Standard- versus intermediate-dose enoxaparin for anti-factor Xa guided thromboprophylaxis in critically ill patients with COVID-19.

The prevalence of venous thromboembolism (VTE) is high in critically ill patients with COVID-19. Dosing of Low Molecular Weight Heparin (LMWH) for thromboprophylaxis in patients with severe COVID-19 is subject to ongoing debate.In this brief report, we describe our study where we retrospectively examined the efficacy of standard- versus intermediate-dosing of enoxaparin in attaining and maintaining accepted prophylactic levels of anti-Factor Xa (anti-FXa) in critically ill patients with COVID-19.We collected data for all patients with confirmed COVID-19 who were treated with enoxaparin for thromboprophylaxis in a single Intensive Care Unit (ICU) in the United Kingdom between 31st March and 16th November 2020. Standard-dose of enoxaparin was 40 mg subcutaneously once daily for patients with normal renal function and body weight between 50 and 100 kg; the intermediate-dose was 40 mg subcutaneously twice daily. Anti-FXa peak concentrations between 0.2-0.4 IU/ml were considered appropriate for thromboprophylaxis.Age, sex, weight, Body Mass Index, APACHE II score, ICU length of stay, initial P/F ratio and creatinine were not statistically significantly different between standard- and intermediate-dose thromboprophylaxis cohorts. In the standard-dose group, the median initial anti-FXa level was 0.13 (interquartile range 0.06-0.18) compared to 0.26 (0.21-0.33) in the intermediate-dose cohort (p < 0.001). On repeated measurement, in the standard dose cohort, 44 of 95 (46%) anti-FXa levels were < 0.2 IU/ml compared with 24 of 132 (18%) levels in the intermediate-dose cohort even after dose-adjustment. There was one radiologically confirmed pulmonary embolism (PE) on computed tomography pulmonary angiogram during hospital admission in each cohort.Our study supports starting intermediate-dose thromboprophylaxis for critically ill patients with COVID-19 to achieve anti-FXa levels in the accepted thromboprophylactic range although further study is required to investigate whether anti-FXa guided thromboprophylaxis is safe and effective in reducing the incidence of VTEs in critically ill patients with COVID-19.

Kinetic profiling of in vivo lung cellular inflammatory responses to mechanical ventilation.

Mechanical ventilation, through overdistension of the lung, induces substantial inflammation that is thought to increase mortality among critically ill patients. The mechanotransduction processes involved in converting lung distension into inflammation during this ventilator-induced lung injury (VILI) remain unclear, although many cell types have been shown to be involved in its pathogenesis. This study aimed to identify the profile of in vivo lung cellular activation that occurs during the initiation of VILI. This was achieved using a flow cytometry-based method to quantify the phosphorylation of several markers (p38, ERK1/2, MAPK-activated protein kinase 2, and NF-κB) of inflammatory pathway activation within individual cell types. Anesthetized C57BL/6 mice were ventilated with low (7 ml/kg), intermediate (30 ml/kg), or high (40 ml/kg) tidal volumes for 1, 5, or 15 min followed by immediate fixing and processing of the lungs. Surprisingly, the pulmonary endothelium was the cell type most responsive to in vivo high-tidal-volume ventilation, demonstrating activation within just 1 min, followed by the alveolar epithelium. Alveolar macrophages were the slowest to respond, although they still demonstrated activation within 5 min. This order of activation was specific to VILI, since intratracheal lipopolysaccharide induced a very different pattern. These results suggest that alveolar macrophages may become activated via a secondary mechanism that occurs subsequent to activation of the parenchyma and that the lung cellular activation mechanism may be different between VILI and lipopolysaccharide. Our data also demonstrate that even very short periods of high stretch can promote inflammatory activation, and, importantly, this injury may be immediately manifested within the pulmonary vasculature.

The use of echocardiography in the management of shock in critical care: a prospective, multi-centre, observational study.

