65 results found
Griffiths M, Meade S, Summers C, et al., 2021, RAND appropriateness panel to determine the applicability of international guidelines on the management of acute respiratory distress syndrome (ARDS) and other strategies in the context of the COVID-19 pandemic, Thorax, ISSN: 0040-6376
Background: COVID-19 has become the commonest cause of ARDS world-wide. Features of the pathophysiology and clinical presentation partially distinguish it from “classical” ARDS. A RAND analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template. Methods: An 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1-9 (where, 1-3 is inappropriate, 4-6 is uncertain and 7-9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into: investigations 16, non-invasive respiratory support 18, basic ICU management of ARDS 20, management of refractory hypoxaemia 8, pharmacotherapy 7, and anticoagulation 7, was completed again. Results: Disagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For ARDS patients with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous-thrombo-embolic disease.Conclusion: The expert panel found no reason to deviate from the evidence based supportive strategies for managing ARDS outlined in recent guidelines.
Patel BV, Haar S, Handslip R, et al., 2021, Natural history, trajectory, and management of mechanically ventilated COVID-19 patients in the United Kingdom, Intensive Care Medicine, Vol: 47, Pages: 549-565, ISSN: 0342-4642
PurposeThe trajectory of mechanically ventilated patients with coronavirus disease 2019 (COVID-19) is essential for clinical decisions, yet the focus so far has been on admission characteristics without consideration of the dynamic course of the disease in the context of applied therapeutic interventions.MethodsWe included adult patients undergoing invasive mechanical ventilation (IMV) within 48 h of intensive care unit (ICU) admission with complete clinical data until ICU death or discharge. We examined the importance of factors associated with disease progression over the first week, implementation and responsiveness to interventions used in acute respiratory distress syndrome (ARDS), and ICU outcome. We used machine learning (ML) and Explainable Artificial Intelligence (XAI) methods to characterise the evolution of clinical parameters and our ICU data visualisation tool is available as a web-based widget (https://www.CovidUK.ICU).ResultsData for 633 adults with COVID-19 who underwent IMV between 01 March 2020 and 31 August 2020 were analysed. Overall mortality was 43.3% and highest with non-resolution of hypoxaemia [60.4% vs17.6%; P < 0.001; median PaO2/FiO2 on the day of death was 12.3(8.9–18.4) kPa] and non-response to proning (69.5% vs.31.1%; P < 0.001). Two ML models using weeklong data demonstrated an increased predictive accuracy for mortality compared to admission data (74.5% and 76.3% vs 60%, respectively). XAI models highlighted the increasing importance, over the first week, of PaO2/FiO2 in predicting mortality. Prone positioning improved oxygenation only in 45% of patients. A higher peak pressure (OR 1.42[1.06–1.91]; P < 0.05), raised respiratory component (OR 1.71[ 1.17–2.5]; P < 0.01) and cardiovascular component (OR 1.36 [1.04–1.75]; P < 0.05) of the sequential organ failure assessment (SOFA) score and raised lactate (OR 1.33 [0.99–1.79
Koh MW, Baldi RF, Soni S, et al., 2021, Secreted extracellular cyclophilin a is a novel mediator of ventilator induced lung injury., American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X
RATIONALE: Mechanical ventilation is a mainstay of intensive care but contributes to the mortality of patients through ventilator induced lung injury. Extracellular Cyclophilin A is an emerging inflammatory mediator and metalloproteinase inducer, and the gene responsible for its expression has recently been linked to COVID-19 infection. OBJECTIVES: Here we explore the involvement of extracellular Cyclophilin A in the pathophysiology of ventilator-induced lung injury. METHODS: Mice were ventilated with low or high tidal volume for up to 3 hours, with or without blockade of extracellular Cyclophilin A signalling, and lung injury and inflammation were evaluated. Human primary alveolar epithelial cells were exposed to in vitro stretch to explore the cellular source of extracellular Cyclophilin A, and Cyclophilin A levels were measured in bronchoalveolar lavage fluid from acute respiratory distress syndrome patients, to evaluate clinical relevance. MEASUREMENTS AND MAIN RESULTS: High tidal volume ventilation in mice provoked a rapid increase in soluble Cyclophilin A levels in the alveolar space, but not plasma. In vivo ventilation and in vitro stretch experiments indicated alveolar epithelium as the likely major source. In vivo blockade of extracellular Cyclophilin A signalling substantially attenuated physiological dysfunction, macrophage activation and matrix metalloproteinases. Finally, we found that patients with acute respiratory distress syndrome showed markedly elevated levels of extracellular Cyclophilin A within bronchoalveolar lavage. CONCLUSIONS: Cyclophilin A is upregulated within the lungs of injuriously ventilated mice (and critically ill patients), where it plays a significant role in lung injury. Extracellular Cyclophilin A represents an exciting novel target for pharmacological intervention.
