Low-flow assessment of current ECMO/ECCO2R rotary blood pumps and the potential effect on hemocompatibility
Extracorporeal carbon dioxide removal (ECCO2R) uses an extracorporeal circuit to directly remove carbon dioxide from the blood either in lieu of mechanical ventilation or in combination with it. While the potential benefits of the technology are leading to increasing use, there are very real risks associated with it. Several studies demonstrated major bleeding and clotting complications, often associated with hemolysis and poorer outcomes in patients receiving ECCO2R. A better understanding of the risks originating specifically from the rotary blood pump component of the circuit is urgently needed.
High-resolution computational fluid dynamics was used to calculate the hemodynamics and hemocompatibility of three current rotary blood pumps for various pump flow rates.
The hydraulic efficiency dramatically decreases to 5–10% if operating at blood flow rates below 1 L/min, the pump internal flow recirculation rate increases 6–12-fold in these flow ranges, and adverse effects are increased due to multiple exposures to high shear stress. The deleterious consequences include a steep increase in hemolysis and destruction of platelets.
The role of blood pumps in contributing to adverse effects at the lower blood flow rates used during ECCO2R is shown here to be significant. Current rotary blood pumps should be used with caution if operated at blood flow rates below 2 L/min, because of significant and high recirculation, shear stress, and hemolysis. There is a clear and urgent need to design dedicated blood pumps which are optimized for blood flow rates in the range of 0.5–1.5 L/min.
KeywordsARDS ECMO ECCO2R ECLS Centrifugal blood pumps
Computational fluid dynamics
Extracorporeal life support (ECLS), which is comprised of extracorporeal membrane oxygenation (ECMO) and extracorporeal carbon dioxide removal (ECCO2R) , is an emerging technology in the field of respiratory medicine used for various indications, including the acute respiratory distress syndrome (ARDS) and acute exacerbations of chronic obstructive pulmonary disease (COPD), or as a bridge to lung transplantation [2, 3, 4, 5, 6, 7, 8]. Recently, the EOLIA trial demonstrated a survival benefit for patients treated with ECMO compared to standard of care in severe ARDS [9, 10]. However, extracorporeal systems have substantial side effects, in particular, bleeding or clotting may occur in many patients. The concept of ECCO2R has been proposed as a safer alternative to ECMO due to the lower blood flow rates and smaller cannulae used. However, greater safety has not been established, and recent studies demonstrate increased bleeding complications in patients treated with ECCO2R [5, 11].
Historically, ECCO2R systems were developed from renal replacement therapy (RRT) and driven by roller pumps [12, 13, 14] or from high-flow extracorporeal membrane oxygenation (ECMO) devices driven by rotary pumps; most of them were centrifugal blood pumps in recent years. Few systems were designed specifically for ECCO2R [15, 16, 17]. In patients with moderate-to-severe ARDS, the SUPERNOVA pilot trial recently demonstrated the feasibility of reducing the intensity of mechanical ventilation by applying ECCO2R, using three different extracorporeal devices with blood flow rates ranging from 300 to 1000 mL/min . However, although all three systems were characterized as “ECCO2R” , there were distinct differences with regard to the efficacy of CO2 removal. Systems derived from RRT devices are limited in blood flow rates (usually up to 500 mL/min), whereas those that are derived from high-flow ECMO devices are, in general, not limited by the blood flow rate, but more by cannula (or catheter) size and membrane lung surface area. In daily clinical practice, systems operating at blood flow rates up to 500 mL/min remove CO2 on the order of 80 mL/min. This can be nearly doubled by doubling the blood flow rate, thereby accounting for approximately 50% of the CO2 production of an adult resting intensive care unit (ICU) patient [19, 20, 21, 22]. Furthermore, ECMO therapy for neonatal and pediatric patients uses comparable blood flow rates with current rotary blood pumps.
Whereas the efficacy and technical determinants of ECCO2R for adults, or low-flow ECMO for neonatal and pediatric patients, are reasonably well characterized, studies have raised the issue of the safety of the treatment [5, 23]. Although the blood flow rates used in ECCO2R are lower, and the cannulae are typically smaller than in high-flow ECMO, bleeding, clotting, and acquired van Willebrand syndrome are nonetheless common complications, influencing the outcome of clinical trials. Of note, hemolysis is one of the major complications, leading to worsening of clinical outcomes and is independently associated with mortality [24, 25, 26]. Studies by Braune et al.  and Karagiannidis et al.  (rotary pumps), as well as del Sorbo et al.  (roller pump), demonstrate significant bleeding complications in patients with acute exacerbation of COPD supported with ECCO2R. Similar observations were reported in neonatal and pediatric patients . Whereas the complications induced by the oxygenator may be reduced by choosing the most appropriate membrane lung , special attention should be given to the blood pumps used at these low blood flow rates. Although blood flow rates may easily be reduced in high-flow ECMO with current rotary pumps, even down to less than 500 mL/min, the flow characteristics change considerably. Rotary blood pumps are developed for a very specific design point, but not for a broad spectrum of blood flow rates from 0 to 8 L/min. The respective components of the pump are dimensioned for this design point to allow for optimal flow guidance, as loss-free and efficient as possible, which may be lost at lower blood flow rates.
