Convalescent Plasma for Covid-19-Induced ARDS in Mechanically Ventilated Patients.

BACKGROUND: Passive immunization with plasma collected from convalescent patients has been regularly used to treat coronavirus disease 2019 (Covid-19). Minimal data are available regarding the use of convalescent plasma in patients with Covid-19-induced acute respiratory distress syndrome (ARDS). METHODS: In this open-label trial, we randomly assigned adult patients with Covid-19-induced ARDS who had been receiving invasive mechanical ventilation for less than 5 days in a 1:1 ratio to receive either convalescent plasma with a neutralizing antibody titer of at least 1:320 or standard care alone. Randomization was stratified according to the time from tracheal intubation to inclusion. The primary outcome was death by day 28. RESULTS: A total of 475 patients underwent randomization from September 2020 through March 2022. Overall, 237 patients were assigned to receive convalescent plasma and 238 to receive standard care. Owing to a shortage of convalescent plasma, a neutralizing antibody titer of 1:160 was administered to 17.7% of the patients in the convalescent-plasma group. Glucocorticoids were administered to 466 patients (98.1%). At day 28, mortality was 35.4% in the convalescent-plasma group and 45.0% in the standard-care group (P = 0.03). In a prespecified analysis, this effect was observed mainly in patients who underwent randomization 48 hours or less after the initiation of invasive mechanical ventilation. Serious adverse events did not differ substantially between the two groups. CONCLUSIONS: The administration of plasma collected from convalescent donors with a neutralizing antibody titer of at least 1:160 to patients with Covid-19-induced ARDS within 5 days after the initiation of invasive mechanical ventilation significantly reduced mortality at day 28. This effect was mainly observed in patients who underwent randomization 48 hours or less after ventilation initiation. (Funded by the Belgian Health Care Knowledge Center; ClinicalTrials.gov number, NCT04558476.).

Adsorptive therapies in sepsis and inflammation: description of the various adsorptive techniques and their failure to improve outcomes.

Blood purification as an adjunctive therapy has been studied for several decades. In this review, we will focus on the most recent studies, particularly on adsorption techniques. These include hemofilters with adsorptive membranes, both endotoxin-specific and non-specific. In addition, we will discuss sorbents that target endotoxins, as well as devices that non-selectively capture viruses and bacteria. For each technique, we will also explore the reasons why blood purification methods have thus far failed to improve survival. Conventionally, reasons for the lack of success in blood purification techniques have been attributed to the need for better patient stratification through bedside measurements of interleukins and endotoxins. The choice of assay is also crucial, with endotoxin activity assays being preferable to other forms of limulus amoebocyte lysate assays. Another critical factor is timing, as administering blood purification at the wrong moment can potentially harm the patient. Mechanistic studies are still lacking for most devices, leaving us to treat patients blindly, except in endotoxin cases. In the context of viruses, especially COVID-19, we require a deeper understanding of the complexities involved in viral replication, as this could significantly impact the efficacy of blood purification techniques. The failures highlighted for each device should be viewed as potential areas for improvement. Despite the challenges, we remain hopeful that these techniques will eventually succeed and prove beneficial in the future.

Emerging Trends in Left Ventricular Thrombus: A Comprehensive Review of Non-Ischemic and Ischemic Cardiopathies, Including Eosinophilic Myocarditis, Chagas Cardiomyopathy, Amyloidosis, and Innovative Anticoagulant Approaches.

This comprehensive review explores the intricate aspects of left ventricular thrombus (LVT), a potential complication in both ischemic and non-ischemic cardiomyopathies. It provides a thorough understanding of left ventricular thrombus, revealing its uncommon incidence in the general population (7 cases per 10,000 patients), predominantly linked to ischemic heart diseases (ICMs) at an 80% prevalence rate. Diagnostic tools, notably transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR), demonstrate varying sensitivity but remain indispensable in specific clinical contexts related to LVT as non-invasive diagnostic modalities. A detailed comparison between ICM patients and those with non-ischemic cardiomyopathy (NICM) who have left ventricular thrombus reveals subtle distinctions with significant clinical implications. This analysis underscores the importance of these imaging techniques in distinguishing between the two conditions. Additionally, we explored the occurrence of LVT in specific non-ischemic cardiomyopathies, including Takotsubo syndrome, hypertrophic cardiomyopathy, eosinophilic myocarditis, Chagas disease, cardiac amyloidosis, and several other conditions. The article further delves into anticoagulation strategies, thoroughly examining their impact on LVT regression and patient outcomes. Pharmacological interventions, with a focus on direct oral anticoagulants, emerge as promising alternatives; however, there is insufficient information on their efficiency and safety, especially in NICM population. In conclusion, this review highlights the complex nature of LVT, incorporating a range of etiopathogenic factors, diagnostic complexities, and evolving therapeutic approaches. It emphasizes the pressing need for ongoing research in this field.

