Although extracorporeal membrane oxygenation (ECMO) was first introduced in the 1970s as a means of supporting severe impairments in gas exchange, original versions of the technology were associated with high device related and patient related complication rates, particularly thrombosis and haemorrhage, with no evidence of benefit over conventional management strategies at the time. Recent advances in ECMO technology have improved its risk-benefit profile, and a growing body of literature in the context of greater experience with its use has sparked a renewed interest in the use of ECMO for respiratory failure. This chapter will review the basic principles underlying the use of ECMO, cannulation strategies, indications and evidence for ECMO in the setting of respiratory failure, as it pertains to the cardiothoracic intensive care unit. Beyond the current considerations for ECMO, we will explore emerging indications that could change the approach to the management of respiratory failure in the intensive care unit in the future.
ECMO refers to an extracorporeal circuit that directly oxygenates and removes carbon dioxide from the blood via an oxygenator, a device that consists of a semipermeable membrane that selectively permits oxygen and carbon dioxide to diffuse between blood and gas compartments. Deoxygenated blood is withdrawn through a drainage cannula via an external pump, typically a centrifugal pump, which creates negative pressure within the drainage cannula and tubing. The blood passes through the oxygenator, where gas exchange occurs, and is returned to the patient through a reinfusion cannula under positive pressure. When blood is both drained from and returned to a vein, it is referred to as venovenous ECMO and provides only gas exchange support. When blood is drained from a vein and returned to an artery, it is referred to as venoarterial ECMO, and the circuit is able to provide both respiratory and circulatory support. The amount of blood flow through the circuit (including the fraction of ECMO blood flow relative to the amount of native cardiac output), the fraction of oxygen delivered through the gas compartment of the oxygenator (referred to as the FDO2), and native lung function are the main determinants of systemic oxygenation for patients supported with ECMO. The rate of gas flow through the oxygenator, known as the sweep gas flow rate, and, to a lesser degree, the blood flow rate are the major determinants of carbon dioxide removal. Extracorporeal circuits are more efficient at carbon dioxide removal than oxygenation, owing to the diffusion properties of the membrane and the manner in which oxygen and carbon dioxide are transported within the blood. Because carbon dioxide can be effectively removed at lower blood flow rates than those typically required for oxygenation, it may be possible to use smaller cannulae, which in turn may be easier and safer to insert. The technique of extracorporeal support for carbon dioxide removal at low blood flow rates is referred to as extracorporeal carbon dioxide removal (ECCO2R). This approach has the potential to support patients with acute hypercapnic respiratory failure and to facilitate reductions in tidal volumes and airway pressures in the acute respiratory distress syndrome that would otherwise be limited by unacceptable levels of respiratory acidosis. An alternative, pumpless configuration that is less frequently employed is arteriovenous ECCO2R (blood drained from a femoral artery and returned to the contralateral femoral vein), in which the patient’s native cardiac output generates blood flow through an oxygenator. Because extracorporeal blood flow tends to be lower, this approach is usually limited to the modulation of carbon dioxide.
Traditionally, venovenous ECMO is implemented by cannulation of a femoral vein for drainage and an internal jugular vein for reinfusion (Figure 24.1). This configuration may result in directing reinfused oxygenated blood toward the port of the drainage cannula. The phenomenon of drawing reinfused, oxygenated blood back into the circuit without passing through the systemic circulation is known as recirculation, which may negatively impact the effect of the ECMO circuit on systemic oxygenation. The development of the bicaval dual lumen cannula (Figure 24.2) has enabled the implementation of venovenous ECMO through a single vein, with the advantages – when positioned properly – of less recirculation and avoidance of femoral cannulation. In order to optimise blood flow and recirculation, cannulation typically requires imaging guidance to ensure that the tip of the cannula is properly positioned in the inferior vena cava and that the reinfusion jet is directed toward the tricuspid valve. The choice of cannula size is based on the physiological needs and size of the patient, and consideration should also be made for any history of chronic indwelling central venous catheters that may have led to stenosis within the venous system.
Figure 24.1 Peripheral VV ECMO using two cannulae. Blood is drained from the IVC using femoral approach. It is then pumped through an oxygenator and returned into the SVC through internal jugular approach. Diagram drawn by Anna Valchanova.
Figure 24.2 VVECMO using bicaval dual lumen cannula. Blood is drained from the IVC and SVC. It is pumped through an oxygenator and returned into the right atrium using the second lumen of the same cannula. Diagram drawn by Anna Valchanova.
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.
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.
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.
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.