REST Trial

The REST trial is pragmatic randomised controlled trial to determine whether Veno-Venous Extracorporeal Carbon Dioxide Removal (VV-ECCO2R) in mechanically ventilated patients with hypoxaemic respiratory failure improves 90 day mortality.

Background Information

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). ARDS is characterised by non-cardiogenic pulmonary oedema (identified by bilateral infiltrates on chest X-ray) alongside a requirement for supplementary oxygen to maintain normal arterial oxygen tension. Acute hypoxaemic respiratory failure and ARDS occur in response to a variety of insults, such as trauma, pneumonia and severe sepsis; affect all age groups; have a high mortality of up to 30-50% and cause a long-term reduction in quality of life for survivors. Acute hypoxaemic respiratory failure has significant resource implications in terms of ICU and hospital stay. The cost per ICU bed-day exceeds £1800 and delivery of critical care to patients with acute hypoxaemic respiratory failure accounts for a significant proportion of ICU capacity. In addition, survivors often have long-term physical and cognitive impairment requiring support in the community and many survivors are unable to return to work 12 months after hospital discharge. The high incidence, mortality, long-term consequences and high economic costs mean that acute hypoxaemic respiratory failure is an extremely important problem.

Over the past few decades significant progress has been made in understanding the pathophysiology of acute hypoxaemic respiratory failure and 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.

Rationale for the Study

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 6 ml/kg PBW and a maximum end-inspiratory Pplat ≤ 30 cmH2O decreased mortality from 40% (in the conventional arm treated with tidal volume less than 12 ml/kg PBW) to 31%. Furthermore in a cohort of 485 patients with hypoxaemic respiratory failure secondary to ARDS, long-term mortality at 2-years was improved in patients compliant with lung protective ventilation during their ICU stay. It is accepted that implementing protective lung ventilation saves lives (estimated 2 patients’ lives/day in the UK extrapolating ARDSNet data to the UK) and is cost effective. Extrapolating US data to the UK, in terms of Quality Adjusted Life Years (QALYs) gained, if an average ICU spent £6000 per patient with ARDS on an intervention in order to achieve more than 90% adherence to low tidal volume ventilation the intervention would still be cost effective.

Recent studies have shown that lung hyperinflation and injury still occur in approximately 30% of ARDS patients even though they are being ventilated using the ARDSNet strategy (13). Additionally, using more protective ventilation compared to conventional protective ventilation was associated with further reduction in mortality as the Pplat decreases below 28 cmH2O (14). This analysis also suggested a beneficial effect of further tidal volume reduction even for patients who already had a Pplat ≤ 30cmH2O. However tidal volume reduction to < 6 ml/kg PBW can be associated with secondary systemic effects associated with raised blood carbon dioxide levels, such as elevated intracranial pressure, pulmonary hypertension, altered myocardial contractility and decreased renal blood flow. Therefore more protective mechanical ventilation strategies are difficult to achieve for most patients on conventional mechanical ventilation for moderate to severe respiratory failure.

Study Design

This is a randomised, allocation concealed, controlled, open, pragmatic clinical and cost effectiveness trial.

In PICO terms:

  • Population Adult patients with acute hypoxaemic respiratory failure
  • Intervention VV-ECCO2R and lower tidal volume mechanical ventilation
  • Comparator Standard care with conventional lung protective mechanical ventilation
  • Outcome Mortality 90 days after randomisation

Inclusion criteria

  • Invasive mechanical ventilation using PEEP ≥ 5cmH2O*
  • Acute and potentially reversible cause of acute respiratory failure as determined by the treating physician
  • Within 48 hours of the onset of hypoxaemia as defined by PaO2/FiO2 ≤ 20 kPa**
    • *Recommended on low tidal volume ventilation ≤ 6 ml/kg PBW
    • **Requires two ABG with a PaO2/FiO2 ≤ 20 kPa separated by at least 6 hours. 48 hour duration begins at the time of 2nd ABG demonstrating PaO2/FiO2 ≤ 20 kPa
    • (ABGs with PaO2/FiO2 ≥ 20 kPa are permitted between the two trial inclusion ABGs).

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 ≤ 3 ml/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 HFOV or APRV
  • 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)
  • Inferior vena cava filter (if using femoral vein catheter)
  • Consent declined
  • Treatment withdrawal imminent within 24 hours
  • Patients not expected to survive 6 months on basis of premorbid health status
  • DNAR (Do Not Attempt Resuscitation) order 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
  • Previously enrolled in the REST trial


The inclusion and exclusion criteria are designed to include those who reflect the general population of critically ill patients with acute hypoxaemic respiratory failure who may benefit from the therapeutic intervention and exclude patients who are unlikely to benefit due to their underlying condition or at increased risk of a complication from ECCO2R.

Objectives

The primary objective is to determine whether VV-ECCO2R and lower tidal volume mechanical ventilation in patients with acute hypoxaemic respiratory failure decreases mortality 90 days after randomisation.

Secondary objectives are to determine the effects of VV-ECCO2R on:

1) Tidal volumes
2) Duration of mechanical ventilation
3) Requirement for ECMO
4) Long-term mortality
5) Health Related Quality of Life
6) Safety
7) Cost-effectiveness in the NHS setting
8) Long term respiratory morbidity

Study Standard

VV-ECCO2R and lower tidal volume mechanical ventilation (target tidal volume of ≤ 3 ml/kg predicted body weight and a Pplat ≤ 25 cmH20)

Study Setting & Sample Size

At least 40 adult intensive care units will be required to recruit 1120 participants (560 in each arm) over 65 months