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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 Novel coronavirus 2019 (COVID-19) can cause severe pneumonia requiring endotracheal intubation in 20-25% of all hospitalized patients. High peak pressures, driving pressures and plateau pressures as well as large tidal volumes are known risk factors for ventilator induced lung injury (VILI). Reported mortality rate of pneumomediastinum in COVID-19 is 60%. Therefore, target pressures are a peak pressure and plateau pressure below 30 cmH2O, tidal volumes below 6ml/kg ideal body weight (IBW) and driving pressure below 15 cmH2O. Cases We report two male COVID-19 patients, aged 64 and 65 years, who developed a pneumomediastinum while undergoing mechanical ventilation with lung protective strategies. Medical histories included obesity, hypertension, type 2 diabetes mellitus and were unremarkable for pulmonary disease. Both were hospitalized with respiratory insufficiency. COVID-19 was confirmed by a positive polymerase chain reaction test and CT-scan findings. Within three days, all patients were admitted to the intensive care unit (ICU) and mechanically ventilated in prone position 16-20 hours/day with lung protective strategies and in accordance with the lower positive end expiratory pressure (PEEP) higher FiO2 strategy. Peak pressures ranged 13-33 cmH2O, driving pressure (DP) ranged 10-15 cmH2O, PEEP 5-12 cmH2O, plateau pressure 14-24 cmH2O with tidal volumes 4-7 ml/kg (4-6 ml/kg while on pressure-controlled ventilation). After 7-10 days CT-scans were repeated because of progressive hypoxemia. In both patients CT-scan showed pneumomediastinum with pneumothorax requiring chest tube insertion in one patient and pneumopericardium in one patient (figure 1). Ventilator settings were lowered while allowing permissive hypercapnia to pH 7.20. Pneumomediastinum resorbed in both patients. During follow up, one patient died of progressive lung disease one month after hospitalization and one patient died from pulmonary hemorrhage one month after ICU-admission. Discussion A recent autopsy series in COVID-19 patients showed that alveolar epithelial damage causes loss of lung compliance. Decreased lung compliance combined with high plateau and peak pressures might predispose to VILI, however our case series shows two patients with pneumomediastinum while on lung protective mechanical ventilation. We hypothesize that alveolar epithelial damage predisposes to VILI rather than mechanical ventilation itself. This was confirmed in reports of COVID-19 patients with pneumomediastinum in the absence of mechanical ventilation. Therefore, the recently described mortality rate of 60% is a sign of severe pulmonary disease rather than a result of pneumomediastinum itself. Furthermore, our case series suggests that developing pneumomediastinum while on lung protective mechanical ventilation in COVID-19 patients predisposes to a high mortality rate.