Clinical trial NCT02654327: pRotective vEntilation With Veno-venouS Lung assisT in Respiratory Failure
Official title: pRotective vEntilation With Veno-venouS Lung assisT in Respiratory Failure
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Acute Respiratory Failure With Hypoxia
Keywords: Extracorporeal
Acute Respiratory Distress Syndrome
Protective Lung Ventilation
Ventilator Induced Lung Injury
Carbon Dioxide Removal
Lung
Lung Injury
Lead sponsor: Belfast Health and Social Care Trust
Sponsor class: OTHER
Collaborators: name: Queen's University, Belfast
name: Northern Ireland Clinical Trials Unit
First posted: 2016-01-13
Enrollment: 1120
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a trial of a new way of treating patients with respiratory failure. The investigators propose to deliver a multi-centre clinical trial to determine whether veno-venous extracorporeal carbon dioxide removal (VV-ECCO2R) and lower tidal volume mechanical ventilation improves outcomes and is cost-effective, in comparison with standard care in patients who are mechanically ventilated for acute hypoxaemic respiratory failure

Detailed description: Acute hypoxaemic respiratory failure requiring mechanical ventilation is a major cause of morbidity and mortality. A significant proportion of affected patients will have the Acute Respiratory Distress Syndrome (ARDS). Mechanical ventilation is often required to provide adequate gas exchange and although it is life-saving in this setting, it is also now known to contribute to the morbidity and mortality in the condition. Ventilators delivering high pressures and volumes cause regional over distension in the injured lung resulting in further inflammation and non-cardiogenic pulmonary oedema. The release of inflammatory mediators from the damaged lung causes systemic inflammation leading to multi-organ failure and death.

The few interventions that have been shown to reduce the high mortality in these patients have targeted ventilator-induced lung injury (VILI). A landmark trial by the ARDSNet trials group found that ventilating patients with acute hypoxaemic respiratory failure secondary to ARDS with a lung protective strategy aiming for a reduced tidal volume of 6ml/kg predicted body weight (PBW) and a maximum end-inspiratory plateau pressure (Pplat) ≤ 30cmH2O decreased mortality from 40% (in the conventional arm treated with tidal volume less than 12ml/kg PBW) to 31%.

Extracorporeal carbon dioxide removal (ECCO2R) in association with mechanical ventilation offers a potentially attractive solution to permit tidal volume reduction to less than 6ml/kg PBW and to achieve low plateau pressures (\< 25cmH2O). Using these extracorporeal circuits, carbon dioxide can be 'dialysed' out of the blood while the lungs are ventilated in a more protective manner. In recent years, more efficient veno-venous devices have become available. These have replaced arterio-venous devices and have the advantage of not requiring arterial puncture. These can achieve carbon dioxide removal with relatively low extracorporeal blood flows (0.4-1 l/min) requiring only a smaller dual lumen venous catheter. In addition these ECCO2R devices use more biocompatible materials making the device more resistant to clot formation and cause less platelet and clotting factor consumption. Therefore only minimal systemic anticoagulation is required which reduces the likelihood of bleeding complications. These devices are now comparable to renal dialysis equipment, which is routinely used safely as standard care in ICUs in the United Kingdom.

Together this highlights the need for a large randomised controlled trial to establish whether VV-ECCO2R in acute hypoxaemic respiratory failure can allow the use of a more protective ventilatory strategy and is associated with improved patient outcomes. Importantly, if there was no benefit, the trial would provide evidence to stop the widespread adoption of an expensive and ineffective or potentially harmful treatment in this setting.

Eligibility criteria: Inclusion Criteria:

* Invasive mechanical ventilation using positive end expiratory pressure (PEEP) ≥ 5cmH2O
* Acute and potentially reversible cause of acute respiratory failure as determined by the treating physician
* Within 48 hours of the onset of hypoxemia as defined by Pa02/Fi02 less than or equal to 20kPA

Exclusion Criteria:

* Age \< 16 years old
* Intubated and mechanically ventilated via an endotracheal or tracheostomy tube ≥ 7 days (168 hours) up to the time of randomisation
* Ability to maintain Vt to ≤ 3ml/kg PBW while maintaining pH ≥ 7.2 as determined by the treating physician
* Receiving, or decision to commence, ECMO in the next 24 hours
* Mechanical ventilation using high frequency oscillation ventilation or airway pressure release ventilation
* Untreated pulmonary embolism, pleural effusion or pneumothorax as the primary cause of acute respiratory failure
* Acute respiratory failure fully explained by left ventricular failure or fluid overload (May be determined by clinical assessment or echocardiography/cardiac output monitoring)
* Left ventricular failure requiring mechanical support
* Contra-indication to limited systemic anticoagulation with heparin
* Unable to obtain vascular access to a central vein (internal jugular or femoral vein)
* Consent declined
* Treatment withdrawal imminent within 24 hours
* Patients not expected to survive 90 days on basis of premorbid health status
* DNAR (Do Not Attempt Resuscitation) order (excluding advance directives) in place
* Severe chronic respiratory disease requiring domiciliary ventilation (except for sleep disordered breathing)
* Severe chronic liver disease (Child Pugh \>11)
* Platelet count \< 40,000 mm3 (Prior to catheter insertion)
* Previously enrolled in the REST trial
* Prisoners

