Mechanical ventilation provides life-saving maintenance of gas exchange, but it can also, paradoxically, cause iatrogenic injury. Recognition of this fact has changed the goals of ventilation from “normalizing” physiology to providing adequate gas exchange while minimizing ventilator-induced lung injury (VILI). VILI results from overdistention of lung units (volutrauma) or repetitive tidal opening and closing of alveoli (atelectrauma), leading to cytokine release and a systemic inflammatory response (biotrauma) (1). To date, the only ventilatory strategy that has convincingly demonstrated improved survival in patients with acute respiratory distress syndrome (ARDS) is one that limits distending volume and pressure—using a tidal volume of 6 mL/kg predicted body weight (PBW) and plateau pressure less than 30 cm H2O (2). To achieve these targets, patients with ARDS have traditionally been managed with controlled ventilator modes, and such patients often require deep sedation and paralysis to control tidal volumes (3).
A new approach has become available—removal of CO2 from the blood using a minimally invasive extracorporeal system resulting in lower CO2 levels while expending less diaphragmatic effort to eliminate it. This approach—extracorporeal CO2 removal (ECCO2R)—is a technique that provides artificial respiratory support by removing CO2 from blood through an external membrane lung (4). It is typically delivered through a venovenous circuit using relatively low blood flow rates (e.g., 0.3–1 L/min) and a small dual-lumen cannula (15–18 Fr) (5) Given the low blood flow rate, there is negligible contribution to systemic oxygenation from ECCO2R. Although the concept is not new (6), recent advances in technology have made these systems smaller and easier to employ in patients with ARDS (7–9). Indeed, the use of ECCO2R is typically associated with a clinical reduction in the intensity of mechanical ventilation delivered to maintain similar physiologic goals (10).
Modern approaches with ECCO2R have largely focused on patients with hypercapnic respiratory failure (9 , 11). It has also been proposed to target lower (3–4 mL/kg PBW) tidal volumes in ARDS patients with the hope of further reducing VILI. Importantly, ECCO2R may also be useful in avoiding other forms of injury, including those from large spontaneous breathing efforts. In this regard, ECCO2R has been shown to reduce spontaneous ventilation proportionally to CO2 clearance in animal models (12). Similarly, modulating sweep gas flow, and thus membrane CO2 clearance, in patients recovering from ARDS on extracorporeal life support produces parallel changes in tidal volume and respiratory effort (13). Thus, ECCO2R may represent an appealing intervention whereby patients with ARDS could be awake and breathing spontaneously on mechanical ventilation—thus avoiding many of the complications of deep sedation and ventilator-induced diaphragm dysfunction—while maintaining a safe tidal volume and transpulmonary pressure—thus minimizing VILI. Any such benefit would have to be weighed against potential complications from this device including bleeding, hemolysis, and vascular injury during cannulation (14).
In this issue of Critical Care Medicine, the study by Duscio et al (15) is a well-designed physiologic study outlining the important determinants of CO2 production in healthy pigs undergoing low-flow ECCO2R using the commercially available ProLUNG system (Estor S.p.A, Pero, Milan, Italy). Of particularly importance is the observation that CO2 removal by the membrane lung was independent of gas flow within the operational range tested (in contrast to higher-flow extracorporeal support systems), thus allowing for a reduction of alveolar minute ventilation and energy expenditure on the lung while maintaining arterial blood CO2 (PaCO2) within therapeutic ranges. However, the utility of the study by Duscio et al (15) was limited in that they used healthy pigs (of a large size to simulate human beings); the results and considerations may be different in the presence of lung pathology, particularly for the clinical situations in which the authors speculate about regarding the potential application of ECCO2R (i.e., patients with severe ARDS). Without data on the performance on their ECCO2R system in a clinically relevant experimental model, the results represent the technical properties of a commercially available device with little opportunity for eventual bench-to-bedside translation. Additional concerns regarding the specific device studied include the use of roller pumps and the potential for increased hemolysis, as well as the relatively higher degree of anticoagulation required (target activated clotting time of 300 s).
Ultimately, the results of the study by Duscio et al (15) are not particularly novel, given that there are a number of commercially available extracorporeal devices that can provide CO2 removal—both with higher-flow extracorporeal membrane oxygenation devices running at lower flow as well as devices that were designed specifically for ECCO2R. Future development should focus on the latter, with all components of the extracorporeal device (i.e., pump, membrane lung, cannula, tubing) designed to optimize function and minimize risk (e.g., clotting) while operating at low blood flow rates. Furthermore, novel techniques to enhance the efficiency of CO2 removal (e.g., electrodialysis, blood acidification) may also facilitate clinically meaningful reductions in CO2 at even lower blood flow rates.
In the end, it is likely not the amount of CO2 that can be removed from a given patient that is important per se, but what that reduction in CO2 can mediate—for instance, a reduction in the intensity of mechanical ventilation delivered in a patient with ARDS or preventing the need for intubation in a patient with an acute exacerbation of chronic obstructive pulmonary disease (COPD). Although based on sound theory, it is unknown if this approach improves outcomes in patients. Although we are not lacking in ECCO2R devices with a range of blood flow rates and operational efficiencies, we lack the rigorous data needed to support the use of these devices in a specific patient population. What is desperately needed are adequately designed and powered clinical trials evaluating the efficacy of ECCO2R in patients with respiratory failure. Data from the recently completed Strategy of Ultraprotective Lung Ventilation with Extracorporeal CO2 Removal for New-Onset Moderate to Severe ARDS (SUPER NOVA) (clinicaltrials.gov NCT02282657) and the ongoing Protective Ventilation with Veno-venous Lung Assist in Respiratory Failure (REST) (NCT02654327) and the Extracorporeal CO2 Removal with the Hemolung [Respiratory Assist System] for Mechanical Ventilation Avoidance During Acute Exacerbation of COPD (VENT-AVOID) (NCT03255057) trials will be helpful. Until then, ECCO2R remains an experimental therapy that should only be used in the context of a clinical trial. After constructing the first laser in 1960, Dr. Theodore H. Mainan described it as “a solution in search of a problem.” Similarly, despite the fact that they can perform as advertised (i.e., remove CO2), ECCO2R is currently a relatively costly and invasive device in search of an evidence-based indication.
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