Feasibility and safety of low-flow extracorporeal CO₂ removal managed with a renal replacement platform to enhance lung-protective ventilation of patients with mild-to-moderate ARDS

Over the past few decades, highly significant progress has been made in understanding the pathophysiology of the acute respiratory distress syndrome (ARDS). Recognition of ventilation-induced lung injuries (VILIs) has led to radical modifications of the ventilatory management of these patients [1, 2]. The landmark trial by the ARDSNet group demonstrated that ventilating ARDS patients with a low tidal volume (VT) of 6 ml/kg (vs 12 ml/kg) significantly decreased mortality [3]. However, recent results showed that lung hyperinflation still occurs in approximately 30% of ARDS patients, despite ventilation with the ARDSNet strategy [4]. That analysis suggested a beneficial effect of VT reduction, even for patients already with plateau pressure (P_plat) < 30 cmH₂O [5]. Decreasing VT and P_plat will also lower the driving pressure, which was recently identified as a major risk factor for mortality in ARDS patients [6].

VT reduction to < 6 ml/kg to achieve very low P_plat induces severe hypercapnia, which raises intracranial pressure, causes pulmonary hypertension, decreases myocardial contractility, reduces renal blood flow, and releases endogenous catecholamines [7, 8]. This strategy is therefore not possible for most ARDS patients on conventional mechanical ventilation (MV) [9]. Extracorporeal carbon-dioxide removal (ECCO₂R) may be used to achieve VT < 6 ml/kg, thereby lowering P_plat and driving pressure in this setting [10‐13]. However, the ability to decrease MV intensity with these ECCO₂R devices, especially those based on a renal replacement therapy (RRT) platform, are limited to animal [14] or single-center [11, 15‐17] studies.

The aim of this prospective, multicenter study was to evaluate the safety and feasibility of a low-flow ECCO₂R device managed by an RRT platform (PrismaLung®; Gambro-Baxter, Meyzieu, France) to enable very low tidal volume ventilation in patients with mild-to-moderate ARDS.

Twenty patients with mild (n = 8) or moderate ARDS (n = 12) were included; 18 underwent jugular cannulation. Patients’ baseline characteristics are reported in Table 1. Neuromuscular blockade, nitric oxide, and prone positioning were applied before inclusion to 16, 9, and 8 patients, respectively. Ventilator settings during the VT reduction phase are presented in Table 2 and Fig. 1. At baseline, all patients received protective ventilation with VT set at 6.10 ± 0.30 ml/kg PBW and PEEP at 13.4 ± 3.6 cmH₂O. VT was gradually lowered to 4 ml/kg for all but one patient (who remained at the 4.5 ml/kg step because PaCO₂ increased > 20% from baseline at the 4.5 ml/kg step despite ECCO₂R; see Table 2). While P_plat was decreased < 25 cmH₂O with VT reduction to 4 ml/kg, PEEP was significantly increased from 13.4 ± 3.6 cmH₂O at baseline to 15.0 ± 3.4 cmH₂O, according to the very low tidal volume ventilation strategy. As a result, the driving pressure was reduced from 13.0 ± 4.8 to 7.9 ± 3.2 cmH₂O (p < 0.05). Mean PaCO₂ increased from 43 ± 8 to 53 ± 9 mmHg and mean pH decreased from 7.39 ± 0.1 to 7.32 ± 0.10 from baseline to 4 ml/kg VT, while RR was not modified. The mean CO₂-removal rate was 51 ± 26 ml/min with 421 ± 40 ml/min blood flow and sweep-gas flow set at 10 ± 0.3 L/min. Importantly, VT and driving pressure reductions with ECCO₂R were not accompanied by significant changes of PaO₂/FiO₂, respiratory-system compliance, and hemodynamic status (Table 2). In the 24 h following ECCO₂R initiation, nitric oxide was applied to four patients, of whom two also received prone positioning. No patients required ECMO for worsening hypoxemia while receiving very low tidal volume ventilation.

Operational characteristics of the ECCO₂R device recorded in the hour following therapy initiation, including access, return, and filter pressures, are presented in Table 3. Overall mean duration of ECCO₂R was 31 ± 21 h. It was continued up to 41 ± 24 h until weaning because of improved respiratory condition for 10 patients and was stopped early because of ECCO₂R-membrane clotting for 10 patients after 20 ± 10 h. The mean daily heparin dose was 19,900 ± 7710 IU/24 h and the mean aPTTr was 1.8 ± 0.6. No cannulation-related complication occurred. One patient suffered a nonfatal cardiac arrest while on ECCO₂R but this was unrelated to the device. Other AEs included two mild hemoptyses that resolved rapidly without embolization and were not related to heparin overdose. The overall day-28 mortality was 15%.

The results of this multicenter pilot study showed that a low-flow ECCO₂R device managed by the RRT platform easily and safely enabled very low tidal volume ventilation with highly significant decreases of P_plat and driving pressure in patients with mild-to-moderate ARDS.

