Morales‑Quinteros et al. Ann. Intensive Care (2019) 9:79 https://doi.org/10.1186/s13613-019-0551-6 REVIEW Open Access Extracorporeal carbon dioxide removal for acute hypercapnic respiratory failure Luis Morales‑Quinteros1* , Lorenzo Del Sorbo2 and Antonio Artigas1,3,4 Abstract In the past, the only treatment of acute exacerbations of obstructive diseases with hypercapnic respiratory failure refractory to medical treatment was invasive mechanical ventilation (IMV). Considerable technical improvements transformed extracorporeal techniques for carbon dioxide removal in an attractive option to avoid worsening respiratory failure and respiratory acidosis, and to potentially prevent or shorten the duration of IMV in patients with exacerbation of COPD and asthma. In this review, we will present a summary of the pathophysiological rationale and evidence of E­ CCO2R in patients with severe exacerbations of these pathologies. Keywords: COPD, Asthma, ECCO2R, Invasive mechanical ventilation, Noninvasive mechanical ventilation Background In recent years, a new generation of ­ECCO2R devices Patients with obstructive lung diseases, such as asthma has been developed. More efficient veno-venous (VV)- and chronic obstructive pulmonary disease (COPD), ECCO2R devices have become available and have may experience acute exacerbations with severe hyper- replaced the arterio-venous approach, having the advan- capnic respiratory failure. Hypercapnia results from tage of not requiring arterial puncture. acute worsening of expiratory flow limitation caused by The new VV-ECCO2R devices offer lower resistance to the increased small airway resistance with consequent blood flow, have smaller priming volumes, and provide development of dynamic alveolar hyperinflation and a much more efficient gas exchange with relatively low intrinsic positive end-expiratory pressure (PEEP). In the extracorporeal blood flows (0.4–1 L/min) [2]. The tech- most severe cases, these may be refractory to conven- nology of these devices is now comparable to that of renal tional therapies and mechanical ventilation, becoming dialysis and has been experimented in several animal and life-threatening. human studies, demonstrating significant reduction in Extracorporeal carbon dioxide removal ­(ECCO2R) rep- arterial ­CO2 and improvement in the work of breathing resents an attractive approach in this setting. [3–6]. The last decade has seen an increasing interest in the provision of extracorporeal support for respiratory fail- Pathophysiological rationale for ­ECCO2R ure, as demonstrated by the progressively increasing in obstructive lung diseases number of scientific publications on this topic. In par- In both asthma and COPD exacerbations, diffuse nar- ticular, remarkable interest has been focused on extra- rowing of the airways results in detrimental physiologi- corporeal carbon dioxide removal ­ (ECCO2R), due to cal consequences. Airway narrowing prevents the lungs the relative ease and efficiency in blood ­CO2 clearance from completely emptying (“air trapping”) due to resist- granted by extracorporeal gas exchangers as compared to ance to expiratory flow and bronchial closure at higher oxygen delivery [1]. than normal lung volumes. Air trapping results in dynamic hyperinflation (DHI) [7] which is the excessive increase in end-expiratory lung volume above the relaxa- *Correspondence: luchomq2077@gmail.com tion volume of the respiratory system, generating intrin- 1 Intensive Care Unit, Hospital Universitario Sagrado Corazón, Barcelona, sic positive end-expiratory pressure (auto-PEEP) [8]. As a Spain Full list of author information is available at the end of the article result, the patient breathes at higher total lung volumes, © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Morales‑Quinteros et al. Ann. Intensive Care (2019) 9:79 Page 2 of 11 due to increased residual volume [9], which may reduce ECCO2R technical aspects and principle tidal ventilation. The net effect is that the work of breath- ECCO2R is designed to remove carbon dioxide (­CO2) ing increases significantly. The diaphragm, intercostal and, unlike extracorporeal