Skip to content

Advertisement

  • Research article
  • Open Access
  • Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

Low flow extracorporeal CO2 removal in ARDS patients: a prospective short-term crossover pilot study

BMC AnesthesiologyBMC series – open, inclusive and trusted201717:155

https://doi.org/10.1186/s12871-017-0445-9

Received: 27 September 2017

Accepted: 12 November 2017

Published: 28 November 2017

Abstract

Background

Lung protective mechanical ventilation (MV) is the corner stone of therapy for ARDS. However, its use may be limited by respiratory acidosis.

This study explored feasibility of, effectiveness and safety of low flow extracorporeal CO2 removal (ECCO2R).

Methods

This was a prospective pilot study, using the Abylcap® (Bellco) ECCO2R, with crossover off-on-off design (2-h blocks) under stable MV settings, and follow up till end of ECCO2R. Primary endpoint for effectiveness was a 20% reduction of PaCO2 after the first 2-h. Adverse events (AE) were recorded prospectively.

We included 10 ARDS patients on MV, with PaO2/FiO2 < 150 mmHg, tidal volume ≤ 8 mL/kg with positive end-expiratory pressure ≥ 5 cmH2O, FiO2 titrated to SaO2 88–95%, plateau pressure ≥ 28 cmH2O, and respiratory acidosis (pH <7.25).

Results

After 2-h of ECCO2R, 6 patients had a ≥ 20% decrease in PaCO2 (60%); PaCO2 decreased 28.4% (from 58.4 to 48.7 mmHg, p = 0.005), and pH increased (1.59%, p = 0.005). ECCO2R was hemodynamically well tolerated. During the whole period of ECCO2R, 6 patients had an AE (60%); bleeding occurred in 5 patients (50%) and circuit thrombosis in 3 patients (30%), these were judged not to be life threatening.

Conclusions

In ARDS patients, low flow ECCO2R significantly reduced PaCO2 after 2 h, Follow up during the entire ECCO2R period revealed a high incidence of bleeding and circuit thrombosis.

Trial registration

https://clinicaltrials.gov identifier: NCT01911533, registered 23 July 2013.

Keywords

Acute respiratory distress syndromeLung protective mechanical ventilationExtracorporeal carbon dioxide removalPlateau pressureDriving pressure

Background

Acute Respiratory Distress Syndrome (ARDS) is a frequently occurring disorder in critically ill patients, and is associated with poor short-term and long-term outcomes [1, 2]. Lung protective mechanical ventilation (MV), i.e. use of a tidal volume (VT) of 6 mL/kg predicted body weight (PBW) and plateau pressure (PPLAT) lower than 30 cmH2O has been shown to lead to improved outcomes [35]. This is likely explained by decreasing overdistention and alveolar wall stress, and consequently decreased local and systematic inflammatory response [6]. Recent data suggest that reducing driving pressure (the difference between PPLAT and positive end-expiratory pressure (PEEP) (PPLAT-PEEP)), using MV with even lower VT, and limiting respiratory rate may offer additional benefit [711].The use of lower VT and lower respiratory rate may be limited by decreased elimination of CO2 with resulting hypercapnia and respiratory acidosis. This may in turn lead to increased pulmonary shunt, elevated intracranial pressure, pulmonary hypertension, decreased myocardial contractility, decreased renal and splanchnic blood flow and the release of endogenous catecholamines [12, 13]. Moderate permissive hypercapnia is generally well tolerated when ventilating in a lung-protective manner. But the effect on survival of hypercapnic acidosis compared to low-tidal volume remains unclear [14]. In patients with normal kidney function, metabolic adaptation will compensate for respiratory acidosis, but this process takes some days.

In 1977 Kolobow et al. evaluated the use of extracorporeal CO2 removal (ECCO2R) in an animal model [15]; subsequently, Gattinoni et al. first used ECCO2R in patients with acute respiratory failure in 1986 [16]. ECCO2R can be performed using a blood flow (Qb) ranging from 300 to 1500 mL/min. Published experience with ECCO2R in ARDS patients consists mainly of cohort studies [1721]. Some authors reported the use of ECCO2R in series with continuous renal replacement therapy (CRRT), offering an additional method of correcting acidosis. In these studies only patients who presented with acute kidney injury and ARDS were included [1719].

Using a previous generation of pumpless arterio-venous ECCO2R, Bein et al. showed that this technique allowed protective MV with VT of 3 mL/kg [22]. Fanelli et al. demonstrated that low-flow ECCO2R can safely be applied to facilitate ultra-protective MV with VT of 4 mL/kg [23]. Since these effects were evaluated over several days, also metabolic adaption and improvement of gas exchange may have contributed to the pH, and the exact contribution of ECCO2R on pH control versus mechanical ventilation is uncertain.

The aim of our pilot study was to explore the short-term (2-h) effects of low-flow ECCO2R in steady state conditions in ARDS patients. In addition, we studied feasibility and adverse events of this treatment with special emphasis on bleeding and thrombosis.