Monitoring of Unfractionated Heparin Therapy in the Intensive Care Unit Using a Point-of-Care aPTT: A Comparative, Longitudinal Observational Study with Laboratory-Based aPTT and Anti-Xa Activity Measurement.

Continuous intravenous unfractionated heparin (UFH) is administered routinely in the intensive care unit (ICU) for the anticoagulation of patients, and monitoring is performed by the activated partial thromboplastin time (APTT) or anti-Xa activity. However, these strategies are associated with potentially large time intervals before dose adjustments, which could be detrimental to the patient. The aim of the study was to compare a point-of-care (POCT) version of the APTT to (i) laboratory-based APTT and (ii) measurements of anti-Xa activity in terms of correlation, agreement and turnaround time (TAT). Thirty-five ICU patients requiring UFH therapy were prospectively included and followed longitudinally for a maximum duration of 15 days. UFH was administered according to a local adaptation of Raschke and Amanzadeh's aPTT nomograms. Simultaneous measurements of POCT-APTT (CoaguCheck® aPTT Test, Roche Diagnostics) on a drop of fresh whole blood, laboratory-based APTT (C.K. Prest®, Stago) and anti-Xa activity (STA®Liquid anti-Xa, Stago) were systematically performed two to six times a day. Antithrombin, C-reactive protein, fibrinogen, factor VIII and lupus anticoagulant were measured. The time tracking of sampling and analysis was recorded. The overall correlation between POCT-APTT and laboratory APTT (n = 795 pairs) was strongly positive (rs = 0.77, p < 0.0001), and between POCT-APTT and anti-Xa activity (n = 729 pairs) was weakly positive (rs = 0.46, p < 0.0001). Inter-method agreement (Cohen's kappa (k)) between POCT and laboratory APTT was 0.27, and between POCT and anti-Xa activity was 0.30. The median TATs from sample collection to the lab delivery of results for lab-APTT and anti-Xa were 50.9 min (interquartile range (IQR), 38.4−69.1) and 66.3 min (IQR, 49.0−91.8), respectively, while the POCT delivered results in less than 5 min (p < 0.0001). Although the use of the POCT-APTT device significantly reduced the time to results, the results obtained were poorly consistent with those obtained by lab-APTT or anti-Xa activity, and therefore it should not be used with the nomograms developed for lab-APTT.

Reduced anticoagulation targets in extracorporeal life support (RATE): study protocol for a randomized controlled trial.

BACKGROUND: Although life-saving in selected patients, ECMO treatment still has high mortality which for a large part is due to treatment-related complications. A feared complication is ischemic stroke for which heparin is routinely administered for which the dosage is usually guided by activated partial thromboplastin time (aPTT). However, there is no relation between aPTT and the rare occurrence of ischemic stroke (1.2%), but there is a relation with the much more frequent occurrence of bleeding complications (55%) and blood transfusion. Both are strongly related to outcome. METHODS: We will conduct a three-arm non-inferiority randomized controlled trial, in adult patients treated with ECMO. Participants will be randomized between heparin administration with a target of 2-2.5 times baseline aPTT, 1.5-2 times baseline aPTT, or low molecular weight heparin guided by weight and renal function. Apart from anticoagulation targets, treatment will be according to standard care. The primary outcome parameter is a combined endpoint consisting of major bleeding including hemorrhagic stroke, severe thromboembolic complications including ischemic stroke, and mortality at 6 months. DISCUSSION: We hypothesize that with lower anticoagulation targets or anticoagulation with LMWH during ECMO therapy, patients will have fewer hemorrhagic complications without an increase in thromboembolic complication or a negative effect on their outcome. If our hypothesis is confirmed, this study could lead to a change in anticoagulation protocols and a better outcome for patients treated with ECMO. TRIAL REGISTRATION: ClinicalTrials.gov NCT04536272 . Registered on 2 September 2020. Netherlands Trial Register NL7969.