membrane oxygen (ECMO), muscles, and even the abdominal muscles are overloaded does not provide significant oxygenation. causing respiratory muscle fatigue and dyspnea [10]. The device consists of a drainage cannula placed in a Pharmacotherapy with bronchodilators and systemic large central vein or artery, a membrane lung (artificial corticosteroids are part of the medical therapies, admin- gas exchanger), and a return cannula into the venous istered specifically to reduce the pathophysiological air- system (Fig. 1). Blood is pumped through the membrane flow obstruction and improve symptoms. lung, and ­CO2 is removed by diffusion. A flowing gas The recognition for the need for noninvasive ventila- known as “sweep gas” containing little or no ­CO2 runs tion (NIV) is indicated if the patient fails to improve clin- along the other side of the membrane, ensuring a diffu- ically and if the level of pH remains less than 7.32 despite sion gradient from blood to the other side, hence pro- medical therapy [11]. However, NIV fails in up to 20–30% moting ­CO2 removal. of patients and IMV is indicated with specific ventilation In contrast to ECMO, where the need for oxygenation strategies, targeting relative short inspiratory time and requires high blood flow rates, ­ECCO2R requires much longer expiratory time [12, 13]. lower blood flow rates, due to the significant differences Overall, the goal of mechanical ventilation is to provide in ­CO2 and oxygen (­O2) kinetics. Almost all the O ­ 2 in adequate gas exchange and reduce the work of breathing blood is carried by hemoglobin, which displays sigmoidal while waiting for airflow obstruction to resolve. How- saturation kinetics. Assuming normal hemoglobin and ever, mechanical ventilation itself may aggravate alveo- venous ­O2 content, each liter of venous blood can only lar hyperinflation by worsening DHI, which may lead carry an extra 40–60 mL of O ­ 2 before the hemoglobin to worsened hypercapnia, barotrauma, alveolar rupture is fully saturated. Blood flows of 5–7 L/min through the leading to pneumothorax and further hemodynamic extracorporeal artificial membrane lung are therefore deterioration [14]. required to supply enough ­O2 for an average adult. Con- Furthermore, if treated with IMV, these patients receive versely, most ­CO2 in blood is dissolved or in the form of sedatives and likely neuromuscular blockade to facilitate bicarbonate, displaying linear kinetics without satura- ventilatory support [15]. Sedation and paralysis preclude tion. Considering that 1 L of blood is transported around mobilization, promoting neuromuscular deconditioning, 500 mL of ­CO2, in a perfectly efficient system flow of 0.5 and potentially contributing to the long-term cognitive L/min would be enough to remove all of the C ­ O2 pro- sequelae of critical illness [16]. duced by an average adult, which is about 250 mL/min [2, When conventional therapeutic options are not suc- 17, 18]. Also, C­ O2 diffuses more readily than ­O2 across cessful, novel therapies such as extracorporeal life sup- extracorporeal membranes because of higher solubility. port are entertained as a possible salvage therapeutic However, in practice, E ­ CCO2R is usually able to remove modality. up to 25% of carbon dioxide production given the limi- During exacerbation, relieving the native lung from at tations of blood flow and membrane efficiency [19]. As least part of the ­CO2 elimination with ­ECCO2R could the rate of C­ O2 clearance greatly depends on the fresh potentially improve the acid–base balance, reduce sweep gas flow through the membrane lung, this is usu- patient’s work of breathing with a consequent reduction ally maximized in the low blood flow ­ECCO2R systems. in respiratory rate and ventilatory drive, and lower alveo- Therefore, the efficiency of ­CO2 clearance of the different lar ventilation. The lower tidal volumes and respiratory available devices is critically determined by other impor- rate result in the extension of the expiratory time, suit- tant parameters, including the size of the cannula, the ing better the high expiratory time constant of the