Combes et al. Critical Care (2020) 24:490 https://doi.org/10.1186/s13054-020-03210-z RESEARCH Open Access ECCO2R therapy in the ICU: consensus of a European round table meeting Alain Combes1,2* , Georg Auzinger3,4†, Gilles Capellier5,6†, Damien du Cheyron7†, Ian Clement8†, Guglielmo Consales9†, Wojciech Dabrowski10†, David De Bels11†, Francisco Javier González de Molina Ortiz12,13†, Antje Gottschalk14†, Matthias P. Hilty15†, David Pestaña16,17†, Eduardo Sousa18†, Redmond Tully19†, Jacques Goldstein20 and Kai Harenski21 Abstract Background: With recent advances in technology, patients with acute respiratory distress syndrome (ARDS) and severe acute exacerbations of chronic obstructive pulmonary disease (ae-COPD) could benefit from extracorporeal CO2 removal (ECCO2R). However, current evidence in these indications is limited. A European ECCO2R Expert Round Table Meeting was convened to further explore the potential for this treatment approach. Methods: A modified Delphi-based method was used to collate European experts’ views to better understand how ECCO2R therapy is applied, identify how patients are selected and how treatment decisions are made, as well as to identify any points of consensus. (Continued on next page) * Correspondence: alain.combes@aphp.fr † Georg Auzinger, Gilles Capellier, Damien du Cheyron, Ian Clement, Guglielmo Consales, Wojciech Dabrowski, David De Bels, Francisco Javier González de Molina Ortiz, Antje Gottschalk, Matthias P. Hilty, David Pestaña, Eduardo Sousa and Redmond Tully contributed equally to this work. 1 Sorbonne Université, INSERM, UMRS_1166-ICAN, Institute of Cardiometabolism and Nutrition, 47, Boulevard de l’Hôpital, F-75013 Paris, France 2 Service de Médecine Intensive-Réanimation, Institut de Cardiologie, APHP Hôpital Pitié–Salpêtrière, F-75013 Paris, France Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Combes et al. Critical Care (2020) 24:490 Page 2 of 10 (Continued from previous page) Results: Fourteen participants were selected based on known clinical expertise in critical care and in providing respiratory support with ECCO2R or extracorporeal membrane oxygenation. ARDS was considered the primary indication for ECCO2R therapy (n = 7), while 3 participants considered ae-COPD the primary indication. The group agreed that the primary treatment goal of ECCO2R therapy in patients with ARDS was to apply ultra-protective lung ventilation via managing CO2 levels. Driving pressure (≥ 14 cmH2O) followed by plateau pressure (Pplat; ≥ 25 cmH2O) was considered the most important criteria for ECCO2R initiation. Key treatment targets for patients with ARDS undergoing ECCO2R included pH (> 7.30), respiratory rate (< 25 or < 20 breaths/min), driving pressure (< 14 cmH2O) and Pplat (< 25 cmH2O). In ae-COPD, there was consensus that, in patients at risk of non-invasive ventilation (NIV) failure, no decrease in PaCO2 and no decrease in respiratory rate were key criteria for initiating ECCO2R therapy. Key treatment targets in ae-COPD were patient comfort, pH (> 7.30–7.35), respiratory rate (< 20–25 breaths/min), decrease of PaCO2 (by 10–20%), weaning from NIV, decrease in HCO3− and maintaining haemodynamic stability. Consensus was reached on weaning protocols for both indications. Anticoagulation with intravenous unfractionated heparin was the strategy preferred by the group. Conclusions: Insights from this group of experienced physicians suggest that ECCO2R therapy may be an effective supportive treatment for adults with ARDS or ae-COPD. Further evidence from randomised clinical trials and/or high-quality prospective studies is needed to better guide decision making. Keywords: Acute respiratory distress syndrome, Chronic obstructive pulmonary disease, CO2 removal, Consensus, Driving pressure, ECCO2R, Gas exchange, Lung protective ventilation, Tidal volume, Therapy experience Background REST (NCT02654327) [2] and SUPERNOVA (NCT0228 Advances in technology to deliver extracorporeal car- 2657) [11, 12, 23] are expected to provide valuable bon dioxide removal (ECCO2R) therapy have simpli- evidence to support decision making. fied this approach, making it easier to deploy for the Given the potential of ECCO2R therapy to provide management of adults with both hypoxaemic and effective supportive treatment for a wide range of patient hypercapnic acute respiratory failure (ARF) [1–4]. In groups, we convened a European ECCO2R therapy patients with acute respiratory distress syndrome Expert Round Table Meeting to better understand how (ARDS), ECCO2R therapy may be used to allow ultra- ECCO2R therapy is applied in key diagnostic groups, e.g. protective lung ventilation (UPLV) and reduce patients with ARDS or ae-COPD, identify how patients ventilator-induced lung injury (VILI) by decreasing are selected, understand how treatment decisions are tidal volume (VT), both plateau (Pplat) and driving made and delineate areas of consensus