Gupta RK, Harrison EM, Ho A, et al., 2021, Development and validation of the ISARIC 4C Deterioration model for adults hospitalised with COVID-19: a prospective cohort study, The Lancet Respiratory Medicine, Vol: 9, Pages: 349-359, ISSN: 2213-2600
BackgroundPrognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions.MethodsWe developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal–external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London).Findings74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal–external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [–0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than
Bleakley C, Singh S, Garfield B, et al., 2021, Right ventricular dysfunction in critically ill COVID-19 ARDS, International Journal of Cardiology, Vol: 327, Pages: 251-258, ISSN: 0167-5273
AIMS: Comprehensive echocardiography assessment of right ventricular (RV) impairment has not been reported in critically ill patients with COVID-19. We detail the specific phenotype and clinical associations of RV impairment in COVID-19 acute respiratory distress syndrome (ARDS). METHODS: Transthoracic echocardiography (TTE) measures of RV function were collected in critically unwell patients for associations with clinical, ventilatory and laboratory data. RESULTS: Ninety patients (25.6% female), mean age 52.0 ± 10.8 years, veno-venous extracorporeal membrane oxygenation (VVECMO) (42.2%) were studied. A significantly higher proportion of patients were identified as having RV dysfunction by RV fractional area change (FAC) (72.0%,95% confidence interval (CI) 61.0-81.0) and RV velocity time integral (VTI) (86.4%, 95 CI 77.3-93.2) than by tricuspid annular plane systolic excursion (TAPSE) (23.8%, 95 CI 16.0-33.9), RVS' (11.9%, 95% CI 6.6-20.5) or RV free wall strain (FWS) (35.3%, 95% CI 23.6-49.0). RV VTI correlated strongly with RV FAC (p ≤ 0.01). Multivariate regression demonstrated independent associations of RV FAC with NTpro-BNP and PVR. RV-PA coupling correlated with PVR (univariate p < 0.01), as well as RVEDAi (p < 0.01), and RVESAi (p < 0.01), and was associated with P/F ratio (p 0.026), PEEP (p 0.025), and ALT (p 0.028). CONCLUSIONS: Severe COVID-19 ARDS is associated with a specific phenotype of RV radial impairment with sparing of longitudinal function. Clinicians should avoid interpretation of RV health purely on long-axis parameters in these patients. RV-PA coupling potentially provides important additional information above standard measures of RV performance in this cohort.
Bloom CI, Drake TM, Docherty AB, et al., 2021, Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK, The Lancet Respiratory Medicine, ISSN: 2213-2600
BackgroundStudies of patients admitted to hospital with COVID-19 have found varying mortality outcomes associated with underlying respiratory conditions and inhaled corticosteroid use. Using data from a national, multicentre, prospective cohort, we aimed to characterise people with COVID-19 admitted to hospital with underlying respiratory disease, assess the level of care received, measure in-hospital mortality, and examine the effect of inhaled corticosteroid use.MethodsWe analysed data from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study. All patients admitted to hospital with COVID-19 across England, Scotland, and Wales between Jan 17 and Aug 3, 2020, were eligible for inclusion in this analysis. Patients with asthma, chronic pulmonary disease, or both, were identified and stratified by age (<16 years, 16–49 years, and ≥50 years). In-hospital mortality was measured by use of multilevel Cox proportional hazards, adjusting for demographics, comorbidities, and medications (inhaled corticosteroids, short-acting β-agonists [SABAs], and long-acting β-agonists [LABAs]). Patients with asthma who were taking an inhaled corticosteroid plus LABA plus another maintenance asthma medication were considered to have severe asthma.Findings75 463 patients from 258 participating health-care facilities were included in this analysis: 860 patients younger than 16 years (74 [8·6%] with asthma), 8950 patients aged 16–49 years (1867 [20·9%] with asthma), and 65 653 patients aged 50 years and older (5918 [9·0%] with asthma, 10 266 [15·6%] with chronic pulmonary disease, and 2071 [3·2%] with both asthma and chronic pulmonary disease). Patients with asthma were significantly more likely than those without asthma to receive critical care (patients aged 16–49 years: adjusted odds ratio [OR] 1·20 [95% CI
Pairo-Castineira E, Clohisey S, Klaric L, et al., 2021, Genetic mechanisms of critical illness in Covid-19, Nature, Vol: 591, Pages: 92-98, ISSN: 0028-0836
Host-mediated lung inflammation is present,1 and drives mortality,2 in critical illness caused by Covid-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.3 Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study(GWAS) in 2244 critically ill Covid-19 patients from 208 UK intensive care units (ICUs). We identify and replicate novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 [Formula: see text] 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 [Formula: see text] 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 [Formula: see text] 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 [Formula: see text] 10-8) in the interferon receptor gene IFNAR2. We identify potential targets for repurposing of licensed medications: using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease; transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice.