res- rate of recirculation of blood in the circuit, the efficiency piratory system with expiratory flow limitation. By these of the pump, the total surface area of the artificial lung, physiological mechanisms, ­ECCO2R can counteract the and the cardiac preload [20, 21]. Importantly, given the vicious circle of dynamic hyperinflation, and its detri- low blood flow through the extracorporeal circuit and the mental respiratory and cardiovascular consequences. The even lower flow achieved when the blood is crossing the derived beneficial effects on respiratory mechanics, ven- large surface area of the artificial gas exchanger, the risk tilatory muscle efficiency, work of breathing, and cardio- of thrombosis plays also a key role in C­ O2 clearance. vascular function may improve gas exchanges and relieve dyspnea. By these mechanisms, ­ECCO2R thus can poten- VV‑ECCO2R tially prevent NIV failure, facilitate weaning from IMV, In the veno-venous configuration, blood is drawn from a and therefore contribute to avoid the unwanted compli- central vein by a draining cannula, using a centrifugal or cations of sedation and immobilization. roller pump to generate flow across the membrane. ­CO2 Morales‑Quinteros et al. Ann. Intensive Care (2019) 9:79 Page 3 of 11 Fig. 1 ECCO2R common configurations. a Minimally invasive veno-venous E­ CCO2R system with a single venous vascular access through a double-lumen cannula that can be inserted in the internal jugular or femoral vein. b Pumpless arterio-venous ­ECCO2R system with the placement of the membrane in the circuit connecting the femoral artery with the contralateral vein. *PaCO2 values are purely indicative is removed by the effect of the “sweep gas,” and blood is m2, which is unsuitable for hemodynamically unstable then returned into the venous circulation (Fig. 1a). Sin- patients [18, 24]. Furthermore, cannulation of a major gle site cannulation is possible using a double-lumen artery can result in distal ischemia [25], although meas- cannula. This approach allows ­ECCO2R through the use uring the artery diameter with ultrasound and selecting a of smaller cannulas (15-19F), commonly introduced via cannula that occupies less than 70% of the lumen reduces the right internal jugular vein. The setup is very simi- this risk [26]. lar to renal replacement therapy, and in fact, some sys- tems are trying to combine the two in one [22, 23] Indications and evidence (NCT02590575). One of the advantages of VV-ECCO2R Chronic obstructive pulmonary disease compared to the AV approach is the less invasiveness by Chronic obstructive pulmonary disease (COPD) is a avoiding arterial cannulation, and the potential for early significant worldwide health burden. Currently, it is mobilization of patients. It is also possible to set up an the fourth leading cause of death worldwide, and is the ­ECCO2R system through cannulation of two central only leading cause of death that is rising, and will likely veins, one for drainage and the other for reinfusion (e.g., become the third cause of death by 2020 [27, 28]. femoral–femoral configuration). Acute exacerbations of COPD (aeCOPD) constitute a significant cause of morbidity and mortality among AV‑ECCO2R these patients. Patients with moderate to severe acute In the AV-ECCO2R configuration, the blood flows from exacerbations develop alveolar hyperinflation that may the femoral artery, usually instrumented with percutane- lead to increased work of breathing, muscle fatigue, and ous cannulation, to the contralateral femoral vein, creat- hypercapnia, creating a vicious loop refractory to medi- ing a pumpless arterio-venous (AV) bypass, equipped cal treatment [29–31]. The standard respiratory support with an artificial gas exchanger across the AV shunt, in this setting is NIV, which however, fails in up to 30% which allows the “sweep gas” to remove ­CO2 (Fig. 1b). of patients with aeCOPD, prompting intubation and IMV This pumpless systems require an arterio-venous pres- [32–34]. In recent meta-analysis and observational stud- sure gradient ≥ 60 mmHg and a cardiac index > 3 L/min/ ies, it has been reported that the