Trial of ECMO to De-Sedate, Extubate Early and Mobilise in Hypoxic Respiratory Failure (REDEEM)

A Randomised Controlled Trial of ECMO to De-Sedate, Extubate Early and Mobilise in Hypoxic Respiratory Failure

To determine whether a strategy of adding venovenous ECMO to mechanical ventilation, as compared to mechanical ventilation alone, increases the number of intensive care free days at day 60, in patients with moderate to severe acute hypoxic respiratory failure.

Mechanically ventilated patients with moderate to severe acute hypoxic respiratory failure are at increased risk of dying, short and long-term health problems and are often very costly to treat. The mechanical ventilator, whilst often lifesaving, may harm patients in two ways i) directly via damage to the lungs (termed ventilator induced lung injury), and ii) indirectly via paralysis and sedation that patients require to tolerate mechanical ventilation. Paralysis and sedation can increase the risk of secondary infections, weakness, prolonged duration of intensive care, as well as long-term physical disability. There is a need to develop new treatments that support patients and at the same time reduce these complications. Extracorporeal membrane oxygenation (ECMO) is a device that supports the lungs by adding oxygen and removing carbon dioxide from the blood. By providing non pulmonary gas exchange, veno-venous (VV) ECMO can reduce the need for the mechanical ventilator. This in turn can reduce the risk of lung damage, and also removes the need for sedating medications so that activities like physiotherapy can begin earlier. The REDEEM trial is a phase 2, investigator initiated, multicentre randomised controlled trial that will recruit 140 patients with moderate to severe acute hypoxic respiratory failure. It is designed to test whether adding ECMO to the mechanical ventilator, as compared to using the mechanical ventilator on its own, leads to an increase in the number of patients who survive and are discharged earlier from the intensive care unit. If the REDEEM trial confirms adding ECMO is more effective than mechanical ventilation alone, it has the potential to change the current paradigm of intensive care treatment of hypoxic respiratory failure, and could lead to changes in practice globally.

Mechanical Ventilation Complication, Hypoxemia, Acute Respiratory Distress Syndrome Due to COVID-19, COVID-19 Respiratory Infection, Pneumonia, Extracorporeal Membrane Oxygenation

Patients allocated to the ECMO strategy be initiated on VV ECMO and commenced on anticoagulation within <24 hours after being enrolled. Following VV ECMO initiation, the sweep gas will be gradually turned up to target a respiratory alkalosis (pH > 7.45; maximum 20% increase every 6 hours; PaCo2 < 35 mmHg), to reduce the patient's intrinsic respiratory drive. Following this, the patient will be de-sedated, and when clinically appropriate, extubated. The awake patient will be assessed daily to participate in physiotherapy: which includes sitting up, sitting out of bed, speech assessment and, where appropriate, mobilisation.

Patients allocated to the standard care arm will receive routine intensive care for hypoxic respiratory failure, including mechanical ventilation with a lung protective strategy (low tidal volumes, pressures and positive end expiratory pressure titration), weaning of sedation and assessment for extubation. Patients who continue to deteriorate will be eligible for initiation of VV ECMO if they meet the ECMO to rescue lung injury in severe ARDS (EOLIA) criteria: Partial pressures of arterial oxygen (PaO2):Fraction of inspired oxygen (FiO2)<50 for 3 hours, PaO2:FiO2<80 for 6 hours, pH<7.25 with PaCO2 >60 for >6 hours.

Days alive and free from ICU to Day 60. Day Day 0 is randomisation day, with any portion of a day is spent in an ICU counted as a day.

Highest (+4 Combative) and lowest (-5 Unarousable) daily Richmond Agitation and Sedation Scores (RASS). The optimal score for early mobilisation of participants on ECMO is 0 Alert and Calm.

Daily assessment for mobilisation by allied health clinicians using the ICU Mobility Scale. The ICU Mobility Scale ranges from 0-Lying in Bed, to 10-Walking Independently without a Gait Aid. Score 7-Walking With the Assistance of 2 or More People is the best outcome achievable for participants on ECMO.

Number of Participants who were randomised to standard care initially and subsequently needed VV-ECMO.

Number of Participants who were randomised to standard care initially and subsequently needed VV-ECMO.

Assessment of 6 domains of functioning for participants at Day 180 follow up via telephone interview. Total possible scores are 48. A lower score indicates a better outcome.

Health-related quality of life reported via telephone interview at Day 180 using the EuroQol EQ5D. Total possible scores are 25. A lower score indicates a better outcome.

Inclusion Criteria: Mechanically ventilated for hypoxic respiratory failure Mechanical ventilation for ≥3days Moderate to severe respiratory failure on the day of inclusion, as demonstrated by: PaO2:FiO2 Ratio <150 for >6 hours despite protective lung ventilation (including tidal volume <6mls/kg predicted body weight), Trial of proning according to local protocol. Exclusion Criteria: Mechanical ventilation duration >7days Need for immediate VV ECMO Clinical Frailty Score of >4 Patient being actively weaned from mechanical ventilation Requirement for veno-arterial (VA) ECMO Severe coagulopathy (INR≥2.0, platelets < 100 or activated partial thromboplastin time (APTT) >50 seconds) Vascular access not suitable for ECMO (includes inferior vena cava filter, deep vein thrombosis, abnormal anatomy, existing femoral access) Insufficient equipment or personnel to commence ECMO Death is deemed imminent by the treating clinician The physician deems the study is not in the patient's interest Participation or Consent is declined OR Unable to identify medical treatment decision maker.

The Management Committee support the view of the International Committee of Medical Journal Editors and the World Health Organisation (WHO) with reference to the ethical obligation to responsibly share data acquired by interventional clinical trials. At the conclusion of the study, the management committee will consider requests from researchers who provide a methodically sound scientific proposal as per the Data Sharing Policy set out in the Australian and New Zealand Intensive Care Research Centre (ANZIC-RC) Terms of Reference. Only de-identified data will be shared and all requests for data must comply with the ethical, regulatory, and legislative requirements governing their jurisdiction.