Smith A, Morgan C, Ledot S, et al., 2021, Veno-venous extracorporeal membrane oxygenation for the acute respiratory distress syndrome: a bridge too far?, Acta Cardiologica: an international journal of cardiology, ISSN: 0001-5385
Veno-Venous Extracorporeal Membrane Oxygenation (VV-ECMO) provides a bridge to recovery in patients with acute respiratory failure due to the acute respiratory distress syndrome (ARDS). Survival in ARDS has improved over 15 years, and VV-ECMO may rescue even the most severe of these patients. Predictors of survival on ICU are based upon the principles of reversibility of the inciting aetiology, and premorbid ‘reserve’ – an imprecise term encompassing comorbidities and frailty. ECMO can support failing organs for prolonged periods, thus sometimes masking trajectories of decline, or unmasking irretrievable intrinsic conditions at a later time point in the critical illness. Clinicians are confronted with new on-treatment dilemmas: how long should we continue this high level of care? Will the patient’s limited respiratory reserve manage off ECMO? Or are we hastening their demise? How long is it justifiable to keep someone on ECMO, if the predicted survival off is ultimately poor, but they are in a stable state whilst supported? The palliative withdrawal from ECMO is unchartered territory that requires further study. We describe two representative cases and discuss the wide ethical issues surrounding the initiation and withdrawal of ECMO.
Juffermans NP, Radermacher P, Laffey JG, 2020, The importance of discovery science in the development of therapies for the critically ill, Intensive Care Medicine Experimental, Vol: 8, Pages: 1-7, ISSN: 2197-425X
Discovery science, a term which encompasses basic, translational, and computational science with the aim to discover new therapies, has advanced critical care. By combining knowledge on inflammatory and genomic pathways with computational methods, discovery science is currently enabling us to optimize clinical trials design by predictive enrichment and to move into the era of personalized medicine for complex syndromes such as sepsis and ARDS. Whereas computational methods are gaining in interest, efforts to invest in basic and translational science in critical care are declining. As basic and translational science is essential to advance our understanding of the pathophysiology of organ failure, this loss of interest may result in failure to discover new therapies for the critically ill. A renewed emphasis on basic and translational science is essential to find solutions for fundamental questions that remain in critical care. This requires a strategy to prioritize basic and translational science as an essential component within the critical care research “toolkit.” Key aspects of this strategy include an increased focus on basic science in critical care medical curricula as well as in critical care platforms such as conferences and medical journals. Training of critical care clinician scientists in basic and translational research will require new organizational models within the academic institutions, as well as the development of new funding opportunities for early career critical care clinician scientists.
Patel BV, Haar S, Handslip R, et al., 2020, Natural history, trajectory, and management of mechanically ventilated COVID-19 patients in the United Kingdom, Publisher: Cold Spring Harbor Laboratory
Background To date the description of mechanically ventilated patients with Coronavirus Disease 2019 (COVID-19) has focussed on admission characteristics with no consideration of the dynamic course of the disease. Here, we present a data-driven analysis of granular, daily data from a representative proportion of patients undergoing invasive mechanical ventilation (IMV) within the United Kingdom (UK) to evaluate the complete natural history of COVID-19.Methods We included adult patients undergoing IMV within 48 hours of ICU admission with complete clinical data until death or ICU discharge. We examined factors and trajectories that determined disease progression and responsiveness to ARDS interventions. Our data visualisation tool is available as a web-based widget (https://www.CovidUK.ICU).Findings Data for 623 adults with COVID-19 who were mechanically ventilated between 01 March 2020 and 31 August 2020 were analysed. Mortality, intensity of mechanical ventilation and severity of organ injury increased with severity of hypoxaemia. Median tidal volume per kg across all mandatory breaths was 5.6 [IQR 4.7-6.6] mL/kg based on reported body weight, but 7.0 [IQR 6.0-8.4] mL/kg based on calculated ideal body weight. Non-resolution of hypoxaemia over the first week of IMV was associated with higher ICU mortality (59.4% versus 16.3%; P<0.001). Of patients ventilated in prone position only 44% showed a positive oxygenation response. Non-responders to prone position show higher D-Dimers, troponin, cardiovascular SOFA, and higher ICU mortality (68.9% versus 29.7%; P<0.001). Multivariate analysis showed prone non-responsiveness being independently associated with higher lactate (hazard ratio 1.41, 95% CI 1.03–1.93), respiratory SOFA (hazard ratio 3.59, 95% CI 1.83–7.04); and cardiovascular SOFA score (hazard ratio 1.37, 95% CI 1.05–1.80).Interpretation A sizeable proportion of patients with progressive worsening of hypoxaemia were also refractory to evid
