Pulmonary vascular permeability
Pulmonary vascular permeability index (PVPi) measurement using PiCCO catheter.
PaO2/FiO2 ratio as measure of gas-exchange
PaO2/FiO2 ratio (PaO2 in mmHg) recorded from electronic patient chart.
Oxygenation index as measure of gas-exchange
Oxygenation index (i.e. mean airway pressure (in cmH2O)*FiO2*100/PaO2) recorded from electronic patient chart.
Driving pressure as an indicator of global lung strain
Driving pressure (plateau pressure - positive end expiratory pressure (PEEP)) in cmH2O, calculated using the respective parameters recorded in the electronic patient chart.
Compliance as a measure of respiratory mechanics
Compliance (tidal volume/driving pressure) in ml/cm H2O, calculated using the respective parameters recorded in the electronic patient chart.
Mechanical power as quantification of the energy load delivered to the lung per positive pressure breath
Mechanical power (0.098*respiratory rate*tidal volume/1000*PEEP + pressure above PEEP) in J/min, calculated using the respective parameters recorded in the electronic patient chart.
Pro-inflammatory cytokines
Pro-inflammatory cytokines IL-6 and IL-8 as biomarkers of inflammation measured in blood samples.
Matrix metalloproteinases as markers of inflammation
Matrix metalloproteinases as biomarkers of inflammation measured in blood samples.
D-dimer as an inflammatory biomarker
D-dimer (in mcg/ml) as a biomarker of inflammation measured in blood samples.
Angiopoietin-1 and -2 as biomarkers of endothelial activation and injury
Measurement of plasma biomarkers of endothelial activation and injury such as angiopoietin-1 and -2 measured in blood samples.
Soluble thrombomodulin as a biomarker of endothelial activation and injury
Measurement of plasma biomarkers of endothelial activation and injury such as soluble thrombomodulin measured in blood samples.
Surfactant as biomarker of lung epithelial injury
Measurement of surfactant as a biomarker of lung injury, measured in blood samples.
Protein biomarkers of lung epithelial injury
Measurement of proteins implicated in epithelial injury such as protein D measured in blood samples.
SOFA score as organ function and outcome measure
Sequential Organ Failure Assessment (SOFA) score (minimum 0, maximum 24 points whereby 24 points is the worst outcome, indicating a mortality >90%) recorded as a measure of organ function and outcome. The SOFA score uses the following parameters to score clinical condition: patient on mechanical ventilation (yes or no), Glasgow Coma Scale (as a measure of neurological status), total serum bilirubin (as a measure of liver function), number of platelets, mean arterial pressure / need for the use of vasopressors, serum creatinine (as a measure of kidney function).
WHO ordinal scale for clinical improvement as functional outcome measure
The WHO Ordinal Scale for Clinical Improvement (0 to 8, where a higher value indicates worse outcome) describes clinical condition using the following categories: Uninfected, Ambulatory (no limitation of activities), Ambulatory (limitation of activities), Hospitalized (no O2 therapy), Hospitalized (O2 by nasal prongs or mask), Hospitalized (O2 by NIV or HFNO), Hospitalized ( invasive menchanical ventilation), Hospitalized (requiring organ support (vasopressors, CVVH, ECMO)), Death.
Morbidity and mortality outcomes
Morbidity and mortality will be described using the following:
Number of ventilator-free days until day 28
Duration of mechanical ventilation in days until day 28
Length of ICU stay in days until day 28
Hospital length of stay in days until day 28
Number of days alive until day 28
28-day mortality
Mortality will be recorded as 28-day mortality (in %).
Hemoglobin cell count as drug safety parameter
Haemoglobin (in mmol/L) as a measure of drug safety.
Blood cell count as drug safety parameter
Blood cell count, i.e. thrombocytes and leucocytes (both x10^9/L) as a measure of drug safety.
Serum creatinine as measure of kidney function
Kidney function, i.e. serum creatinine (mmol/L) as a measure of drug safety.
Estimated glomerular filtration rate as measure of kidney function
Estimated glomerular filtration rate (in ml/min) as a measure of drug safety.
Electrolytes as drug safety parameters
Electrolytes sodium and potassium (both in mmol/L) recorded as a measure of kidney function.
Liver enzymes as drug safety parameter
Liver enzymes, i.e., AST, ALT, Alkaline Phosphatase, γ-glutamyl transferase (all in U/L).
Serum bilirubin as drug safety parameter
Total serum bilirubin (in micromol/L) as a measure of liver function.
NT-proBNP as drug safety parameter
NT-proBNP (in pg/ml), i.e. B-type natriuretic peptide, as a biomarker of cardiac stress and strain.
Reporting of adverse and serious adverse events
The following events will be recorded:
Adverse events:
Pulmonary embolism, not leading to circulatory of pulmonary instability.
Infections requiring antibiotic therapy
Non-life-threatening infusion reactions.
Serious adverse events:
Death (any cause)
Cardiopulmonary:
Extracorporeal membrane oxygenation
Arrythmias requiring resuscitation.
Thrombo-embolic events with life-threatening circulatory or pulmonary instability
Spontaneous bleeding, requiring blood transfusion or surgical intervention.
Myocardial infarction
Renal replacement therapy
Liver failure (bilirubin SOFA score >4)
Thrombocytopenia (<50^109/L), diffuse intravascular coagulation, leukopenia (<2^109/L), anaemia (Hb <4mmol/L).
Intracranial bleeding or ischemic stroke.
Life-threatening infusion reactions, requiring additional vasopressor, fluid support, corticosteroids and antihistamines.
Any unexpected serious event judged as an "untoward medical occurrence".
Corrected QT interval on ECG
The corrected QT interval on ECG will be recorded using a 12-lead ECG.
Total concentration as a pharmacokinetic measure of imatinib
Measurement of imatinib total concentration (Cmax) in blood samples.
Free fraction as a pharmacokinetic measure of imatinib
Measurement of imatinib free fraction (ƒP) in blood samples.
Imatinib metabolite AGP
Measurement imatinib metabolite AGP (alpha-1-acid glycoprotein in mg/ml) in blood samples.
Imatinib metabolite albumin
Measurement imatinib metabolite albumin (in g/L).
Thoracic ultrasound
Thoracic ultrasound will be performed in a subset of 35-40 patients to evaluate and compare extravascular lung water measurements obtained by PiCCO.