Daily use of extracorporeal CO2 removal in a critical care unit: indications and results

Background While outcome improvement with extracorporeal CO2 removal (ECCO2R) is not demonstrated, a strong pathophysiological rational supports its use in the setting of acute respiratory distress syndrome (ARDS) and COPD exacerbation. We aimed to describe our single-center experience of ECCO2R indications and outcome. Methods Patients treated with ECCO2R in our medial ICU, from March 2014 to November 2017, were retrospectively enrolled. Primary end point was evolution of ventilator settings during the two first days following ECCO2R start. Results Thirty-three patients received ECCO2R. Seventeen were managed with Hemolung®, 10 with Prismalung®, 4 with ILA®, and 2 with Cardiohelp®. Indications for ECCO2R were mild or moderate ARDS (n = 16), COPD exacerbation (n = 11), or uncontrolled hypercapnia due to other causes (n = 6). Four patients were not intubated at the time of ECCO2R start. Median duration of ECCO2R treatment was 7 days [5–10]. In ARDS patients, between baseline and day 2, median tidal volume and driving pressure decreased from 5.3 [4.4–5.9] mL/kg and 10 [8–15] to 3.8 [3.3–4.1] mL/kg and 9 [8–11], respectively. Prone positioning was performed in 10 of the 16 patients, without serious adverse event. In COPD patients, between baseline and day 2, median ventilation minute and PaCO2 decreased significantly from respectively 7.6 [6.6–8.7] L/min and 9.4 [8.4–10.1] kPa to 5.8 [4.9–6.2] L/min and 6 [5.3–6.8] kPa. Four out of 11 COPD patients were extubated while on ECCO2R. Device thrombosis occurred in 5 patients (15%). Hemolysis was documented in 16 patients (48%). One patient died of intracranial hemorrhage, while on ECCO2R. Twenty-four patients were discharged from ICU alive. Twenty-eight day mortality was 31% in ARDS, 9% in COPD patients, and 50% in other causes of refractory hypercapnic respiratory failure. Conclusion ECCO2R was useful to apply ultra-protective ventilation among ARDS patients and improved PaCO2, pH, and minute ventilation in COPD patients. Electronic supplementary material The online version of this article (10.1186/s40560-018-0304-x) contains supplementary material, which is available to authorized users.


Background
There is not yet enough data to make strong recommendation about extracorporeal CO 2 removal (ECCO 2 R) devices, as the benefits-risks ratio is not established. Because of its low flow, this technology is unable to provide adequate extracorporeal oxygenation. However, 350 to 500 mL/min is sufficient to remove half of CO 2 production, making ECCO 2 R an interesting tool in several situations.
First, in the setting of acute respiratory distress syndrome (ADRS), it is well established that low tidal volume and limited plateau pressure are associated with better survival [1]. Recent guidelines recommend to aim for tidal volume of 4-8 mL/kg of predicted body weight (PBW) and plateau pressure less than 30 cmH 2 O [2]. However, ventilator-induced lung injury (VILI) due to hyperinflation has been documented even with low tidal volume [3]. Because some data suggest that decreasing plateau pressure, even if it is < 30 cmH 2 O, might be associated with reduced mortality [4], using tidal volume lower than 6 mL/kg has been proposed [5]. Three studies have showed the feasibility and safety of ultra-protective ventilation, with 4 mL/kg tidal volume and plateau pressure < 25 cmH 2 O [6][7][8]. However, at this time, no prospective trial has demonstrated an impact on outcome.
Second, in the setting of chronic obstructive pulmonary disease (COPD) exacerbation, noninvasive ventilation is the first option [9]. Indeed, the need for invasive mechanical ventilation is associated with higher mortality [10]. By providing extracorporeal CO 2 clearance, ECCO 2 R might decrease respiratory rate and limit auto-PEEP, resulting in reduced respiratory work. Three case-control studies have suggested that ECCO 2 R decrease the intubation rate of severe COPD exacerbation [11][12][13]. It might also allow an earlier extubation and rehabilitation.
Finally, ECCO 2 R might also be useful in the setting of refractory respiratory acidosis with pH < 7.20 despite usual care. For example, successful treatment of near-fatal asthma using ECCO 2 R has been reported [14].
In this monocentric retrospective cohort study, we aimed to describe indications, ventilatory settings, gas exchanges, and outcome of patients receiving ECCO 2 R in our ICU.