Bleakley C, Smith MR, Garfield B, et al., 2020, Contrast echocardiography in VV-ECMO dependent COVID-19 patients, Journal of the American Society of Echocardiography, Vol: 33, Pages: 1419-1420, ISSN: 0894-7317
George PM, Barratt SL, Condliffe R, et al., 2020, Respiratory follow-up of patients with COVID-19 pneumonia, Thorax, Vol: 75, Pages: 1009-1016, ISSN: 0040-6376
The COVID-19 pandemic has led to an unprecedented surge in hospitalised patients with viral pneumonia. The most severely affected patients are older men, individuals of black and Asian minority ethnicity and those with comorbidities. COVID-19 is also associated with an increased risk of hypercoagulability and venous thromboembolism. The overwhelming majority of patients admitted to hospital have respiratory failure and while most are managed on general wards, a sizeable proportion require intensive care support. The long-term complications of COVID-19 pneumonia are starting to emerge but data from previous coronavirus outbreaks such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) suggest that some patients will experience long-term respiratory complications of the infection. With the pattern of thoracic imaging abnormalities and growing clinical experience, it is envisaged that interstitial lung disease and pulmonary vascular disease are likely to be the most important respiratory complications. There is a need for a unified pathway for the respiratory follow-up of patients with COVID-19 balancing the delivery of high-quality clinical care with stretched National Health Service (NHS) resources. In this guidance document, we provide a suggested structure for the respiratory follow-up of patients with clinicoradiological confirmation of COVID-19 pneumonia. We define two separate algorithms integrating disease severity, likelihood of long-term respiratory complications and functional capacity on discharge. To mitigate NHS pressures, virtual solutions have been embedded within the pathway as has safety netting of patients whose clinical trajectory deviates from the pathway. For all patients, we suggest a holistic package of care to address breathlessness, anxiety, oxygen requirement, palliative care and rehabilitation.
Drake TM, Docherty AB, Harrison EM, et al., 2020, Outcome of hospitalization for COVID-19 in patients with interstitial lung disease: an international multicenter study., American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 1656-1665, ISSN: 1073-449X
RATIONALE: The impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established. OBJECTIVES: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age, sex and comorbidity matched population. METHODS: An international multicenter audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death. MEASUREMENTS AND MAIN RESULTS: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and co-morbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of <80% had an increased risk of death versus patients with FVC ≥80% (HR 1.72, 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR 2.27, 1.39-3.71). CONCLUSIONS: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Ridge CA, Desai SR, Jeyin N, et al., 2020, Dual-energy CT pulmonary angiography (DECTPA) quantifies vasculopathy in severe COVID-19 pneumonia, Radiology: Cardiothoracic Imaging, Vol: 2, ISSN: 2638-6135
BackgroundThe role of dual energy computed tomographic pulmonary angiography (DECTPA) in revealing vasculopathy in coronavirus disease 2019 (COVID-19) has not been fully explored.PurposeTo evaluate the relationship between DECTPA and disease duration, right ventricular dysfunction (RVD), lung compliance, D-dimer and obstruction index in COVID-19 pneumonia.Materials and MethodsThis institutional review board approved this retrospective study, and waived the informed consent requirement. Between March-May 2020, 27 consecutive ventilated patients with severe COVID-19 pneumonia underwent DECTPA to diagnose pulmonary thrombus (PT); 11 underwent surveillance DECTPA 14 ±11.6 days later. Qualitative and quantitative analysis of perfused blood volume (PBV) maps recorded: i) perfusion defect ‘pattern’ (wedge-shaped, mottled or amorphous), ii) presence of PT and CT obstruction index (CTOI) and iii) PBV relative to pulmonary artery enhancement (PBV/PAenh); PBV/PAenh was also compared with seven healthy volunteers and correlated with D-Dimer and CTOI.ResultsAmorphous (n=21), mottled (n=4), and wedge-shaped (n=2) perfusion defects were observed (M=20; mean age=56 ±8.7 years). Mean extent of perfusion defects=36.1%±17.2. Acute PT was present in 11/27(40.7%) patients. Only wedge-shaped defects corresponded with PT (2/27, 7.4%). Mean CTOI was 2.6±5.4 out of 40. PBV/PAenh (18.2 ±4.2%) was lower than in healthy volunteers (27 ±13.9%, p = 0.002). PBV/PAenh correlated with disease duration (β = 0.13, p = 0.04), and inversely correlated with RVD (β = -7.2, p = 0.001), persisting after controlling for confounders. There were no linkages between PBV/PAenh and D-dimer or CTOI.ConclusionPerfusion defects and decreased PBV/PAenh are prevalent in severe COVID-19 pneumonia. PBV/PAenh correlates with disease duration and inversely correlates with RVD. PBV/PAenh may be an important marker of vasculopathy in severe COVID-19 pneumonia
