Study

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 admission

FLUDRO Domain Inclusion Criteria 1. Within 72 hours of admission to an ICU

FLUDRO Domain Exclusion Criteria

1. Known hypersensitivity to fludrocortisone

2. An inability to receive fludrocortisone due to lack of enteral access

3. An indication to prescribe fludrocortisone for a reason that is unrelated to a current episode of pneumonia or acute respiratory failure, such as Addison's disease

4. Belief of the treating clinical team that study participation would not be in the best interest of the patient

FAST-3 Domain Inclusion Criteria (must meet all 3 of the following)

1. Patient is in a PRACTICAL eligible platform state and requires advanced respiratory support (ARS) defined as one of the following:

a. Invasive mechanical ventilation with FiO2 \> 40% b. Non-Invasive Ventilation (\> 4 hours consecutively with FiO2 \> 40%) defined as: i. CPAP or BiPAP (any settings or interface) ii. HFNC (flow \> 40 liter per minute)

2. PaO2/FiO2 \< 300 mm Hg or SpO2/FiO2 \< 315 (if PaO2/FiO2 unavailable due to lack of arterial blood gas at the time of screening). For SpO2/FiO2, criteria are SpO2 ≤ 97% on FiO2 ≥ 40% on both of the 2 hours immediately preceding eligibility assessment. If an arterial blood gas can be obtained, then a PaO2/FiO2 ratio is preferable.

3. Patient commenced advanced respiratory support \< 48 hours prior to randomization.

FAST-3 Domain Exclusion Criteria

1. Patient commenced advanced respiratory support \> 48 hours to time of randomization.

2. Known history of severe chronic pulmonary disease e.g., pre-infection requirement for home oxygen therapy or presence of chronic hypercapnia (PaCO2 \> 60 mmHg); mild - moderate disease is still eligible in the absence of chronic hypercapnia or need for chronic oxygen therapy.

3. Currently enrolled in another trial studying investigational anti-inflammatory therapy, excluding established treatments used in clinical practice such as corticosteroids.

4. Known allergy to furosemide or sulfonamide drugs. If the patient is allergic to sulfonamide drugs but has received in the past or is currently receiving furosemide without incident, they can be enrolled since cross-reactivity between furosemide and sulfonamide agents is rare.

ESCAPE Domain Inclusion Criteria

1. Patients with severe AHRF who have an underlying immunocompromised condition

2. Within 48 hours of fulfilling the AHRF inclusion criteria as well as PaO2/FiO2 \<300 or a SaO2/FiO2 \< 315 on non-invasive respiratory support (venturi mask, non-invasive ventilation or high flow nasal oxygen as per the FiO2 requirements above) or invasive ventilation.

Patients may be enrolled from the wards or ICU.

Immunocompromised patients include:

1. Any patients requiring long term (\>30 days) corticosteroids (\>20 mg/day),

2. Any patients receiving non-corticosteroid immunosuppressive medications within the prior 3 months,

3. Acquired or inherited immunodeficiency syndrome,

4. Recipients of solid organ transplant,

5. Active hematologic malignancy (diagnosis or receiving treatment within prior 6 months),

6. Active solid tumor (diagnosis or receiving treatment within the prior 6 months) or

7. Any patients who have undergone allogeneic or autologous hematopoietic cell transplant in the prior 6 months (HCT).

ESCAPE Domain Exclusion Criteria

1. Patients whom are deemed palliative.

WAVEFORM Domain Inclusion Criteria

1\. Patient is intubated at the time of eligibility assessment.

WAVEFORM Domain Exclusion Criteria

1. PaO2/FiO2 \>300 mm Hg or (S/F \>250, if PaO2/FiO2 has not been measured) at the time of eligibility assessment.

2. Duration of mechanical ventilation during current ICU admission is ≥72 hours.

3. Receiving ECLS without continuous invasive mechanical ventilatory support.

IMV-ECLS Domain Inclusion Criteria

1\. Patients with AHRF (as defined in platform inclusion criteria #1 above) who have been consented for cannulation for VV-ECLS or who have been initiated on VV-ECLS within 6 hours at the time of randomization

IMV-ECLS Domain Exclusion Criteria 1. Patients receiving ECLS for the primary intention of extracorporeal CO2 removal 2. Patients expected to be liberated from ECLS within \<24 hours 3. History of recent pneumothorax or pneumomediastinum (\<3 months at the time of eligibility assessment/randomization) 4. Patients receiving ECLS for the primary intention of bridge to lung transplantation (at the time of eligibility assessment/randomization)

IMPROV Domain Inclusion Criteria

1. Patients receiving invasive mechanical ventilation for AHRF as defined by the PRACTICAL platform trial criteria above.

2. Within 7 calendar days of intubation

IMPROV Domain Exclusion Criteria

1. Patient is expected to be liberated from mechanical ventilation within 24 hours

2. Known or suspected 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. Known pneumothorax or pneumomediastinum without chest tube placement sustained during current ICU admission\* (re-confirm immediately prior to randomization)

5. Patient is admitted primarily for acute brain injury (stroke, traumatic brain injury, etc.)

6. Previously diagnosed chronic neuromuscular disorder

7. Patient has an implantable cardiac defibrillator or pacemaker

8. Planned to be transferred to another hospital before ICU discharge

9. Already receiving a regimen of inspiratory muscle training using external resistive device or diaphragm neurostimulation