Efficacy and safety of intravenous imatinib in COVID-19 ARDS: a randomized, double-blind, placebo-controlled clinical trial.

PURPOSE: A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. RESULTS: 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI - 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (- 1.17 ml/kg, 95% CI - 1.87 to - 0.44). CONCLUSIONS: IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).

The diagnostic accuracy of lung ultrasound to determine PiCCO-derived extravascular lung water in invasively ventilated patients with COVID-19 ARDS (preprint)

Background: Lung ultrasound (LUS) is a non-invasive method to detect and quantify pulmonary edema. However, it remains uncertain how components of the LUS examination should be aggregated into a score for quantifying pulmonary edema. We examined the diagnostic accuracy of various LUS scores with the extravascular lung water index (EVLWi) assessed with PiCCO in patients with moderate-to-severe COVID-19 ARDS. Methods: In this predefined secondary analysis of a multicenter randomized-controlled trial (InventCOVID), patients were included within 48h after intubation and underwent LUS and EVLWi measurement at two time points (first and fourth study day). EVLWi and ∆EVLWi were used as reference standard. Two 12-region scores (global LUS and LUS-ARDS), an 8-region anterior-lateral score and a 4-region B-line score were used as index tests. Pearson correlation was performed and the area under the receiver operating characteristics curve (AUROCC) for severe pulmonary edema (EVLWi>15mL/kg) was calculated. Results: 26 of 30 patients (87%) had complete LUS and EVLWi measurements at time point 1 and 24 of 29 patients (83%) at time point 2. The global LUS (r=0.54), LUS-ARDS (r=0.58) and anterior-lateral score (r=0.54) were significantly correlated with EVLWi, while the B-line score was not (r=0.32). ∆global LUS (r=0.49) and ∆anterior-lateral LUS (r=0.52) were significantly correlated with ∆EVLWi, while correlation of ∆LUS-ARDS (r=0.43) and ∆B-lines (r=0.32) did not reach statistical significance. AUROCC for EVLWi>15ml/kg was 0.73 for the global LUS, 0.79 for the anterior-lateral and 0.85 for the LUS-ARDS score. Conclusions: The global LUS, LUS-ARDS and antero-lateral score can quantify PiCCO-derived pulmonary edema measurements in COVID-19 ARDS. The LUS-ARDS score showed the highest diagnostic accuracy for severe pulmonary edema. Trial registration: ClinicalTrials.gov identifier NCT04794088, registered on 11 March 2021. European Clinical Trials Database number 2020-005447-23.

Biomarkers of alveolar epithelial injury and endothelial dysfunction are associated with scores of pulmonary edema in invasively ventilated patients.

BACKGROUND: Pulmonary edema is a central hallmark of Acute Respiratory Distress Syndrome (ARDS). Endothelial dysfunction and epithelial injury contribute to permeability but their differential contribution to pulmonary edema development remains understudied. METHODS: Plasma levels of surfactant protein-D (SP-D), soluble receptor for advanced glycation end products (sRAGE) and angiopoietin-2 (Ang-2) were measured in a prospective, multicenter cohort of invasively ventilated patients. Pulmonary edema was quantified using the radiographic assessment of lung edema (RALE) and global lung ultrasound (LUS) score. Variables were collected within 48 hours after intubation. Linear regression was used to examine the association of the biomarkers with pulmonary edema. RESULTS: In 362 patients, higher SP-D, sRAGE and Ang-2 concentrations were significantly associated with higher RALE and global LUS scores. After stratification by ARDS subgroups (pulmonary, non-pulmonary, COVID, non-COVID), the positive association of SP-D levels with pulmonary edema remained, while sRAGE and Ang-2 showed less consistent associations throughout the subgroups. In a multivariable analysis, SP-D levels were most strongly associated with pulmonary edema when combined with sRAGE (RALE score: ßSP-D = 6.79 units/log10 pg/mL, ßsRAGE = 3.84 units/log10 pg/mL, R2 = 0.23; global LUS score: ßSP-D = 3.28 units/log10 pg/mL, ßsRAGE = 2.06 units/log10 pg/mL, R2 = 0.086), while Ang-2 did not further improve the model. CONCLUSION: Biomarkers of epithelial injury and endothelial dysfunction were associated with pulmonary edema in invasively ventilated patients. SP-D and sRAGE showed the strongest association, suggesting that epithelial injury may form a final common pathway in the alveolar-capillary barrier dysfunction underlying pulmonary edema.

Prognostic Value of the Radiographic Assessment of Lung Edema Score in Mechanically Ventilated ICU Patients.

INTRODUCTION: The Radiographic Assessment of Lung Edema (RALE) score provides a semi-quantitative measure of pulmonary edema. In patients with acute respiratory distress syndrome (ARDS), the RALE score is associated with mortality. In mechanically ventilated patients in the intensive care unit (ICU) with respiratory failure not due to ARDS, a variable degree of lung edema is observed as well. We aimed to evaluate the prognostic value of RALE in mechanically ventilated ICU patients. METHODS: Secondary analysis of patients enrolled in the 'Diagnosis of Acute Respiratory Distress Syndrome' (DARTS) project with an available chest X-ray (CXR) at baseline. Where present, additional CXRs at day 1 were analysed. The primary endpoint was 30-day mortality. Outcomes were also stratified for ARDS subgroups (no ARDS, non-COVID-ARDS and COVID-ARDS). RESULTS: 422 patients were included, of which 84 had an additional CXR the following day. Baseline RALE scores were not associated with 30-day mortality in the entire cohort (OR: 1.01, 95% CI: 0.98-1.03, p = 0.66), nor in subgroups of ARDS patients. Early changes in RALE score (baseline to day 1) were only associated with mortality in a subgroup of ARDS patients (OR: 1.21, 95% CI: 1.02-1.51, p = 0.04), after correcting for other known prognostic factors. CONCLUSIONS: The prognostic value of the RALE score cannot be extended to mechanically ventilated ICU patients in general. Only in ARDS patients, early changes in RALE score were associated with mortality.

Water-soluble inclusion complexes for a novel anti-viral agent with low toxicity;Oseltamivir with the β-cyclodextrins

An innovative sonication method has been developed to produce inclusion complexes (ICs) of Oseltamivir (OTV) which is a potentially water-soluble anti-viral agent with lesser cytotoxicity. Proton signals and chemical shifts of OTV without any ambiguity confirm the formation of ICs with β-Cyclodextrin (B-CD) and Hydroxypropyl-β-cyclodextrin (H-CD). ICs are also supported by their atomic percentages as secondary evidence using XPS analysis. Analysis of drug release at three pH levels revealed the slow release of the OTV from ICs and also suitable for viral inactivation. A very less cytotoxic ability on cancer cell lines and enhanced the viral inactivation of OTV after being made into water-soluble ICs. © 2022 Elsevier B.V.