs. non-HTx/VAD units in patients undergoing V-A ECLS for cardiogenic shock. METHODS AND RESULTS: Systematic search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses was performed using PubMed/MEDLINE databases until 30 November 2019. Articles reporting in-hospital/30-day mortality and centre's HTx/VAD status were included. In-hospital outcomes and long-term survival were analysed in subgroup meta-analysis. A total of 174 studies enrolling n = 13 308 patients were included with 20 series performed in non-HTx/VAD centres (1016 patients, 7.8%). Majority of patients underwent V-A ECLS for post-cardiotomy shock (44.2%) and acute myocardial infarction (20.7%). Estimated overall in-hospital mortality was 57.2% (54.9-59.4%). Mortality rates were higher in non-HTx/VAD [65.5% (59.8-70.8%)] as compared with HTx/VAD centres [55.8% (53.3-58.2%)], P < 0.001. Estimated late survival was 61.8% (55.7-67.9%) without differences between non-HTx/VAD and HTx/VAD centres: 66.5% (30.3-1.02%) vs. 61.7% (55.5-67.8%), respectively (P = 0.797). No differences were seen with respect to ECLS duration, limb complications, and reoperations for bleeding, kidney injury, and sepsis. Yet, weaning rates were higher in HTx/VAD vs. non-HTx/VAD centres: 58.7% (56.2-61.1%) vs. 48.9% (42.0-55.9%), P = 0.010. Estimated rate of bridge to heart transplant was 6.6% (5.2-8.3%) with numerical, yet not statistically significant, difference between non-HTx/VAD [2.7% (0.8-8.3%)] as compared with HTx/VAD [6.7% (5.3-8.6%)] (P = 0.131). CONCLUSIONS: Survival after V-A ECLS differed according to centre's HTx/VAD status. Potentially different risk profiles of patients must be taken account for before definite conclusions are drawn.

Nitric Oxide Ventilation Improves Recirculation and Right Ventricular Function During Veno-Venous Extracorporeal Membrane Oxygenation in a COVID-19 Patient.

Patients with coronavirus disease 2019 (COVID-19) are prone to pulmonary artery hypertension (PAH) and right ventricular pressure overload due to severe bilateral infiltrates, high ventilation pressures, persistent hypoxemia, pulmonary fibrosis, and/or pulmonary embolism. In patients on extracorporeal membrane oxygenation (ECMO), this potentially leads to increased recirculation. In the current report, the authors present a case in which continuous inhaled nitric oxide (iNO)-enriched ventilation was effective in terms of PAH and recirculation reduction in a COVID-19 patient on veno-venous ECMO.

Extracorporeal Life Support in Hemorrhagic Conditions: A Systematic Review.

Extracorporeal life support (ECLS) is indicated in refractory acute respiratory or cardiac failure. According to the need for anticoagulation, bleeding conditions (e.g., in trauma, pulmonary bleeding) have been considered a contraindication for the use of ECLS. However, there is increasing evidence for improved outcomes after ECLS support in hemorrhagic patients based on the benefits of hemodynamic support outweighing the increased risk of bleeding. We conducted a systematic literature search according to the PRISMA guidelines and reviewed publications describing ECLS support in hemorrhagic conditions. Seventy-four case reports, four case series, seven retrospective database observational studies, and one preliminary result of an ongoing study were reviewed. In total, 181 patients were identified in total of 86 manuscripts. The reports included patients suffering from bleeding caused by pulmonary hemorrhage (n = 53), trauma (n = 96), postpulmonary endarterectomy (n = 13), tracheal bleeding (n = 1), postpartum or cesarean delivery (n = 11), and intracranial hemorrhage (n = 7). Lower targeted titration of heparin infusion, heparin-free ECLS until coagulation is normalized, clamping of the endotracheal tube, and other ad hoc possibilities represent potential beneficial maneuvers in such conditions. Once the patient is cannulated and circulation restored, bleeding control surgery is performed for stabilization if indicated. The use of ECLS for temporary circulatory or respiratory support in critical patients with refractory hemorrhagic shock appears feasible considering tailored ECMO management strategies. Further investigation is needed to better elucidate the patient selection and ECLS management approaches.

