Low-flow CO₂ removal in combination with renal replacement therapy effectively reduces ventilation requirements in hypercapnic patients: a pilot study

Lung-protective strategies are the mainstay of mechanical ventilation in patients with ARDS and other inflammatory pulmonary disorders, as the use of lower tidal volumes and plateau pressures improves survival rates by reducing pulmonary stress and strain [1, 2]. In addition, there is a growing body of evidence that a further reduction in the mechanical stress resulting from positive pressure ventilation by further decreasing tidal volumes may be even more “lung protective” [3‐5]. Whereas low tidal volume ventilation has been shown to reduce pulmonary inflammation and consequently mortality, it is often accompanied by hypercapnic acidosis, which will even be more pronounced under “ultra-protective” ventilation strategies. Although elevated PaCO₂ levels in this setting (“permissive hypercapnia”) are often well tolerated and deemed to be safe [1‐3], the degree to which hypercapnia may be tolerable or even beneficial by directly supporting anti-inflammation remains unclear [6‐9]. Very recent data have shown a positive correlation between hypercapnic acidosis and mortality [10, 11], thereby casting doubt on the uncritical toleration of hypercapnic acidosis under lung-protective mechanical ventilation. On the other hand, many patients with ARDS present with multi-organ failure, e.g., due to septic shock, and consequently exhibit massive metabolic acidosis in combination with severe cardiovascular instability. This may further limit the concept of permissive hypercapnia since an additional decrease in pH may be considered unsafe in such patients. This problem is even more pronounced when aiming for an additional reduction in the invasiveness of mechanical ventilation by further reducing tidal volumes.

Although there are no conclusive data showing a reduction in mortality, there is evidence that extracorporeal CO₂ removal (ECCO₂R) can effectively normalize severe hypercapnia and facilitate ultra-protective ventilation strategies [12‐15]. Whereas extracorporeal membrane oxygenation (ECMO) is becoming more and more widespread in the therapy of patients with severe ARDS and provides total decarboxylation in addition to oxygenation, such high-flow systems require substantial resources and carry a considerable risk of complications and are therefore limited to patients with severe hypoxemia [16‐22]. Total extracorporeal CO₂ removal can be achieved with less invasive techniques such as pumpless extracorporeal lung assist (pECLA) and other mid-flow systems [23, 24], but these techniques still require specialized vascular access and are therefore invasive and expensive.

On the other hand, it has repeatedly been demonstrated that even low-flow systems adapted from conventional renal replacement platforms with blood flow rates under 500 ml/min can achieve significant CO₂ elimination (“respiratory dialysis”) [25‐27]. Extracorporeal CO₂ removal based on renal replacement platforms may be especially useful in mechanically ventilated patients with multi-organ failure, since in one- to two-thirds of those patients there is an indication for renal replacement therapy [28, 29]. Furthermore, concomitant lung and kidney injury may exhibit significant detrimental interaction (“organ cross talk”) [30, 31], which may negatively affect outcome. Because no additional vascular access other than the dialysis catheter is required, the implementation of a hollow-fiber gas exchanger in the renal replacement circuit could be an attractive therapeutic option in such patients.

Though the use of such combinations of ECCO₂R and continuous renal replacement therapy (CRRT) has been reported [27, 32, 33], until recently no certified combination therapy has been available. In this pilot study, we describe for the first time the effectiveness of a commercially available combination of ECCO₂R and CRRT regarding decarboxylation and ventilation as well as other clinical parameters.

Using a standardized protocol of ventilation based on current ARDS Network recommendations, we were able to demonstrate that the investigated combination therapy was able to ameliorate respiratory acidosis and effectively reduce the invasiveness of mechanical ventilation in hypercapnic critically ill patients while providing efficient renal replacement therapy and exhibiting a positive effect on hemodynamics in terms of vasopressor requirements. While combinations of ECCO₂R and CRRT have previously been reported, our study provides the first description of a certified and labeled combination therapy on a commercially available organ support platform. The system was able to eliminate CO₂ at a rate between 40 and 50 ml/min, thereby reducing arterial PCO₂ significantly by about 10%. The additional integration of a membrane lung into a renal replacement circuit has first been described by Forster et al. [32], who were able to show a reduction in acidosis and decreased vasopressor requirements in ten hypercapnic patients. This concept was taken one step further by Allardet-Servent et al. [33], who were able to realize an ultra-protective ventilation strategy in 11 patients with ARDS using a similar combination. In both of these studies, membrane lungs with surfaces of about 0.7 m² were used, which resulted in a higher CO₂ removal rate and more pronounced correction of acidosis compared to our system, which incorporated a significantly smaller membrane lung (0.32 m²). As has recently been shown by Karagiannidis et al. [35], in low-flow ECCO₂R the effectiveness of CO₂ extraction is mainly a function of the membrane size. Whereas smaller membrane lungs may have advantages with regard to costs and likelihood of clotting, membrane size must be considered the most important limiting factor of the presented system. Another factor pertaining to combinations of ECCO₂R and CRRT is the relative position of membrane lung and hemofilter, which may affect CO₂ removal. In [33], the incorporation of the membrane lung downstream of the hemofilter was significantly less effective than in an upstream position. In our study, the CO₂ removal rate of the combined system was about 5% lower than the elimination rate of the membrane lung alone, hinting at the same effect. We suggest that the substitution of bicarbonate-rich replacement fluids as a consequence of renal replacement therapy leads to an increase in the CO₂ content of extracorporeal blood, thereby counteracting the overall effectiveness of CO₂ removal by “loading” the blood with CO₂. It would be interesting to investigate whether the use of citrate-based solutions which could also provide effective anticoagulation is associated with a more pronounced CO₂ removal effect. Due to the relatively high citrate dosing requirements at the investigated blood flow (400 ml/min), no such combination is currently available.