Methods

Setting and patients

A prospective pilot study was conducted in the Intensive Care Unit of Ghent University Hospital, between December 2013 and May 2015. The ICU comprises a 14 beds medical, a 22 beds surgical and 10 beds cardiac surgical ICU. A convenience sample of 10 patients was included. Patients had to meet all of the following criteria for inclusion: 1. acute onset of moderate or severe ARDS, with a PaO2/FiO2 < 150 mmHg [24], 2. at least two hours of MV applying a VT of 8 mL/kg PBW or less, with a positive end-expiratory pressure (PEEP) of 5 cmH2O or more, and FiO2 titrated to maintain an arterial oxygen saturation of 88–95% (PaO2 55–80 mmHg), 3. PPLAT of 28cmH2O or higher, 4. respiratory acidosis with pH < 7.25, 5. informed consent obtained from the patient or the proxy. Exclusion criteria were: 1. age < 18 years, 2. pregnancy, 3. obesity with a body mass index higher than 30 kg/m2, 4. contraindication for anticoagulation with unfractionated heparin, 5. Underlying chronic restrictive cause of respiratory acidosis, such as severe chest wall abnormalities.

Inhaled nitric oxide, muscle relaxants, and prone positioning were administered according to the discretion of the attending physician. PBW was calculated based upon patients’ length (measured with a measuring tape), for male patients: 50 + 0.91 · (cm of height – 152.4) kg, and for female patients: 45.5 + 0.91 · (cm of height – 152.4) kg [3]. Sedation was monitored at 8-h intervals, using the Richmond Agitation Sedation Score (RASS).

Study design

This paper discusses the results of a prospective single center pilot study with a crossover design.

To assess the immediate effects of ECCO2R on gas exchange, we used a crossover design alternating periods with (“on”) and without (“off”) ECCO2R. The first 2-h study period without ECCO2R started as soon as the venous access for ECCO2R was in place. Following this, a first 2-h “on”-period was initiated with a Qb of 300 mL/min. The fraction of delivered oxygen via the oxygenator was kept at 1.0 with a gas flow of 7 L/min during “on”-periods. Hereafter followed the second 2-h “off”-period by setting the gas flow through the ECCO2R oxygenator at 0 L/min. Qb remained unchanged during this second “off”-period. During these 3 study periods, the settings for MV remained unchanged. After this second “off”-period, a second “on”- period was started, the gas flow was set again at 7 L/min and the Qb was increased to 400–500 mL/min. This “on”-period lasted as long as clinically indicated.

Extracorporeal CO2 removal

Veno-venous ECCO2R was performed with the Abylcap® (Bellco®) device, mounted on a “Bellco” extracorporeal therapy machine. The Lynda® with a theoretical maximal Qb of 400 mL/min was used in the first 7 patients and the Amplya with a theoretical maximal Qb of 500 mL/min in the others.

A dedicated team of intensivists, dialysis nurses, ICU nurses, and perfusionists managed the extracorporeal therapy.

The Abylcap® device contains the Lilliput 2 (LivaNova) oxygenator; this is a polymethylpentene hollow fiber oxygenator, phosphorylcholine coated, with a surface of 0.67m2 and a priming volume of 90 mL. The priming volume of the entire heparin-coated set without oxygenator is 109 mL. Venous access was obtained preferentially via the femoral vein with a 24 cm, 13.5 French double lumen catheter (Niagara, Bard). Blood was pumped through the oxygenator via a non-occlusive roller pump.

Anticoagulation was performed with unfractionated heparin (UFH). After an initial bolus dose of 10 IU UFH/kg, heparin infusion was titrated to achieve an activated clotting time (ACT) of 180–220 s. ACT was measured every 30 to 60 min and once heparin titration was stable, every 4 h. ACT was monitored with the Medtronic ACT plus® system or the Hemochron ® signature elite.

Mechanical ventilation

During the first six hours of the study period, the treating physicians were advised not to change the MV settings. This allowed evaluating the effects of ECCO2R alone during this initial study period. From the start of the second “on”-period, MV was left at the discretion of the treating physician; with the only recommendation that of ventilating the patient as lung-protective as possible. Practically, MV settings were aimed toward PPLAT < 25cmH2O and VT < 6 mL/PBW. The “higher FiO2 and lower PEEP” protocol of the ALVEOLI study was proposed [25]. We recommended setting of respiratory rate lower than 30/min. Inversed ratio was not allowed.

Data management & analysis

During the first 6-h study period, MV parameters, arterial blood gas analysis and ECCO2R parameters were collected every two hours. Hereafter, data were recorded per 8 h. In addition, all adverse events, with special emphasis on bleeding events, thrombosis, and transfusion requirements were prospectively recorded.

The Murray score was calculated using the calculator on the “Cesar-trial” website http://cesar.lshtm.ac.uk/murrayscorecalculator.htm.

In order to have an objective judgment for bleeding, this was scored according the Bleeding Academic Research Consortium (BARC), and the Global Utilization of Streptokinase and Tpa for Occluded arteries (GUSTO) definitions for bleeding [26]. For a detailed description of the BARC and GUSTO definitions, please find an additional file as an online supplement (Additional file 1).

The primary endpoint was a reduction of 20% in arterial carbon dioxide pressure (PaCO2) after the two hours of ECCO2R therapy. Secondary endpoints were the short-term effect of ECCO2R on pH, feasibility of performing the technique, and bleeding and circuit thrombosis during ECCO2R treatment. In addition, we report the ventilation parameters and blood gasses after 5-d of ECCO2R.