Armstrong-James D, Youngs J, Bicanic T, et al., 2020, Confronting and mitigating the risk of COVID-19 Associated Pulmonary Aspergillosis (CAPA), European Respiratory Journal, Vol: 56, Pages: 1-10, ISSN: 0903-1936
Cases of COVID-19 associated pulmonary aspergillosis (CAPA) are being increasingly reported and physicians treating patients with COVID-19-related lung disease need to actively consider these fungal co-infections.The SARS-CoV-2 (COVID-19) virus causes a wide spectrum of disease in healthy individuals as well as those with common comorbidities . Severe COVID-19 is characterised acute respiratory distress syndrome (ARDS) secondary to viral pneumonitis, treatment of which may require mechanical ventilation or extracorporeal membrane oxygenation (ECMO) . Clinicians are alert to the possibility of bacterial co-infection as a complication of lower respiratory tract viral infection; for example a recent review found that 72% of patients with COVID-19 received antimicrobial therapy . However, the risk of fungal co-infection, in particular COVID-19 associated pulmonary aspergillosis (CAPA), remains underappreciated.Fungal disease consistent with invasive aspergillosis (IA) has been observed with other severe Coronaviruses such as Severe Acute Respiratory Syndrome (SARS-CoV-2003) [4, 5] and Middle East Respiratory Syndrome (MERS-CoV) . From the outset of the COVID-19 pandemic, there were warning signs of secondary invasive fungal infection; Aspergillus flavus was isolated from the respiratory tract from one of 99 patients in the first COVID-19 cohort from Wuhan to be reported in any detail  and Aspergillus spp. were isolated from 2/52 (3.8%) of a subsequent cohort of critically unwell patients from this region . More recently, retrospective case series from Belgium , France , The Netherlands  and Germany  have reported evidence of CAPA in an alarming 20–35% of mechanically ventilated patients.
Arachchillage DJ, Remmington C, Rosenberg A, et al., 2020, Anticoagulation with argatroban in patients with acute antithrombin deficiency in severe COVID‐19, British Journal of Haematology, Vol: 190, Pages: e286-e288, ISSN: 0007-1048
Patel BV, Arachchillage DJ, Ridge CA, et al., 2020, Pulmonary angiopathy in severe COVID-19: physiologic, imaging and hematologic observations, American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 690-699, ISSN: 1073-449X
Rationale: Clinical and epidemiologic data in coronavirus disease 2019 (Covid-19) have accrued rapidly since the outbreak but few address the underlying pathophysiology. Objectives: To ascertain the physiologic, hematologic and imaging basis of lung injury in severe Covid-19 pneumonia. Methods: Clinical, physiologic and laboratory data were collated. Radiologic (computed tomography pulmonary angiography [CTPA, n=39] and dual-energy CT [DECT, n=20]) studies were evaluated: observers quantified CT patterns (including the extent of abnormal lung and the presence/extent of dilated peripheral vessels) and perfusion defects on DECT. Coagulation status was assessed using thromboelastography (TEG). Measurements and Results: In 39 consecutive patients (M:F 32:7; mean age, 53±10 years [range 29-79 years]; black and ethnic minority, n=25 [64%]), there was a significant vascular perfusion abnormality and increased physiologic dead-space (dynamic compliance, 33.7±14.7 mls/cmH2O; Murray Lung Injury Score, 3.14±0.53; mean ventilatory ratios, 2.6±0.8) with evidence of hypercoagulability and fibrinolytic ‘shutdown’. The mean CT extent (±SD) of normally-aerated lung, ground-glass opacification and dense parenchymal opacification were 23.5±16.7%, 36.3±24.7% and 42.7±27.1%, respectively. Dilated peripheral vessels were present in 21/33 (63.6%) patients with at least two assessable lobes (including 10/21 [47.6%] with no evidence of acute pulmonary emboli). Perfusion defects on DECT (assessable in 18/20 [90%]), were present in all patients (wedge-shaped, n=3; mottled, n= 9; mixed pattern, n=6). Conclusions: Physiologic, hematologic and imaging data show not only the presence of a hypercoagulable phenotype in severe Covid-19 pneumonia but also markedly impaired pulmonary perfusion likely caused by pulmonary angiopathy and thrombosis.
Montgomery H, Rehill N, Camporota L, et al., 2020, COVID-19: UK frontline intensivists' emerging learning, Journal of the Intensive Care Society, Pages: 1-3, ISSN: 1751-1437
The Intensive Care Society held a webinar on 3 April 2020 at which representatives from 11 of the most COVID-19 experienced hospital trusts in England and Wales shared learning around five specific topic areas in an open forum. This paper summarises the emerging learning and practice shared by those frontline clinicians.