Though the resulting drop in PaCO₂, as is expected in a low-flow setting, is not sufficient to completely correct respiratory acidosis, implementation of the system still allowed for a significant decrease both in tidal volume (− 0.8 ml/kg) and plateau pressure (− 2.9 cmH₂O) and in driving pressure (− 2.7 cmH₂O). Since the study protocol did not require neuromuscular blockade to prevent spontaneous breathing and consequently only a quarter of the patients received neuromuscular blocking agents at some point during the study, there was considerable heterogeneity in response to plateau pressure reduction following implementation of ECCO₂R with some patients counteracting the decreased inspiratory pressures by actively increasing spontaneous breathing efforts, thus mitigating the effect on tidal volume reduction.

In a recent study on the efficacy and safety of low-flow ECCO₂R using the same platform in patients without renal failure, a more pronounced reduction in tidal volume and plateau pressure was reported [36]. In that study, all patients were paralyzed, making tidal volume reductions more easy to achieve. Also, the severity of illness was significantly different with a mean SOFA score of 9 as compared to 14 in our study. It is important to note that patients with combined respiratory and renal failure may constitute a different target group for ECCO₂R than patients with isolated respiratory failure. In established multi-organ failure with often severe concomitant metabolic acidosis, there is typically an indication for renal replacement therapy, making the integration of an additional gas exchanger in the circuit much less invasive since vascular access is already in place. Our data show that combining ECCO₂R with CRRT in the setting multi-organ failure, while being less effective than stand-alone therapies, can still significantly enhance lung protection and may therefore have beneficial effects. In contrast to [36], this effect can be achieved without further raising PaCO₂, thus providing much better control of pH. Interestingly, while the additional surface of the hemofilter might be expected to activate coagulation, incidence of circuit clotting was much lower in the combination therapy than in the stand-alone procedure.

As it has been concluded by Gattinoni et al., ventilator-associated lung injury essentially results from the application of mechanical power to the lungs in order to actively eliminate CO₂ from the circulation [37, 38]. The components of this mechanical power are tidal volume, driving pressure, PEEP, flow and respiratory rate. Any additional CO₂ elimination is therefore capable of reducing the power applied to the lungs and consequently should attenuate ventilator-associated lung injury. This is mirrored in our study by significantly decreased tidal volumes and driving pressures. Although this rationale may seem compelling and comparable strategies have been able to show reduced systemic and pulmonary inflammation in experimental [39, 40] as well as in clinical ARDS [14, 27], to date it has not been demonstrated that ultra-protective ventilation strategies per se can improve clinically relevant patient outcomes.

Although partial extracorporeal CO₂ elimination must therefore still be regarded as experimental at this juncture, due to its easy implementation and management, the combination of low-flow ECCO₂R and CRRT nevertheless constitutes a safe and effective add-on therapy for ventilated patients with renal failure. Since the procedure runs on an established renal replacement platform and therefore only requires integration of a small membrane lung as well as a moderate increase in blood flow without need for specialized vascular access, the potential for complications seems low. Under systemic anticoagulation, the combined system exhibited reasonable circuit lifetimes and we observed no procedure-related bleeding or other relevant adverse events. This is in marked contrast to ECMO or even mid-flow ECCO₂R therapies where higher blood flows can provide total CO₂ removal but require large-bore and often multiple vascular access which is associated with significant bleeding risk and other local as well as systemic complications [12‐14, 16]. We therefore conclude that combined ECCO₂R and CRRT with the investigated system is a feasible and safe approach. However, due to the limited running time of the hemofilter for renal replacement, the system has to be discarded after 72 h, leading potentially to higher costs in prolonged treatments.

Our study has several limitations. In order to keep interference with local practice standards at the three centers at a minimum, no explicit ventilation strategy other than compliance with ARDS Network recommendations was stipulated. After the initial data collections, ventilation strategy was left to the discretion of the treating physician leading to considerable heterogeneity among the study population. With a growing number of spontaneously breathing patients over the study period, the effect of ECCO₂R on ventilation is blurred to a considerable degree. Since neuromuscular blockade was not required, even the initial data collections may be significantly influenced by spontaneous breathing efforts. As expected in combined lung and renal failure, metabolic acidosis significantly contributes to overall acid base status. Consequently, in a number of patients, while ECCO₂R led to a significant drop in PaCO₂, marked overall acidosis remained, preventing a reduction in ventilator settings by the treating physician. We therefore cannot exclude that the overall effect on ventilation is confounded to some degree in this study. Furthermore, the study included only patients who already exhibited severe hypercapnia. Our data therefore allow no statement on the efficiency of the system in a normocapnic or only mildly hypercapnic environment. Due to the limited running time of the system (72 h), we also cannot provide data on long-term clinical effects.

In this study, we present the first description of a combination of extracorporeal CO₂ removal and renal replacement therapy on a commercially available organ support platform in mechanically ventilated hypercapnic patients with renal failure. The investigated combination therapy was able to ameliorate hypercapnic acidosis and allow for a decrease in ventilation pressures while providing adequate renal replacement therapy. The system was easy to implement and manage; no severe procedure-related adverse events were observed. Whether strategies aiming at correcting hypercapnia and/or providing ultra-protective ventilation are beneficial for patients with combined lung and renal failure in terms of outcome remains to be demonstrated in future investigations.