A statistical package (SPSS Statistics version 22 (IBM®) was used to perform statistical analysis. Since the small number of patients included, data were considered not normally distributed. Variables were reported as median [inter quartile range] or number (proportion). Comparison of related variables was tested with the Wilcoxon Signed Rank test. A p-value of 0.05 was considered significant.

Results

The baseline characteristics of the included patients are presented in Table 1. The median duration of ECCO2R therapy was 6 days [5; 12]. Four patients were initiated on CRRT during the study. CRRT was started at earliest after 10 h of ECCO2R therapy, so after the initial “off-on-off” evaluation. When CRRT was used, this was with separate vascular access. The maximum Qb during the second on-period of ECCO2R was 400 mL/min [399; 410]. At day 1 median heparin dosage was 19.5 IU/kg/h [11.0; 25.4] with an ACT of 211 s [186; 225].
Table 1

Baseline characteristics

Baseline characteristics

N (%) or median [IQR]

Number of patients included

10 (100%)

Age (y)

50.5 [34.8; 63.3]

Gender

Male 6 (60%)/female 4 (40%)

SAPS 3 score

72.5 [61.0; 79.3]

Characteristics at inclusion

 Length of ICU stay before inclusion (h)

26 [20.5; 67.5]

 Days with ARDS criteria on CT scan or chest radiography on the day of inclusion

2 [1; 3.25]

 SAPS 3 score

69.5 [57.75; 79.25]

 Vasopressor use

10 (100%)

 RRT use

0

 PaCO2 (mmHg)

68.3 [57.7; 86.2]

 pH

7.21 [7.11; 7.23]

 PaO2/FiO2 (mmHg)

83 [67.6; 121.1]

 Murray score

3.5 [3.2; 3.5]

 Moderate ARDS (PaO2/FiO2: 100–200 mmHg)

4 (40%)

 Severe ARDS (PaO2/FiO2 < 100 mmHg)

6 (60%)

 Nitric Oxide inhalation

6 (60%)

 Neuromuscular blockers

10 (100%)

 Prone ventilation

2 (20%)

 PPLAT (cmH2O)

31.5 [28.8; 35.5]

 Driving pressure (PPLAT –PEEP) (cmH2O)

19.0 [17.5; 24.0]

 VT/PBW (mL/kg)

6.9 [6.31; 7.48]

y Years, SAPS 3 simplified acute physiology score 3, RRT Renal replacement therapy, PaCO 2 Partial pressure of arterial carbon dioxide, PaO 2 /FiO 2 the ration of partial pressure of arterial oxygen and fraction of inspired oxygen, P PLAT Plateau pressure, V T tidal volume, PBW Predicted body weight

ICU survival was 70%, hospital survival was 60%, and survival at day 28, and 90 was respectively 60% and 60%. In 4 patients, ECCO2R was the upper limit of life support, as after team discussions, these patients were not deemed to be candidates for extracorporeal membrane oxygenation (ECMO) therapy. Three patients died in the ICU because of limitations in therapy unrelated to ECCO2R.

Short term effects of ECCO2R

The protocol required settings of the MV to be unaltered during the 6-h crossover, in order to be able to study the short-term effects of ECCO2R in steady state conditions. In one patient the treating physician modified MV settings during the first off period, with resulting decrease of PaCO2 (132 to 58 mmHg). In order to secure the detection of the effect of ECCO2R, ventilation conditions remained unchanged for the next four hours. PCO2 values of this patient have been withdrawn from analysis of the first “off” -period (fig. 1a). Median PaCO2 remained stable during the first 2-h “off”-period (delta change −8.6% [−11.4; 3.0], p = 0.441), decreased during the “on”-period (−28.4% [−12.2; −34.3], p = 0.005), and subsequently increased during the second “off”-period (32.6% [18.5; 36.8], p = 0.005). During the 2-h on period 6 patients (60%) had a decrease in PaCO2 of 20% or greater (fig. 1b).
Figure 1
Fig. 1

Evolution of PaCO2 during the 6-h off-on-off period. a: Evolution of PaCO2 during the first 2-h off period. b: Evolution of PaCO2 during the first 2-h on period. c: Evolution of PaCO2 during the second 2-h off period. d: Evolution of pH during the first 2-h off period. e: Evolution of pH during the first 2-h on period. f: Evolution of pH during the second 2-h off period. This figure was created with Excel (Office)

Median pH remained stable during the first 2-h “off”-period (delta change 0.28% [−0.07; 0.76], p = 0.078) (figure1d), increased during the first “on”-period (1.59% [0.49; 2.02], p = 0.005) (fig. 1e), and decreased again during the second “off”-period (−1.28% [−1.50; −0.77], p = 0.005) (fig. 1f).

Feasibility and adverse events

Insertion of the double lumen catheter was troublesome in 2 patients (20%). One patient (10%) had transfusion of 1 unit of RBCs after insertion of the catheter. One patient (10%) had premature cessation after 6-h of ECCO2R for presumed hemorrhagic pericardial effusion. This finding was not confirmed after cessation of therapy.