Feasibility of measuring myocardial performance index of the right ventricle in anesthetized patients.

OBJECTIVE: Myocardial performance index, the sum of the 2 isovolumic times divided by the ejection time, contains information on global systolic and diastolic function. This study was performed to determine the feasibility of right ventricular myocardial performance index measurements if measured by transesophageal echocardiography in patients under general anesthesia and positive-pressure ventilation. DESIGN: A prospective cohort study. SETTING: A tertiary care university hospital. PARTICIPANTS: Twenty patients undergoing elective coronary artery bypass graft surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The feasibility of the right ventricular myocardial performance index measurements was assessed in awake patients by using transthoracic echocardiography and reassessed in the same patients under general anesthesia and positive-pressure ventilation using transesophageal echocardiography. The time from the cessation to the onset of 2 consecutive right ventricular inflows was measured as time A; the time from the onset to the cessation of right ventricular ejection was measured as time B. Myocardial performance index was calculated as follows: (time A-time B)/time B. A first reader independently measured all recordings twice to assess intrareader variability and a second reader once to assess interreader variability. Variability (%) was calculated as the mean absolute difference between 2 readings divided by their mean. The myocardial performance index could be measured for all patients. The point estimates of inter- and intraobserver variability of the right ventricular myocardial performance index measurements were 4.3% to 5% in awake patients and 17.8% to 19.6% in anesthetized patients. CONCLUSIONS: This finding questions the use of right ventricular myocardial performance index measurements in anesthetized patients under positive-pressure ventilation.

Prothrombotic hemostasis disturbances in patients with severe COVID-19: Individual daily data.

This data article accompanies the manuscript entitled: "Prothrombotic Disturbances of hemostasis of Patients with Severe COVID-19: a Prospective Longitudinal Observational Cohort Study" submitted to Thrombosis Research by the same authors. We report temporal changes of plasma levels of an extended set of laboratory parameters during the ICU stay of the 21 COVID-19 patients included in the monocentre cohort: CRP, platelet count, prothrombin time; Clauss fibrinogen and clotting factors II, V and VIII levels, D-dimers, antithrombin activity, protein C, free protein S, total and free tissue factor pathway inhibitor, PAI-1 levels, von Willebrand factor antigen and activity, ADAMTS-13 (plasma levels); and of two integrative tests of coagulation (thrombin generation with ST Genesia) and fibrinolysis (global fibrinolytic capacity - GFC). Regarding hemostasis, we used double-centrifuged frozen citrated plasma prospectively collected after daily performance of usual coagulation tests. Demographic and clinical characteristics of patients and thrombotic and hemorrhagic complications were also collected from patient's electronic medical reports.

Severe influenza/respiratory syncytial virus infections and hospital antimicrobial stewardship opportunities: impact of a 4-year surveillance including molecular diagnosis.

OBJECTIVE: To assess the prevalence of influenza and respiratory syncytial virus (RSV) in adults hospitalized for a respiratory infection in the winter months and to evaluate the impact of a viral diagnosis on empirical antimicrobial management (antibiotics and antivirals). DESIGN: Observational cohort study. SETTING: Acute-care university hospital. PATIENTS: The study included 963 adult patients hospitalized over a 4-year surveillance period. METHODS: Annual surveillance timelines were defined according to epidemiological criteria related to the circulation of RSV and influenza viruses in the general population. Patients were screened following a severe acute respiratory infection (SARI) case definition at the emergency department and were enrolled for molecular assay targeting influenza/RSV viruses after oral informed consent. Epidemiological and clinical data were recorded prospectively, microbiological investigations, antimicrobial management, and outcome data were reviewed retrospectively. RESULTS: An influenza or RSV virus was documented in 316 of 963 patients (33%). Optimization of antimicrobial management (AM) was achieved in 162 of 265 patients (61%) with a positive viral diagnosis and no bacterial infection at admission (AM treatment not initiated, n = 111; discontinued, n = 51). In contrast, only 128 of 462 patients (28%) with negative microbiological investigations did not have AM treatment initiated (n = 116) or had such treatment discontinued (n = 12). Early, targeted antiviral treatment was prescribed in 235 of 253 patients (93%) confirmed with influenza. Epidemiological, clinical, and outcome data were similar in both groups. CONCLUSION: Epidemiological surveillance associated with influenza/RSV molecular diagnosis in adults hospitalized for severe winter respiratory infections dramatically enhanced antimicrobial management.