Patients
We performed a retrospective chart review of all patients admitted to our tertiary regional intensive care unit (ICU) and started on ECCO 2 R from March 2014 to November 2017. Cases were identified through a prospectively maintained electronic database.
Ethical issues ECCO 2 R therapy was started while all patients were on high-intensity treatment. Families were informed of the rescue treatment and the benefits-risks ratio. As a rule, all COPD patients required either to be intubated or to fail noninvasive ventilation (NIV) or refuse intubation to be started on ECCO 2 R. Four ARDS patients were involved in ongoing studies related to ECCO 2 R.

ECCO 2 R system
Four veno-venous ECCO 2 R systems were used, including ILA® (Novalung, Germany), Hemolung® (ALung Technologies, Inc., Pittsburgh, PA, USA), Prismalung® (Baxter Healthcare/Gambro Lund, Sweden), and CardioHelp® (Maquet, Germany). CardioHelp® was the only system using two venous cannulas. Others were associated to dual-lumen catheters, usually inserted by jugular access. There was no protocol guiding the choice of ECCO 2 R device, which was let to the clinician in charge. When renal replacement therapy was required, Prismalung® was preferentially used. ECCO 2 R weaning strategy was let to clinician's discretion.

Data recording
Demographic data collected included age, gender, primary admission diagnosis, cause of respiratory failure, and any known comorbidities. Physiologic data collected included vasopressor therapy and renal replacement therapy. Ventilatory data included ventilator mode, respiratory rate, tidal volume, plateau pressure when available, minute ventilation, and results of daily arterial blood gases (Additional file 1). ECCO 2 R-related data included indication of extracorporeal support, type of device, blood flow, sweep gas flow, and anticoagulation level evaluated by anti-Xa activity. Ventilation settings were gathered just before starting ECCO 2 R, at 4 hourly intervals for the first 24 h, and at day 2. Arterial blood gases were recorded once a day for 48 h. ECCO 2 R-related or potentially linked complications included bleeding, catheter or pump thrombosis, hemolysis, thrombocytopenia, obvious local infection, and bacteremia. Bleeding at catheter insertion site was considered if associated with at least one red blood cell transfusion. Because plasma-free hemoglobin assessment was not available in our center, hemolysis was defined as anemia associated to haptoglobin less than 0,1 g/L. Thrombocytopenia was defined as a platelet count inferior to 150 G/L or a decrease of more than 50% since ECCO 2 R start.

Statistical analysis
Qualitative variables were expressed as number percentage. Quantitative variables were expressed as median and interquartile range. Comparisons between two qualitative variables were performed using the Fischer exact test. Comparisons between two quantitative variables were performed using the Wilcoxon test. For the study of the evolution of quantitative variables over time among patients, the Wilcoxon rank sum test was performed. All analyses were performed using SAS 9.4.

Description of the overall population
Over 4 years, 33 patients received ECCO 2 R therapy, including 16 mild or moderate ARDS patients, and 11 COPD patients with severe exacerbation. The remaining six patients had refractory hypercapnic acidosis secondary to severe acute asthma (n = 2), nosocomial pneumonia, bronchiolitis obliterans, exacerbation of pulmonary fibrosis, and bilateral bronchial compression by germinal tumor. Among ARDS patients who received ECCO 2 R, three were enrolled in SUPERNOVA study (NCT02282657), and one in PRISMA-LUNG study [15]. All COPD patients except one were intubated. Among COPD patients, 7 (63%) benefited from long-term oxygen therapy and 4 (36%) from noninvasive home ventilation. Baseline characteristics of the study population are shown in Table 1.

Description of ECCO 2 R therapy in ARDS patients
Results of ECCO2R therapy in ARDS patients are shown in Table 3 [22][23][24][25][26][27][28] respectively. Twenty-four hours after ECCO 2 R start, tidal volume significantly decreased to 3.9 [3.5-4.2] mL/kg, without increase of PaCO 2 . Although there was no difference for plateau pressure, driving pressure significantly decreased to 7 [6-10] cmH 2 O. The decrease of respiratory rate was not significant. However, minute ventilation significantly decreased to 4.6 [3.9-5.8] L/min. Neuromuscular blockers were respectively used in 94, 81, and 56% of patients at baseline, day 1, and day 2. Among the 16 ARDS patients, 10 were proned while on ECCO 2 R support. Among those 10 patients, two supported by ILA®, one by Hemolung®, and one by Prismalung® had three sessions of prone positioning or more.