During ECCO2R, bleeding was observed in 5 patients (Table 2). Patient 3 had a nosebleed and was bleeding at the insertion points of the ECCO2R catheter and the central venous catheter. Patient 4 was bleeding at the insertion point of the ECCO2R catheter, had a pharyngeal bleeding and hematuria. Patient 5 was bleeding during insertion of the catheter. Patient 7 had minor bleeding during tracheal and pharyngeal aspirations. Patient 9 was bleeding at the insertion point of the ECCO2R catheter. According to the GUSTO criteria and BARC definitions, bleeding was scored in 4 patients (40%) as moderate or 3a, and in 1 patient (10%) as mild or 2 [26]. Five patients (50%) received transfusion of red blood cells. In none of the patients, bleeding resulted in hemodynamic instability.

In 3 patients (30%), clots were observed in the circuit. In 2 patients (20%), clotting of the circuit occurred after temporary stop of the heparin infusion because of increased ACT results.

We observed transient and short-lasting alkalemia (defined as pH > 7.45) in 8 patients (80%).
Table 2

Bleeding, clotting in circuit and transfusion needs

Patient no

Clotting in circuit

Bleeding

Transfusion

Cumulative Units of PC during ECCO2R

GUSTO bleeding criteria

BARC type

1

   

0

 

0

2

   

0

 

0

3

 

Y

Y

4

moderate

3a

4

Y

Y

Y

4

moderate

3a

5

Y

Y

Y

3

moderate

3a

6

   

1

 

0

7

 

Y

 

0

mild

2

8

   

1

 

0

9

 

Y

Y

3

moderate

3a

10

Y

 

Y

2

 

0

total

3/10

5/10

5/10

1.5 [0; 3.25]

  

Y” yes, an empty box means no, PC Packed Cells, GUSTO Global Utilization of Streptokinase and Tpa for Occluded arteries definition of bleeding, BARC Bleeding Academic Research Consortium definition for bleeding

Evolution of ventilation and blood gasses after 5-d ECCO2R

Plateau pressure, PPLAT-PEEP and VT/PBW were significantly reduced after 5 days of therapy (Table 3). This was accompanied with a steady increase of bicarbonate and pH. Median pH at the moment of decision of weaning from ECCO2R was 7.42 [7.39; 7.44].

A significant increase in PaO2/FiO2 was noted, indicating amelioration of ARDS.
Table 3

Evolution in ventilatory measurements

 

Inclusion

Day 2

Day 3

Day4

Day 5

Difference

% change

p

PPLAT (cmH2O)

31.5 [28.8; 35.5]

25.0 [22.5; 30.5]

26.0 [22.0; 29.5]

25.0 [22.0; 27.0]

24.0 [21.0; 26.0]

10.0 [4.5; 12.5]

−31.4 [−36.2; −15.4]

0.008

VT (mL)

334 [317; 469]

300 [270; 353]

318 [270; 390]

300 [251; 344]

308 [243; 347]

69.0 [20.0; 90.0]

−20.9 [−26.3; −5.17]

0.008

VT/PBW (mL/kg)

6.85 [6.31; 7.48]

5.60 [4.90; 6.05]

5.80 [4.75; 6.45]

5.30 [4.55; 6.20]

5.00 [4.55; 5.95]

1.6 [0.8; 2.15]

−23.7 [−31.3; −13.9]

0.008

Driving Pressure: PPLAT –PEEP (cmH2O)

19.0 [17.5; 24.0]

14.0 [11.0; 18.5]

15.0 [11.0; 19.0]

15.0 [11.0; 17.0]

14.0 [10.0; 16.5]

9.0 [3.5; 12]

−39.1 [−52.2; −21.7]

0.012

PEEP (cmH2O)

12.0 [9.0; 12.75]

11.0 [8.5; 14.5]

11.0 [8.0; 13,5]

10.0 [8.0; 11.50]

10.0 [8.0; 10.0]

2.0 [−1.0; 2.0]

16.7 [−16.7; 16.7]

0.305

Respiratory Rate

32.0 [27.8; 33.0]

30.0 [27.5; 31.5]

30.0 [27.0; 31.5]

30.0 [27.0; 33.5]

30.0 [26.0; 33.5]

3.0 [−1.0; 6.0]

9.1 [−3.0; 20.0]

0.235

pH

7.21 [7.11; 7.23]

7.33 [7.29; 7.38]

7.38 [7.31; 7.42]

7.39 [7.34; 7.44]

7.43 [7.40; 7.44]

0.23 [0.20; 0.26]

3.19 [2.77; 3.63]

0.008

PaO2/FiO2 (mmHg)

83.0 [67.6; 105.4]

131.4 [90.2; 212.7]

137.2 [118.9; 223.8]

142.0 [116.1; 245.5]

233.6 [135.7; 320.1]

91.9 [29.9; 213.8]

144.0 [30.8; 232.2]

0.011

PaCO2 (mmHg)

68.3 [57.3; 86.2]

50.3 [42.9; 63.9]

51.5 [48.2; 62.2]

56.8 [46.6; 63.1]

59.3 [48.2; 60.9]

14.6 [4.0; 35.8]

22.2 [6.9; 38.0]

0.021

HCO3

22.6 [22.1; 29.6]

25.7 [20.3; 34.1]

25.7 [25.3; 30.0]

