Background
Acute respiratory distress syndrome (ARDS) is a common clinical syndrome characterised by
life threatening respiratory failure requiring mechanical ventilation. Although lifesaving,
mechanical ventilation can cause further injury to the lungs, known as ventilator-induced
lung injury (VILI). Strategies to mitigate VILI in ARDS have proven to improve patient
outcomes. ARDS patients that have severe lung failure, despite mechanical ventilation, often
require veno-venous extracorporeal membrane oxygenation (ECMO). ECMO uses an artificial
membrane lung to take over gas exchange. This allows reduction in injurious ventilator
settings thereby also reducing VILI.
While the indications for ECMO initiation are standardised in the UK and ECMO utilisation is
increasing,there remains uncertainty as to the best approach to mechanical ventilation whilst
patients are receiving ECMO and what strategies are maximally attenuating VILI during its
use. Importantly it is known that despite the reduction in ventilatory pressures and volumes
facilitated by ECMO, these sickest and most fragile lungs continue to be susceptible to VILI.
A reduction in respiratory rate (RR) to near apnoeic ventilation (2 breaths per minute) seems
to be associated with the greatest physiological reduction in VILI components, whilst
maintaining important physiological mechanisms such as surfactant production which rely on
some lung inflation. Employing a near apnoeic ventilation strategy may be associated with
faster resolution of ARDS resulting in reduced duration of ECMO, ventilation and ICU stay,
and healthcare costs.
Rationale
Interventions which mitigate VILI lead to less lung inflammation/oedema and better outcomes
in ARDS patients. However, the recent REST trial of extracorporeal carbon dioxide removal
showed that the resultant modest reduction in volume and pressure had no clinical effect.
Hence, a modest reduction in ventilation may not be as effective as an almost complete
absence (near apnoeic) of ventilation. The latter can only be achieved alongside ECMO
support. Reductions in respiratory rate to near apnoeic ventilation have multiple effects on
VILI, including:
Modulation of disease activity through reduced opening and closing of lung units
(atelectrauma);
Reductions in frequency of applied driving pressure and overall intensity of minute
ventilation (barotrauma)
Prevention of overdistension of the aerated lung (volutrauma)
Attenuation of circulating markers of lung injury and inflammation ('biotrauma')
Reduced development of aberrant fibrosis within the lung [9]. Patients on ECMO are prone
to pulmonary fibrosis, for which VILI is known to be major contributor
Multinational surveys of mechanical ventilation during ECMO support show that 45.7% of
centres used a moderate respiratory rate (10-20 breaths per minute) delivered with ~10-15
cmH2O PEEP and 10-15 cmH2O driving pressure. Evidence shows a 3% increase in the hazard of
death for every 1 cmH2O increase in ventilator driving pressure during ECMO support. Taken
together, international experience and trend show that ventilator mechanical power (a measure
of the energy transmitted to the lung) is a major determinant of VILI and is only modestly
decreased by the currently employed moderate ventilation strategies which mainly reduce the
driving pressure applied per breath. Mechanical power is, however, significantly reduced by
lower respiratory rates. Near apnoeic ventilation during ECMO is clinically feasible with gas
exchange and oxygen delivery being maintained by ECMO.
The ROMEO trial
The investigators have conducted a detailed search of PubMed, Ovid, Cochrane databases,
Google Scholar and the WHO International Clinical Trials Registry Platform. To-date, no large
prospective studies have or are addressing the use of near apnoeic ventilation during ECMO.
Consequently, a multicentre randomised open label study of near apnoea ventilation versus
standard of care is planned. This future multicentre trial will be powered for patient
centred outcomes (e.g., time to ECMO decannulation and mortality) together with a trial cost
utility analysis at 12 months.
To demonstrate the feasibility of our trial design, we will conduct a 50 patient feasibility
study at Guy's and St Thomas' NHS Foundation Trust. This will evaluate the feasibility of the
intervention (ability to recruit; ability to deliver the ventilator strategy; ability to
deliver the ECMO weaning strategies), the physiological changes induced by near apnoea
ventilation together with the impact on plasma and broncho-alveolar lavage biomarkers and
collect exploratory data on clinical outcomes.
As there is a paucity of evidence regarding predictors of ECMO weaning success, we will
evaluate comprehensive physiological data obtained during each weaning trial attempt to
evaluate the patient-ventilator-membrane lung interactions.