PURPOSE: Echocardiography is recommended as a first-line tool in the assessment of patients with shock. The current provision of echocardiography in critical care is poorly defined. The aims of this work were to evaluate the utilisation of echocardiography in patients presenting to critical care with shock, its impact on decision making, and adherence to governance guidelines. METHODS: We conducted a prospective, multi-centre, observational study in 178 critical care units across the United Kingdom (UK) and Crown Dependencies, led by the UK's Trainee Research in Intensive Care Network. Consecutive adult patients (≥ 18 years) admitted with shock were followed up for 72 h to ascertain whether they received an echocardiogram, the nature of any scan performed, and its effect on critical treatment decision making. RESULTS: 1015 patients with shock were included. An echocardiogram was performed on 545 (54%) patients within 72 h and 436 (43%) within 24 h of admission. Most scans were performed by the critical care team (n = 314, 58%). Echocardiography was reported to either reduce diagnostic uncertainty or change management in 291 (54%) cases. Patients with obstructive or cardiogenic shock had their management altered numerically more often by echocardiography (n = 15 [75%] and n = 100 [58%] respectively). Twenty-five percent of echocardiograms performed adhered to current national governance and image storage guidance. CONCLUSION: Use of echocardiography in the assessment of patients with shock remains heterogenous. When echocardiography is used, it improves diagnostic certainty or changes management in most patients. Future research should explore barriers to increasing use of echocardiography in assessing patients presenting with shock.

PIM-COVID study: protocol for a multicentre, longitudinal study measuring the psychological impact of surviving an intensive care admission due to COVID-19 on patients in the UK.

INTRODUCTION: Psychological distress is common in intensive care unit (ICU) survivors and is anticipated in those who were treated for severe COVID-19 infection. This trainee-led, multicentre, observational, longitudinal study aims to assess the psychological outcomes of ICU survivors treated for COVID-19 infection in the UK at 3, 6 and/or 12 months after ICU discharge and explore whether there are demographic, psychosocial and clinical risk factors for psychological distress. METHODS AND ANALYSIS: Questionnaires will be provided to study participants 3, 6 and/or 12 months after discharge from intensive care, assessing for anxiety, depression, post-traumatic stress symptoms, health-related quality of life and physical symptoms. Demographic, psychosocial and clinical data will also be collected to explore risk factors for psychological distress using latent growth curve modelling. Study participants will be eligible to complete questionnaires at any of the three time points online, by telephone or by post. ETHICS AND DISSEMINATION: The PIM-COVID study was approved by the Health Research Authority (East Midlands - Derby Research and Ethics Committee, reference: 20/EM/0247). TRIAL REGISTRATION NUMBER: NCT05092529.

A Systematic Review of Anticoagulation Strategies for Patients with Atrial Fibrillation in Critical Care.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia in critically ill patients. There is a paucity of data assessing the impact of anticoagulation strategies on clinical outcomes for general critical care patients with AF. Our aim was to assess the existing literature to evaluate the effectiveness of anticoagulation strategies used in critical care for AF. METHODS: A systematic literature search was conducted using MEDLINE, EMBASE, CENTRAL, and PubMed databases. Studies reporting anticoagulation strategies for AF in adults admitted to a general critical care setting were assessed for inclusion. RESULTS: Four studies were selected for data extraction. A total of 44,087 patients were identified with AF, of which 17.8 to 49.4% received anticoagulation. The reported incidence of thromboembolic events was 0 to 1.4% for anticoagulated patients, and 0 to 1.3% in nonanticoagulated patients. Major bleeding events were reported in three studies and occurred in 7.2 to 8.6% of the anticoagulated patients and in up to 7.1% of the nonanticoagulated patients. CONCLUSION: There was an increased incidence of major bleeding events in anticoagulated patients with AF in critical care compared with nonanticoagulated patients. There was no significant difference in the incidence of reported thromboembolic events within studies between patients who did and did not receive anticoagulation. However, the outcomes reported within studies were not standardized, therefore, the generalizability of our results to the general critical care population remains unclear. Further data are required to facilitate an evidence-based assessment of the risks and benefits of anticoagulation for critically ill patients with AF.

