Strategy of Ultra-Protective Lung Ventilation With Extracorporeal CO2 Removal for New-Onset Moderate ARDS: A Prospective Multicenter Randomized Clinical Trial

Acute respiratory distress syndrome (ARDS) represents a form of lung injury that occurs in response to various predisposing events, characterized by inflammation, increased pulmonary vascular permeability and loss of aerated lung tissue. The diagnosis of ARDS is based on severe hypoxemia and bilateral radiographic opacities occurring within 7 days of a known clinical insult or worsening respiratory symptoms. Central to the pathophysiology of ARDS is the presence of fibrin-rich exudates (hyaline membranes) due to activation of coagulation and inhibition of fibrinolysis. ARDS accounts for 10 % of all ICU admissions and for 23% of patients requiring mechanical ventilation (MV). Hospital mortality of ARDS patients remains high, ranging from 34% with mild ARDS, up to 46% with severe ARDS. Notably, severe and critical forms of coronavirus disease 2019 (COVID-19) are almost invariably associated with ARDS.

Ventilator Induced Lung Injury (VILI) MV is a lifesaving form of support for patients with ARDS since it decreases the oxygen cost of breathing, improves gas exchange and provides time for resolution of the underlying etiology of ARDS. However, it has been consistently shown that MV may contribute to ventilator-induced lung injury (VILI) characterized by progression of pulmonary damage, worsening of the pulmonary inflammatory process, increased alveolar-capillary permeability and therefore leading to the translocation of inflammatory mediators from the lungs into the systemic circulation with consequent failure of distal organs (biotrauma). A randomized clinical trial showed that ventilating ARDS patients with a tidal volume (VT) of 6 ml/kg (calculated from predicted body weight, PBW), and with a maximum end-inspiratory plateau pressure (PPLAT) of 30 cmH2O decreased mortality from 40 % (seen in the conventional arm treated with a VT of 12 ml/kg PBW) to 31%. Recently, Amato and coworkers showed that the delta pressure (∆P), i.e. the difference between PPLAT and positive end-expiratory pressure (PEEP) (∆P = PPLAT -PEEP) ≤ 14 cmH2O was strongly associated with survival, demonstrating that interventions to obtain protective ventilatory settings (reductions in VT or increases in PEEP) were beneficial only if associated with decreases in ΔP.

Extra-corporeal CO2 Removal (ECCO2-R) The use extracorporeal support to remove carbon dioxide (CO2) to permit the use of low volume/low pressure ventilation with minimal impact on PaCO2 was proposed in 1977. It was suggested that applying low VT and low peak inspiratory pressures ("lung rest") at a low respiratory rate could minimize damage to the compromised lungs. With this technique, oxygenation and removal of carbon dioxide were dissociated: oxygenation occurred predominantly through the lungs, and a variable portion of the carbon dioxide was removed through an artificial lung (extracorporeal CO2removal: ECCO2-R). The key potential advantage to this approach over extracorporeal membrane oxygenation (ECMO) is the use of lower blood flow through the extracorporeal circuit potentially with fewer side effects. Low VT ventilation (3-4 ml/kg of PBW) was associated with a significant decrease in inflammatory markers when compared with standard low volume, low pressure ventilation. Furthermore, the resulting hypercapnia was easily controlled by ECCO2-R. A randomized clinical trial showed that VT of 3 ml/kg of PBW was easy and safe to be implemented with extracorporeal CO2-removal. Clinical outcome, evaluated as days free from mechanical ventilation through day 28, significantly improved in ECCO2R patients compared to control, when analyzing patients with PaO2/FiO2<150.

A multicenter study designed to assess safety and feasibility of ECCO2R in ARDS showed that more than 80% of patients with moderate ARDS could achieve ultra-protective ventilation goals by using ECCO2R. The incidence of severe adverse events related to ECCO2R was low (~2%). Efficacy and safety of ECCO2R A was higher for devices that used blood flow rates in the range of 1000-1500 ml/min. A post-hoc analysis showed that restricting enrollment to patients with compliance of the respiratory system ≤ 40 ml/cmH2O and decrease in ∆P ≥ 5 cmH2O would increase predicted benefit in terms of clinical outcomes in a randomized clinical trial of VT of 3 ml/kg of PBW with ECCO2R (enrichment strategy). Moreover, recent data show that there is no safe upper limit for PPLAT or ΔP, consistent with the fact that since the mortality rate in ARDS patients with ΔP values ≤ 14 cmH2O is still as high as 20%. Patient outcomes may therefore be improved by aggressively lowering ventilatory variables such as VT, PPLAT, or ΔP as facilitated by ECCO2R devices that remove CO2. In addition, ECCO2R might further decrease VILI by allowing lower respiratory rates, which have been shown to be lung protective.

OBJECTIVE The objective of this multicenter, prospective, randomized, comparative open trial is to determine if early ECCO2R allowing ultraprotective mechanical ventilation (VT 4 ml/kg) improves the outcomes of patients with ARDS.