Adsorptive Therapies in Sepsis and Inflammation: Description of the Various Adsorptive Techniques and their Failure to Improve Outcomes

ABSTRACT Blood purification as an adjunctive therapy has been studied for several decades. In this review, we will focus on the most recent studies, particularly on adsorption techniques. These include hemofilters with adsorptive membranes, both endotoxin-specific and non-specific. In addition, we will discuss sorbents that target endotoxins, as well as devices that non-selectively capture viruses and bacteria. For each technique, we will also explore the reasons why blood purification methods have thus far failed to improve survival. Conventionally, reasons for the lack of success in blood purification techniques have been attributed to the need for better patient stratification through bedside measurements of interleukins and endotoxins. The choice of assay is also crucial, with endotoxin activity assays being preferable to other forms of limulus amoebocyte lysate assays. Another critical factor is timing, as administering blood purification at the wrong moment can potentially harm the patient. Mechanistic studies are still lacking for most devices, leaving us to treat patients blindly, except in endotoxin cases. In the context of viruses, especially COVID-19, we require a deeper understanding of the complexities involved in viral replication, as this could significantly impact the efficacy of blood purification techniques. The failures highlighted for each device should be viewed as potential areas for improvement. Despite the challenges, we remain hopeful that these techniques will eventually succeed and prove beneficial in the future.

Persistent heparin-induced thrombocytopenia: danaparoid cross-reactivity or delayed-onset heparin-induced thrombocytopenia? A case report.

Clinical suspicion of immune heparin-induced thrombocytopenia (HIT) requires cessation of heparin and initiation of an alternative anticoagulant. The platelet count will subsequently recover. This case report describes the clinical course of a patient after a cardiovascular surgery. HIT was clinically and biologically confirmed. Unexpectedly, the platelet count did not recover despite the arrest of heparin. Danaparoid was initiated, and thrombocytopenia persisted. Danaparoid cross-reactivity was suspected, and laboratory assay was performed. Results were misinterpreted because no comparative buffer control was performed to ensure that the platelet aggregation was caused by danaparoid. Moreover, plasma/serum must be diluted to demonstrate this effect. Danaparoid cross-reactivity was incorrectly concluded, and the patient was switched to bivalirudin. The severe thrombocytopenia persisted. Plasmapheresis was started, and platelet count finally increased. The clinical course suggested a delayed-onset HIT. This case report illustrates the need for appropriate testing to differentiate drug cross-reactivity from delayed-onset HIT.

Assessment of Left Ventricular Dimensions by Transoesophageal Echocardiography in Patients During Coronary Artery Bypass Surgery.

OBJECTIVE: Normative values of left ventricular (LV) end-diastolic area and diameter (EDA and EDD) for intraoperative transoesophageal echocardiography (TEE) have not been established. We aimed to define the ranges of LV EDA and EDD for intraoperative TEE examinations in patients undergoing coronary artery bypass graft (CABG) surgery. METHODS: A MEDLINE search for studies reporting LV EDA and EDD in CABG patients was performed. Individual-level dataset from 333 anaesthetised and mechanically ventilated patients with preserved LV function (study population) were received from 8 studies. EDA and calculated EDD values in the study population were compared with summary mean EDD values obtained by transthoracic echocardiography (TTE) in 2 studies of 500 awake patients with coronary artery disease (CAD). Further, the influence of prespecified factors on EDD was evaluated through a multivariate regression model. RESULTS: LV EDA and EDD values measured by TEE in anaesthetised CABG patients were 16.7±4.7 cm2 and 4.6±0.6 cm, respectively. EDD values measured by TEE in anaesthetised patients were 10% to 13% less those measured by TTE in 2 studies of awake patients (p<0.001). Body surface area, age and fractional area change but not sex were factors that affected LV EDD. CONCLUSION: LV EDD values measured by intraoperative TEE in anaesthetised and mechanically ventilated CABG patients were 10% to 13% less than those measured by TTE in awake CAD patients. This finding indicates that independent normative values specific for intraoperative TEE should be established for guiding intraoperative clinical decisions.

Accuracy of tissue Doppler estimation of the right atrial pressure in anesthetized, paralyzed, and mechanically ventilated patients.