Patel S, Bear D, Patel B, et al., 2020, Clinical application of ultrasound in intensive care unit-acquired weakness, Ultraschall in der Medizin, Vol: 41, Pages: 244-261, ISSN: 0172-4614
Intensive care unit-acquired weakness (ICUAW) is common and prolongs the duration of mechanical ventilation and ICU length of stay and is also a leading cause of physical restriction up to five years later. Developing diagnostic tools that allow early identification and risk stratification in all critically ill patients is vital. Ultrasound is a cheap, reproducible and noninvasive imaging modality that can be used to assess multiple muscle groups. It has advantages over other imaging techniques that entail risks of radiation as well as the logistical concerns of moving critically ill patients. Ultrasound muscle indices can be monitored over time and may serve as predictors for ventilatory weaning and long-term outcomes. The diaphragm is frequently perturbed during critical illness, specifically when mechanical ventilation is initiated. Diaphragm thickness and excursion have been shown to support extubation strategy with the former serving as a marker of inspiratory effort in the absence of more specialist tests. The techniques are reproducible with appropriate training and practice and have been applied in clinical trials. Peripheral skeletal muscle ultrasound has been the subject of intense research in ICU-acquired muscle weakness. The technique has also been found to be reproducible and can serve as a surrogate marker to current volitional and non-volitional tests in the assessment of muscle ICUAW. This article outlines the application of musculoskeletal ultrasound and its role in the early recognition of ICUAW in three distinct muscle groups: (1) diaphragm (2) rectus femoris and introduces the potential of (3) parasternal muscles.
Tavazzi G, Dammassa V, Corradi F, et al., 2020, Correlation between echocardiographic and hemodynamic variables in cardiothoracic intensive care unit, Journal of Cardiothoracic and Vascular Anesthesia, Vol: 34, Pages: 1263-1269, ISSN: 1053-0770
Objectivesthe echocardiographic indices have not been validated in critically ill population. We investigated the correlation between some echocardiographic and hemodynamics parameters.DesignProspective Spontaneous non-interventional observational study.SettingAdult cardiothoracic intensive care unit, single center (Royal Brompton Hospital, London UK).ParticipantsConsecutive adult patients admitted to cardiothoracic intensive care unit for severe respiratory failure, primary cardio-circulatory failure and post-aortic surgery.InterventionsClinical, hemodynamic parameters (stroke volume – SV, cardiac output – CO, mean arterial pressure – MAP, and cardiac power index – CPI) and echocardiographic indices of ventricular function (left ventricular total isovolumic time – t-IVT, mitral annular plane systolic excursion – MAPSE, and left ventricular fraction – LVEF) were evaluated offline.Measurements and main results117 patients were studied (age 57.2 ± 19; 60.6% male). t-IVT showed an inverse correlation with SV, CO, MAP and CPI (respectively r: -67%; -38%; -45%; -51%). MAPSE exhibited a positive correlation with SV, CO, MAP and CPI (respectively r: 43%; 44%; 34%; 31%). LVEF did not show any correlation. In the multivariate analysis the association of t-IVT and hemodynamics was confirmed for SV, CO, MAP and CPI with the highest partial correlation between t-IVT and MAP (R = -58%).ConclusionsMAPSE and t-IVT are two reproducible and reliable echocardiographic indices of systolic function and ventricular efficacy associated with hemodynamic variables in cardiothoracic critically ill patients, while LVEF did not show any correlation.
Jayakody Arachchillage DR, Laffan M, Khanna S, et al., 2020, Frequency of thrombocytopenia and heparin induced thrombocytopenia in patients receiving extracorporeal membrane oxygenation compared to cardiopulmonary bypass and the limited sensitivity of pre-test probability score, Critical Care Medicine, Vol: 48, Pages: e371-e379, ISSN: 0090-3493
Objectives:To ascertain:i)the frequency of thrombocytopeniaand heparininducedthrombocytopenia (HIT), ii)positive predictive value (PPV) of the pre-test probability score (PTPS) in identifying HIT iii)clinical outcome of HITin adult patients receiving veno-venous (VV)-extracorporeal membraneoxygenation(ECMO)or veno-arterial (VA)-ECMO, comparedto cardiopulmonary bypass (CPB). Design: A single-centre, retrospective, observational cohort study from January 2016 to April 2018Setting: Tertiary referral centre for cardiac and respiratory failure Patients:Patients who received ECMOfor>48hrs or had CPB during specified period Interventions: None.Measurements and Main Results:Clinical and laboratory data were collected retrospectively. PTPS and HIT testing results were collected prospectively. Mean age (standard deviation) of the EMCO and CPB cohorts were 45.4 (±15.6) and 64.9 (±13), p< 0.00001.Median duration of CPB was 4.6 [2-16.5]hrs compared to 170.4[70-1008] hrson ECMO.Moderateand severethrombocytopenia were more common in