in the group. pressures and respiratory rate, while also controlling respiratory acidosis [5–14]. In patients with acute ex- Methods acerbations of chronic obstructive pulmonary disease Research questions and objectives (ae-COPD) with severe respiratory acidosis and hyper- The ECCO2R therapy Expert Round Table Meeting was capnic respiratory failure, ECCO2R therapy may be held in Brussels in July 2019 and was attended by 14 applied to prevent intubation in patients at risk of clinicians who regularly provide ECCO2R therapy in non-invasive ventilation (NIV) failure [15]. It may also hospitals across Europe in order to provide a European be used to hasten weaning from mechanical ventilation perspective on ECCO2R therapy. Each attendee was a (MV) and early extubation in those who require inva- senior clinician/intensivist invited based on their experi- sive ventilation [10, 15–17]. ence delivering ECCO2R therapy, with and without However, there is currently limited evidence regarding continuous renal replacement therapy, using different the use of ECCO2R therapy in these indications, with devices. The attendees had direct clinical experience available data limited to the description of single cases with a wide range of ECCO2R devices, including ALung, or to case series that include a small number of patients iLA, Prismalung and PALP (the later had been removed [16, 18–21], as well as a few retrospective matched from the market at the time of the meeting due to loss cohort studies [15, 22]. Additionally, questions remain of the distribution agreement). In addition, several of the on how best to implement a therapy that might be attendees are principal investigators in recently com- associated with serious side-effects [1]. Ongoing and pleted or ongoing clinical trials, including randomised published trials such as VENT-AVOID (NCT03255057), controlled trials such as REST and SUPERNOVA. Combes et al. Critical Care (2020) 24:490 Page 3 of 10 Conflict of interest declarations for the attendees can be questionnaire, circulated post-meeting, designed to fol- found at the end of the manuscript. low up on discussion points raised at the face-to-face The meeting objectives were to better define and meeting, with results analysed anonymously. Details on understand the application of ECCO2R therapy in key the process for information gathering and the questions indications (ARDS and ae-COPD), to identify patient are provided in Additional file 1. selection criteria and when to initiate and stop/wean Target values for ventilation parameters of interest— patients from treatment and to determine points of criteria for initiation of ECCO2R therapy and treatment consensus and differences in clinical practice in those targets for ECCO2R therapy in both ARDS and ae- centres represented at the meeting. A non-systematic COPD—were collected during the three rounds of search of MEDLINE, ClinicalTrials.gov and other sites questioning. These values were subsequently evaluated was performed to identify key studies and trials to sup- for consensus. To facilitate the analysis of the responses port the development of the questions and the content for certain questions, a scoring system was employed. of the meeting. Participants were asked to score their responses in order of importance, giving them a score (e.g. from 1 to 8, de- Data collection and analysis pending on the number of variables). Scores were then A modified Delphi-based method (Fig. 1) was used to combined to give a total score for each parameter, with collate the clinicians’ views in three rounds of question- higher scores indicating a higher perceived importance. ing [24]. The meeting questions as well as the pre- To determine whether a consensus was reached or not meeting and post-meeting questionnaires were based on participant responses to the questions, a developed by JG and KH before being reviewed and threshold of ≥ 80% of participants in agreement was used approved by AC. JG and KH were present as Baxter to define if consensus was reached, a level that has been employees and moderators, but were not permitted to used in previous analyses [25]. Majority agreement provide answers or responses, either to the survey ques- indicates that ≥ 50% of participants agreed, but consen- tions or during the meeting. Round 1 data were sus level was not reached, and no agreement means that collected via an interactive PDF questionnaire circulated < 50% of participants agreed. The report was drafted by in advance of the meeting, and results were analysed an- an independent medical writing company (SciMentum, onymously. Round 2 data were collected during the Nucleus Global) and paid for by Baxter in line with meeting, attendees were divided into 4 subgroups and Good Publication Practice 3. The various drafts were the questions were presented by an independent facilita- reviewed and approved by AC before being reviewed