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First Experience With a New Miniaturized Pump-Driven Venovenous Extracorporeal CO2 Removal System (iLA Activve): A Retrospective Data Analysis

Hermann, Alexander; Staudinger, Thomas; Bojic, Andja; Riss, Katharina; Wohlfarth, Philipp; Robak, Oliver; Sperr, Wolfgang R.; Schellongowski, Peter

doi: 10.1097/MAT.0000000000000073

iLA Activve is a new minimally invasive device for extracorporeal CO2 removal (ECCO2-R) using a miniaturized pump, a special gas exchange membrane, and a double-lumen cannula. We retrospectively analyzed our experiences in 12 patients with hypercapnic respiratory failure undergoing ECCO2-R. Indication for ECCO2-R was hypercapnia due to terminal lung failure during bridging to lung transplantation, pneumonia, and chronic obstructive lung disease or asthma. The median duration of ECCO2-R was 8 days (range 2–30). Seven patients were successfully weaned and five died. Patients with primarily hypoxic lung failure were significantly longer ventilated before ECCO2-R and had a higher mortality rate. Complications were retroperitoneal hematoma after cannulation in one patient and repeated system changes because of clotting in two patients. We observed effective CO2 removal in all patients, with significant reduction in ventilation pressures and minute volumes at median blood flow rates of 1.2–1.4 L/min. The iLA Activve system using venous double-lumen cannulas proved to be an effective method for ECCO2-R. Invasiveness of ventilation could be reduced. Additional severe impairment of oxygenation and prolonged mechanical ventilation before ECCO2-R are factors of adverse prognosis. The use of ECCO2-R should be thoroughly reconsidered in these cases.

From the Department of Medicine I, Intensive Care Unit 13i2, Medical University of Vienna, General Hospital of Vienna, Waehringer Guertel, Vienna, Austria.

Disclosure: T.S. and P.S. received speaker fees from Novalung.

Reprint Requests: Peter Schellongowski, MD, Department of Medicine I, Intensive Care Unit 13i2, Medical University of Vienna, General Hospital of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Email:

Extracorporeal CO2 removal (ECCO2-R) has the ability to enable tidal volume reduction even beyond current standard of care lung-protective ventilation from the currently recommended 6 ml/kg ideal body weight toward the range of 3–4 ml/kg. Although this concept called “ultraprotective ventilation” has been shown to be feasible1,2 and to possibly reduce ventilation-associated pulmonary inflammation,3 no definitive proof of beneficial effects on outcome in patients with severe respiratory failure exists to date.1 In isolated hypercapnic lung failure like in acute exacerbated chronic obstructive lung disease (AECOPD) or in terminal chronic lung failure during bridging to lung transplantation, ECCO2-R may effectively support noninvasive ventilation with the aim to avoid intubation or facilitate weaning from the ventilator.4–6 For effective CO2 elimination, low blood flows from 300 to 1,500 ml/min are sufficient.7 Until recently, ECCO2-R was performed as venovenous extracorporeal membrane oxygenation (VV-ECMO) with low blood flow.8 Recently, novel systems were developed like the DECAP Smart (Hemodec, Salerno, Italy), resembling a gas exchange membrane inserted into a hemofiltration circuit,9 or a pumpless arteriovenous system (“Interventional Lung Assist” [iLA]; Novalung, Heilbronn, Germany) capable to remove CO2 up to 50–60%.2,10 The latter method requires the cannulation of a femoral artery bearing the risk of limb ischemia or bleeding complications in up to 12% of patients, despite following an algorithm of precautions.2 To date, no clinical data using the newly developed iLA Activve system (Novalung) have been published. In the present study, we report on our first experiences with this miniaturized venovenous pump-driven system connected to a single venous double-lumen cannula for the purpose of CO2 elimination in 12 critically ill patients. The aim was to describe indications, efficiency of gas exchange, required gas and blood flow settings, as well as safety and complication rate of the system.

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iLA Activve is a compact extracorporeal gas exchange system driven by a small centrifugal pump and thus resembles a miniaturized VV-ECMO system able to handle blood flow rates from 0.5 to 8 L/min, depending on cannula size and gas exchange membranes used. In our setting, a minimally invasive approach for low- to mid-range blood flow was chosen: The gas exchange membrane used was an iLA membrane ventilator, a polymethylpentene hollow fiber membrane not containing heat exchange fibers optimized for blood flows between 0.5 and 4.5 L/min with a gas exchange area of 1.3 m2. Resistance to blood flow is as low as 7 mm Hg at a blood flow of 1.5 L/min.11–14 A unicaval venous double-lumen cannula (Novaport twin, Novalung) allowed for a single femoral or jugular venous access. The size of the cannulas was 22 F and 17 cm in length for jugular and 24 F and 27 cm for femoral access. To maximize hemocompatibility, tubings and cannulas are heparin coated. Circulating extracorporeal blood volume is approximately 450 ml. Jugular access was the first choice in all patients unless it did not seem advisable (sedated patients with other catheters inserted into the right jugular vein, very small jugular vein, or presence of thrombosis by ultrasound).