Description of ECCO 2 R therapy in COPD patients
Results of ECCO 2 R therapy in COPD patients are shown in Table 4. Median baseline tidal volume, respiratory rate, minute ventilation, and PaCO 2 were 5.5 [5.5-5.9

Description of ECCO 2 R therapy in non-intubated patients
Only four patients were not intubated at the beginning of ECCO 2 R therapy. Patient no. 1 was a 61-year-old man who had a history of kidney transplantation. He had refractory hypercapnic COPD exacerbation with NIV failure. He received 2 days of ECCO 2 R by Hemolung® device until successful weaning without need for intubation. Patient no. 2 was a 90-year-old woman with refractory hypercapnic pneumonia without hypoxemia. She was weaned from Prismalung® device after 5 days, but she died 48 h later in  Table 5.

Complications
No decannulation was reported during the studied period. Thrombocytopenia was the most frequently reported adverse event (72%

Discussion
In this retrospective chart review, we aimed to describe our experience of ECCO 2 R devices and to help clinician volunteers to use those devices beyond the scope of experimental studies. We have found that ECCO 2 R system allowed ultra-protective ventilation in ARDS patients by decreasing tidal volume. We also found that ECCO 2 R was effective to reduce minute ventilation and improve blood pH in ventilated COPD patient. Furthermore, it  allowed extubation in some patients while on extracorporeal support. In the setting of ARDS patients, our results are in line with those of the three main studies assessing veno-venous low-flow ECCO 2 R. Indeed, in a recent pilot study in 15 mild to moderate ARDS patients, the use of Hemolung® allowed ultra-protective ventilation with tidal volume of 4 mL/kg [8]. Some similar results have been observed with Polystan SAFE® (Maquet, Rastatt, Germany), a membrane lung connected to a veno-venous hemofiltration system [6]. Interestingly, in our ARDS cohort, 6 of the 16 patients have benefited from Prismalung® device, connected to a renal replacement machine. In a recently published proof-of-concept study, Prismalung® allowed ultra-protective ventilation in 20 mild-to-moderate ARDS patients. However, mean duration treatment was only 31 h (± 22), limiting conclusion about longer use and safety [15]. Although significant, the reduction of driving pressure secondary to tidal volume decrease was quite small in our study. This could be due to a relatively low tidal volume at baseline. Indeed, in our practice, we usually target low plateau pressure, with tidal volume lower than 6 mL/kg as reported by other authors [16]. After ECCO 2 R start, we have noted a trend to decrease of respiratory rate. This is another potential aspect of the ultra-protective strategy, as some authors have suggested that respiratory rate could be a determinant of VILI [17]. Because median baseline PaO 2 /FiO 2 ratio was 145 [116-161] mmHg, patients were a priori susceptible to have an indication for prone positioning. It is noteworthy that 10 have benefited from this therapy without any adverse event. Because prone positioning has been found to decrease mortality in ADRS with PaO 2 /FiO 2 ratio less than 150 mmHg, it is mandatory that novel therapy do not limit its use [18]. While neuromuscular blockers use in moderate to severe ARDS is recommended for 48 h [19], we have noted a trend towards early interruption. This might be explained by the early improvement of oxygenation and the control of hypercapnia. In this situation, our clinicians favored decrease sedations and awakeness.
In the three largest studies enrolling COPD patients, the primary end point was the avoidance of intubation [11][12][13]. In our cohort, only one COPD patient has benefited from such pre-intubation strategy. However, whether ECCO 2 R should be started before or after intubation is still a matter of debate. Indeed, because NIV failure is hard to predict, and ECCO 2 R is associated with additional septic and hemorrhagic risks, appropriate selection of patients which might benefit from ECCO 2 R is difficult. Considering this, our policy is to start ECCO 2 R early after intubation. Moreover, such strategy may facilitate insertion of the ECCO 2 R catheter, allowing safe conditions, as no complication was reported during catheter insertion in our patients. In our cohort, 50% of the patients were started on day 1 and 75% before day 3 of mechanical ventilation. While the global effect of ECCO 2 R was the lowering of minute ventilation and PaCO 2 , in our cohort, it was more marked during the 24 first hours. This might be potentially explained by the decrease of sedative use, resulting in more patients with spontaneous ventilation, with uncontrolled tidal volume and respiratory rate.

