Ventilators are being set to deliver dangerously small breaths—just 3 millilitres per kilogram of body weight—to patients with failing lungs, while a machine outside the body removes carbon dioxide from their blood to prevent the ventilator itself from causing further injury. This matters because standard mechanical ventilation, while lifesaving, can damage already-inflamed lungs. Doctors face a trade-off: deliver enough oxygen but risk ventilator-induced lung injury, or use gentler settings that may not sustain the patient. The trial tests whether adding veno-venous extracorporeal carbon dioxide removal—a technology that scrubs CO₂ from the blood—allows clinicians to safely use ultra-protective ventilation without compromising gas exchange. If the approach works, it could change how intensive care units manage respiratory failure across the NHS. Instead of accepting lung damage as an unavoidable side effect of ventilation, clinicians could prevent it. The trial also tracks long-term outcomes—quality of life, respiratory symptoms, and need for home oxygen at one year—so the impact extends beyond hospital survival to how patients fare after discharge. The technology itself is already used in some centres, but this trial aims to generate the robust evidence needed to decide whether it should become standard practice.
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DESIGN: Randomised, allocation concealed, controlled, open, phase 3 pragmatic clinical and cost-effectiveness trial with an internal pilot. Patients will be randomised in 1:1 ratio and will be stratified by recruitment centre. SETTING: At least 40 Intensive Care Units (ICUs) within UK NHS hospitals with a patient case mix typical of UK critical care practice. These ICUs will be selected from an established network of ICUs with a proven track record of successful participation in clinical trials. POPULATION: Adult patients with moderately severe acute type 1 (hypoxaemic) respiratory failure. INCLUSION CRITERIA: The inclusion criteria are designed to identify patients prior to the induction of significant ventilator associated lung injury. Age greater than 16 years; invasively mechanically ventilated for 7 days or less; a reversible cause of respiratory failure; within 48 hours of the onset of hypoxaemia as defined by the partial pressure of oxygen (PaO2) divided by the inspired oxygen concentration (FiO2) (PF ratio) less than 20kPa (on a Positive End Expiratory Pressure (PEEP) of greater than 5cmH2O) for more than 6 hours. EXCLUSION CRITERIA: ECMO indicated; pulmonary embolism, pneumothorax or pleural effusion as primary cause of respiratory failure; anticoagulation contraindicated; unable to obtain vascular access; consent declined; treatment withdrawal imminent within 24 hours or treating clinician not committed to full therapeutic support; severe chronic respiratory disease (domiciliary mechanical ventilation); severe left ventricular failure. HEALTH TECHNOLOGY: The application of veno-venous extracorporeal carbon dioxide removal (VVECCO2R) to achieve more protective ventilation defined as a tidal volume (Vt) of 3ml/kg predicted body weight (PBW) and Pplat less than 25cmH2O. CONTROL TREATMENT: Standard care of hypoxaemic respiratory failure with conventional lung protective mechanical ventilation MEASUREMENT OF OUTCOMES AND COSTS: The primary outcome is survival at 90 days after randomisation. Secondary outcomes include tidal volume reduction, ventilator free days at 28 days, ECMO use, mortality (28 days, 6 mths and 1 year), adverse event rate, health related quality of life at 6 mths and 1 year(EQ-5D-5L). Long term respiratory morbidity will be assessed by the St George’s Respiratory Questionnaire at 1 year and the need for home oxygen at 6 mths and 1 year. There are no core outcome sets for this population. SAMPLE SIZE: 560 per group will be required to detect a 23% relative reduction (9% absolute reduction) in 90 day mortality, assuming a control group mortality of 41%, with 90% power at a p value of 0.05 with a 3% dropout (typical of ICU trials in the UK to date). The control group mortality has been estimated from 2 independent sources; 1) data from the Intensive Care National Audit & Research Centre (ICNARC) have shown that in patients ventilated in ICU within the first 24 hours of admission with a PF ratio less than 20kPa, ICU mortality was 41% and 2) the recent NIHR HTA funded OSCAR trial in patients with respiratory failure which recruited a similar population to the planned study population found 30-day mortality in the control group was 41%. We have assumed that 90-day control group mortality will be at least 41%. The estimated treatment effect size would be clinically significant and achievable from the extension of the risk reduction observed in a previous randomised controlled trial of lung protective ventilation.
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