Title: pRotective vEntilation with veno-venouS lung assisT in respiratory failure. The REST Trial
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: 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.

Lay abstract: When people are very ill their lungs often stop working. This is called respiratory failure. As a result, breathing becomes difficult and they need to be treated in an intensive care unit (ICU) where they will be connected to a machine to help their breathing. This is called mechanical ventilation. Respiratory failure is common in the UK; about 100,000 people each year need treatment with mechanical ventilation. Almost half of these patients die. Although there is evidence that mechanical ventilation does save lives, it can be linked with damage to the lungs. A mechanical ventilator acts like bellows as air is forced into the lungs under pressure. If the pressure needed to help the patient breathe is too high this can cause lung damage. New devices are now available to help patients breathe. These devices help remove carbon dioxide from the patient’s blood, which is one of the main functions of the lungs. This may allow more gentle mechanical ventilation. This more gentle ventilation may cause less harm to the lungs and improve the outcome of patients with respiratory failure. These new devices involve a tube called a catheter being placed in a large blood vessel called a vein. Blood passes from the patient through the device where it is “washed” to remove carbon dioxide before it is returned to the patient. Kidney dialysis uses very similar equipment. Kidney dialysis is common for patients admitted to intensive care units and doctors are used to putting this type of catheter into patients on the ICU. These new devices may help doctors and nurses care for patients with respiratory failure, but there is not enough information about the devices to help them decide whether they are helpful or not. We will run a research study of 1120 patients with respiratory failure who have been admitted to about 40 ICUs in the UK. Our study is called a 'randomised controlled trial'. This kind of trial is the best way to find out if a treatment really works or not. In this study there will be two groups of people. One group will receive the best level of care that is advised by current NHS guidelines and the other group will best care but in addition be treated with the device to remove carbon dioxide from their blood. The treatment a patient will receive is decided at random by a computer programme. At the end of the study we will know whether this new device reduces death from respiratory failure and look at the long-term survival and quality of life of the patients in the study. We will also look at the cost of using the new device compared to usual care. Patients treated on the intensive care unit are often unconscious or sedated and cannot be asked if they agree to take part in medical research. However, in order to develop new treatments to improve the long term health of these patients we need to be able to include them in studies. In these cases a relative or other person who is close to the patient can decide whether the patient would have been likely to be interested in the study. These arrangements are considered to be ‘best practice’ and are governed by law. Studies in the intensive care unit can be difficult for a number of reasons. At the start of this study we will see how many patients per month are included in the study, and if this is below the number we would like we will think about ways to increase the number of patients who can be included.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: RESPIRATORY