29.1 [27.9; 39.3]

35.3 [29.4; 41.9]

−7.6 [−12.1; −3.2]

−34.2 [−51.2; −14.8]

0.021

FiO2

0.83 [0.68; 1.00]

0.55 [0.40; 0.75

0.55 [0.35; 0.73]

0.60 [0.35; 0.73]

0.50 [0.35; 0.73]

0.25 [0.05; 0.5]

45.5 [5.9; 50.0]

0.017

Data are expressed as median [IQ25; IQ75]. Difference: the median of the difference between the data at time of inclusion and at day 5

Discussion

In this prospective crossover pilot study in patients with moderate or severe ARDS, we found that with stable MV settings, low flow ECCO2R resulted in a rapid decrease of PaCO2 with almost one-third. During the whole treatment period, we observed a high incidence of bleeding and thrombosis.

In our study, we evaluated the short-term effects of ECCO2R in steady state MV conditions, using study periods of 2-h. It is therefore reasonable to presume that changes in PaCO2 can be attributed to the effects of ECCO2R only, and were not obscured by an improvement of respiratory function, metabolic compensation, or change in settings of the mechanical ventilator. This is an important aspect that was not studied before. Several other studies have reported the beneficial effects of ECCO2R on PaCO2 in ARDS patients. However these differed from our study in study design, the non-reporting of short-term effects, combined use with CRRT, and the use of other devices such as pumpless arterio-venous devices [17, 19, 2123, 27]. An important advantage of this low flow veno-venous ECCO2R treatment is that Qb up to 500 mL/min can be achieved by using a catheter that is also used for CRRT, making it a less invasive technique compared with others that are using an arterial catheter or large bore wire-reinforced ECMO cannulas [22, 23, 2730]. However, it should be noted that despite our use of relatively small-bore catheters of 13.5F, catheter insertion was difficult in two patients.

We observed some variability in response to ECCO2R. A possible explanation for this may be a difference in volume of distribution of CO2. Two main components that determine CO2 removal are Qb and sweep gas flow. Here we used a Qb of 300 mL/min during the first “on”- period of our study, in which we demonstrated an almost 30% decrease of CO2. In the second “on”-period, a median Qb of 400 mL/min allowed adequate removal of CO2. Our findings are in contrast to others who have reported higher Qb. For instance, Karagiannidis et al. suggested in their study in pigs a QB of 750 to 1000 mL/min for efficient CO2 removal [31], and Bein et al. used in vivo a Qb of 2.2 L/min for the A-V iLA device [27, 32]. An explanation for the efficacious CO2 removal despite low Qb in our study may be the deep sedation used in our patients, limiting CO2 production. Another determinant for CO2 removal is sweep gas flow. In this study the sweep gas flow was kept at 7 L/min, with a FiO2 of 1.0, since we found in a previous study that CO2 removal rate only marginally improved above gas flows of 6 L/min [33].

After 5 days of ECCO2R we observed a marked decrease in PPLAT, PPLAT-PEEP and VT. This resulted in a more lung protective strategy of MV with ventilation settings of VT, PPLAT and driving pressure below the currently recommended [710]. Decreased VT, PPLAT and PPLAT-PEEP without an increase in PaCO2 may offer benefits for ARDS patients, since it may lead to a further decrease of inflammatory mediators in broncho-alveolar fluid and systemic circulation, which in turn may contribute to less lung damage and improved outcomes [17, 23]. Since pH was still 7.43 at day 5, it might have been feasible to achieve even more pronounced decreases of mechanical ventilation settings.

Adequate anticoagulation remains challenging in the management of ECCO2R-patients. In our study, 30% of all patients experienced some form of circuit thrombosis. This was accompanied with a temporal increase in PaCO2 and consequent change of the ventilator to less lung protective settings. We also observed bleeding and need for transfusion of red blood cells in 50% of patients. Others have also reported bleeding and blood loss as an important complication of ECCO2R [22, 27, 34]. This complication seems to occur more frequently in ECCO2R compared to CRRT (16%), a well-established extracorporeal therapy for AKI [35]. We can only speculate on the etiology of bleeding in these patients. Potential causes could be the poor correlation of both ACT and aPTT with the heparin concentration [36, 37], and the activation of platelets and induction of other coagulation abnormalities by unfractionated heparin and/or the ECCO2R circuit [38].The use of visco-elastic monitoring such as TEG, RoTEM or Sonoclot, preferable in combination with a platelet function test may allow better monitoring of coagulation in these patients.

Strengths of our study are the prospective crossover design with detailed short-term evaluation of the effects of ECCO2R. This allowed us to evaluate the effects of ECCO2R with the patient serving as its own control. In addition, we reported the adverse events, more in particular bleeding, meticulously and in a structured way according to the validated GUSTO and BARC scales. As until now, no RCT’s have proven advantage over permissive hypercapnia, it is important to quote the principle ‘primum non nocere’ to guide clinicians considering ECCO2R. Finally, this study evaluated ECCO2R in moderate (n = 4) and severe ARDS patients (n = 6), and as such reflects the recommended cohort of ARDS patients that may benefit of ECCO2R [24]. We want to discuss the following limitations of this pilot study. We report data on a small number of patients in a single center setting. Second, we may have underestimated the short-term effects of ECCO2R during the first six hours of our study period as we only used a Qb of 300 mL/min. Third, reduction of VT, PPLAT and driving pressure were the main goals of management of MV in this study. Recently, the large epidemiologic LUNG SAFE study showed that a lower respiratory rate is also associated with better patient outcomes [39]. These results were not available at time of the initiation of the study, and decreasing respiratory rate was therefore not set as a goal for MV here. Finally, we can only speculate on the efficacy of ECCO2R using low Qb in patients who are more awake.