(0)
Numbers are n (%) and median (interquartile range), except for * which corresponds to min and max.
RBC red blood cells only resulted in loss of 250 mL of blood, corresponding to the circuit volume of purge.
Because, no trial demonstrating its clinical benefit has been published, ECCO 2 R systems are not widely used. Indeed, in a recent survey, among 239 French ICUs, only 15% declared having used at least once ECCO 2 R between 2010 and 2015 [20]. However, ECCO 2 R technology has improved, and because of a strong rational, several randomized trials enrolling ARDS and COPD patients are ongoing [21]. The mortality rate in our ARDS and COPD patients is in the lower range [16,22], and early use of ECCO2R might contribute to our results. If well-designed studies bring proof of the ECCO 2 R benefit, a very large number of patients would be concerned, asking the question of where to perform ECCO 2 R. Indeed, in the setting of ECMO, a large retrospective cohort analysis has suggested a negative link between ECMO cases volume and hospital mortality [23]. As well as the concept of "ECMO center," the need for "ECCO 2 R center" has to be assessed.
Our study has several limitations. First, because of the retrospective design, some data are lacking. Whereas tidal volume, respiratory rate, and positive end expiratory pressure are monitored hourly by the nurses in our unit, plateau pressure is usually monitored by the clinicians and not systematically reported in the medical record. It explains why complete data on plateau pressure and driving pressure were available for only 8 on 16 ARDS patients. Second, heterogeneity and small sample size limit internal validity. However, ECCO 2 R is not widely used, and previous studies in the setting of ECCO 2 R have included no more than 40 ARDS patients [7] and 25 COPD patients [12,13]. Third, we reported a single-center experience limits the generalization of our conclusions. For example, our paramedical team is widely used to prone positioning and extracorporeal circulations. Even if prone positioning in patients receiving ECCO 2 R has only concerned a few patients, team practice might have decreased the risk of severe adverse events such as accidental decannulation. Our patients represent 256 ECCO 2 R days. Fourth, except in the setting of SUPERNOVA or PRIS-MALUNG studies, we did not have preset criteria for ECCO 2 R implantation, which was left to the clinician's judgment. Fifth, we reported only initial ECCO 2 R settings. However, because of maximal CO 2 is targeted, sweep gas was usually kept at his maximal value. ECCO 2 R rotation per minute (RPM) was set to reach a blood flow of at least 300, 450, 700 and 1000 mL/min, with Prismalung®, Hemolung®, ILA®, and CardioHelp® respectively. ECCO 2 R RPM were decreased only when significant hemolysis was documented. Finally, plasma-free hemoglobin assessment was not available in our center, resulting in a more difficult diagnosis of hemolysis.

Conclusion
In ARDS patients, ECCO 2 R use was associated with a significant decrease of tidal volume and driving pressure during the first 48 h of therapy. Prone positioning was performed in 10 (62%) patients without adverse event. In COPD patients, ECCO 2 R use was associated with a significant decrease of minute ventilation, normalization of pH, and decrease of PaCO 2 . Although ECCO 2 R therapy was globally well tolerated, a case of fatal intracranial hemorrhage points out that this procedure cannot be dissociated from the potential risks of anticoagulation in critically ill patients.

Additional file
Additional file 1: Figure S1. Scatter plots representing evolution of tidal volume (a), respiratory rate (b), plateau pressure (c) and driving pressure (d) of the 16 ARDS patients. (DOCX 80 kb)

Availability of data and materials
The datasets analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions HW helped analyze the data, write the manuscript, and perform the literature search. FA, FB, NB, CCh, CP, CCl, ED, JCN, GL, GP, and GC helped analyze the data and write the manuscript. All authors read and approved the final manuscript.

Consent for publication
According to French law, written inform consent is not required for a retropective case series. All patients (or proxy) admitted in our ICU are informed that medical data may be used for research. If they wish, they may refuse that (approved by an Ethic Committee on March 2013). In this clinical case, no opposition was expressed for using data for research.

Competing interests
Pr Capellier has received lecture fees from Baxter and Alung. Prismalung® devices were provided by Baxter. The other authors declare that they have no competing interests.

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