by tor. Open questions were used to encourage freedom of the full author team. All authors provided their approval response, and the meeting was designed to allow the to submit and meet the ICMJE criteria for authorship. attendees adequate time to consider and respond to the questions based on their experience. Attendees could Results respond to the questions either through anonymous Attendee clinical experience electronic voting or by inputting responses into a micro- Twelve clinicians completed the pre-meeting survey: computer, with responses collected and discussed openly eight worked in Combined Surgical and Medical inten- by the group. Round 3 was a second interactive PDF sive care units (ICUs), while the others were employed Fig. 1 Overview of the five-step Delphi method used in the Round Table Meeting. Each step was a distinct process that was completed before the following step was initiated. Results and discussions from each step were independently analysed and used to inform the direction and content of the following steps, e.g. if the group were split on a topic, then clarifying questions were crafted to guide the discussions in the following step(s) to identify and explore points of consensus or difference. GPP3, Good Publication Practice 3 Combes et al. Critical Care (2020) 24:490 Page 4 of 10 in Medical ICUs (n = 2), Surgical ICUs (n = 2) and 6.1–7.0 or 7.1–8.0 mL/kg PBW were also considered to Cardiac Surgery ICUs (n = 2); respondents could be be reasonable targets. When asked in the post-meeting employed at more than one type of centre. ICUs had a survey (Round 3) about the preferred ventilation mode median of 20 beds/unit and 400–2000 admissions/year. used for patients with ARDS undergoing LPV, the group Extracorporeal membrane oxygenation (ECMO) experi- were split with respect to pressure control (pressure ence of participants ranged from 0 to 80 veno-venous assist) (n = 8) and flow control (volume assist) (n = 6) ECMO procedures/year and 0 to 220 veno-arterial modes of ventilation. These recommendations agreed ECMO procedures/year. with the most recent guidelines for the ventilation man- agement of patients with ARDS [27, 28]. Indications and rationale for ECCO2R based on pre- There was consensus among the group (91% [2 meeting survey participants were unavailable for this question, 11 of Analysis of the Round 1 pre-meeting survey responses n = 12/14 voted in favour]) that the primary revealed that ARDS was considered the primary indica- treatment goal of ECCO2R therapy for patients with tion for ECCO2R therapy by 7 participants, while 3 ARDS was to apply UPLV via managing CO2 levels. participants considered ae-COPD to be the primary indi- For initiating ECCO2R therapy in patients with ARDS, cation. Severe asthma was also mentioned as another driving pressure (≥ 14 cmH2O) followed by Pplat (≥ potential ECCO2R indication, although less frequently. 25 cmH2O) was considered the most important The median number of ARDS admissions (as per the criteria, and this was confirmed in the post-meeting Berlin definition [26]) was 60 patients per centre per survey (Tables 1 and 2). Additional key parameters year, with some centres admitting up to 500 patients per included pH (< 7.25), reducing VT to < 6 mL/kg PBW, year. While the most common criteria stated in the pre- PaCO2 (> 60–80 mmHg), respiratory rate (≥ 25 to > meeting responses for initiating ECCO2R therapy in 30 breaths/min), PaO2/FiO2 (100–200) and PEEP patients with ARDS were to manage hypercapnia with (combined findings from Rounds 2 and 3). acidosis, although specific criteria varied across the Participants were evenly split during the meeting on ICUs, likewise, weaning criteria shared at Round 1 varied the primary rationale for ECCO2R therapy, being rescue significantly, with no clearly consistent management therapy in patients with ARDS undergoing injurious pattern being identified between centres. However, most MV, i.e. those with very high plateau and driving participants (92%) indicated that they would place pressures despite reduced VT and PEEP (n = 7), or to patients with ARDS in the prone position when using facilitate UPLV to prevent the deleterious effects of MV ECCO2R therapy. The number of ae-COPD admissions in patients already undergoing LPV (n = 7). Based on the ranged from 0 to 250 patients per centre per year results of the post-meeting survey, a consensus was (median 50). Participants indicated that ECCO2R reached among the group (12/14, 86% of participants) therapy was predominantly initiated to prevent intub- that ECCO2R was a strategy they would consider select- ation in patients at risk of NIV failure or to facilitate ing for rescue in patients with ARDS. Typical character- extubation in patients who had been intubated after NIV istics for initiating ECCO2R in a rescue situation failure. obtained as part of the post-meeting survey are summarised in Table 