The system contains a touch screen monitor to adjust pump speed and to monitor pressures and system performance. Figure 1 shows the system in a patient with cystic fibrosis and graft failure after lung transplantation during bridging to re-transplantation after extubation on ECCO2-R (patient 3 in Table 1).

Table 1

Table 1

Figure 1

Figure 1

Patients were eligible for extracorporeal CO2 elimination when either being hypercapnic leading to respiratory acidosis with a pH of less than 7.25 despite optimized respiratory support or if inacceptable invasive ventilation with inspiratory pressure of more than 35 mbar was necessary to eliminate CO2. After filling the system with 0.9% saline or Ringer’s lactate and checking it for air bubbles, the cannula was inserted percutaneously by Seldinger’s technique and then connected to the system. A target blood flow between 1 L/min and a maximum of 2 L/min was reached by titrating up pump speed. Venous suction pressure was kept below −80 mm Hg to avoid hemolysis. Heparin was started to reach an activated partial thromboplastin time (aPTT) of 50–60 seconds. Oxygen flow through the membrane was started at 2 L/min and increased by steps of 2 L/min every 30 minutes by concomitantly reducing tidal volumes and respiratory rate in ventilated patients until a normalization of pH and acceptable ventilator settings were achieved. According to our ward’s routine protocol, daily reassessments of sedation status and sedation goals were performed. In all patients, the possibility of spontaneous breathing and mental status were assessed at least twice daily and spontaneous breathing trials were performed if clinical criteria according to weaning protocols were met.

The prospectively done routine documentation included demographic data of patients, underlying disease, reason for admission, severity of illness expressed by admission SAPS II score, vital parameters, daily routine blood chemistry, and blood cell counts as well as blood gas analysis at least every 4 hours together with documentation of ventilator settings and machine-related parameters (pump speed, blood flow, and gas flow), in addition to indication for ECCO2-R, duration of extracorporeal therapy, reason for end of ECCO2-R (e.g., weaning, death, “full” ECMO, and lung transplant), changes of components, type of cannula, complications during the course of the therapy, survival, kind of anticoagulation, and body temperature. Indication for full ECMO support was defined as acutely life-threatening hypoxia necessitating blood flows higher than 2 L/min or as PaO2/FiO2 < 80 plus FiO2 > 90% and optimized positive end-expiratory pressure (PEEP) for >12 hours, despite prone position. In our institution, for VV-ECMO a 27 F or 31 F Avalon cannula or a femoro-jugular setting using two cannulas is connected to a circuit containing a gas exchange membrane with integrated heat exchanger.

We retrospectively assessed PaO2/FiO2 ratio and lung injury score15 before inserting the system, as well as duration of mechanical ventilation before inclusion. The study protocol was approved by the local ethical review board according to Austrian law regulations.

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Statistical Analysis

Descriptive statistics were performed by calculating median and range for continuous and percentages for categorical variables. Nonparametric tests were chosen because of the small population studied. To compare groups of indications, the Mann–Whitney U test was used for continuous variables and the Fisher’s exact test was used to compare dichotomous variables. To compare the changes over time, a nonparametric one-way analysis of variance for repeated measures (Friedman test) was used. Dunn’s multiple comparison post-test was used to compare pairs of time points. Calculations were performed by a statistics software package (GraphPad Prism; GraphPad Software, San Diego, CA). Differences with a p less than 0.05 were considered statistically significant.

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Between March 2012 and July 2013, 12 patients experiencing hypercapnic lung failure were treated with the iLA Activve system. Demographics and clinical data before ECCO2-R are shown in Table 1. Indication for ECCO2-R was marked hypercapnia with respiratory acidosis in all cases. According to indication and cause of lung failure, two major groups of patients could be defined: patients undergoing ECCO2-R for primarily hypercapnic lung failure (n = 6) due to obstructive lung disease or fibrosis and patients with primarily hypoxic lung failure plus marked hypercapnia (n = 6). Three patients with primarily hypercapnic lung failure were treated during bridging to lung transplantation or re-transplantation: one patient was treated for AECOPD, one for refractory status asthmaticus, and one for infectious triggered exacerbation of drug-induced lung fibrosis 5 days after weaning from long-term ECMO. The goal of ECCO2-R in these patients was avoidance of intubation in AECOPD in one patient or enabling spontaneous breathing or weaning from mechanical ventilation in the remaining five patients. The group of patients with primarily hypoxic lung failure did not fulfill criteria for full ECMO support, yet underwent highly invasive mechanical ventilation. Major goal of ECCO2-R was therefore to achieve less invasive ventilation settings by reducing tidal volumes, thus enabling higher PEEP levels or spontaneous breathing. Four of these patients had been ventilated for more than 2 weeks before ECCO2-R.