Conclusions

We showed the feasibility of CO2 removal with a low flow ECCO2R device in patients with moderate and severe ARDS. Crossover design allowed us to evaluate the short-term effects of ECCO2R in steady state conditions, with the patient serving as his own control, and demonstrated an almost one-third decrease of PaCO2 within a 2-h study period. However, ECCO2R treatment was associated with bleeding in half of the patients and circuit thrombosis in one third. These complications should be explored in greater detail and may be a major barrier for larger studies on efficacy of ECCO2R.

Abbreviations

ACT: 

activated clotting time

AE: 

adverse events

aPTT: 

activated partial tromboplastin time

ARDS: 

acute respiratory distress syndrome

BARC: 

Bleeding Academic Research Consortium

COPD: 

chronic obstructive pulmonary disease

CRRT: 

continuous renal replacement therapy

ECCO2R: 

extracorporeal CO2 removal

GUSTO: 

Global Utilization of Streptokinase and Tpa for Occluded arteries

MV: 

mechanical ventilation

PaCO2

arterial carbon dioxide pressure

PaO2/ FiO2

the ratio of the arterial oxygen partial pressure to fractional inspired oxygen

PBW: 

predicted body weight

PC: 

packed cells

PEEP: 

positive end-expiratory pressure

PPLAT

plateau pressure

Qb: 

blood flow

RBC: 

Red blood cells

RRT: 

renal replacement therapy

SAPS 3: 

simplified acute physiology score 3

VT

tidal volume

Declarations

Acknowledgements

We wish to thank the whole team of specialized RRT nurses: Stefaan Claus, Liesbeth De Cuyper, Terry De Grande, Jonathan De Rudder, Martine Dick, Els Holvoet, Ann Scheir. Also, the study nurses: Stephanie Bracke, Charlotte Clauwaert, Luc De Crop, Daisy Vermeiren. Graphs were made by: Jorien De Loor. In addition, we wish to express our gratitude to Jacques Devriendt, MD and Greet Hermans, MD, PhD the investigators of the 2 other academic centers who participated in the study but were not able to include patients. We also thank all nurses and physicians of the ICU for the detection of possible inclusions and for the careful change and follow-up of MV settings.

Funding

Bellco offered a grant that provided the disposables used for the study patients. Bellco did not have access to the design, the analysis, nor the results of this study.

Availability of data and materials

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

Study concept and design: HP, EH, PD, FDS, SE, CR: Acquisition of data: HP, Analysis and interpretation of data: HP, SE, EH: Drafting the manuscript: HP, EH: Critical revision of the manuscript for important intellectual content: EH, SE, FDS, PD: Supervision: EH: All authors read and approved the final manuscript.

Ethics approval and consent to participate

This study was conducted in agreement with the declaration of Helsinki and approved by the Ethics Committee of the Ghent University Hospital (EC 2013/505). Inclusion was only possible after obtaining written informed consent from the patient or the proxy.

Consent for publication

Not applicable.

Competing interests

H. Peperstraete: speaker honoraria for an educational program of Bellco.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis 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. 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.

Authors’ Affiliations

(1)
Intensive Care Unit, Ghent University Hospital, Ghent, Belgium
(2)
Renal Division, Ghent University Hospital, Ghent, Belgium
(3)
Ghent University, Ghent, Belgium
(4)
Department of Cardiac Surgery, Ghent University Hospital, Ghent, Belgium
(5)
Research Foundation-Flanders (FWO), Brussels, Belgium

