1. persistent septic shock (\>24 hours) with a mean arterial pressure (map) ≤65 mm hg and serum lactate level \>4 mmol/l (36 mg/dl) despite adequate volume resuscitation and vasopressor use (norepinephrine \>0.2 μg/kg/min) for \>6 hours 2. major trauma in the past 5 days 3. presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last year 4. pre-existing severe cardiopulmonary disease including, but not limited to, interstitial lung disease; severe copd (gold stage iv or fev1\<30% predicted); heart failure (estimated left ventricular ejection fraction \< 40%); or a chronic lung condition requiring home oxygen treatment 5. an underlying clinical condition that, in the opinion of the investigator, would make it very unlikely for the patient to be successfully weaned from ventilation due to severe underlying diseases (e.g., severe malnutrition, severe neurological disease) 6. patients considered inappropriate for critical care (e.g., being considered for palliative care) 7. currently receiving extracorporeal membrane oxygenation (ecmo) 8. severe chronic liver disease with child-pugh score \>12 (appendix 1) 9. white blood count \<2.5 x 109/l; hemoglobin \<4.0 mmol/l (6.5g/dl); platelets \<50 x 109/l 10. alt or ast \>10x upper limit of normal (uln) or bilirubin \>3x uln 11. women who are pregnant or breast-feeding 12. use of drugs with strong cyp3a4 induction potential, such as carbamazepine, efavirenz, enzalutamide, phenobarbital, phenytoin, hypericum, mitotane, nevirapine, primidone, rifabutin and rifampicin 13. inability of the icu staff to initiate administration of study treatment within 48 hours of intubation 14. enrolled in a concomitant clinical trial of an investigational medicinal product 15. in the opinion of the investigator, progression to death is highly probable, irrespective of the provision of treatments

1. persistent septic shock (\>24 hours) with a mean arterial pressure (map) ≤65 mm hg and serum lactate level \>4 mmol/l (36 mg/dl) despite adequate volume resuscitation and vasopressor use (norepinephrine \>0.2 μg/kg/min) for \>6 hours 2. major trauma in the past 5 days 3. presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last year 4. pre-existing severe cardiopulmonary disease including, but not limited to, interstitial lung disease; severe copd (gold stage iv or fev1\<30% predicted); heart failure (estimated left ventricular ejection fraction \< 40%); or a chronic lung condition requiring home oxygen treatment 5. an underlying clinical condition that, in the opinion of the investigator, would make it very unlikely for the patient to be successfully weaned from ventilation due to severe underlying diseases (e.g., severe malnutrition, severe neurological disease) 6. patients considered inappropriate for critical care (e.g., being considered for palliative care) 7. currently receiving extracorporeal membrane oxygenation (ecmo) 8. severe chronic liver disease with child-pugh score \>12 (appendix 1) 9. white blood count \<2.5 x 109/l; hemoglobin \<4.0 mmol/l (6.5g/dl); platelets \<50 x 109/l 10. alt or ast \>10x upper limit of normal (uln) or bilirubin \>3x uln 11. women who are pregnant or breast-feeding 12. use of drugs with strong cyp3a4 induction potential, such as carbamazepine, efavirenz, enzalutamide, phenobarbital, phenytoin, hypericum, mitotane, nevirapine, primidone, rifabutin and rifampicin 13. inability of the icu staff to initiate administration of study treatment within 48 hours of intubation 14. enrolled in a concomitant clinical trial of an investigational medicinal product 15. in the opinion of the investigator, progression to death is highly probable, irrespective of the provision of treatments

persistent septic shock (>24 hours) with a mean arterial pressure (map) ≤65 mm hg and serum lactate level >4 mmol/l (36 mg/dl) despite adequate volume resuscitation and vasopressor use (norepinephrine >0.2 μg/kg/min) for >6 hours major trauma in the past 5 days presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last year pre-existing severe cardiopulmonary disease including, but not limited to, interstitial lung disease; severe copd (gold stage iv or fev1<30% predicted); heart failure (estimated left ventricular ejection fraction < 40%); or a chronic lung condition requiring home oxygen treatment an underlying clinical condition that, in the opinion of the investigator, would make it very unlikely for the patient to be successfully weaned from ventilation due to severe underlying diseases (e.g., severe malnutrition, severe neurological disease) patients considered inappropriate for critical care (e.g., being considered for palliative care) currently receiving extracorporeal membrane oxygenation (ecmo) severe chronic liver disease with child-pugh score >12 (appendix 1) white blood count <2.5 x 109/l; hemoglobin <4.0 mmol/l (6.5g/dl); platelets <50 x 109/l alt or ast >10x upper limit of normal (uln) or bilirubin >3x uln women who are pregnant or breast-feeding use of drugs with strong cyp3a4 induction potential, such as carbamazepine, efavirenz, enzalutamide, phenobarbital, phenytoin, hypericum, mitotane, nevirapine, primidone, rifabutin and rifampicin inability of the icu staff to initiate administration of study treatment within 48 hours of intubation enrolled in a concomitant clinical trial of an investigational medicinal product in the opinion of the investigator, progression to death is highly probable, irrespective of the provision of treatments