in-hospital mortality Morales‑Quinteros et al. Ann. Intensive Care (2019) 9:79 Page 4 of 11 of patients with aeCOPD requiring IMV is as high as from MV. With ­ECCO2R, none of the patients failing 25–39% [35–38]. NIV required endotracheal intubation, and both patients Patients with COPD requiring IMV develop a consider- with difficult weaning from NIV were weaned. However, able reduction in respiratory muscle strength, with higher only three of the 11 IMV patients were liberated suc- risk of prolonged weaning and/or failure to wean, com- cessfully. Moreover, significant complications arose in a pared to other causes of acute hypercapnic respiratory number of patients: bleeding requiring blood transfusion failure. Up to 60% of the ventilatory time in these patients was reported in three patients, deep vein thrombosis was is spent for weaning [39] and is very likely to require a diagnosed in one patient after removal of the ­ECCO2R tracheotomy. The prolonged time on IMV results in an catheter, one patient experienced pneumothorax due to increased potential risk of ventilator-induced lung injury, catheter insertion, and one died from hemorrhage when ventilator-associated pneumonia, and ventilator-induced the iliac vein was perforated during ­ECCO2R catheter diaphragmatic dysfunction, in addition to the above- placement. mentioned complications associated with prolonged Del Sorbo et al. [4] compared 25 patients with aeCOPD sedation and immobilization. treated with NIV + VV ­ECCO2R versus 21 historical con- trols treated with NIV alone with regard to the cumula- Evidence and clinical trials of ­ECCO2R in aeCOPD to date tive incidence of intubation. They reported that E ­ CCO2R One of the first reports on the application of ­ECCO2R to with a 14-Fr dual-lumen catheter and blood flow rates of support respiratory function of a COPD patient was pub- 177–333 mL/min not only improved respiratory acidosis lished in Pesenti et al. [40]. However, the technique was but also reduced the need for intubation by 75% (12% vs. abandoned due to technical complications. 33%; p = 0.047) and significantly reduced the in-hospital As the medical community regained interest in mortality (8% vs. 35%; p = 0.035). However, this came ­ECCO2R, investigators began applying the technique to with a cost of 52% prevalence of E ­ CCO2R-related side prevent intubation or to assist weaning from IMV in this effects and led the authors to suggest the end point of patients’ population. Several studies in both VV and AV future studies should be long-term mortality. configurations were published, including a meta-analysis Braune et al. [43] in the ECLAIR study showed that (Table 1). IMV was avoided in 56% of cases treated with VV ­ECCO2R, which was associated with a high incidence of ECCO2R to avoid IMV complications. However, in this study, there was an inclu- Brederlau et al. [41] described their experience in three sion of patients with relative contraindications to NIV, patients that failed NIV for severe aeCOPD. They applied and there was an unexpectedly high incidence of hypox- a pumpless AV E ­ CCO2R device with the goal of avoid- emic patients [44]. ing endotracheal intubation. The E ­ CCO2R flow ranged Finally, Morelli et al. [45] confirmed the efficacy of VV between 1.1 and 1.6 L/min, with the sweep gas flow vary- ­ECCO2R (with a flow rate of 250–450 mL/min through ing from 3 to 10 L/min. Shortly after beginning E ­ CCO2R, a 13-Fr dual-lumen cannula) in reducing the P ­ aCO2 in a the ­PaCO2 fell significantly, and also the respiratory rate series of 30 patients with acute hypercapnic respiratory dropped from 38, 45, and 37 breaths/min to 15, 25, and failure due to aeCOPD, who refused endotracheal intu- 18 breaths/min, respectively. bation after failing NIV. The duration of ­ECCO2R was Kluge et al. [5] in the same year evaluated the safety 2–16 days, and it was possible to prevent endotracheal and efficacy of using an AV pumpless extracorporeal lung intubation in 27 patients. assist in 21 COPD patients who did not respond to NIV and compared them to 21 matched controls treated with ECCO2R to facilitate weaning