The "sex gap" in COVID-19 trials: a scoping review.

BACKGROUND: Many studies investigate the role of pharmacological treatments on disease course in Corona Virus Disease 2019 (COVID-19). Sex disparities in genetics, immunological responses, and hormonal mechanisms may underlie the substantially higher fatality rates reported in male COVID-19 patients. To optimise care for COVID-19 patients, prophylactic and therapeutic studies should include sex-specific design and analyses. Therefore, in this scoping review, we investigated whether studies on pharmacological treatment in COVID-19 were performed based on a priori sex-specific design or post-hoc sex-specific analyses. METHODS: We systematically searched PubMed, EMBASE, UpToDate, clinical trial.org, and MedRxiv for studies on pharmacological treatment for COVID-19 until June 6th, 2020. We included case series, randomized controlled trials, and observational studies in humans (≥18 years) investigating antiviral, antimalarial, and immune system modulating drugs. Data were collected on 1) the proportion of included females, 2) whether sex stratification was performed (a priori by design or post-hoc), and 3) whether effect modification by sex was investigated. FINDINGS: 30 studies were eligible for inclusion, investigating remdesivir (n = 2), lopinavir/ritonavir (n = 5), favipiravir (n = 1), umifenovir (n = 1), hydroxychloroquine/chloroquine (n = 8), convalescent plasma (n = 6), interleukin-6 (IL-6) pathway inhibitors (n = 5), interleukin-1 (IL-1) pathway inhibitors (n = 1) and corticosteroids (n = 3). Only one study stratified its data based on sex in a post-hoc analysis, whereas none did a priori by design. None of the studies investigated effect modification by sex. A quarter of the studies included twice as many males as females. INTERPRETATION: Analyses assessing potential interference of sex with (side-)effects of pharmacological therapy for COVID-19 are rarely reported. Considering sex differences in case-fatality rates and genetic, immunological, and hormonal mechanisms, studies should include sex-specific analyses in their design to optimise COVID-19 care. FUNDING: None.

Monitoring of Unfractionated Heparin in Severe COVID-19: An Observational Study of Patients on CRRT and ECMO.

Objective Severe cases of coronavirus disease 2019 (COVID-19) can require continuous renal replacement therapy (CRRT) and/or extracorporeal membrane oxygenation (ECMO). Unfractionated heparin (UFH) to prevent circuit clotting is mandatory but monitoring is complicated by (pseudo)-heparin resistance. In this observational study, we compared two different activated partial thromboplastin time (aPTT) assays and a chromogenic anti-Xa assay in COVID-19 patients on CRRT or ECMO in relation to their UFH dosages and acute phase reactants. Materials and Methods The aPTT (optical [aPTT-CS] and/or mechanical [aPTT-STA] clot detection methods were used), anti-Xa, factor VIII (FVIII), antithrombin III (ATIII), and fibrinogen were measured in 342 samples from 7 COVID-19 patients on CRRT or ECMO during their UFH treatment. Dosage of UFH was primarily based on the aPTT-CS with a heparin therapeutic range (HTR) of 50-80s. Associations between different variables were made using linear regression and Bland-Altman analysis. Results Dosage of UFH was above 35,000IU/24 hours in all patients. aPTT-CS and aPTT-STA were predominantly within the HTR. Anti-Xa was predominantly above the HTR (0.3-0.7 IU/mL) and ATIII concentration was >70% for all patients; mean FVIII and fibrinogen were 606% and 7.5 g/L, respectively. aPTT-CS correlated with aPTT-STA ( r 2 = 0.68) with a bias of 39.3%. Correlation between aPTT and anti-Xa was better for aPTT-CS (0.78 ≤ r 2 ≤ 0.94) than for aPTT-STA (0.34 ≤ r 2 ≤ 0.81). There was no general correlation between the aPTT-CS and ATIII, FVIII, fibrinogen, thrombocytes, C-reactive protein, or ferritin. Conclusion All included COVID-19 patients on CRRT or ECMO conformed to the definition of heparin resistance. A patient-specific association was found between aPTT and anti-Xa. This association could not be explained by FVIII or fibrinogen.