References

  1. Acute Respiratory Distress Syndrome The Berlin Definition. JAMA. 2012;307:2526–33.Google Scholar
  2. Dowdy DW, Eid MP, Dennison CR, Mendez-Tellez PA, Herridge MS, Guallar E, Pronovost PJ, Needham DM. Quality of life after acute respiratory distress syndrome: a meta-analysis. Intensive Care Med. 2006;32:1115–24.View ArticlePubMedGoogle Scholar
  3. The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000, 342:1301–1308.Google Scholar
  4. Tonelli AR, Zein J, Adams J, Ioannidis JPA. Effects of interventions on survival in acute respiratory distress syndrome: an umbrella review of 159 published randomized trials and 29 meta-analyses. Intensive Care Med. 2014;40:769–87.View ArticlePubMedPubMed CentralGoogle Scholar
  5. Serpa Neto A, Cardoso SO, Manetta JA, Pereira VGM, Espósito DC, Pasqualucci M, De OP DMCT, Schultz MJ. Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA. 2012;308:1651–9.View ArticlePubMedGoogle Scholar
  6. Bein T, Grasso S, Moerer O, Quintel M, Guérin C, Deja M, Brondani A, Mehta S. The standard of care of patients with ARDS: ventilatory settings and rescue therapies for refractory hypoxemia. Intensive Care Med. 2016;42:699–711.View ArticlePubMedPubMed CentralGoogle Scholar
  7. Hager DN, Krishnan JA, Hayden DL, Brower RG. Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med. 2005;172:1241–5.View ArticlePubMedPubMed CentralGoogle Scholar
  8. Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, Gandini G, Herrmann P, Mascia L, Quintel M, Slutsky AS, Gattinoni L, Ranieri VM. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2007;175:160–6.View ArticlePubMedGoogle Scholar
  9. Needham DM, Colantuoni E, Mendez-Tellez PA, Dinglas VD, Sevransky JE, Dennison Himmelfarb CR, Desai SV, Shanholtz C, Brower RG, Pronovost PJ. Lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study. BMJ. 2012;344:–e2124.Google Scholar
  10. Amato MBP, Meade MO, Slutsky AS, Brochard L, Costa ELV, Schoenfeld DA, Stewart TE, Briel M, Talmor D, Mercat A, J-CM R, CRR C, Brower RG. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372:747–55.View ArticlePubMedGoogle Scholar
  11. Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A. For the LUNG SAFE investigators and the ESICM trials group: epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315:788–13.View ArticlePubMedGoogle Scholar
  12. Feihl FF, Perret CC. Permissive hypercapnia. How permissive should we be? Am J Respir Crit Care Med. 1994;150:1722–37.View ArticlePubMedGoogle Scholar
  13. Feihl F, Eckert P, Brimioulle S, Jacobs O, Schaller M-D, Mélot C, Naeije R. Permissive hypercapnia impairs pulmonary gas exchange in the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2000;162:209–15.View ArticlePubMedGoogle Scholar
  14. Marhong J, Fan E. Carbon dioxide in the critically ill: too much or too little of a good thing? Respir Care. 2014;59:1597–605.View ArticlePubMedGoogle Scholar
  15. Kolobow T, Gattinoni L, Tomlinson TA, Pierce JE. Control of breathing using an extracorporeal membrane lung. Anesthesiology. 1977;46:138–41.View ArticlePubMedGoogle Scholar
  16. Gattinoni L, Pesenti A, Mascheroni D, Marcolin R, Fumagalli R, Rossi F, Iapichino G, Romagnoli G, Uziel L, Agostoni A. Low-frequency positive-pressure ventilation with extracorporeal CO2 removal in severe acute respiratory failure. JAMA. 1986;256:881–6.View ArticlePubMedGoogle Scholar
  17. Terragni PP, Del Sorbo L, Mascia L, Urbino R, Martin EL, Birocco A, Faggiano C, Quintel M, Gattinoni L, Ranieri VM. Tidal volume lower than 6 ml/kg enhances lung protection: role of extracorporeal carbon dioxide removal. Anesthesiology. 2009;111:826–35.View ArticlePubMedGoogle Scholar
  18. Forster C, Schriewer J, John S, Eckardt K-U, Willam C. Low-flow CO2 removal integrated into renal-replacement circuit can reduce acidosis and decrease vasopressor requirements. Crit Care. 2013;17:R154.View ArticlePubMedPubMed CentralGoogle Scholar
  19. Allardet-Servent J, Castanier M, Signouret T, Soundaravelou R, Lepidi A, Seghboyan J-M. Safety and efficacy of combined extracorporeal CO2 removal and renal replacement therapy in patients with acute respiratory distress syndrome and acute kidney injury. Crit Care Med. 2015;43:2570–81.View ArticlePubMedPubMed CentralGoogle Scholar
  20. Deniau B, Ricard JD, Messika J, Dreyfuss D, Gaudry S. Use of extracorporeal carbon dioxide removal (ECCO2R) in 239 intensive care units: results from a French national survey. Intensive Care Med. 2016;42:624–5.View ArticlePubMedGoogle Scholar
  21. Moss CE, Galtrey EJ, Camporota L, Meadows C, Gillon S, Ioannou N, Barrett NA, Retrospective Observational A. Case series of low-flow Venovenous extracorporeal carbon dioxide removal use in patients with respiratory failure. ASAIO J. 2016;62:458–62.View ArticlePubMedGoogle Scholar
  22. Bein T, Weber-Carstens S, Goldmann A, Müller T, Staudinger T, Brederlau J, Muellenbach R, Dembinski R, Graf BM, Wewalka M, Philipp A, Wernecke K-D, Lubnow M, Slutsky AS. Lower tidal volume strategy (≈3 ml/kg) combined with extracorporeal CO2 removal versus “conventional” protective ventilation (6 ml/kg) in severe ARDS. Intensive Care Med. 2013;39:847–56.View ArticlePubMedPubMed CentralGoogle Scholar
