Purpose A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed... Show morePurpose 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. Show less
Diephuis, E.; Borgie, C. de; Tomsic, A.; Winkelman, J.; W.J. van boven; Bouma, B.; ... ; Koolbergen, D. 2020
Background: Excessive bleeding, incomplete wound drainage, and subsequent accumulation of blood and clots in the pericardium have been associated with a broad spectrum of bleeding-related... Show moreBackground: Excessive bleeding, incomplete wound drainage, and subsequent accumulation of blood and clots in the pericardium have been associated with a broad spectrum of bleeding-related complications after cardiac surgery. We developed and studied the continuous postoperative pericardial flushing (CPPF) method to improve wound drainage and reduce blood loss and bleeding-related complications.Methods: We conducted a single-center, open-label, ITT, randomized controlled trial at the Academic Medical Center Amstserdam. Adults undergoing cardiac surgery for non-emergent valvular or congenital heart disease (CHD) were randomly assigned (1:1) to receive CPPF method or standard care. The primary outcome was actual blood loss after 12-hour stay in the intensive care unit (ICU). Secondary outcomes included bleeding-related complications and clinical outcome after six months follow-up.Findings: Between May 2013 and February 2016, 170 patients were randomly allocated to CPPF method (study group; n = 80) or to standard care (control group; n = 90). CPPF significantly reduced blood loss after 12-hour stay in the ICU (-41%) when compared to standard care (median differences -155 ml, 95% confidence interval (CI) -310 to 0; p=0.001). Cardiac tamponade and reoperation for bleeding did not occur in the study group versus one and three in the control group, respectively. At discharge from hospital, patients in the study group were less likely to have pleural effusion in a surgically opened pleural cavity (22% vs. 36%; p = 0.043).Interpretation: Our study results indicate that CPPF is a safe and effective method to improve chest tube patency and reduce blood loss after cardiac surgery. Larger trials are needed to draw final conclusions concerning the effectiveness of CPPF on clinically relevant outcomes. (C) 2020 The Author(s). Published by Elsevier B.V. Show less