from IMV IMV. The use of AV E ­ CCO2R resulted in the decrease of Cardenas et al. [46] made the first attempt to use mod- ­PaCO2 after 24 h and obviated the need for IMV in 90% ern ECLS components for VV ­ECCO2R in a patient with of the experimental arm. Although the experimental aeCOPD. They demonstrated a successful reduction in group had a shorter hospital length of stay, there was no ­PaCO2, minute ventilation, and ventilator pressures. significant difference in mortality at 28 days (19% with Burki et al. [42] in a subgroup of 11 patients receiving ­ECCO2R vs. 24% without ­ECCO2R) or 6 months (both IMV, ­ECCO2R allowed the weaning from mechanical groups 33%) compared to the control group. ventilator in only three patients. Burki et al. [42] treated 20 hypercapnic COPD patients Abrams et al. [3] reported five older patients (age with VV ­ECCO2R through a 15.5-Fr dual-lumen can- 73 ± 8.7 years) with aeCOPD who failed NIV, requiring nula achieving a mean blood flow of 430 mL/min. Of the IMV. After an average of 16.5 ± 5.9 h of IMV, ­ECCO2R 20 patients, seven were at risk of failing NIV, two were was initiated. By using a dual-lumen cannula (20–23 difficult to wean from NIV, and 11 had failed liberation Fr) with blood flow rates of 1–1.7 Lt/min, with a sweep Table 1 Relevant clinical studies of ­ECCO2R in COPD References No. of patients ECCO2R characteristics Time on ­ECCO2R Major results Configuration Blood Sweep flow (L/min) Membrane (material); surface flow (mL/ in ­m2 min) ECCO2R to avoid mechanical ventilation Kluge et al. [5] 21 Femoral AV with 13- to 15-Fr 1100 Not reported PMP; 1.3 ­(iLA®) 9 days 19 (90%) PECLA patients did not arterial cannula and 13- to require intubation 17-Fr venous cannula Two major and seven minor bleeding complications during PECLA No significant difference in Morales‑Quinteros et al. Ann. Intensive Care 28-day (24 vs. 19%, p = 0.85), 6-month mortality (33 vs. 33%), or hospital length of stay (23 vs. 42 days, p = 0.06) Significantly fewer tracheosto‑ mies in PECLA group (10 vs. (2019) 9:79 67%, p = 0.004) Del Sorbo et al. [4] 25 Modified continuous VV 255 8 PLP; 1.35 (Hemodec 1–2 days Significantly higher risk of intuba‑ hemofiltration system with ­DecapSmart®) tion in NIV-only group (HR 0.27; membrane 95% CI 0.07–0.98) lung via 14-Fr single dual-lumen 13 patients experienced adverse cannula (femoral) events: three had bleeding, one had vein perforation, and nine had device malfunction Braune et al. [43] 25 VV configuration via a 22 or 1300 Not reported PMP; 1.3 (Novalung iLA Activve) 8.5 days Intubation was avoided in 14 out 24-Fr single dual-lumen can‑ of all 25 ­ECCO2R patients (56%) nula (femoral or jugular) Seven ­ECCO2R patients were intubated because of progres‑ sive hypoxemia and four due to ventilatory failure despite ­ECCO2R and NIV Nine ­ECCO2R patients (36%) suffered from major bleeding complications 90-day mortality rates were 28 vs. 28% Page 5 of 11 Table 1 (continued) Study No. of patients ECCO2R characteristics Time on ­ECCO2R Major results 2 Configuration Blood Sweep flow (mL/min) Membrane surface ­(m ) flow (mL/ min) ECCO2R to facilitate liberation from mechanical ventilation Abrams et al. [3] 5 VV configuration via a 20- to 1700 1–7 PMP; 0.98 (Maquet PALP 8 days Mean (SD) time to ambulation 24-Fr single dual-lumen CardioHelp) after ­ECCO2R initiation was jugular 29.4 ± 12.6 h catheter using lower flow on Four patients were discharged ECMO system home, and one underwent planned lung transplantation Morales‑Quinteros et al. Ann. Intensive Care Only two minor bleeding com‑ plications Cardenas et al. [46] 1 VV configuration with pediatric 800 10 PMP; 1.8 (Quadrox-d, Maquet) 3.6 days Patient extubated 48 h after dual-lumen jugular cannula decannulation. No complica‑ tions reported Roncon et al. [47] (2019) 9:79 ECCO2R with mixed indications Burki [42] 20 VV configuration via a 15.5-Fr 430 Not reported PLP with a base of siloxane 2–192 h 20 hypercapnic COPD patients single dual-lumen catheter layer; 0.59 (ALung Hemolung received ­ECCO2R in three (femoral or jugular) RAS) distinct groups: group 1 (n = 7) NIV patients with high