Platform of Randomized Adaptive Clinical Trials in Critical Illness

PRACTICAL Platform Inclusion Criteria: 1. Acute hypoxemic respiratory failure meeting all of the following criteria; 1. New or worsening respiratory symptoms developing within 2 weeks prior to the onset of need for oxygen or respiratory support 2. Receiving any of the following types of oxygen or respiratory support for at least 4 hours prior to the time of randomization; supplemental oxygen at 10 L/min or higher, high flow nasal oxygen (at any flow rate), invasive ventilator support, extra-corporeal life support (ECLS), or non-invasive ventilator support 3. Minimum FiO2 ≥ 0.40 (for venturi mask, high flow nasal cannula, or invasive or non-invasive ventilation) or oxygen flow rate ≥10 L/min on face mask for at least 4 hours at the time of evaluation for eligibility unless already on extra-corporeal life support 2. Age ≥ 18 years 3. Hypoxemia not primarily attributable to acute heart failure, fluid overload, or pulmonary embolism (PE) PRACTICAL Platform Exclusion Criteria: 1. Extubation is planned or anticipated on the day of screening 2. ICU discharged is planned or anticipated on the day of screening 3. If the patient is moribund and deemed unlikely to survive 24 hours (as determined by the clinical team) 4. If the patient is being transitioned to a fully palliative philosophy of care EXPAND-ECLS Domain Inclusion Criteria: 1. Receiving invasive Endotracheal mechanical ventilation for ≤ 72 hours.5 days 2. Early Moderate-severe hypoxemic respiratory failure with a PaO2/FiO2≤150200 mmHg for at least 6 hours EXPAND-ECLS Domain Exclusion Criteria: 1. Patients over 70 years of age. 2. Currently receiving any form of ECLS (e.g., Venovenous, venoarterial, or hybrid configuration). 3. Chronic hypercapnic respiratory failure defined as PaCO2 \> 60 mmHg in the outpatient setting. 4. Home mechanical ventilation (non-invasive ventilation or via tracheotomy) except for CPAP/BiPAP used solely for sleep-disordered breathing. 5. Actual body weight exceeding 1 kg per centimeter of height. 6. More than 48 hours have passed since meeting inclusion criteria. 7. Severe hypoxemia with PaO2/FiO2 \< 80mmHg for \> 6 hours at time of screening. 8. Severe hypercapnic respiratory failure with pH \< 7.25 and PaCO2 \> 60 mmHg for \> 6 hours at time of screening. 9. Expected mechanical ventilation duration \< 48 hours at time of screening. 10. Confirmed diffuse alveolar hemorrhage from vasculitis. 11. Contraindications to limited anticoagulation (e.g., active GI bleeding, bleeding diathesis). 12. Previous hypersensitivity/anaphylactic reaction to heparin or heparin-induced thrombocytopenia 13. Neurologic conditions at risk for or undergoing treatment for intracranial hypertension 14. Underlying illness with life expectancy \< 1 year 15. Pregnancy (due to unknown effects of PaCO2 changes on placental blood flow) 16. Respiratory failure known or suspected to be caused by COVID-19. IMV Domain Inclusion Criteria: 1. Intubated patients, not on ECLS, with low normalized respiratory elastance (\<2.5 cm H2O/(ml/kg predicted body weight)) at the time of eligibility assessment OR 2. Intubated patients, not on ECLS, with high normalized respiratory system elastance (≥2.5 cm H2O/(ml/kg predicted body weight)) at the time of eligibility assessment OR 3. FOR STUDY SITES PARTICIPATING IN THE LDPVS INTERVENTION: Patient is on ECLS at the time of eligibility assessment. Note: Patients in this state are only eligible for the LPV or LDPVS intervention 4. FOR STUDY SITES PARTICPATING IN THE EIT INTERVENTION: PaO2/FiO2 (if available) \< 200 mm Hg at randomization. If PaO2/FiO2 has not been measured, SpO2 = 97% on FiO2 =60%. IMV Domain Exclusion Criteria: 1. PaO2/FiO2 \>300 mm Hg or (S/F \>250, if PaO2/FiO2 has not been measured) at the time of randomization 2. Chronic hypercapnic respiratory failure defined as PaCO2\>60mmHg in the outpatient setting 3. Home mechanical ventilation (non-invasive ventilation or via tracheotomy), not including nocturnal CPAP applied by nasal or face mask or home tracheotomy if not ventilated 4. Severe hypoxemia with PaO2/FiO2\<80mmHg for \>6 consecutive hours at the time of randomization 5. Severe hypercapnic respiratory failure with pH\<7.25 and PaCO2\>60mmHg for \>6 consecutive hours at the time of randomization 6. Anticipated duration of mechanical ventilation is \<48 hours from the time of screening 7. Duration of mechanical ventilation during current ICU admission is \>72 hours 8. Previously diagnosed neuromuscular disorder 9. Current diagnosis of severe acute brain injury (e.g. ischemic or hemorrhagic stroke, traumatic brain injury) with Glasgow Coma Scale ≤ 8 10. Baseline weight prior to or at hospital admission less than 35 kilograms 11. Receiving extracorporeal life support without continuous invasive mechanical ventilatory support CORT-E2 Domain Early Cohort Inclusion Criteria 1. Within 72 hours of admission to an ICU 2. New unilateral or bilateral airspace disease CORT-E2 Domain Early Domain Exclusion Criteria 1. Receiving only low flow oxygen therapy less than or equal to 15L/min 2. Corticosteroid use during the 14 days prior to screening 3. Existing indication for corticosteroids 4. High suspicion for/or confirmed COVID infection 5. Acute traumatic brain injury during the index hospital admission 6. Allergy to dexamethasone CORT-E2 Domain Extended Cohort Inclusion Criteria 1. Are admitted to an ICU 2. Have already received 10 days of corticosteroid specifically for acute respiratory failure, this will include patients: (a) randomized to corticosteroid arm in Early Cohort, (b) patients with COVID receiving corticosteroids as standard of care , (c) and others who have received corticosteroids for AHRF 3. Ongoing AHRF requiring HFNC, NIV (continuous positive airway pressure \[CPAP\] or bilevel) or invasive ventilation CORT-E2 Domain Extended Cohort Exclusion Criteria 1. An alternate indication for ongoing corticosteroids 2. Acute traumatic brain injury this hospital admi