Severe Acute Respiratory Distress Syndrome

The acute respiratory distress syndrome (ARDS) remains among the most common indications for ECMO for respiratory failure worldwide, although evidence supporting its use remains limited. Positive pressure ventilation, although often necessary for more severe forms of ARDS, is known to exacerbate lung injury, and a ventilation strategy that targets low tidal volumes and airway pressures has been established as one of the few interventions that improves outcomes in ARDS, along with prone ventilation. The potential role for ECMO in ARDS is two-fold. In patients with respiratory failure so severe that the ventilator is insufficient to support gas exchange (or can do so only at the expense of unacceptably high airway pressures), ECMO may serve as salvage therapy to manage refractory hypoxaemia or hypercapnia. Alternatively, in patients whose respiratory system compliance is so severely reduced that standard-of-care low tidal volume ventilation cannot be achieved due to unacceptable levels of respiratory acidosis, ECMO (or more specifically ECCO₂R) can facilitate reductions in tidal volumes by correcting the associated hypercapnia.

As previously stated, the evidence supporting ECMO for ARDS has significant limitations. Prospective randomised controlled trials in the era of early device technology failed to show a benefit to ECMO in severe ARDS, with high mortality rates in both arms. In the first randomised trial with relatively modern ECMO technology for ARDS, entitled Conventional Ventilation or ECMO for Severe Adult Respiratory Failure (CESAR), 180 subjects with severe, potentially reversible respiratory failure were randomised to conventional mechanical ventilation or referral to a specialised centre for consideration of ECMO. Subjects referred for consideration of ECMO, compared to those receiving conventional management, had a significantly lower rate of death or severe disability at 6 months (37% versus 53%, RR 0.69, p = 0.03). These findings must be interpreted with caution given limitations in study design. Because it was designed as a pragmatic study, lung-protective ventilation was recommended but not mandated for the conventional arm, and only 70% of those subjects received such a strategy at any point in the study. Among those referred for consideration of ECMO, only 76% ultimately received ECMO, making it difficult to quantify the effect of ECMO itself on outcomes. One reasonable conclusion to draw from this study is that referral to an ECMO-capable centre may improve outcomes when compared with usual care in that setting. Non-randomised observational studies have shown conflicting results of the impact of ECMO on survival in severe ARDS, with a large amount of data derived from the influenza A (H1N1) epidemic. Propensity analysis of patients in the UK matched on their likelihood of receiving ECMO for severe ARDS due to influenza suggested a mortality benefit from ECMO (24% versus 47%, relative risk 0.51; 95% CI 0.31–0.84, p = 0.008). These findings contrast with other matched propensity analyses from a separate but similar French cohort, highlighting the limitations of non-randomised retrospective studies. To help address the role and impact of ECMO on patients with severe ARDS, the ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial is being conducted; patients who remain in severe, refractory ARDS despite optimal standard of care ARDS management (including low tidal volume ventilation, with the option for prone positioning, neuromuscular blockade and other rescue therapies) are randomised to either ECMO or ongoing conventional support.

Several prognostic scores have been proposed in order to identify patients most likely to benefit from ECMO in ARDS. The Predicting Death for Severe ARDS on VV-ECMO (PRESERVE) score, which attempts to predict 6 month survival based on several pre-ECMO measurements (age, body mass index, immunocompromised status, prone position, days of mechanical ventilation, sepsis related organ failure assessment (SOFA), positive end-expiratory pressure (PEEP) and plateau pressure), was externally validated in a cohort of venovenous ECMO patients, with an AUCof 0.75 (95% CI 0.57 to 0.92; p = 0.01). A more recent prediction model that utilised a combination of pre-ECMO and ECMO day 1 data in a cohort of subjects receiving venovenous ECMO for severe ARDS demonstrated high discrimination with an area under curve of 0.79 (p = 0.03). With negative and positive predictive values of 81% and 82%, this model performed better than several other proposed scoring systems, including the PRESERVE score.

Beyond short-term mortality prediction modelling, little is known about the long-term functional, neurocognitive and psychiatric outcomes of ARDS survivors who received ECMO. Existing data suggest that such patients may have similar or potentially worse long-term neuropsychiatric sequelae compared with those who did not receive ECMO, though differences in severity of critical illness probably contribute to such findings.