Four patients received a 24 F femoral and eight patients a 22 F jugular double-lumen cannula. Within the first 4 hours on the iLA Activve system, effective CO2 removal was observed in all patients with concomitant normalization of pH. Tidal volumes and inspiratory peak pressures as well as minute volumes could be reduced significantly within the first 24 hours. Table 2 lists the course of clinical parameters during the first 48 hours of treatment. Eleven patients received heparin from the beginning, one did not due to bleeding diathesis. In one patient, a retroperitoneal hematoma occurred immediately after cannulation of the femoral vein, probably because of inadvertent puncture of the artery necessitating surgical drainage of the hematoma. During this intervention, the cannula was changed to the right jugular vein without further complications. No further bleeding events were observed. Overall, platelet count decreased significantly within the first 48 hours, yet remained stable in patients with prolonged treatment. In one patient, the system had to be changed four times due to clotting of the membrane after 7, 8, 14, and 20 days, respectively, despite anticoagulation to the preset goal and even after increased heparin dose to achieve a higher aPTT of 70–80 seconds. In another patient, a system change due to clotting was necessary after 3 days.

Table 2

Table 2

The median duration of ECCO2-R was 8 days (range 2–30 days). Six patients were successfully weaned from the system and survived to hospital discharge, one patient (patient 9 in Table 1) had to be switched to VV-ECMO due to deterioration of oxygenation on the second day and survived, and five patients died while being treated. Nonsurvivors had a significantly poorer oxygenation and were ventilated significantly longer before initiating ECCO2-R. Primarily hypercapnic respiratory failure was associated with a better outcome (Table 3). Five patients were awake and breathing spontaneously during ECCO2-R: One patient experiencing AECOPD (patient 1 in Table 1) was treated for failure of noninvasive ventilation, thus avoiding intubation. One patient (patient 3) was treated during bridging to lung transplantation and could be extubated the day following initiation of ECCO2-R. He was successfully bridged to transplantation breathing spontaneously. One patient during bridging to transplantation, one patient with refractory status asthmaticus, and one patient with pulmonary fibrosis could be weaned to assisted spontaneous breathing via a tracheostomy cannula allowing communication and mobilization after 2 (patients 2 and 6) and 3 days (patient 5), respectively.

Table 3

Table 3

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Extracorporeal CO2 removal has become increasingly popular during the past years. While to date no reliable data to prove any benefit on outcome by removing CO2 from the blood while applying so called ultraprotective ventilation exist,1 several articles on beneficial effects regarding avoidance of intubation or at least enabling spontaneous breathing in patients experiencing hypercapnic lung failure have been published.5,6,11,16,17 Effective CO2 elimination can be achieved at blood flows as low as 300 ml/min, reaching a maximum at approximately 1,000 ml/min7 and does not require the higher blood flows typically needed to correct hypoxemia. Therefore, an ideal device to achieve effective extracorporeal CO2 elimination should be able to provide low blood flow without having issues with circuit thrombosis, should be easy to handle and of minimal invasivity, as well as should enable the patient to be awake, breathing spontaneously, and being mobile. Our setting allowed for low extracorporeal blood volume, an easy to place single cannula, and a low-resistance gas exchange membrane specially optimized for low- and mid-range blood flows. In case of developing severe hypoxia, however, a change of settings allowing for higher blood flows might be necessary.

The main results of our retrospective analysis show that the iLA Activve system removed CO2 efficiently and enabled fast resolution of acidosis. As a consequence, a significant reduction in inspiratory pressures and minute ventilation could be achieved. Reduction of tidal volumes to “protective ventilation” settings is an established strategy to avoid ventilator-associated lung injury to improve outcome.18 In our study, no major oxygenation effect could be observed. Except for one patient, who required full ECMO support after 2 days of ECCO2-R, oxygenation could be maintained despite reduction of tidal volumes.