2. A majority (10/14, 71% of Use of ECCO2R therapy in patients with ARDS participants) indicated that they would select ECCO2R During the Expert Round Table Meeting and post- as a means of facilitating UPLV for patients with ARDS, meeting survey (Rounds 2 and 3, respectively), the group and typical characteristics for selecting patients are considered the ventilation parameters for implementa- summarised in Table 2. tion of a lung protective ventilation (LPV) strategy in all For both potential indications, patients would not be patients with ARDS and agreed upon the following considered suitable for an ECCO2R strategy if they met targets: driving pressure, 10–14 cmH2O; positive end- the indications for ECMO, such as severe or refractory expiratory pressure (PEEP), 10–14 cmH2O; Pplat, 25– ARDS [29] and presence of severe right heart failure 29 cmH2O; and respiratory rate either 20–25 or 25–30 (ECMO may be a more adequate treatment for these pa- breaths/min, although most of the group would target a tients), in cases where anticoagulation is contraindicated respiratory rate of 25 breaths/min. There was some vari- and for those with major comorbidities and/or predicted ation in responses among the group when asked about survival of < 1 year. target pH, with half of participants opting for a target The group considered treatment targets for their pH value of 7.25–7.30, while others indicated the target patients with ARDS undergoing ECCO2R. A consensus should be > 7.30 (n = 4), < 7.25–7.30 (n = 2) or < 7.20 was reached regarding driving pressure (< 14 cmH2O) (n = 1). Finally, the panellists thought VT should be set and respiratory rate (< 25 or < 20 breaths/min). There at 6.0 mL/kg of predicted body weight (PBW), although was majority agreement with respect to targets for Pplat Combes et al. Critical Care (2020) 24:490 Page 5 of 10 Table 1 ECCO2R treatment criteria for patients with ARDS Parameter Target Score Initiation criteria Driving pressure ≥ 14 cmH2O 31 Consensus Pplat ≥ 25 cmH2O 22 Consensus PaCO2 > 60–80 mmHg 21 Majority agreement pH < 7.25 20 Majority agreement Reduce VT to < 6 mL/PBW – 18 Majority agreement Respiratory rate ≥ 25 to > 30 14 Majority agreement PaO2/FiO2 100–200 10 Majority agreement PEEP – 8 No agreement Treatment targets Driving pressure < 14 cmH2O 66* Consensus Pplat < 25 cmH2O 57* Majority agreement† Respiratory rate < 25 or < 20 breaths/min 44* Consensus pH > 7.30 39* Majority agreement VT ≤6 mL/PBW 39* Majority agreement PaCO2 < 50–55 mmHg 30 Majority agreement Criteria for ECCO2R treatment considered to be of importance and selected from the provided list. Target describes any potential target values identified, with ‘–’ indicating that no target parameter was provided or considered relevant. Score indicates the combined total score, with higher scores indicating a higher perceived importance. Consensus means a consensus threshold (≥ 80%) was reached, majority agreement means ≥ 50% agreed but consensus level was not reached, and no agreement means < 50% agreed *Based on the post-meeting survey. †Note, for Pplat, a consensus threshold of 80% was not reached in the meeting; in the post-meeting survey, it was rated as the second most important target (< 25 cmH2O), pH (> 7.30 [Rounds 2 and 3]), PaCO2 (< Use of ECCO2R therapy in patients with ae-COPD 50 or < 55 mmHg) and VT (≤ 6 mL/kg PBW). Other tar- There was consensus during the meeting that patients get parameters were not proposed by the group with ae-COPD who should receive ECCO2R therapy (Table 1). The expected average length of time patients were those at risk of NIV failure, as well as patients re- with ARDS would remain on ECCO2R therapy was sug- cently initiated on MV after NIV failure to allow for gested to be 1–3 days (n = 5) and 4–6 days (n = 9). early extubation within 24 h of initiating ECCO2R Following discussion during the meeting on a therapy. Other patient groups would be considered (e.g. protocol for weaning from ECCO2R in patients with patients on prolonged MV who require weaning from ARDS, a protocol was proposed and reviewed as part invasive ventilation and patients who are refusing intub- of the post-meeting survey (Table 3). The group ation), but a consensus was not reached. voted on each step and reached consensus (92% of The group agreed that for patients with ae-COPD at participants, n = 13) that this proposal was a suitable risk of NIV failure, ‘no decrease in PaCO2’ and ‘no weaning strategy. Table 3 ECCO2R weaning protocol for patients with ARDS Table 2 Typical characteristics for initiating ECCO2R for rescue Weaning criteria and steps for weaning for ECCO2R in ARDS* therapy and to facilitate ultra-protective ventilation in ARDS ECCO2R will be applied for at least 48 h Parameter Target for initiation in: Target for initiation in: PaO2/FiO2 > 200 mmHg before testing weaning possibility Rescue Ultra-protective ventilation Set VT at 6 mL/PBW