Clinical and epidemiologic data in coronavirus disease (COVID-19) have accrued rapidly since the outbreak, but few address the underlying pathophysiology.
To ascertain the physiologic, hematologic, ...and imaging basis of lung injury in severe COVID-19 pneumonia.
Clinical, physiologic, and laboratory data were collated. Radiologic (computed tomography (CT) pulmonary angiography
= 39 and dual-energy CT DECT,
= 20) studies were evaluated: observers quantified CT patterns (including the extent of abnormal lung and the presence and extent of dilated peripheral vessels) and perfusion defects on DECT. Coagulation status was assessed using thromboelastography.
In 39 consecutive patients (male:female, 32:7; mean age, 53 ± 10 yr range, 29-79 yr; Black and minority ethnic,
= 25 64%), there was a significant vascular perfusion abnormality and increased physiologic dead space (dynamic compliance, 33.7 ± 14.7 ml/cm H
O; 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,
= 3; mottled,
= 9; mixed pattern,
= 6).
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.
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.
Invasive mechanical ventilation is a key supportive therapy for patients on intensive care. There is increasing emphasis on personalised ventilation strategies. Clinical decision support systems ...(CDSS) have been developed to support this. We conducted a narrative review to assess evidence that could inform device implementation.
A search was conducted in MEDLINE (Ovid) and EMBASE. Twenty-nine studies met the inclusion criteria. Role allocation is well described, with interprofessional collaboration dependent on culture, nurse:patient ratio, the use of protocols, and perception of responsibility. There were no descriptions of process measures, quality metrics, or clinical workflow. Nurse-led weaning is well-described, with factors grouped by patient, nurse, and system. Physician-led weaning is heterogenous, guided by subjective and objective information, and ‘gestalt’. No studies explored decision-making with CDSS. Several explored facilitators and barriers to implementation, grouped by clinician (facilitators: confidence using CDSS, retaining decision-making ownership; barriers: undermining clinician's role, ambiguity moving off protocol), intervention (facilitators: user-friendly interface, ease of workflow integration, minimal training requirement; barriers: increased documentation time), and organisation (facilitators: system-level mandate; barriers: poor communication, inconsistent training, lack of technical support). One study described factors that support CDSS implementation.
There are gaps in our understanding of ventilation practice. A coordinated approach grounded in implementation science is required to support CDSS implementation. Future research should describe factors that guide clinical decision-making throughout mechanical ventilation, with and without CDSS, map clinical workflow, and devise implementation toolkits. Novel research design analogous to a learning organisation, that considers the commercial aspects of device design, is required.
Febuxostat is a widely prescribed drug for the treatment of gout, which is a highly prevalent disease worldwide and is a major cause of disability in mankind. Febuxostat suffers from several ...limitations such as gastrointestinal disturbances and low oral bioavailability. Thus, to improve patient compliance and bioavailability, transdermal drug delivery systems of Febuxostat were developed for obtaining enhanced permeation. Cubosomes of Febuxostat were prepared using a bottom-up approach and loaded into a microneedle using a micromolding technique to achieve better permeation through the skin. Optimization of the process and formulation parameters were achieved using our design of experiments. The optimized cubosomes of Febuxostat were characterized for various parameters such as % entrapment efficiency, vesicle size, Polydispersity index, Transmission electron microscopy, in vitro drug release, Small angle X-ray scattering, etc. After loading it in the microneedle it was characterized for dissolution time, axial fracture force, scanning electron microscopy, in vitro drug release, pore closure kinetics, etc. It was also evaluated for various ex vivo characterizations such as in vitro cell viability, ex vivo permeation, ex vivo fluorescence microscopy and histopathology which indicates its safety and better permeation. In vivo pharmacokinetic studies proved enhanced bioavailability compared with the marketed formulation. Pharmacodynamic study indicated its effectiveness in a disease-induced rat model. The developed formulations were then subjected to the stability study, which proved its stability.