risk of IMV; group 2 (n = 2) could not be weaned from NIV; and group 3 (n = 11) on IMV and failed to wean IMV avoided in all patient in group 1 Both patients in group 2 weaned from NIV In group 3, three patients weaned, and IMV was reduced in two patients One patient died due to a retro‑ peritoneal hemorrhage (during cannulation) PMP poly-4-methyl-1-pentene, PLP polypropylene Page 6 of 11 Morales‑Quinteros et al. Ann. Intensive Care (2019) 9:79 Page 7 of 11 gas flow from 1 to 7 L/min, they were able to extubate reverse airflow obstruction. β2 agonists and steroids are all five patients within 24 h of treatment (median dura- the mainstays of treatment [12]. Other available adjunct tion of MV post E ­ CCO2R = 4 h, range 1.5–21.5 h). Once therapies including anticholinergics, magnesium sulfate, extubated, patients were rehabilitated while on ­ECCO2R, methylxanthines, ketamine, and heliox have been utilized with a mean time to ambulation of 29.4 ± 12.6 h after with varying results [48]. ­ECCO2R. Moreover, all patients survived to hospital Despite advances in asthma therapy, asthma mortal- discharge. ity has remained stable in recent years. One reason is the Roncon-Albuquerque Jr. et al. [47] using a pediatric occurrence of status asthmaticus, which can be unre- VV ECMO system (with blood flow rates of 0.9 L/min sponsive to initial treatment and may lead to hypercapnic through a 19 Fr dual-lumen cannula placed in the right respiratory failure despite maximal therapy, and in the jugular vein) in two patients with aeCOPD reported early most severe cases requires IMV. extubation after 72 h and patient mobilization out of bed Approximately, 4% of all patients hospitalized for acute at day 6. asthma require IMV, which is associated with increased in-hospital mortality compared with patients who do not Future studies on E­ CCO2R for COPD require mechanical ventilation (7 vs. 0.2%) [49]. More data will be forthcoming on the application of Although necessary, mechanical ventilation may aggra- ­ECCO2R in the management of patients with COPD vate alveolar hyperinflation as it was described above. To exacerbations from a number of ongoing or planned clin- prevent these potential detrimental effects, E­ CCO2R has ical trials (Table 2). been applied as rescue therapy. Despite the strong physiological rationale, the exist- ECCO2R as an adjunct to IMV for refractory asthma ing data are not sufficient to support the routine use of was first reported in 1981 [50]. Subsequently, several ­ECCO2R in patients with aeCOPD, as randomized con- case series have been reported (Table 3) [51–55]. In the trolled trials investigating the efficacy of ­ ECCO2R in international Extracorporeal Life Support Organization improving important patient centered outcome are lack- (ELSO) registry, the use of ECMO for asthma has been ing, and the intervention is associated with a high rate of reported in 24 adult patients between 1986 and 2006. complications. Hypercapnia, rather than hypoxemia, was the main gas Furthermore, the relevant incidence of E ­ CCO2R-related exchange derangement treated with ECMO, suggesting complications considerably affects the choice of the tar- that a less invasive approach, such as low flow E ­ CCO2R, get patient population of randomized controlled tri- could also be suitable in these cases. Indeed, the use of als, and hence their inclusions and exclusion criteria. ­ECCO2R in patients with asthmatic exacerbation has The application of E ­ CCO2R to prevent IMV in aeCOPD been reported, although in a limited number of cases. patients at high risk of NIV failure has a remark- able potential clinical impact, but exposes a number of patients, who will not require IMV, to the unnecessary Complications risk of ­ECCO2R-related complications. The application Although ­ECCO2R seems to be effective in improving or of ­ECCO2R in aeCOPD patients intubated after NIV fail- mitigating hypercapnic acidosis and possibly in reducing ure to accelerate liberation from IMV exposed patients the rate of endotracheal intubation, its use is associated simultaneously to the complications of two invasive with a