Platform of Randomized Adaptive Clinical Trials in Critical Illness

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)
• •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
• •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.
• •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%.
• •1. Within 72 hours of admission to an ICU
• •2. New unilateral or bilateral airspace disease
• •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
• •1\. Within 72 hours of admission to an ICU
• •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.
• •1. Patients with severe AHRF who have an underlying immunocompromised condition
• •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).
• •1\. Patients receiving invasive mechanical ventilation for AHRF as defined by the PRACTICAL platform trial criteria above.
• •2\. Within 7 calendar days of intubation