and PEEP 5–10 cmH2O Driving pressure > 15 to 20 cmH2O > 13 to 15 cmH2O Driving pressure should be < 14 cmH2O Pplat > 30 to 35 cmH2O ≥ 25 cmH2O Respiratory rate should be 20–30 breaths/min PaCO2 ≥ 60 mmHg ≥ 60 mmHg Reduce gas flow to zero, using 2 L/min decremental steps pH < 7.25–7.30 < 7.25–7.30 While weaning, pH should remain > 7.30 and respiratory rate < 25 Respiratory rate > 20 to 30 breaths/min > 20 breaths/min breaths/min PaO2/FiO2 < 150 < 150 Patient will be weaned off ECCO2R therapy after a minimum of 12 h of PEEP > 8 to 15 ≥8 stability under these settings (including pH > 7.30 and respiratory rate < 25 breaths/min) Responses were captured during the post-meeting survey (Round 3) and general themes were identified *A consensus was reached for all of these criteria and steps Combes et al. Critical Care (2020) 24:490 Page 6 of 10 decrease in respiratory rate’ while on NIV were both key consensus on specific pH), respiratory rate (< 20–25 initiation criteria for ECCO2R therapy (Table 4). These breaths/min), decrease of PaCO2 by 10–20%, weaning criteria were considered indicative of NIV failure. from NIV, decrease in HCO3− and maintaining haemo- Clinical signs of respiratory failure and pH (< 7.25 [n = dynamic stability. Consensus on a weaning protocol for 5] or 7.25–7.30 [n = 6]) would be considered as initiation patients with ae-COPD was reached during the meeting criteria by most of the participants. Baseline PaCO2 and (Table 5). respiratory rate as main triggers were favoured by less than half of participants. For patients with ae-COPD Anticoagulation strategy for patients receiving ECCO2R who had already been intubated, criteria for initiating Responses obtained during Round 1 (pre-meeting sur- ECCO2R therapy varied (Table 4). vey) showed that heparin was the preferred choice of Factors for excluding patients with ae-COPD from anticoagulant used during ECCO2R therapy (~ 80% of ECCO2R typically included patients with end-stage participants stated that heparin was their anticoagulant disease (the group highlighted that markers for this in- of choice). This was confirmed in the post-meeting clude severe functional limitation and cachexia); contra- survey, in which unfractionated heparin was the indications to anticoagulation; problems with vascular anticoagulant of choice for the majority (~ 90% of partic- access; patient’s wishes, e.g. refusal to be intubated, ex- ipants). The proposed heparin anticoagulation protocol cept in cases where ECCO2R therapy represented the agreed by the group is shown in Table 6. Lastly, argatro- last resource accepted by the patient; poor quality of life; ban was the group’s preferred anticoagulant in case of and the patient not being a candidate for MV. proven heparin-induced thrombocytopenia (HIT). Treatment targets for patients with ae-COPD receiving ECCO2R therapy were, in order of perceived importance Discussion (Table 5), comfortable patient, pH (> 7.35/7.30; no The responses obtained from the Expert Round Table Meeting and accompanying pre- and post-meeting sur- veys have provided further insights into the use of Table 4 ECCO2R treatment initiation criteria for patients with ECCO2R therapy across Europe. During a typical Delphi ae-COPD process [24], 100% agreement is rare, and any consensus Initiation criteria for patients at risk of NIV failure is the result of multiple rounds of voting and discussion Parameter that lead to a convergence of opinion. However, in areas No decrease in PaCO2 while on NIV Consensus where clinical evidence is limited, as is the case for No decrease in respiratory rate while on NIV Consensus ECCO2R therapy in patients with ARDS and ae-COPD, Clinical signs of respiratory failure Majority agreement using a modified Delphi method may offer insight into pH 7.25–7.30 Majority agreement the current practice of experienced users, which could help inform decision making in local clinical practice. Baseline PaCO2 No agreement Additionally, the use of the Delphi method to guide Baseline respiratory rate No agreement these discussions and reach points of consensus will be Initiation criteria for patients who are already intubated of potential benefit for the design of future trials. Specif- - Patients who look like they will not be extubated early without ically, the discussions provide insight relevant to inclu- ECCO2R sion criteria, guidance on the management of patients ○ Previous intubation for ae-COPD while receiving ECCO2R therapy and possible primary ○ Has failed a spontaneous breathing trial due to increased and secondary endpoints. dyspnoea Key areas of consensus for the use of ECCO2R therapy ○ Reintubation after first extubation attempt despite NIV in the treatment of patients with ARDS or ae-COPD ○ Patients with severe bronchospasm who are difficult/impossible were identified. There was consensus among the group to ventilate adequately or otherwise not responding to