range of vascular, hematological, and other com- treatments. In both scenarios, given the high mortal- plications (Table 4). ity rate associated with IMV in this obviously vulnerable Arterial cannulation is associated with higher risk patient population, these studies should be powered to than venous catheterization, with specific complications demonstrate a mortality benefit. including distal limb ischemia, compartment syndrome The development of new E ­ CCO2R technology with less of the lower limb requiring fasciotomy or limb amputa- associated complications will allow the study of ­ECCO2R tion, as devastating consequences [18]. also in patients with milder severity of aeCOPD or even The occurrence of bleeding events is the most frequent in stable COPD patients to prevent the occurrence of complication of ­ECCO2R. The low flow renders systemic exacerbations. anticoagulation mandatory, increasing the risk of sig- nificant bleeding including cerebral, gastrointestinal, and Severe acute asthma nasopharyngeal bleeds. In the studies on E ­ CCO2R for Asthma is an inflammatory disorder of the airways char- COPD to date, the rate of clinically significant hemor- acterized by airway hyperactivity with bronchospasm, rhagic complications ranges between 2% and 50% [56]. mucosal swelling, and mucus production. The standard Thrombocytopenia is also commonly observed, as well treatment of severe acute asthma consists of measures to as hemolysis. Table 2 Ongoing or completed clinical studies of ­ECCO2R in COPD ClinicalTrials.gov number Title Type of study Hypothesis/primary outcome Estimated enrollment Device Status ECCO2R to avoid mechanical ventilation NCT02564406 Extracorporeal ­CO2 removal in Interventional single-group trial Retrospectively assess the efficacy 35 patients ProLUNG [Estor] Completed hypercapnic patients and safety of noninvasive ventilation-plus-extracorporeal ­CO2 removal in patients who fail NIV and refuse endotracheal intubation Primary outcome: Number of patients who avoided endotra‑ Morales‑Quinteros et al. Ann. Intensive Care cheal intubation NCT03692117 Prospective cohort study Primary outcome: Incidence of 30 patients Not specified Recruiting avoiding endotracheal intubation ECCO2R as an alternative or adjunct to invasive mechanical ventilation (2019) 9:79 NCT03255057 Extracorporeal ­CO2 removal for Multicenter randomized controlled ECCO2R can be safely used to 500 patients Hemolung Recruiting mechanical ventilation avoidance trial avoid or reduce time on invasive during acute exacerbation of mechanical ventilation compared COPD (VENT-AVOID) to COPD patients treated with standard-of-care mechanical ventilation alone Primary outcome: Ventilator-free days at day 60 from randomization ECCO2R physiological studies NCT02586948 Physiological study of minimally Interventional single-group trial The addition of minimally invasive 12 patients Hemolung Completed invasive ­ECCO2R in exacerba‑ ­ECCO2R is likely to limit dynamic tions of COPD requiring invasive hyperinflation in COPD patients mechanical ventilation (EPHEBE) requiring invasive mechanical ven‑ tilation for an acute exacerbation while improving gas exchange Primary outcome: PEEPi at baseline and after ­ECCO2R by the device and adjustment of ventilator set‑ tings, expressed in cmH20 NCT02590575 Interventional single-group trial Test the effectiveness of a mem‑ 20 patients Prismalung Completed brane gas exchange device in the veno-venous circulation of con‑ tinuous renal replacement therapy for the purpose of CO2 elimina‑ tion and pH compensation The primary outcome is the modi‑ fication of the P ­ aCO2 and/or the ventilator settings (tidal volume VT and plateau pressure Pplat) Page 8 of 11 Table 3 Case series of ­ECCO2R for near fatal asthma References ECCO2R technique Major findings Sakai et al. [52] Extracorporeal lung assist (ECLA); 22 Fr drainage and 18 Fr return femoro-femoral 23 year old cannula with a median blood flow rate of 1.7–2 L/min Gas exchange with IMV before ­ECCO2R: pH 7.02, ­paCO2 100 mmHg, ­PaO2 50 mmHg ­(FiO2 Morales‑Quinteros et al. Ann. Intensive Care 100%) Weaning achieved after 20 h