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Background: A central hallmark of ARDS is hypoxemic respiratory failure due to increased pulmonary capillary leakage. The kinase inhibitor imatinib was shown to reverse vascular leak. This study aimed to investigate the effect of intravenous imatinib on pulmonary edema in patients with COVID-19 ARDS. Method(s): This multicentre, randomised, double-blind, placebo-controlled clinical trial (ClinicalTrial.gov identifier NCT04794088) included adult patients admitted to the ICU with moderate or severe COVID-19 ARDS. Patients were randomised 1:1 to receive 200mg intravenous imatinib or placebo twice daily for seven days or until ICU discharge. The change in extravascular lung water index between day 1 and day 4, measured using a PiCCO catheter, was chosen as the primary endpoint. Secondary outcomes included the PaO2/FiO2 ratio, number of ventilator free days, length of ICU admission and 28-day mortality rate. Study drug safety was assessed by daily screening of the patient records for adverse and serious adverse event occurrence and by performing ECGs and targeted clinical laboratory tests to monitor renal, liver and cardiac function. Result(s): Between March 2021 and 2022, 67 predominantly male (58%) patients with a mean age of 63+/-10 years were randomized to receive imatinib or placebo. No adverse events were considered to be related to study drug administration. At the moment of the submission, data cleaning is still ongoing. Conclusion(s): Thus far, intravenous imatinib administration seems safe and feasible in patients with COVID-19 related ARDS.
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INTRODUCTION: The COVID-19 pandemic resulted in a global mechanical ventilator shortage for treatment of severe acute respiratory failure. Development of novel breathing devices have been proposed as a low cost, rapid solution when full-featured ventilators are unavailable. We report the design, bench testing, and preclinical animal data for an 'Automated Bag Breathing Unit' (ABBU). METHODS: ABBU design uses a motor-driven wheel assembly for bag compression, calibrated for tidal volume (Vt), respiratory rate, inspiratory time, manual PEEP, and pressure-sensing assist with a modified 6' patient circuit. Berkshire pigs (n=5, weight 60.5±21.5 kg) were ventilated for 6 hours. PaCO2 and PaO2 in arterial blood were measured with varying Vt (200, 400, 600, 800 mL), rate (10, 20, 30, 40 bpm), and PEEP (5, 10, 15) in a healthy and injured swine model with synchronous and asynchronous ABBU operation. RESULTS: Bench testing with a Michigan dual-lung simulator yielded consistent Vt delivery at compliances of 0.02, 0.04 and 0.07 (L/cmH20). Dependence of the fraction of inspired oxygen (FiO2) with minute ventilation (VE) for a fixed inlet O2 flow rate (5 L/min) in ABBU was measured (47% - 98% FiO2 for 16-4 L/min VE respectively). FiO2 improved with higher O2 flows up to 15 L/min. Gas exchange was evaluated in a porcine model before and after saline lavage induced lung injury. When increasing Vt or rate, ABBU lowered PaCO2 to physiological levels (≤40 mmHg) from induced-hypercapnia, before and after saline lung injury. Changes from high to low PaCO2 positively correlated with changes in VE. Incremental PEEP trials improved PaO2 levels. Patient assist was studied while the animal was under light anesthesia. Of 1650 breaths, there were 1190 true positives, 416 true negatives, 44 false negatives, and no false positives. ABBU was able to maintain appropriate O2 and CO2 blood concentrations during spontaneous synchronous breathing. CONCLUSIONS: ABBU provides both oxygenation and ventilation across a range of respiratory parameter settings that support a lung protective ventilation strategy in most adults. A human clinical trial is required to establish safety and efficacy for patients with diverse etiologies of respiratory failure.