Previous animal models of acute lung injury (ALI) are limited as they only reproduce part of the complex pathobiology of clinical ALI. Here we develop a translational mouse model of ALI, which not ...only reflects the major clinical and pathological features but also enables investigation into ALI resolution. Anaesthetised mice underwent orotracheal instillation of hydrochloric acid. During the immediate period after instillation, mice were carefully maintained with supplemental oxygen to avoid mortality. At specified time-points, lung injury was assessed by analysis of blood gases, respiratory mechanics, bronchoalveolar lavage fluid, alveolar fluid clearance and lung histology. Animals exhibited significant weight loss, decreased oxygenation, increased respiratory elastance and pulmonary inflammation (intra-alveolar leukocyte influx/cytokine levels and histological injury scores). Moreover, mice displayed alveolar-capillary barrier dysfunction/epithelial injury as reflected by increased alveolar protein, lung wet/dry weight ratio and soluble receptor for advanced glycation end-products, as well as reduced alveolar fluid clearance. These injury parameters peaked between days 1 and 3, followed by almost complete recovery over days 5-10. Histology showed evidence of fibrosis on day 10. The results indicate that this resolving model of acid aspiration represents a powerful experimental tool to investigate the injurious, inflammatory, fibrotic, and resolving and reparative processes of ALI.
Background There is a lack of contemporary data on cardiogenic shock (CS) in‐hospital mortality trends. Methods and Results Patients with CS admitted January 1, 2004 to December 31, 2018, were ...identified from the US National Inpatient Sample. We reported the crude and adjusted trends of in‐hospital mortality among the overall population and selected subgroups. Among a total of 563 949 644 hospitalizations during the period from January 1, 2004, to December 30, 2018, 1 254 358 (0.2%) were attributed to CS. There has been a steady increase in hospitalizations attributed to CS from 122 per 100 000 hospitalizations in 2004 to 408 per 100 000 hospitalizations in 2018 ( P trend <0.001). This was associated with a steady decline in the adjusted trends of in‐hospital mortality during the study period in the overall population (from 49% in 2004 to 37% in 2018; P trend <0.001), among patients with acute myocardial infarction CS (from 43% in 2004 to 34% in 2018; P trend <0.001), and among patients with non–acute myocardial infarction CS (from 52% in 2004 to 37% in 2018; P trend <0.001). Consistent trends of reduced mortality were seen among women, men, different racial/ethnic groups, different US regions, and different hospital sizes, regardless of the hospital teaching status. Conclusions Hospitalizations attributed to CS have tripled in the period from January 2004 to December 2018. However, there has been a slow decline in CS in‐hospital mortality during the studied period. Further studies are necessary to determine if the recent adoption of treatment algorithms in treating patients with CS will further impact in‐hospital mortality.
The ability of the alveolar epithelium to prevent and resolve pulmonary edema is a crucial determinant of morbidity and mortality in acute lung injury (ALI). TNF has been implicated in ALI ...pathogenesis, but the precise mechanisms remain undetermined. We evaluated the role of TNF signaling in pulmonary edema formation in a clinically relevant mouse model of ALI induced by acid aspiration and investigated the effects of TNF p55 receptor deletion, caspase-8 inhibition, and alveolar macrophage depletion on alveolar epithelial function. We found that TNF plays a central role in the development of pulmonary edema in ALI through activation of p55-mediated death signaling, rather than through previously well-characterized p55-mediated proinflammatory signaling. Acid aspiration produced pulmonary edema with significant alveolar epithelial dysfunction, as determined by alveolar fluid clearance (AFC) and intra-alveolar levels of the receptor for advanced glycation end-products. The impairment of AFC was strongly correlated with lung caspase-8 activation, which was localized to type 1 alveolar epithelial cells by flow cytometric analysis. p55-deficient mice displayed markedly attenuated injury, with improved AFC and reduced caspase-8 activity but no differences in downstream cytokine/chemokine production and neutrophil recruitment. Caspase-8 inhibition significantly improved AFC and oxygenation, whereas depletion of alveolar macrophages attenuated epithelial dysfunction with reduced TNF production and caspase-8 activity. These results provide in vivo evidence for a novel role for TNF p55 receptor-mediated caspase-8 signaling, without substantial apoptotic cell death, in triggering alveolar epithelial dysfunction and determining the early pathophysiology of ALI. Blockade of TNF-induced death signaling may provide an effective early-phase strategy for ALI.
