Platform of Randomized Adaptive Clinical Trials in Critical Illness

PRACTICAL Platform Inclusion Criteria:

1. Acute hypoxemic respiratory failure meeting all of the following criteria;

2. New or worsening respiratory symptoms developing within 2 weeks prior to theonset of need for oxygen or respiratory support

3. Receiving any of the following types of oxygen or respiratory support for atleast 4 hours prior to the time of randomization; supplemental oxygen at 10L/min or higher, high flow nasal oxygen (at any flow rate), invasive ventilatorsupport, extra-corporeal life support (ECLS), or non-invasive ventilatorsupport

4. Minimum FiO2 ≥ 0.40 (for venturi mask, high flow nasal cannula, or invasive ornon-invasive ventilation) or oxygen flow rate ≥10 L/min on face mask for atleast 4 hours at the time of evaluation for eligibility unless already onextra- corporeal life support

5. Age ≥ 18 years

6. Hypoxemia not primarily attributable to acute heart failure, fluid overload, orpulmonary 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 bythe clinical team)

4. If the patient is being transitioned to a fully palliative philosophy of care

ULTIMATE Domain Inclusion Criteria:

1. Endotracheal mechanical ventilation for ≤5 days

2. Early moderate-severe hypoxemic respiratory failure with a PaO2/FiO2≤200 mmHg for atleast 6 hours

ULTIMATE Domain Exclusion Criteria:

1. Patients over 65 years of age

2. Currently receiving any form of ECMO (ex. venovenous, venoarterial, or hybridconfiguration)

3. Δ PL-dyn ≤20 or Static Δ P≤15 cm H2O while receiving VT 6mL/kg (i.e. normalizedelastance ≤ 2.5 cmH2O/mL/kg)

4. Chronic hypercapnic respiratory failure defined as PaCO2>60mmHg in the outpatientsetting

5. Home mechanical ventilation (non-invasive ventilation or via tracheotomy), not CPAP

6. Actual body weight exceeding 1kg per centimeter of height

7. More than 48 hours have passed since meeting inclusion criteria

8. Severe hypoxemia with PaO2/FiO2<80mmHg for >6 hours at time of screening

9. Severe hypercapnic respiratory failure with pH<7.25 and PaCO2>60mmHg for >6 hours attime of screening

10. Expected mechanical ventilation duration <48 hours at time of screening

11. Confirmed diffuse alveolar hemorrhage from vasculitis

12. Contraindications to limited anticoagulation (ex. active GI bleeding, bleedingdiathesis)

13. Pregnancy-due to unknown effects of PaCO2 changes on placental blood flow

14. 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 cmH2O/(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 thetime of eligibility assessment. Note: Patients in this state are only eligible forthe LPV or LDPVS intervention

IMV Domain Exclusion Criteria:

1. PaO2/FiO2 >300 mm Hg or (S/F >250, if PaO2/FiO2 has not been measured) at the timeof randomization

2. Chronic hypercapnic respiratory failure defined as PaCO2>60mmHg in the outpatientsetting

3. Home mechanical ventilation (non-invasive ventilation or via tracheotomy), notincluding nocturnal CPAP applied by nasal or face mask or home tracheotomy if notventilated

4. Severe hypoxemia with PaO2/FiO2<80mmHg for >6 consecutive hours at the time ofrandomization

5. Severe hypercapnic respiratory failure with pH<7.25 and PaCO2>60mmHg for >6consecutive hours at the time of randomization

6. Anticipated duration of mechanical ventilation is <48 hours from the time ofscreening

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 mechanicalventilatory 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 respiratoryfailure, this will include patients: (a) randomized to corticosteroid arm in EarlyCohort, (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] orbilevel) or invasive ventilation

CORT-E2 Domain Extended Cohort Exclusion Criteria

1. An alternate indication for ongoing corticosteroids

2. Acute traumatic brain injury this hospital admission