ECMO compared to CPB throughout (p<0.0001).Thrombocytopenia increased in CPB patients on day2 but was 4normal in 83% compared to 42.3 % ofECMOpatients at day 10. Patients on ECMO also followed a similar pattern of platelet recoveryfollowing cessation of ECMO. The incidences of HIT in ECMO and CPB were 6.4% (19/298) and 0.6% (18/2998) respectivelyp<0.0001). There was no difference in prevalence of HIT in patients on VV-ECMO (9/156, 5.7%) vs VA-ECMO (11/142, 7.7%), p=0.81. The PPV of the PTPS in identifying HIT in patients post-CPB and on ECMO were 56.25% (18/32) and 25% (15/60) respectively. Mortalitywas not different with (6/19, 31.6%) or without (89/279, 32.2%) HIT in patients on ECMO,p=0.79. Conclusions Thrombocytopenia is already common at ECMO initiation. HIT is more frequent in both VV-and VA-
O'Dea K, Tan YY, Shah S, et al., 2020, Monocytes mediate homing of circulating microvesicles to the pulmonaryvasculature during low-grade systemic inflammation, Journal of Extracellular Vesicles, Vol: 9, Pages: 1-16, ISSN: 2001-3078
Microvesicles (MVs), a plasma membrane-derived subclass of extracellular vesicles, are produced and released into the circulation during systemic inflammation, yet little is known of cell/tissue-specific uptake of MVs under these conditions. We hypothesized that monocytes contribute to uptake of circulating MVs and that their increased margination to the pulmonary circulation and functional priming during systemic inflammation produces substantive changes to the systemic MV homing profile. Cellular uptake of i.v.-injected, fluorescently labelled MVs (J774.1 macrophage-derived) in vivo was quantified by flow cytometry in vascular cell populations of the lungs, liver and spleen of C57BL6 mice. Under normal conditions, both Ly6Chigh and Ly6Clow monocytes contributed to MV uptake but liver Kupffer cells were the dominant target cell population. Following induction of sub-clinical endotoxemia with low-dose i.v. LPS, MV uptake by lung-marginated Ly6Chigh monocytes increased markedly, both at the individual cell level (~2.5-fold) and through substantive expansion of their numbers (~8-fold), whereas uptake by splenic macrophages was unchanged and uptake by Kupffer cells actually decreased (~50%). Further analysis of MV uptake within the pulmonary vasculature using a combined model approach of in vivo macrophage depletion, ex vivo isolated perfused lungs and in vitro lung perfusate cell-based assays, indicated that Ly6Chigh monocytes possess a high MV uptake capacity (equivalent to Kupffer cells), that is enhanced directly by endotoxemia and ablated in the presence of phosphatidylserine (PS)-enriched liposomes and β3 integrin receptor blocking peptide. Accordingly, i.v.-injected PS-enriched liposomes underwent a redistribution of cellular uptake during endotoxemia similar to MVs, with enhanced uptake by Ly6Chigh monocytes and reduced uptake by Kupffer cells. These findings indicate that monocytes, particularly lung-marginated Ly6Chigh subset monocytes, become a dominant
Handslip R, Mumby S, Calfee CS, et al., 2020, Necrosome complex release and necroinflammation in hyper-inflammatory ARDS, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, Pages: 1-2, ISSN: 1073-449X
Derry J, Patel BV, Adcock IM, et al., 2018, Comparison of mechanisms of repair and regeneration in experimental models of acute respiratory distress syndrome, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A39-A39, ISSN: 0040-6376
Background The acute respiratory distress syndrome (ARDS) is a clinical condition with multiple aetiologies. Previous work has presented two relevant, distinct animal models of ARDS. A murine model of aspiration using acid, in which the lung injury begins to resolve after 48 hours, and another of infection using LPS, that continues to deteriorate. It has been suggested that alveolar epithelial regeneration is implicated in disease progression to different extents between the models.We hypothesised that the wnt and retinoic acid pathways are involved in regeneration and resolution of these murine models of ARDS, and that there is greater activation of these pathways in the aspiration compared to the infection model. Currently, management of ARDS is irrespective of lung injury aetiology, and these mechanisms may prove relevant for pathway modulation for future therapy.Methods Mice were administered either 25 µl intratracheal 0.1 M hydrochloric acid (aspiration model, n=5), 25 µg LPS (infection model, n=6) or sham treated (controls, n=6) and sacrificed at 48 hours. Lung tissue was homogenised. mRNA and protein levels of regenerative pathway genes were quantified, through reverse-transcription polymerase chain reaction and Western blotting.Results Significant upregulation of all 9 regenerative genes studied was seen in the acid model compared to controls. Rac-2 mRNA (wnt pathways) was the only regenerative gene in the LPS-injured mice to show a significant upregulation compared to controls (67.39±25.73 vs 0.32±0.13 ΔCTx1010p<0.05). Significant differences between the acid and LPS models were seen in the mRNA levels of Daam-2 (wnt pathways, figure 1) and Retinol Binding Protein-1 (RBP-1) from the retinoic acid pathway (26.130±2.812 vs 4.893±0.564 ΔCTx105, p<0.05). There were inter-model differences in protein levels, most apparent in β-catenin (β-catenin dependen