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).
Transthoracic echocardiography (TTE) measures of RV function were collected in critically unwell patients for associations with clinical, ventilatory and laboratory data.
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).
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.
•Critical COVID-19 patients in ICU are reliant on echocardiography to identify cardiac complications.•There is a high incidence of RV radial dysfunction in this group.•RV radial impairment correlates with markers of cardiac stress.•Conventional echocardiographic measures of longitudinal function may miss the extent of RV impairment.•RV-PA coupling provides additional information on RV performance in critically ill patients with COVID-19.
To ascertain: 1) the frequency of thrombocytopenia and heparin-induced thrombocytopenia; 2) positive predictive value of the Pretest Probability Score in identifying heparin-induced thrombocytopenia; ...and 3) clinical outcome of heparin-induced thrombocytopenia in adult patients receiving venovenous- or venoarterial-extracorporeal membrane oxygenation, compared with cardiopulmonary bypass.
A single-center, retrospective, observational cohort study from January 2016 to April 2018.
Tertiary referral center for cardiac and respiratory failure.
Patients who received extracorporeal membrane oxygenation for more than 48 hours or had cardiopulmonary bypass during specified period.
None.
Clinical and laboratory data were collected retrospectively. Pretest Probability Score and heparin-induced thrombocytopenia testing results were collected prospectively. Mean age (± SD) of the extracorporeal membrane oxygenation and cardiopulmonary bypass cohorts was 45.4 (± 15.6) and 64.9 (± 13), respectively (p < 0.00001). Median duration of cardiopulmonary bypass was 4.6 hours (2-16.5 hr) compared with 170.4 hours (70-1,008 hr) on extracorporeal membrane oxygenation. Moderate and severe thrombocytopenia were more common in extracorporeal membrane oxygenation compared with cardiopulmonary bypass throughout (p < 0.0001). Thrombocytopenia increased in cardiopulmonary bypass patients on day 2 but was normal in 83% compared with 42.3% of extracorporeal membrane oxygenation patients at day 10. Patients on extracorporeal membrane oxygenation also followed a similar pattern of platelet recovery following cessation of extracorporeal membrane oxygenation. The frequency of heparin-induced thrombocytopenia in extracorporeal membrane oxygenation and cardiopulmonary bypass were 6.4% (19/298) and 0.6% (18/2,998), respectively (p < 0.0001). There was no difference in prevalence of heparin-induced thrombocytopenia in patients on venovenous-extracorporeal membrane oxygenation (8/156, 5.1%) versus venoarterial-extracorporeal membrane oxygenation (11/142, 7.7%) (p = 0.47). The positive predictive value of the Pretest Probability Score in identifying heparin-induced thrombocytopenia in patients post cardiopulmonary bypass and on extracorporeal membrane oxygenation was 56.25% (18/32) and 25% (15/60), respectively. Mortality was not different with (6/19, 31.6%) or without (89/279, 32.2%) heparin-induced thrombocytopenia in patients on extracorporeal membrane oxygenation (p = 0.79).
Thrombocytopenia is already common at extracorporeal membrane oxygenation initiation. Heparin-induced thrombocytopenia is more frequent in both venovenous- and venoarterial-extracorporeal membrane oxygenation compared with cardiopulmonary bypass. Positive predictive value of Pretest Probability Score in identifying heparin-induced thrombocytopenia was lower in extracorporeal membrane oxygenation patients. Heparin-induced thrombocytopenia had no effect on mortality.
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