  23. Fanelli V, Ranieri MV, Mancebo J, Moerer O, Quintel M, Morley S, Moran I, Parrilla F, Costamagna A, Gaudiosi M, Combes A. Feasibility and safety of low-flow extracorporeal carbon dioxide removal to facilitate ultra-protective ventilation in patients with moderate acute respiratory distress sindrome. Crit Care. 2016:1–7.Google Scholar
  24. Ferguson ND, Fan E, Camporota L, Antonelli M, Anzueto A, Beale R, Brochard L, Brower R, Esteban A, Gattinoni L, Rhodes A, Slutsky AS, Vincent J-L, Rubenfeld GD, Thompson BT, Ranieri VM. The berlin definition of ARDS: an expanded rationale, justification, and supplementary material. Intensive Care Med. 2012;38:1573–82.View ArticlePubMedGoogle Scholar
  25. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, Schoenfeld D, Thompson BT. National Heart, Lung, and Blood Institute ARDS clinical trials network: higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004;351:327–36.View ArticlePubMedGoogle Scholar
  26. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the bleeding academic research consortium. Circulation. 2011;123:2736–47.View ArticlePubMedGoogle Scholar
  27. Bein T, Weber F, Philipp A, Prasser C, Pfeifer M, Schmid F-X, Butz B, Birnbaum D, Taeger K, Schlitt HJ. A new pumpless extracorporeal interventional lung assist in critical hypoxemia/hypercapnia. Crit Care Med. 2006;34:1372–7.View ArticlePubMedGoogle Scholar
  28. Kluge S, Braune SA, Engel M, Nierhaus A, Frings D, Ebelt H, Uhrig A, Metschke M, Wegscheider K, Suttorp N, Rousseau S. Avoiding invasive mechanical ventilation by extracorporeal carbon dioxide removal in patients failing noninvasive ventilation. Intensive Care Med. 2012;38:1632–9.View ArticlePubMedGoogle Scholar
  29. Abrams DC, Brenner K, Burkart KM, Agerstrand CL, Thomashow BM, Bacchetta M, Brodie D. Pilot study of extracorporeal carbon dioxide removal to facilitate extubation and ambulation in exacerbations of chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2013;10:307–14.View ArticlePubMedGoogle Scholar
  30. Sharma AS, Weerwind PW, Strauch U, van Belle A, Maessen JG, Wouters EFM. Applying a low-flow CO2 removal device in severe acute hypercapnic respiratory failure. Perfusion. 2016;31:149–55.View ArticlePubMedGoogle Scholar
  31. Karagiannidis C, Kampe KA, Sipmann FS, Larsson A, Hedenstierna G, Windisch W, Mueller T. Veno-venous extracorporeal CO2 removal for the treatment of severe respiratory acidosis: pathophysiological and technical considerations. Crit Care. 2014;18:R124.View ArticlePubMedPubMed CentralGoogle Scholar
  32. Schultz MJ, Juffermans NP, Matthay MA. From protective ventilation to super-protective ventilation for acute respiratory distress syndrome. Intensive Care Med. 2013;39:963–5.View ArticlePubMedPubMed CentralGoogle Scholar
  33. Eloot S, Peperstraete H, De Somer F, Hoste E. Assessment of the optimal operating parameters during extracorporeal CO2 removal with the Abylcap® system. Int J Artif Organs. 2017;39:580–5.Google Scholar
  34. Del Sorbo L, Pisani L, Filippini C, Fanelli V, Fasano L, Terragni P, Dell’Amore A, Urbino R, Mascia L, Evangelista A, Antro C, D’Amato R, Sucre MJ, Simonetti U, Persico P, Nava S, Ranieri VM. Extracorporeal Co2 removal in Hypercapnic patients at risk of noninvasive ventilation failure. Crit Care Med. 2015;43:120–7.View ArticlePubMedGoogle Scholar
  35. Bai M, Zhou M, He L, Ma F, Li Y, Yu Y, Wang P, Li L, Jing R, Zhao L, Sun S. Citrate versus heparin anticoagulation for continuous renal replacement therapy: an updated meta-analysis of RCTs. Intensive Care Med. 2017;41:2098–110.View ArticleGoogle Scholar
  36. De Waele JJ, Van Cauwenberghe S, Hoste E, Benoit D, Colardyn F. The use of the activated clotting time for monitoring heparin therapy in critically ill patients. Intensive Care Med. 2003;29:325–8.View ArticlePubMedGoogle Scholar
  37. Nankervis CA, Preston TJ, Dysart KC, Wilkinson WD, Chicoine LG, Welty SE, Nelin LD. Assessing heparin dosing in neonates on venoarterial extracorporeal membrane oxygenation. ASAIO J. 2007;53:111–4.View ArticlePubMedGoogle Scholar
  38. Kalbhenn J, Neuffer N, Zieger B, Schmutz A, Extracorporeal I. CO2 removal really “Safe” and ‘less’ invasive? Observation of blood injury and coagulation impairment during ECCO2R. ASAIO J. 2017;63:666–71.View ArticlePubMedGoogle Scholar
  39. The LUNG SAFE Investigators and the ESICM Trials Group, Laffey JG, Bellani G, Pham T, Fan E, Madotto F, Bajwa EK, Brochard L, Clarkson K, Esteban A, Gattinoni L, van Haren F, Heunks LM, Kurahashi K, Laake JH, Larsson A, DF MA, McNamee L, Nin N, Qiu H, Ranieri M, Rubenfeld GD, Thompson BT, Wrigge H, Slutsky AS, Pesenti A. Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study. Intensive Care Med. 2016;42:1865–76.View ArticleGoogle Scholar

Copyright

© The Author(s). 2017

Advertisement