Total energy determinants (i.e., mechanical power) are transmitted to the lung by the ventilator-generated volume, pressure, flow, and RR [21]. Decreasing MV intensity and, thereby limiting VILI, requires a diminution of the total mechanical power transferred to the lung [21]. More than 15 years ago, it was demonstrated that volume-limited ventilation with 6 ml/kg PBW significantly lowered ARDS-associated mortality [3]. However, recent data suggested that some ARDS patients are exposed to hyperinflation and overdistension, despite protective ventilation with 6 ml/kg VT and P_plat limited to < 30 cmH₂O. Pertinently, Hager et al. [5] demonstrated that lower P_plat was associated with less mortality and that no safe low P_plat threshold could be identified in patients with acute lung injury/ARDS. Furthermore, based on a prospective series of 485 consecutive patients with acute lung injury on MV, Needham et al. [22] showed that, compared with a mean VT < 6.5 ml/kg PBW, the adjusted hazard ratios for 2-year mortality for a mean VT of 6.5–8.5 ml/kg PBW was 1.59 (95% CI 1.19–2.14; p = 0.001). Amato et al. [6] recently reported that, in addition to VT, P_plat, and PEEP, normalizing VT to respiratory-system compliance (C_rs) and using a ratio as an index indicating the “functional” size of the lung might provide a better predictor of ARDS patients’ outcomes than VT alone. That ratio, termed the driving pressure (ΔP = VT / C_rs), can be routinely calculated as the P_plat – PEEP for patients who are not making inspiratory efforts. Their analyses indicated that VT reductions or PEEP increases driven by random treatment-group assignment were beneficial only when associated with ΔP decreases and that no other ventilation variable had such a mediating effect on mortality [6]. More recently, lower ΔP was also was also associated with lower ARDS-patient mortality in the large LUNG-SAFE cohort [23].

Furthermore, reducing VT to 4 ml/kg PBW in patients already receiving protective ventilation was associated with less inflammatory and morphological signs of VILI in ARDS patients [11]. This particular study used ECCO₂R to mitigate the respiratory acidosis, and its potent deleterious effects [7, 8, 24], which developed in all patients receiving VT < 6 ml/kg IBW [10, 11]. Results based on previous case series using various ECCO₂R devices showed the feasibility of this strategy in ARDS patients, although AEs (e.g., cannulation-related accidents, limb ischemia, hemorrhage, hemolysis, infections, pump malfunction, membrane clotting, and catheter displacement) were reported [10, 11, 25‐28].

Our results demonstrated that this strategy might be safely, efficiently, and easily applied to ARDS patients in most ICUs worldwide, because it did not require specific or large venous accesses and the RTT platform we used is widely available with minimal modification of existing devices and a simple software update. ECCO₂R with this RRT platform has indeed obtained promising results in animals [14]. By decreasing VT to 4 ml/kg PBW and adjusting PEEP to a lower P_plat target of 23–25 cmH₂O, we were able to drastically decrease the driving pressure to < 8 cmH₂O, which might mean less VILI and ultimately fewer deaths [6]. Importantly, we did not observe worsening oxygenation that might have indicated lung derecruitment following the mean airway-pressure decrease [28, 29], although some patients with the most severe forms of ARDS continued to receive nitric oxide or prone positioning following ECCO2R initiation. The PEEP increase resulting from the ventilator strategy used might have counterbalanced that potential hazard [11, 13, 28, 30]. The absence of worsening oxygenation also argues against alveoli nitrogen washout and potential absorption atelectasis, which is less likely to occur in low-flow ECCO2R than during high-flow VV-ECMO.

Several limitations of our work should be addressed. First, because our population was small, this study should only be considered “a proof-of-concept” demonstrating the feasibility and safety of the strategy tested. We cannot rule out that there is still a substantial risk of adverse events that could have been missed in this small study. Second, our population included only patients with mild or moderate ARDS. Because severe ARDS patients might experience greater PaCO₂ increases and more severe hypoxemia after VT reduction, the Prismalung® performance remains unknown in this context. Third, to achieve VT reduction down to 4 ml/kg in a larger population of patients without the risks of inducing major PaCO₂ increases not compensated by the low-flow ECCO₂R device, we also applied the modified EXPRESS strategy to patients with mild ARDS. Because of higher PEEP settings in this population of patients with higher compliance, it should be acknowledged that this approach may induce overdistension despite lowering the driving pressure. In addition, potential benefits of a very low tidal volume ventilation strategy have only been suggested in moderate-to-severe ARDS patients until now [10, 11]. Fourth, we did not evaluate lung morphological and inflammatory markers or the long-term clinical efficacy of the device. Fifth, due to its smaller membrane oxygenator surface, the CO₂-removal rate of the Prismalung® was lower than those reported in other studies using similar blood flows [17, 28], explaining the gradual increase in PaCO₂ observed during the VT reduction phase. This mild respiratory acidosis might have been corrected by increasing the RR, at the expense of an increase in mechanical power. Indeed, the physicians treating these patients decided to tolerate this mild acidosis, as recent data also suggest an increased RR might be associated with a poorer ARDS prognosis [31]. Lastly, despite our heparin-infusion protocol that also included a bolus at catheter insertion, 50% of the treated patients experienced membrane clotting before the end of the experimental protocol, as reported previously for other case series given low-flow ECCO₂R [11, 15]. This technical downside deserves further investigations as it could limit the efficacy and impact the cost–benefit ratio of the device. The development of regional circuit anticoagulation strategies, with blood flows up to 500 ml/min, might enhance ECCO₂R membrane duration, as was the case for RRT hemofilters [32].

In summary, our pilot study findings demonstrated that a low-flow ECCO₂R device managed by an RRT platform enabled very low tidal volume ventilation with moderate increase in PaCO₂ in patients with mild-to-moderate ARDS. This less-invasive ECCO₂R technique was easily and safely implemented. However, before this technique can be widely disseminated, more data are needed to demonstrate the clinical benefit of VT, P_plat, and driving pressure reductions rendered possible by ECCO₂R [33]. The ongoing international randomized clinical trials SUPERNOVA (ClinicalTrials.gov identifier: NCT02282657) and REST (Clinical-Trials.gov identifier: NCT02654327) focused on moderate ARDS will help clarify this potential.