medical that the primary treatment goal of ECCO2R therapy for treatment patients with ARDS was to apply UPLV via managing ○ Patients who remain hypercapnic and not improving with MV CO2 levels; this is in agreement with the findings of a - No hypoxemia preventing extubation systematic literature review [30]. The group reached a - MV < 72 h consensus that, when initiating ECCO2R therapy in pa- - Patients with home NIV and good quality of life tients with ARDS, driving pressure (≥ 14 cmH2O) followed by Pplat (≥ 25 cmH2O) was the most important Criteria for ECCO2R treatment considered to be of importance and selected from the provided list. Target describes any potential target values identified. criteria to consider. Higher PEEP, lower peak and plat- Consensus means a consensus threshold (≥ 80%) was reached, majority eau pressures and lower respiratory rate have been agreement means ≥ 50% agreed but consensus level was not reached, and no agreement means < 50% agreed shown to correlate with improved survival in patients Scoring and ranking was not conducted for this section during the meeting with ARDS [7, 11, 31]. However, only the driving Combes et al. Critical Care (2020) 24:490 Page 7 of 10 Table 5 ECCO2R treatment targets and weaning protocol for patients with ae-COPD Treatment targets for patients with ae-COPD Parameter Target Score Comfortable patient – 27 pH > 7.35/7.30, no consensus on specific pH 23 Respiratory rate < 20–25 breaths/min 19 Decrease of PaCO2 by 10–20% – 18 Weaning from NIV – 9 Decrease in HCO3− – 9 Maintaining haemodynamic stability – 7 ECCO2R weaning protocol for patients with ae-COPD 1. Patient weaned from NIV for > 6 h a. Excluding patients on home NIV or candidates for long-term NIV 2. Intubated patients weaned from MV for > 6 h 3. SpO2 ≥ 88% with supplemental O2 if needed 4. Reduce sweep gas flow rate by 1–3 L/min; check arterial blood gas after 1 h for: a. pH ≥7.35 with respiratory rate < 25 breaths/min b. PaO2 > 55 mmHg c. SpO2 > 88% d. FiO2 < 40% 5. Repeat sweep gas reduction until zero gas flow reached, while arterial blood gas targets maintained 6. Remove ECCO2R after 6 h of stability of the aforementioned criteria Treatment targets for ECCO2R considered to be of importance and selected from the provided list. Target describes any potential target values identified. Score indicates the combined total score, with higher scores indicating a higher perceived importance. Consensus means a consensus threshold (≥ 80%) was reached, majority agreement means ≥ 50% agreed but consensus level was not reached, and no agreement means < 50% agreed. The ECCO2R weaning protocol for patients with ae-COPD was developed and voted on during the meeting, with all attendees in agreement pressure was associated with increased mortality using a in this patient group. Indeed, a lower pH was recently multilevel mediation analysis in a large retrospective co- shown to be independently associated with ICU hort study of patients with ARDS [32]. It is therefore mortality in the large prospective LUNG SAFE registry perhaps not surprising that the key treatment targets for [31]. Most of the group also agreed that ECCO2R should ECCO2R in ARDS identified by the group were reduc- be initiated at PaCO2 levels > 60–80 mmHg. While it tions in driving pressure and respiratory rate. was suggested that permissive hypercapnia provided A pH of < 7.25 was also considered by most of the protection against lung injury in terms of lung perme- group to be a criterion for initiation of ECCO2R therapy ability, oxygenation and lung mechanics [33], more recent data have shown a positive correlation between Table 6 Heparin anticoagulation strategy hypercapnic acidosis and mortality [34, 35]. Raising pH 1. Anticoagulation with intravenous unfractionated heparin, preferably (> 7.30 or > 7.25) and decreasing PaCO2 levels were applied to the extracorporeal circuit considered important treatment targets, indicating that 2. Monitor aPTT or anti-Xa or both there is a perception that ECCO2R is an important a. To obtain an aPTT of 1.5–2.0 times normal baseline (45–70 s), or therapy for the management of respiratory acidosis. anti-Xa activity of 0.3–0.5 UI/mL The experts were evenly split on the primary rationale 3. Initial bolus of heparin for ECCO2R therapy, either as a rescue therapy in a. 40–80 units/kg PBW patients with ARDS undergoing injurious MV, or to facilitate UPLV to prevent VILI. The results from the b. Bolus will not be performed in patients already on full anticoagulation post-meeting survey highlighted that the group agreed that they would at least consider selecting ECCO2R as a c. Bolus routinely performed when guidewires have been inserted/or after catheter insertion strategy in both settings. Ongoing (NCT02654327) [11] 4. Patients with proven HIT-2 randomised trials may help clarify the role of ECCO2R, allowing UPLV in patients with acute hypoxemic