Less Severe Forms of ARDS

Aside from its ability to support refractory hypoxaemic or hypercapnic respiratory failure in severe ARDS, ECMO may have the benefit of reducing lung injury even further than the current standard of care by facilitating the implementation of very low tidal volumes, airway pressures and respiratory rates through the use of ECCO₂R. This strategy, sometimes referred to as ‘lung rest’, or ‘ultra-protective’ ventilation, is already practised at many ECMO centres for patients with severe ARDS, and additional research is being conducted to systematically characterise current ventilation practices for these patients in order to help guide optimal management strategies. Data demonstrating the efficacy of such an approach, which may extend to less severe forms of ARDS, are limited but promising. Analysis of the ARDS Network’s ARMA trial of conventional (12 ml per kg and plateau airway pressure <50 cmH₂O) versus low tidal volume ventilation (6 ml per kg, plateau airway pressure <30 cmH₂O) that established the current standard of care for ventilation strategies in ARDS suggests that subjects in the conventional group would have benefited from tidal volume reduction regardless of plateau pressure quartile. A prospective cohort study has demonstrated an independent linear relationship between lower tidal volume and decreased mortality that extends below 6 ml per kg. Reductions in tidal volumes (from 6.3 ml per kg to 4.2 ml per kg) and plateau airway pressures (from 29.1 to 25 cmH₂O) with the assistance of ECCO₂R to manage hypercapnia and acidaemia have been shown to reduce inflammatory markers associated with lung injury in a single-centre cohort of patients with ARDS. In a more recent clinical trial comparing ECCO₂R assisted very low tidal volume ventilation (approximately 3 ml per kg predicted body weight) to conventional low tidal volume ventilation (approximately 6 ml per kg) in patients with moderate to severe ARDS, those with more severe hypoxaemia were found in post hoc analysis to have a greater number of ventilator-free days when very low tidal volumes were used (40.9 versus 28.2, p = 0.033). Two prospective randomised trials comparing very lung protective ventilation to standard of care ventilation practices in less severe forms of ARDS or hypoxaemic respiratory failure are currently being designed and conducted, and may help to determine whether such a strategy translates into reductions in lung injury and improvement in clinical outcomes.

Acute Hypercapnic Respiratory Failure

Because of the relative ease with which ECCO₂R can correct hypercapnia at lower blood flow rates than are needed to provide oxygenation, there is great promise in using ECCO₂R for the management of acute hypercapnic respiratory failure, potentially eliminating the need for invasive mechanical ventilation in some patients. In COPD, the use of the ventilator is associated with multiple complications, including dynamic hyperinflation and elevations in intrinsic PEEP, ventilator associated pneumonia, and impaired delivery of aerosolised medications, and failure of non-invasive ventilation requiring invasive mechanical ventilation is associated with mortality as high as 30%. Several case series and cohort studies have demonstrated the feasibility of avoidance of or rapid weaning from invasive mechanical ventilation, with ECCO₂R used to manage gas exchange. In a matched cohort study of acute exacerbations of COPD comparing the combination of non-invasive ventilation plus ECCO₂R to historical controls receiving non-invasive ventilation alone, the ECCO₂R group had a significantly lower risk of intubation (HR 0.27; 95% CI, 0.07–0.98, p = 0.047), though there was a high adverse event rate related to ECCO₂R. The rate of adverse events in this study may also have been related, in part, to the specific device used. Additional benefits of ECCO₂R over mechanical ventilation may include increased success with early mobilisation. Although safety of early mobilisation during invasive mechanical ventilation has been well documented, it may have even greater success with ECCO₂R because of better control of dyspnoea with ECCO₂R. Ultimately, more data are needed to identify patients most likely to benefit from this overall approach, as well as the cost effectiveness of such a strategy, before it should be implemented outside the research setting. The benefit of ECCO₂R in hypercapnic respiratory failure may extend beyond COPD, particularly for patients with refractory status asthmaticus, where the avoidance of positive pressure ventilation is preferred.

Lung Transplantation and Primary Graft Dysfunction

ECMO had long been considered a relative contraindication to lung transplantation because of poor outcomes, especially when used as salvage therapy for patients failing invasive mechanical ventilation. However, in the era of improved technology and earlier implementation, recent studies have reported improved post-transplant survival, particularly when performed at centres with more extensive experience. In a systematic review of 441 patients across 14 studies supported with ECMO (the majority of whom were also receiving invasive mechanical ventilation) while awaiting transplantation, mortality and 1-year survival ranged from 10% to 50% and 50% to 90%, respectively. The heterogeneity of patients and outcomes suggests that patient selection and bridging technique are probably important factors in optimising post-transplant survival. Given the potential for complications from invasive mechanical ventilation, a non-intubated ECMO strategy may be considered for select transplant candidates who would otherwise be ventilator dependent. The combination of endotracheal extubation and early mobilisation may further improve outcomes and prevent loss of transplant eligibility due to deconditioning. A major limitation to the use of ECMO for end-stage respiratory failure remains the lack of a destination device therapy. Patients with severe, irreversible respiratory failure, who are not lung transplant candidates, should therefore not be offered ECMO.

Primary graft dysfunction (PGD) is a form of acute lung injury that is the leading cause of early death after lung transplantation. Similar to its ability to support gas exchange in ARDS, ECMO may be used to manage PGD while underlying causes are treated and the allograft recovers. ECMO supported severe PGD may have comparable survival to less severe PGD without ECMO support, particularly when instituted early, though long-term effects on allograft function have not been reported.