Primary outcomes:
measure: All cause mortality
timeFrame: 90 days after randomisation
Secondary outcomes:
measure: Tidal volume (ml/kg Predicted Body Weight)
timeFrame: day 2 and day 3 after randomisation
measure: Ventilator free days
timeFrame: 28 days after randomisation
measure: Duration of ventilation in survivors
timeFrame: 28 days after randomisation
measure: Need for Extracorporeal Membrane Oxygenation (ECMO)
timeFrame: 7 days after randomisation
measure: Mortality rate
timeFrame: 28 days, 6 months and 1 year after randomisation
measure: Health Related Quality of Life
timeFrame: 6 months and 1 year after randomisation
measure: Adverse Event Rate
timeFrame: 28 days
measure: Health & Social Care Service costs
timeFrame: 6 months and 1 year after randomisation
measure: St George Respiratory Questionnaire
timeFrame: 1 year after randomisation
measure: Need for home oxygen
timeFrame: 6 months and 1 year after randomisation
measure: Post Traumatic Stress Syndrome Questionnaire (PTSS-14)
timeFrame: 1 year after randomisation
measure: Montreal Cognitive Assessment (MoCA-BLIND) or AD8 Dementia Screening Interview (AD8)
timeFrame: 1 year after randomisation
Other outcomes:
measure: Right Ventricular function
timeFrame: Baseline & Day 2/Day 3
Locations:
city: Belfast
country: United Kingdom
facility: Belfast Health and Social Care Trust
Study officials:
References:
citation: Acute Respiratory Distress Syndrome Network; Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1301-8. doi: 10.1056/NEJM200005043421801.
citation: Fitzgerald M, Millar J, Blackwood B, Davies A, Brett SJ, McAuley DF, McNamee JJ. Extracorporeal carbon dioxide removal for patients with acute respiratory failure secondary to the acute respiratory distress syndrome: a systematic review. Crit Care. 2014 May 15;18(3):222. doi: 10.1186/cc13875.
citation: Terragni PP, Del Sorbo L, Mascia L, Urbino R, Martin EL, Birocco A, Faggiano C, Quintel M, Gattinoni L, Ranieri VM. Tidal volume lower than 6 ml/kg enhances lung protection: role of extracorporeal carbon dioxide removal. Anesthesiology. 2009 Oct;111(4):826-35. doi: 10.1097/ALN.0b013e3181b764d2.
citation: Bein T, Weber-Carstens S, Goldmann A, Muller T, Staudinger T, Brederlau J, Muellenbach R, Dembinski R, Graf BM, Wewalka M, Philipp A, Wernecke KD, Lubnow M, Slutsky AS. Lower tidal volume strategy ( approximately 3 ml/kg) combined with extracorporeal CO2 removal versus 'conventional' protective ventilation (6 ml/kg) in severe ARDS: the prospective randomized Xtravent-study. Intensive Care Med. 2013 May;39(5):847-56. doi: 10.1007/s00134-012-2787-6. Epub 2013 Jan 10.
citation: Boyle AJ, McDowell C, Agus A, Logan D, Stewart JD, Jackson C, Mills J, McNamee JJ, McAuley DF. Acute hypoxaemic respiratory failure after treatment with lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal: long-term outcomes from the REST randomised trial. Thorax. 2023 Aug;78(8):767-774. doi: 10.1136/thorax-2022-218874. Epub 2022 Oct 5.
citation: McNamee JJ, Gillies MA, Barrett NA, Perkins GD, Tunnicliffe W, Young D, Bentley A, Harrison DA, Brodie D, Boyle AJ, Millar JE, Szakmany T, Bannard-Smith J, Tully RP, Agus A, McDowell C, Jackson C, McAuley DF; REST Investigators. Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure: The REST Randomized Clinical Trial. JAMA. 2021 Sep 21;326(11):1013-1023. doi: 10.1001/jama.2021.13374.
citation: Stokes JW, Gannon WD, Rice TW. Extracorporeal Carbon Dioxide Removal or Extracorporeal Membrane Oxygenation: Why Should We Care? Crit Care Med. 2021 May 1;49(5):e546-e547. doi: 10.1097/CCM.0000000000004844. No abstract available.