Five patients died while receiving iLA Activve treatment and seven were weaned successfully and survived. Adverse outcome was associated with worse gas exchange expressed by higher lung injury scores and poorer oxygenation. We also found time of mechanical ventilation before establishing ECCO2-R to be negatively associated with outcome. Similar results have been reported in patients on ECMO19–21 and might reflect severe and irreversible damage of lung parenchyma. In patients with hypercapnia due to severe structural damage of lung parenchyma without the option of transplantation, ECCO2-R as “bridge to recovery” obviously seems less fruitful. None but one of the patients fulfilled inclusion criteria for full ECMO support and none died due to hypoxia. In one patient (patient 9 in Table 1), oxygenation deteriorated and the setting of the extracorporeal circuit was modified to allow full VV-ECMO support. The aim of ECCO2-R in the group of patients with primarily hypoxic lung failure was to achieve more protective ventilator settings and also to enable partial spontaneous ventilation for possible improvement of oxygenation. Although none of these patients could be weaned to full assisted breathing being awake, this concept could be mostly accomplished. We assume that the high mortality derives from patient selection. Most patients had been ventilated for more than 2 weeks before transfer to our ward and initiation of ECCO2-R. In comparable situations, extracorporeal gas exchange with the intention of bridging to recovery should at least be thoroughly reconsidered.

Possible advantages of using a miniaturized centrifugal pump have been described in the past.22 Easy insertion of cannulas, simple filling and starting the extracorporeal circuit, less extracorporeal blood volume, and sustainable mobility of patients offer an intriguing perspective for a more widespread use of these systems. Nevertheless, application of a pump-driven extracorporeal lung assist device is still associated with a considerable rate of complications, particularly mechanical, thromboembolic, and bleeding events.19,23,24 With the development of novel techniques like heparin coating of tubes and cannulas, new materials for gas exchange membranes, magnetically suspended centrifugal pumps, and a new generation of cannulas, the incidence of complications seems to have decreased.25–29 No reports on the use of the miniaturized pump-driven systems described herein exist to date. Less extracorporeal blood volume, a smaller surface of the circuit, smaller pumps, and specially developed membranes with minimal resistance to blood flow may contribute to even lower rates of side effects. However, in a case series of five patients with chronic obstructive lung disease using a bicaval jugular cannula connected to a conventional VV-ECMO circuit, effective CO2 elimination and ambulation could be achieved without major device-related complications.6 Any possible advantages of the setting described herein because of lower membrane resistance or smaller extracorporeal volume cannot be derived from our data. With both settings, moderate anticoagulation with an aPTT goal of approximately 50 seconds was feasible.

One major complication—a retroperitoneal hematoma due to an inadvertent arterial puncture of the artery while trying to place the cannula—occurred in one patient. In another two patients, the circuit had to be changed repeatedly due to clotting of the membrane. Changing the circuit due to loss of efficacy and membrane clotting can be observed with all extracorporeal gas exchange procedures. In our patients, circuit changes were performed without adverse sequelae for patients and were not regarded as major complications. No signs of major hemolysis were observed. Platelet count decreased significantly to a clinically moderate extent. A decrease in platelet count is well-known in patients on extracorporeal circuits.30 Heparin was used to increase aPTT to a moderate level of 50–60 seconds, which seems to be sufficient for effective anticoagulation without a significant risk of bleeding. Despite the lack of a heating system, no major loss of body temperature occurred in our patients. Temperature management could be achieved using blankets and heated beds.

The aim of our study was to report a first experience on a novel system used as an extracorporeal CO2—elimination device. We herein report on a very heterogeneous group of patients, thus limiting interpretation of any comparisons. Some patients were receiving ECCO2-R for reduction in tidal volumes and airway pressures, and others were receiving it for primarily hypercapnic respiratory failure as bridge to recovery or transplantation. Extracorporeal CO2 removal has the potential to be applied to patients with varying forms of respiratory failure; however, because of the small number of patients and the retrospective nature of our analysis, the presented data are encouraging but should be regarded as preliminary. Reports on larger series of patients will be necessary to optimize indications and settings, as well as to avoid complications.

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Our first report on a series of 12 patients with hypercapnic lung failure undergoing ECCO2-R using a newly developed device (iLA Activve) proves that effective decarboxylation leading to reduction of ventilation pressures and facilitating spontaneous breathing is feasible. Additional severe impairment of oxygenation or prolonged mechanical ventilation before ECCO2-R are factors of adverse prognosis. The use of ECCO2-R should be thoroughly reconsidered in these cases. Although the complication rate seems to be moderate, because of the complexity of management this kind of therapy should be limited to experienced centers.

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ECCO2-R; iLA Activve; hypercapnia; decarboxylation; extracorporeal

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