Arachchillage DJ, Khanna S, Vandenbriele C, et al., 2018, Incidence of Thrombocytopenia and Heparin induced thrombocytopenia in patients receiving Extracorporeal Membrane Oxygenation (ECMO) compared to cardiopulmonary bypass and the limited sensitivity of pre-test probability score, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: American Society of Hematology, ISSN: 0006-4971
Patel BV, Barrett NA, Vuylsteke A, 2018, ECMO for severe acute respiratory distress syndrome, New England Journal of Medicine, Vol: 379, Pages: 1090-1091, ISSN: 0028-4793
Patel BV, Barrett NA, Vuylsteke A, 2018, Correspondance: ECMO for severe acute respiratory distress syndrome, New England Journal of Medicine, Vol: 379, Pages: 1090-1093, ISSN: 0028-4793
Arachchillage DRJ, Passariello M, Laffan M, et al., 2018, Intracranial haemorrhage and early mortality in patients receiving extracorporeal membrane oxygenation for severe respiratory failure, Seminars in Thrombosis and Hemostasis, Vol: 44, Pages: 276-286, ISSN: 0094-6176
Intracranial hemorrhage (ICH) is a serious complication in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) and is associated with high mortality. It is unknown whether ICH may be a consequence of the ECMO or of an underlying disease. The authors first aimed to assess the incidence of ICH at initiation and during the course of VV-ECMO and its associated mortality. The second aim was to identify clinical and laboratory measures that could predict the development of ICH in severe respiratory failure. Data were collected from a total number of 165 patients receiving VV-ECMO from January, 2012 to December, 2016 in a single tertiary center and treated according to a single protocol. Only patients who had a brain computed tomography within 24 hours of initiation of ECMO (n = 149) were included for analysis. The prevalence and incidence of ICH at initiation and during the course of VV-ECMO (at median 9 days) were 10.7% (16/149) and 5.2% (7/133), respectively. Thrombocytopenia and reduced creatinine clearance (CrCL) were independently associated with increased risk of ICH on admission; odds ratio (95% confidence interval): 22.6 (2.6–99.5), and 10.8 (5.6–16.2). Only 30-day (not 180-day) mortality was significantly higher in patients with ICH on admission versus those without (37.5% [6/16] vs 16.4% [22/133]; p = 0.03 and 43.7% [7/16] vs 26.3% [35/133]; p = 0.15, respectively). Reduced CrCL and thrombocytopenia were associated with ICH at initiation of VV-ECMO. The higher incidence of ICH at initiation suggests it is more closely related to the severity of the underlying lung injury than to the VV-ECMO itself. ICH at VV-ECMO initiation was associated with early mortality.
Tatham KC, O'Dea KP, Romano R, et al., 2018, Intravascular donor monocytes play a central role in lung transplant ischaemia-reperfusion injury, Thorax, Vol: 73, Pages: 350-360, ISSN: 1468-3296
Rationale Primary graft dysfunction in lung transplant recipients derives from the initial, largely leukocyte-dependent, ischaemia-reperfusion injury. Intravascular lung-marginated monocytes have been shown to play key roles in experimental acute lung injury, but their contribution to lung ischaemia-reperfusion injury post transplantation is unknown.Objective To define the role of donor intravascular monocytes in lung transplant-related acute lung injury and primary graft dysfunction.Methods Isolated perfused C57BL/6 murine lungs were subjected to warm ischaemia (2 hours) and reperfusion (2 hours) under normoxic conditions. Monocyte retention, activation phenotype and the effects of their depletion by intravenous clodronate-liposome treatment on lung inflammation and injury were determined. In human donor lung transplant samples, the presence and activation phenotype of monocytic cells (low side scatter, 27E10+, CD14+, HLA-DR+, CCR2+) were evaluated by flow cytometry and compared with post-implantation lung function.Results In mouse lungs following ischaemia-reperfusion, substantial numbers of lung-marginated monocytes remained within the pulmonary microvasculature, with reduced L-selectin and increased CD86 expression indicating their activation. Monocyte depletion resulted in reductions in lung wet:dry ratios, bronchoalveolar lavage fluid protein, and perfusate levels of RAGE, MIP-2 and KC, while monocyte repletion resulted in a partial restoration of the injury. In human lungs, correlations were observed between pre-implantation donor monocyte numbers/their CD86 and TREM-1 expression and post-implantation lung dysfunction at 48 and 72 hours.Conclusions These results indicate that lung-marginated intravascular monocytes are retained as a ‘passenger’ leukocyte population during lung transplantation, and play a key role in the development of transplant-associated ischaemia-reperfusion injury.
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