persistent septic shock (>24 hours) with a mean arterial pressure (map) ≤65 mm hg and serum lactate level >4 mmol/l (36 mg/dl) despite adequate volume resuscitation and vasopressor use (norepinephrine >0.2 μg/kg/min) for >6 hours major trauma in the past 5 days presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last year pre-existing severe cardiopulmonary disease including, but not limited to, interstitial lung disease; severe copd (gold stage iv or fev1<30% predicted); heart failure (estimated left ventricular ejection fraction < 40%); or a chronic lung condition requiring home oxygen treatment an underlying clinical condition that, in the opinion of the investigator, would make it very unlikely for the patient to be successfully weaned from ventilation due to severe underlying diseases (e.g., severe malnutrition, severe neurological disease) patients considered inappropriate for critical care (e.g., being considered for palliative care) currently receiving extracorporeal membrane oxygenation (ecmo) severe chronic liver disease with child-pugh score >12 (appendix 1) white blood count <2.5 x 109/l; hemoglobin <4.0 mmol/l (6.5g/dl); platelets <50 x 109/l alt or ast >10x upper limit of normal (uln) or bilirubin >3x uln women who are pregnant or breast-feeding use of drugs with strong cyp3a4 induction potential, such as carbamazepine, efavirenz, enzalutamide, phenobarbital, phenytoin, hypericum, mitotane, nevirapine, primidone, rifabutin and rifampicin inability of the icu staff to initiate administration of study treatment within 48 hours of intubation enrolled in a concomitant clinical trial of an investigational medicinal product in the opinion of the investigator, progression to death is highly probable, irrespective of the provision of treatments

1. persistent septic shock (>24 hours) with a mean arterial pressure (map) ≤65 mm hg and serum lactate level >4 mmol/l (36 mg/dl) despite adequate volume resuscitation and vasopressor use (norepinephrine >0.2 μg/kg/min) for >6 hours 2. major trauma in the past 5 days 3. presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last year 4. pre-existing severe cardiopulmonary disease including, but not limited to, interstitial lung disease; severe copd (gold stage iv or fev1<30% predicted); heart failure (estimated left ventricular ejection fraction < 40%); or a chronic lung condition requiring home oxygen treatment 5. an underlying clinical condition that, in the opinion of the investigator, would make it very unlikely for the patient to be successfully weaned from ventilation due to severe underlying diseases (e.g., severe malnutrition, severe neurological disease) 6. patients considered inappropriate for critical care (e.g., being considered for palliative care) 7. currently receiving extracorporeal membrane oxygenation (ecmo) 8. severe chronic liver disease with child-pugh score >12 (appendix 1) 9. white blood count <2.5 x 109/l; hemoglobin <4.0 mmol/l (6.5g/dl); platelets <50 x 109/l 10. alt or ast >10x upper limit of normal (uln) or bilirubin >3x uln 11. women who are pregnant or breast-feeding 12. use of drugs with strong cyp3a4 induction potential, such as carbamazepine, efavirenz, enzalutamide, phenobarbital, phenytoin, hypericum, mitotane, nevirapine, primidone, rifabutin and rifampicin 13. inability of the icu staff to initiate administration of study treatment within 48 hours of intubation 14. enrolled in a concomitant clinical trial of an investigational medicinal product 15. in the opinion of the investigator, progression to death is highly probable, irrespective of the provision of treatments

1. persistent septic shock (>24 hours) with a mean arterial pressure (map) ≤65 mm hg and serum lactate level >4 mmol/l (36 mg/dl) despite adequate volume resuscitation and vasopressor use (norepinephrine >0.2 μg/kg/min) for >6 hours 2. major trauma in the past 5 days 3. presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last year 4. pre-existing severe cardiopulmonary disease including, but not limited to, interstitial lung disease; severe copd (gold stage iv or fev1<30% predicted); heart failure (estimated left ventricular ejection fraction < 40%); or a chronic lung condition requiring home oxygen treatment 5. an underlying clinical condition that, in the opinion of the investigator, would make it very unlikely for the patient to be successfully weaned from ventilation due to severe underlying diseases (e.g., severe malnutrition, severe neurological disease) 6. patients considered inappropriate for critical care (e.g., being considered for palliative care) 7. currently receiving extracorporeal membrane oxygenation (ecmo) 8. severe chronic liver disease with child-pugh score >12 (appendix 1) 9. white blood count <2.5 x 109/l; hemoglobin <4.0 mmol/l (6.5g/dl); platelets <50 x 109/l 10. alt or ast >10x upper limit of normal (uln) or bilirubin >3x uln 11. women who are pregnant or breast-feeding 12. use of drugs with strong cyp3a4 induction potential, such as carbamazepine, efavirenz, enzalutamide, phenobarbital, phenytoin, hypericum, mitotane, nevirapine, primidone, rifabutin and rifampicin 13. inability of the icu staff to initiate administration of study treatment within 48 hours of intubation 14. enrolled in a concomitant clinical trial of an investigational medicinal product 15. in the opinion of the investigator, progression to death is highly probable, irrespective of the provision of treatments