The ratio of tricuspid peak early inflow velocity to peak early diastolic velocity of the lateral tricuspid annulus (the E/Ea ratio) measured by transthoracic echocardiography has been reported to correlate with right atrial (RA) pressure. In this study, the correlation between the E/Ea ratio and RA pressure was tested in 44 anesthetized, paralyzed, and mechanically ventilated patients by transesophageal echocardiography. Mean RA pressure and the following echocardiographic data were recorded simultaneously: tricuspid peak early inflow velocities by Doppler echocardiography, peak early diastolic velocity of the lateral tricuspid annulus by tissue Doppler imaging, and right ventricular and left ventricular end-diastolic areas. Linear regression did not indicate a correlation between the E/Ea ratio and RA pressure (r = -0.11, p = 0.48) or between the E/Ea ratio and the right or left ventricular end-diastolic area index; it revealed a weak correlation between RA pressure and the inspiratory plateau pressure and body mass index. In conclusion, the E/Ea ratio failed to predict RA pressure or planimetric indexes of ventricular preload in anesthetized, paralyzed, and mechanically ventilated patients. In these patients, RA pressure was largely influenced by extracardiac factors.

Transesophageal Doppler echocardiographic detection of intramyocardial collateral flow to the right coronary artery and changes in the flow to the inferior left ventricular wall immediately after coronary artery bypass grafting.

This study examined the feasibility of Doppler transesophageal echocardiography (TEE) to detect collateral flow to the myocardium supplied by the right coronary artery (RCA) in the inferior left ventricular wall. Forty-four patients who underwent elective coronary artery bypass grafting (CABG) were prospectively studied. Presence of collateral flow to the RCA was diagnosed on preoperative angiography using the Rentrop score and by intraoperative Doppler TEE. Agreement of the 2 methods was analyzed by calculating the kappa coefficient. Collateral flow was present on preoperative angiography in 19 patients and absent in 25 patients. Intraoperative TEE detected collateral flow in the inferior wall in 15 patients (79%) with and 3 patients (12%) without angiographic collaterals, resulting in a kappa coefficient for agreement of 0.67 (95% confidence interval 0.45 to 0.90). Baseline collateral flow disappeared after CABG in 12 of 14 patients with grafting of the RCA but persisted in all patients without such grafting. Physiologic flow in the inferior wall was detected by TEE in a total of 27 patients at baseline and in 38 patients after CABG (p = 0.0018); its peak velocity increased after surgery only in the subgroup of patients with grafting of the RCA. In conclusion, these findings indicate that Doppler TEE may detect collateral flow in the inferior left ventricular wall, and that there are typical changes in collateral and physiologic flow after CABG.

Transcranial doppler assessment of cerebral perfusion in critically ill septic patients: a pilot study.

BACKGROUND: The aim of this study is to evaluate the feasibility and efficacy of Transcranial Doppler (TCD) in assessing cerebral perfusion changes in septic patients. METHODS: Using TCD, we measured the mean velocity in the middle cerebral artery (VmMCA, cm/sec) and calculated the pulsatility index (PI), resistance index (RI) and cerebral blood flow index (CBFi = 10*MAP/1.47(PI)) on the first day of patients' admission or on the first day of sepsis development; measurements were repeated on the second day. Sepsis was defined according to standard criteria. RESULTS: Forty-one patients without any known neurologic deficit treated in our 24-bed Critical Care Unit were assessed (Sepsis Group = 20, Control Group = 21). Examination was feasible in 91% of septic and 85% of non-septic patients (p = 0.89). No difference was found between the two groups in mean age, mean arterial pressure (MAP) or APACHE II score. The pCO2 values were higher in septic patients (46 ± 12 vs. 39 ± 4 mmHg p < 0.01). No statistically significant higher values of VmMCA were found in septic patients (110 ± 34 cm/sec vs. 99 ± 28 cm/sec p = 0.17). Higher values of PI and RI were found in septic patients (1.15 ± 0.25 vs. 0.98 ± 0.16 p < 0.01, 0.64 ± 0.08 vs. 0.59 ± 0.06 p < 0.01, respectively). No statistically significant lower values of CBFi were found in septic patients (497 ± 116 vs. 548 ± 110 p = 0.06). CONCLUSIONS: Our results suggest cerebral vasoconstriction in septic compared to non-septic patients. TCD is an efficient and feasible exam to evaluate changes in cerebral perfusion during sepsis.