An understanding of the capabilities and complications of blood pumps at lower blood flow rates is essential for upcoming clinical trials of ECCO2R for patients with ARDS and acute exacerbation of COPD. We therefore sought to investigate the behavior of current ECMO and ECCO2R blood pumps with regard to hemocompatibility when operating at low blood flow rates. Since computational fluid dynamics (CFD) has been proven to accurately predict the behavior of blood pumps [27, 28, 29, 30, 31], this dedicated method was used to simulate the behavior of three currently used rotary blood pumps across a wide flow range.
Material and methods
Detailed geometries of the Xenios DP3 (Xenios AG, Heilbronn, Germany), Getinge Rotaflow (Getinge, Gothenburg, Sweden), and LivaNova Revolution (London, UK) pumps were derived from micro-CT scans and manual measurements using computer-aided design. The meshing of the pump’s internal blood volume was determined with tetrahedral elements and refined prism layers at the walls yielding up to 15.2 million mesh elements. Transient result averaging of the simulation results was performed over two impeller revolutions following five revolutions to ensure transient stability. The unsteady Reynolds-averaged Navier-Stokes (RANS) momentum and mass equations were iteratively solved using the commercial element-based finite volume method (ebFVM) solver CFX (ANSYS CFX, ANSYS, Inc., Canonsburg, PA, USA) and the sliding mesh approach. The blood was modeled with a shear-dependent viscosity  and a density of 1059 kg m−3. Convergence was monitored by the scalar variable residuals and stabilized predictions of the simulation parameters of this study. Detailed information is provided in the online data supplement. To briefly summarized the following.
Operation range and evaluation parameters
The low blood flow operation ranged between 0.5 and 4 L/min and a lower (150 mmHg) and upper (250 mmHg) pressure head target for typical CO2 removal applications. Identical pressure head at a given pump flow was achieved following speed adjustments for each pump (Additional file 3).
Hydraulic efficiency, secondary flows, and recirculation ratio
Hemolysis index and shear stress
Sij is the strain rate tensor, and μ is the dynamic viscosity of the blood.
Of note, numerical blood damage models are under continuous development and cannot fully substitute for experimental hemolysis testing. Nevertheless, numerical hemolysis results show a high correlation with experimental hemolysis results and are a reasonable substitute in the comparative pump analysis of this study.
Platelets of 32 non-septic patients, treated with ECCO2R (blood flow rates < 2 L/min) for acute exacerbation of COPD or for ARDS, were retrospectively analyzed in our institution from 2014 to 2018.
Additional file 1 demonstrates the typical clinical scenario and side effects of ECCO2R. Platelets in 32 non-septic patients, treated with ECCO2R (blood flow rates < 2 L/min) for acute exacerbation of COPD or for ARDS, dropped by nearly half on average from 242 ± 101 (× 1000/μL) on day 0 to 127 ± 48 (× 1000/μL) on day 13 (Additional file 1A). Additional file 1B demonstrates the typical appearance of clotting within the pump, inducing severe hemolysis as a side effect of the treatment. Three frequently used rotary blood pumps (DP3, Rotaflow, and Revolution) were therefore experimentally evaluated by means of high-resolution CFD.
The hydraulic efficiency of the three blood pumps is demonstrated in Fig. 1. Of note, with decreasing pump flows, all systems present decreasing hydraulic efficiencies towards lower blood flow rates. At 0.5 L/min, the efficiency of the DP3 is only 7% against 150 mmHg of pressure head and 6.2% against 250 mmHg of pressure head; likewise, the hydraulic efficiency of Rotaflow (5.5; 4.7%) and Revolution (3.2; 2.7%) dramatically decreased, barely reaching 12% efficiency at 1 L/min. The DP3 system shows the best hydraulic efficiency at low flows, while the efficiency curves of the Rotaflow show a better trend towards flow rates above 4 L/min.
Higher rotational speeds create an offset towards lower hydraulic efficiency for all systems, meaning that the amount of loss increases.
For the first time, the present comparative study demonstrates systematically the potentially deleterious effects of currently used rotary blood pumps when operated at blood flow rates below 2 L/min, as is done in the clinical use of ECCO2R or neonatal and pediatric ECMO applications. By means of CFD, we could demonstrate that (a) the hydraulic efficiency dramatically decreases to 5–10% if operating at blood flow rates below 1 L/min, (b) the recirculation rate increases 6–12-fold in these flow ranges, and (c) adverse effects are increased due to multiple exposures to high shear stress. The deleterious consequences include a steep increase in hemolysis and destruction of platelets.