a. Argatroban protocol, e.g. 0.5–2.0 μg/kg/min respiratory failure. Combes et al. Critical Care (2020) 24:490 Page 8 of 10 To the best of our knowledge, this is the first publica- across Europe; evidence from a larger group of intensi- tion of a proposed weaning strategy for ECCO2R in pa- vists from multiple regions of the world may be required tients with ARDS. The group reached a consensus to support these observations. Certain topics were not regarding a strategy for weaning patients from ECCO2R covered due to the scope of the meeting. Firstly, the in this setting. It was agreed that ECCO2R therapy questions covered current practice and did not explore if should be applied for at least 48 h in patients with practices, e.g. inclusion policies of the respective centres, ARDS, and that a test for PaO2/FiO2 > 200 mmHg while had changed over time. Secondly, certain rarer indica- maintaining a driving pressure < 14 cmH2O should be tions, e.g. lung transplant, were not covered, as the carried out to determine weaning possibility. It was also meeting focussed on the broader population of patients agreed that patients should be stable for a minimum of requiring ECCO2R therapy, e.g. patients with ARDS or 12 h at the ventilation parameters outlined (see Table 3) ae-COPD. These questions could be covered as part of a before any weaning attempt takes place [11]. follow-up meeting. Additionally, while the authors took In a randomised study exploring the role of helium/oxy- every opportunity to ensure all relevant major articles gen in ae-COPD, the rate of patients failing on NIV and were cited, the purpose of the meeting was to under- requiring MV was 15% [36]. Identifying the subgroup of stand current practice as opposed to conducting a com- patients with ae-COPD at high risk of NIV failure is in- prehensive literature analysis. Finally, the experiences deed crucial to improve their outcomes by deploying ef- outlined are the physicians’ respective personal experi- fective preventive strategies. The panel identified ‘lack of ences and are not a replacement for formal guidelines. decrease in PaCO2’ and ‘respiratory rate during NIV’ as The reader should consider their patients’ needs and important indicators of increased risk of NIV failure and local guidelines when performing ECCO2R therapy. an indication for ECCO2R initiation. The group also felt that it was important to allow enough time to show that Conclusions NIV was ineffective before initiating ECCO2R therapy. The insights from this group of experienced physicians Furthermore, there are numerous factors involved in NIV suggested that ECCO2R therapy may be a useful and ef- failure, and the benefit of ECCO2R for this patient group fective supportive treatment for adults in the ICU with is still a matter of debate due to lack of data from rando- both ARDS and ae-COPD. They have however mised clinical trials [15, 22]. highlighted an urgent need for further evidence in the For patients with ae-COPD who are already intubated, form of randomised clinical trials and/or high-quality the intended use of ECCO2R therapy is to rapidly allow prospective studies to help guide decision making. On- extubation, to facilitate oral nutrition and early physio- going and published trials such as VENT-AVOID therapy and to prevent muscle deconditioning [3]. (NCT03255057), REST (NCT02654327) [2] and SUPER- Treatment targets identified by the group clearly fit in NOVA (NCT02282657) [11, 12, 23] should provide the with the strategy of reducing the duration of MV and data to support these guidelines. are in line with published data and wider views on the use of ECCO2R therapy [1, 19]. The VENT-AVOID trial Supplementary information (NCT03255057) is currently randomising patients to Supplementary information accompanies this paper at https://doi.org/10. further investigate the benefits of ECCO2R therapy in 1186/s13054-020-03210-z. patients at risk of NIV failure or who already have been intubated after NIV failure. Additional file 1: Expanded methods. Details on the process for information gathering and the questions. Anticoagulation with intravenous unfractionated hep- arin was the preferred strategy of the group. This reflects recent studies in the literature in which unfractionated Abbreviations ae-COPD: Acute exacerbations of chronic obstructive pulmonary disease; heparin appears to be the anticoagulant most frequently aPTT: Activated partial thromboplastin time; ARDS: Acute respiratory distress used in this setting [10, 11]. The post-meeting survey syndrome; ARF: Acute respiratory failure; ECCO2R: Extracorporeal carbon highlighted that anticoagulant activity should be moni- dioxide removal; ECMO: Extracorporeal membrane oxygenation; FiO2: Fraction of inspired oxygen; HIT: Heparin-induced thrombocytopenia; tored using activated partial thromboplastin time (aPTT) ICU: Intensive care unit; LPV: Lung protective ventilation; MV: Mechanical and/or anti-Xa; the monitoring approach remains ventilation; NIV: Non-invasive ventilation; PaCO2: Partial pressure of carbon dependent on local practice. For patients with proven dioxide; PBW: Predicted body weight; PEEP: Positive end-expiratory pressure; Pplat: Plateau pressure; SpO2: Oxygen saturation; UPLV: Ultra-protective lung HIT, argatroban was the group’s preferred anticoagulant ventilation; VILI: Ventilator-induced lung injury; VT: Tidal volume [37, 38]. Acknowledgements Limitations Supported by Baxter Inc. Medical writing support was provided by Daniel Johnson and Ruth Brown of SciMentum Inc. (Nucleus Global), funded by The findings presented here relate to the experiences of Baxter Inc., under the authors’ conceptual direction and based on feedback a relatively small number of physicians from centres from the authors. Combes et al. Critical Care (2020) 24:490 Page 9 of 10 Authors’ contributions 2. McNamee JJ, Gillies MA, Barrett NA, Agus AM, Beale R, Bentley A, et al. All authors participated in the discussions in the Round Table Meeting as pRotective vEntilation with veno-venouS lung assisT in respiratory failure: a well as the questionnaire rounds, contributed data, critically reviewed the protocol for a multicentre randomised controlled trial of extracorporeal manuscript providing interpretation of the data and their implications and carbon dioxide removal in patients with acute hypoxaemic respiratory provided approval for the final version to be published. failure. J Intensive Care Soc. 2017;18:159–69. 3. Brodie D, Slutsky AS, Combes A. Extracorporeal life support for adults with Authors’ information respiratory failure and related indications: a review. JAMA. 2019;322:557–68. FJGDM: Member of the Acute Respiratory Failure Working Group and Chair 4. Combes A, Pesenti A, Ranieri VM. Fifty years of research in ARDS. Is of the Nephrological Intensive Care Working Group of the Spanish Society of extracorporeal circulation the future of acute respiratory distress syndrome Critical and Intensive Care Medicine and Coronary Units (Sociedad Española management? Am J Respir Crit Care Med. 2017;195:1161–70. de Medicina Intensiva, Críticos y Unidades Coronarias [SEMICYUC]). 5. Needham DM, Colantuoni E, Mendez-Tellez PA, Dinglas VD, Sevransky JE, Dennison Himmelfarb CR, et al. Lung protective mechanical ventilation and Funding two year survival in patients with acute lung injury: prospective cohort The meeting and associated expenses as well as the publication of this study. BMJ. 2012;344:e2124. research was supported by Baxter Inc. 6. Terragni PP, Del Sorbo L, Mascia L, Urbino R, Martin EL, Birocco A, et al. Tidal volume lower than 6 ml/kg enhances lung protection: role of Availability of data and materials extracorporeal carbon dioxide removal. Anesthesiology. 2009;111:826–35. Not applicable. 7. Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiology, patterns of care, and mortality for patients with acute Ethics approval and consent to participate respiratory distress syndrome in intensive care units in 50 countries. JAMA. Not applicable. 2016;315:788–800. 8. Fanelli V, Ranieri MV, Mancebo J, Moerer O, Quintel M, Morley S, et al. Consent for publication Feasibility and safety of low-flow extracorporeal carbon dioxide removal to Not applicable. facilitate ultra-protective ventilation in patients with moderate acute respiratory distress sindrome. Crit Care. 2016;20:36. Competing interests 9. Schmidt M, Jaber S, Zogheib E, Godet T, Capellier G, Combes A. Feasibility All authors received financial compensation from Baxter for travel and and safety of low-flow extracorporeal CO2 removal managed with a renal accommodation for attending the meeting. MPH has received financial replacement platform to enhance lung-protective ventilation of patients compensation from Baxter for travel and accommodation in the past. with mild-to-moderate ARDS. Crit Care. 2018;22:122. 10. Augy JL, Aissaoui N, Richard C, Maury E, Fartoukh M, Mekontso-Dessap A, Author details et al. A 2-year multicenter, observational, prospective, cohort study on 1 Sorbonne Université, INSERM, UMRS_1166-ICAN, Institute of extracorporeal CO2 removal in a large metropolis area. J Intensive Care. Cardiometabolism and Nutrition, 47, Boulevard de l’Hôpital, F-75013 Paris, 2019;7:45. France. 2Service de Médecine Intensive-Réanimation, Institut de Cardiologie, 11. Combes A, Fanelli V, Pham T, Ranieri VM. European Society of Intensive Care APHP Hôpital Pitié–Salpêtrière, F-75013 Paris, France. 3Department of Critical Medicine Trials Group and the “Strategy of Ultra-Protective lung ventilation Care, King’s College Hospital, London SE5 9RS, UK. 4Department of Critical with Extracorporeal CO2 Removal for New-Onset moderate to severe ARDS” Care, Cleveland Clinic, London SW1Y 7AW, UK. 5Service de Médecine (SUPERNOVA) investigators. 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