of ECLA was commenced Extubation 2 days after ECLA No complications reported Elliot et al. [53] Femoral AV pumpless extracorporeal lung assist (PECLA) Case 1: 74 year old. Gas exchange with IMV before ­ECCO2R: pH 6.87, ­paCO2 147 mmHg. 15-Fr arterial cannula and 17-Fr venous cannula with a mean extracorporeal blood flow Extubation after 48 h of ECLA. Complications: Coagulation of membrane that needed (2019) 9:79 of 1.5 L/min changing. Bleeding through femoral artery Case 2: 52 year old. Gas exchange with IMV before ­ECCO2R: pH 7.2, ­paCO2 130 mmHg. ­ECCO2R duration: 5 days Extubated on intensive care day 11. No complications reported Jung et al. [54] Femoral AV pumpless extracorporeal lung assist (PECLA) 42 year old 15-Fr arterial cannula and 17-Fr venous cannula with a mean extracorporeal blood flow No gas exchange before IMV reported. Patient successfully extubated and transferred of > 1.5 L/min from the ICU on day 14 of admission No complications reported Brenner et al. [51] Dual-lumen catheter 20–23 Fr bicaval, inserted into the right internal jugular vein with Case 1: 48 years old. Gas exchange with IMV before ­ECCO2R: pH 6.94, ­paCO2 147 mmHg, blood flow of 1.3 to 1.8 L/min ­PaO2 416 mmHg (­ FiO2 100%). Successfully extubated while on ­ECCO2R and discharged from ICU. No complications reported Case 2: 59 years old. Gas exchange with IMV before ­ECCO2R: pH 7.12, ­paCO2 78 mmHg, ­PaO2 112 mmHg (­ FiO2 100%). ­ECCO2R duration: 9 days. Ventilator support discontinued on day 28 due to critical illness neuromyopathy Schneider et al. [55] Awake dual-lumen catheter 22 Fr bicaval, inserted into the right internal jugular vein 67 years old with blood flow of 0.6–1.5 L/min Gas exchange before ­ECCO2R (on NIV): pH 7.24, ­paCO2 61 mmHg, ­PaO2 289 mmHg ­(FiO2 100%) Thirty-four hours after initiating ­ECCO2R, the patient was weaned entirely from NIV, and the cannula could be removed without any complication. On day 4, the patient was discharged from the ICU without the need for supplemental oxygen and 6 days later, discharged from hospital without any impairment IMV invasive mechanical ventilation, NIV noninvasive mechanical ventilation Page 9 of 11 Morales‑Quinteros et al. Ann. Intensive Care (2019) 9:79 Page 10 of 11 Table 4 ECCO2R-related complications Authors’ contributions All the authors have contributed equally for the elaboration of this article. All Patient-related complications Anticoagulation-related bleeding authors read and approved the final manuscript. Hemolysis Heparin-induced thrombocytopenia Funding Acquired coagulopathy This article did not receive sponsorship for publication. Recirculation Availability of data and materials Catheter-related complications Catheter-site bleeding Data sharing not applicable to this article as no datasets were generated or Catheter malposition, dislodgement analyzed during the current study. or kinking Catheter infection Ethics approval and consent to participate Vascular occlusion Not applicable. Thrombosis Hematoma, aneurism, pseudoaneu‑ Consent for publication rysm formation Not applicable. Device-related complications Pump failure Oxygenator failure Competing interests Heat-exchanger malfunction The authors declare that they have no competing interests. Clot formation Air embolism Author details 1 Intensive Care Unit, Hospital Universitario Sagrado Corazón, Barcelona, Spain. 2 Interdepartmental Division of Critical Care Medicine, Toronto General Hospi‑ tal, University of Toronto, Toronto, Canada. 3 Critical Care Center, ParcTaulí Hos‑ Conversely, thrombus formation is higher at lower pital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat blood flow rates because of increased exposure time to Autònoma de Barcelona, Sabadell, Spain. 4 CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. the membrane lung and circuit. Clots may detach and enter the patient’s bloodstream, plugging the mem- Received: 18 February 2019 Accepted: 24 June 2019 brane or obstructing the cannula if anticoagulation is not achieved. References Conclusion 1. Boyle AJ, Sklar MC, McNamee JJ, et al. 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