Hypercoagulopathy in Severe COVID-19: Implications for Acute Care.

COVID-19 was first described in late 2019 and has since developed into a pandemic affecting more than 21 million people worldwide. Of particular relevance for acute care is the occurrence of COVID-19-associated coagulopathy (CAC), which is characterised by hypercoagulability, immunothrombosis and venous thromboembolism, and contributes to hypoxia in a significant proportion of patients. This review describes diagnosis and treatment of CAC in the emergency department and in intensive care. We summarise the pathological mechanisms and common complications of CAC such as pulmonary thrombosis and venous thromboembolic events and discuss current strategies for thromboprophylaxis and therapeutic anti-coagulation in the acute care setting.

Anticoagulation strategies in critical care for the treatment of atrial fibrillation: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Atrial fibrillation (AF) is the most common cardiac arrhythmia in critically ill patients and is associated with an increased risk of thromboembolic events and mortality. Oral anticoagulation for thromboembolism prophylaxis is a key component of managing AF in the general population and is recommended by National Institute for Health and Care Excellence guidelines. However, assessment tools used to aid decision making about anticoagulation have not yet been validated in the critical care setting. There is a paucity of data assessing the impact of anticoagulation strategies on clinical outcomes in critically ill patients with AF. We present a protocol for a systematic review and meta-analysis to evaluate the effectiveness of anticoagulation strategies for AF used specifically in critical care. METHODS AND ANALYSIS: We will conduct a systematic review of the literature by searching MEDLINE, EMBASE, CENTRAL and PubMed databases for articles published from January 1990 to October 2019. Studies reporting anticoagulation strategies for AF in adults (>18 years) admitted to a general critical care setting will be assessed for inclusion. Outcomes of interest will include (1) percentage of patients started on anticoagulation in critical care for AF, (2) incidence of thromboembolism, (3) incidence of bleeding events, (4) intensive care unit (ICU) mortality, (5) hospital mortality, (6) ICU length of stay and (7) hospital length of stay. We will conduct a meta-analysis of trials. Risk of bias will be assessed using the Cochrane Risk of Bias tool for randomised trials or the Newcastle-Ottawa Risk of Bias assessment tool for non-randomised studies. This protocol and subsequent systematic review will be reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. ETHICS AND DISSEMINATION: This proposed systematic review will include data extracted from published studies; therefore, ethical approval is not required. The results of this review will be published in clinical specialty journals and presented at international meetings and conferences. TRIAL REGISTRATION NUMBER: CRD42020158237.

Sources of alveolar soluble TNF receptors during acute lung injury of different etiologies.

Elevated soluble tumor necrosis factor-α receptor (sTNFR) levels in bronchoalveolar lavage fluid (BALF) are associated with poor patient outcome in acute lung injury (ALI). The mechanisms underlying these increases are unknown, but it is possible that pulmonary inflammation and increased alveolar epithelial permeability may individually contribute. We investigated mechanisms of elevated BALF sTNFRs in two in vivo mouse models of ALI. Anesthetized mice were challenged with intratracheal lipopolysaccharide or subjected to injurious mechanical ventilation. Lipopolysaccharide instillation produced acute intra-alveolar inflammation, but minimal alveolar epithelial permeability changes, with increased BALF sTNFR p75, but not p55. Increased p75 levels were markedly attenuated by alveolar macrophage depletion. In contrast, injurious ventilation induced substantial alveolar epithelial permeability, with increased BALF p75 and p55, which strongly correlated with total protein. BALF sTNFRs were not increased in isolated buffer-perfused lungs (devoid of circulating sTNFRs) subjected to injurious ventilation. These results suggest that lipopolysaccharide-induced intra-alveolar inflammation upregulates alveolar macrophage-mediated production of sTNFR p75, whereas enhanced alveolar epithelial permeability following mechanical ventilation leads to increased BALF p75 and p55 via plasma leakage. These data provide new insights into differential regulation of intra-alveolar sTNFR levels during ALI and may suggest sTNFRs as potential markers for evaluating the pathophysiology of ALI.