The use of ECCO2R is rapidly growing, and it remains a promising application of ECLS for ARDS or acute exacerbations of COPD, although there is currently no clear clinical indication for which there is high-quality evidence. Several studies are ongoing or planned for both applications. Although the rationale for the indications is clear, and the prevailing theory is that ECCO2R should be safer than ECMO in clinical practice, a concerning number of side effects have been reported in feasibility studies. As an example, major bleeding events occurred in more than 50% of patients in a trial aimed at avoiding invasive mechanical ventilation in patients with acute exacerbations of COPD , although this group of patients is not typically prone to bleeding when compared with patients who have severe sepsis. Bleeding may occur from loss of fibrinogen in the setting of its binding to the oxygenator, as well as circuit components, including the blood pumps, affecting the number and function of platelets, as shown in these experiments. Our current data on recirculation, high shear stress, and hemolysis are in line with the observed side effects and are at least in part responsible for this effect. This is of major importance, since, for instance, hemolysis is independently associated with mortality in some groups of patients .
From an engineering perspective, operating current blood pumps at low blood flow rates leads to low hydraulic efficiencies aggravating shear stress-induced blood trauma (Figs. 2, 3, and 4). The general efficiency slope of all systems suggests that the maximum efficiency point was designed for higher blood flow rates. Therefore, for all three blood pumps studied, the use of low blood flow rates for ECCO2R means this use is considerably removed from the design point of the pumps, meaning the optimal use that the pumps were designed for. The backflows (Fig. 3) must be pumped effectively through the impeller in addition to the actual pump flow, indicating that low pump flow does not also imply low impeller flow. The internal recirculation as presented in Fig. 2 causes multiple exposures to high shear stresses that are not physiologic, especially in the secondary gaps. All secondary flow paths induce fluid flow usually involving low volumetric flow rates and high shear stresses . Given this, the ratio between the main flow and secondary flow at low flow rates might be causally related to the elevated complication risk. All pump systems show an increase of the hemolysis index when operated at blood flow rates below 2 L/min, which is further aggravated below 1 L/min. This is assumed to be a result of (a) the increased residence time of the blood within the pump, in the setting of reducing the pump flow itself and (b) unfavorable internal recirculation (Fig. 2), in combination with (c) multiple exposures to the respective shear stresses (Figs. 3 and 4) of the pump systems considered in this study. The results indicate a fundamental problem of hemocompatibility of all tested pumps for the low-flow operation as used for current ECCO2R applications.
Therefore, the concept of ECCO2R, which has been proposed as a safer alternative to ECMO due to the lower blood flow rates and smaller cannulae, used is questionable. In fact, the degree of adverse effects attributable to ECCO2R in clinical trials has been notably high, belying this notion. The role of blood pumps in contributing to adverse effects at the lower blood flow rates used during ECCO2R so far has not been well described. This study demonstrates that, at least in the case of the three pumps studied here, the role is significant. Current rotary blood pumps, such as the DP3, Rotaflow, or Revolution, should be used with caution if operated at blood flow rates below 2 L/min, because of significant and high recirculation, shear stress, and hemolysis.
Hemolysis, platelet function, and bleeding complications should be closely monitored in routine clinical practice and certainly within the context of clinical trials.
Limitations of the study
Blood damage models are under continuous development and subjected to certain limitations. The strength of current hemolysis models is the qualitative rather than the quantitative analysis. For example, in the context of a high blood recirculation, important correlations such as the cell damage history, which might influence the way a blood cell reacts when exposed to shear stress, are not taken into account. However, numerical predictions and experimentally determined hemolysis results show a very high correlation . Moreover, this study focuses on three frequently used rotary blood pumps. Other rotary pumps or different pump systems (e.g., roller pumps) were not tested and may behave differently. Further experimental hemolysis testing of low pump flows is therefore advised to also illustrate quantitative differences in the hemolytic performance of the pumps considered in this study and other pump systems in general. However, our results are in line with recent data of flow-induced platelet activation, also demonstrating pump thrombogenicity due to long residence time .
The role of blood pumps in contributing to adverse effects at the lower blood flow rates used during ECCO2R is shown to be significant in this study. Current rotary blood pumps should be used with caution if operated at blood flow rates below 2 L/min, because of significant and high recirculation, shear stress, and hemolysis. There is a clear and urgent need to design dedicated blood pumps for ECCO2R and neonatal/pediatric ECMO applications, which are optimized for blood flow rates in the range of 0.5–1.5 L/min.
We are grateful to Marek Weiler, Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Germany, for helping with the micro-CT scans.
SG, FH, and CK designed the study. SG and FH performed the CFD calculation. SG wrote the main draft of the manuscript. All authors contributed to the final drafting of the manuscript and read and approved the final manuscript.
This study was in part funded by the German Federal Ministry of Education and Research No. 13GW0219B.
Ethics approval and consent to participate
Consent for publication
The manuscript has been read and its submission approved by all co-authors.
CK received travel grants and lecture fees from Maquet, Rastatt, Germany. WW received fees for advisory board meetings and lectures from Maquet Cardiopulmonary, Rastatt, Germany. CK and WW received an open research grant for the hospital from Maquet Cardiopulmonary, Rastatt, Germany. DB reports serving as the co-chair of the trial steering committee for the VENT-AVOID trial sponsored by ALung Technologies; serving on the medical advisory boards for Baxter, BREETHE, and Hemovent (unpaid); and previously serving on the medical advisory board of ALung Technologies. SGH is half-time employed at enmodes GmbH Aachen. FH, JA, LV, and US declare that they have no competing interests.
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