Extracorporeal carbon dioxide removal for patients with acute respiratory failure: a systematic review and meta-analysis

Figures & data

Figure 1. Flow chart of study selection.

Table 1. Basic characteristics of included studies.

Studies	Country	Study design	Target population/setting	Patients (N)	Males (%)	Age (year)	PaO2/FIO2 ratio	PaCO2 (mmHg)	Intervention	Control
Bein et al. [18]	Germany and Austria	RCT	Patients with ARF secondary to severe ARDS/ICU	I: 40 C: 39	I: 95 C: 77	I: 49.8 ± 12 C: 48.7 ± 17	<200 I: 152 ± 37 C: 168 ± 37	I: 57.3 ± 12 C: 54.3 ± 9	Low tidal volumes mechanical ventilation (3 ml/kg) with AV-ECCO2R	Mechanical ventilation using conventional tidal volumes (6 ml/kg)
McNamee et al. [19]	UK	RCT	Patients receiving iMV for ARF/ICU	I: 202 C: 210	I: 68 C: 62	I: 60 (51, 69) C: 62 (50, 70)	<150 I: 118.1 (96.0, 134.3) C: 115.5 (93.8, 132.8)	I: 53.8 (47.3, 62.7) C: 54.6 (48.0, 62.3)	Low tidal volumes mechanical ventilation with VV-ECCO2R	Lung protective ventilation alone
Morris et al. [20]	America	RCT	Patients with ARF secondary to severe ARDS/ICU	I: 21 C: 19	I: 38 C: 47	I: 33 ± 3.1 C: 38 ± 3.3	I: 62.6 ± 4.2 C: 63.8 ± 3.8	I: 50 ± 3 C: 48 ± 4	LFPPV + VV- ECCO2R	Standardized CPPV
Barrett et al. [21]	UK	RCT	Patients presenting with ARF due to AECOPD/ICU	I: 9 C: 9	I: 56 C: 33	I: 65 (63, 71) C: 69 (61, 71)	/	I: 73.1 (61.1, 73.4) C:68.9 (67.1, 77.3)	VV-ECCO2R added to NIV	Standard therapy using NIV
Azzi et al. [22]	France	Observational	Patients with consecutive AECOPD who experienced NIV failure/ICU	I: 26 C: 25	I: 77 C: 68	I: 67 ± 12 C: 72 ± 11	/	I: 86 ± 21 C: 82 ± 24	VV-ECCO2R	iMV after failing NIV
Braune et al. [23]	Germany, Austria, Netherlands	Observational	Patients with ARF secondary to COPD refractory to NIV/ICU	I: 25 C: 25	I: 48 C: 52	I: 67 (51, 83) C: 69 (55, 82)	I: 209.3 (106.2, 476.0) C: 201.0 (58.0, 466.0)	I: 81.5 (53.8, 126) C: 79.5 (48.4, 117)	Pump-driven, VV-ECCO2R device	iMV after failing NIV
Del Sorbo et al. [24]	Italy	Observational	Patients treated with NIV for ARF due to AECOPD/ICU	I: 25 C: 21	/	I: 70.7 ± 7.1 C: 70.4 ± 9.8	I: 211 (138, 248) C: 187 (141, 245)	I: 74 (64, 89) C: 78 (70, 88)	NIV-Plus VV-ECCO2R	NIV-Only
Kluge et al. [25]	Germany	Observational	Patients with ARF secondary to COPD unresponsive to NIV/ICU	I: 21 C: 21	I: 48 C: 43	I: 58 (27, 80) C: 58 (23, 79)	I: 208 (153, 396) C: 179 (113, 591)	I: 84.0 (54.2, 131) C: 65.0 (39.2, 108)	AV-ECCO2R therapy by means of a PECLA device	iMV after failing NIV
İnal et al. [26]	Turkey	Observational	Patients with ARF secondary to COPD or ARDS (data about COPD is collected)/ICU	I: 49 C: 207	I: 45 C: 45	I: 68 (51, 93) C: 69 (41, 97)	I: 129 ± 13 C: 133 ± 14	I: 78 ± 21 C: 75 ± 18	VV-ECCO2R therapy in addition to conventional treatments	Conventional treatments alone

iMV: invasive mechanical ventilation; ARF: acute respiratory failure; COPD: chronic obstructive pulmonary disease; ARDS: acute respiratory distress syndrome; ICU: intensive care unit; NIV: noninvasive ventilation; ECCO₂R: extracorporeal carbon dioxide removal; PECLA: pumpless extracorporeal lung-assist.

Table 2. Clinical outcomes and complications of included studies.

Studies	Clinical outcomes				Adverse events
	Mortality	Length of stay (days)	Intubation/extubation	Respiratory parameters
Bein et al. [18]	Hospital: 7/40 (18%) vs 6/39 (15%)	ICU: 31.3 ± 23 vs 22.9 ± 11; hospital: 46.7 ± 33 vs 35.1 ± 17	VFD-28 (days): 10.0 ± 8 vs 9.3 ± 9; VFD-60 (days): 33.2 ± 20 vs 29.2 ± 21; non-pulmonary organ failure free days-60 (days): 21.0 ± 14 vs 23.9 ± 15	/	AV-ECCO2R related adverse events: 3/40
McNamee et al. [19]	28-day: 76/200 (38%) vs 74/207 (36%); 90-day: 83/200 (42%) vs 81/205 (40%)	ICU: 14 (7, 26) vs 13 (7, 22); hospital: 22 (8, 39) vs 18 (9, 35)	VFD-28 (days): 7.1 ± 8.8 vs 9.2 ± 9.3;	pH: 7.30 (7.25, 7.37) to 7.31 ± 0.09 vs 7.30 (7.24, 7.37) to 7.31 ± 0.1; PaCO2 (mmHg): 53.8 (47.3, 62.7) to 55.8 ± 14.4 vs 54.6 (48, 62.3) to 56.6 ± 13.8; P/F ratio: 118.1 (96, 134.3) to 153.1 ± 84 vs 115.5 (93.8, 132.8) to 145.1 ± 48.3; RR: 24 (20, 28) to 23.9 ± 5.02 vs 24 (20, 28) to 23.9 ± 5.24	Adverse events: 106/202 vs 48/210; major adverse events: 62/202 vs 18/210
Morris et al. [20]	28-day: 14/21 (67%) vs 11/19 (58%)	ICU: 23.8 ± 18.3 vs 24.2 ± 19.2; hospital: 26.9 ± 22.5 vs 28.8 ± 24.8	CPPV duration (days): 4.46 ± 10.1 vs 19.3 ± 16.1; ECCO2R duration (days): 8.7 ± 1.7	/	Number of patients with major complications (not number of episodes): 34 vs 16 Major bleeding: 17/21 vs 1/19;
Barrett et al. [21]	Hospital: 3/9 (33%) vs 1/9 (11%); ICU: 3/9 (335) vs 0/9 (0%); 90-day: 4/9 (44%) vs 2/9 (22%)	ICU: 6.7 (5.5, 7.3) vs 1.9 (1.7, 2.2); hospital: 10 (9.2, 14.1) vs 5.2 (4.3, 8.9)	NIV duration (days): 0.3 ± 0.1 vs 1.6 ± 1.5	pH: 7.27 (7.25, 7.29) to 7.39 (7.37, 7.42) vs 7.27 (7.21, 7.27) to 7.38 (7.36, 7.40); PaCO2 (kPa): 9.34 (8.49, 10.2) to 8.02 (6.57, 8.3) vs 9.16 (8.23, 10.02) to 7.40 (7.16, 8.08); RR: 29 (26, 32) to 17 (16, 23) vs 24 (20, 28) to 20.5 (20, 22.75)	No severe or life-threatening complications in either group.
Azzi et al. [22]	28-day: 3/26 (12%) vs 4/25 (16%); 90-day: 4/26 (15%) vs 7/25 (28%); ICU: 2/26 (8%) vs 7/25 (28)	ICU: 18 ± 14 vs 30 ± 43; hospital: 29 ± 22 vs 49 ± 53	Intubation rate: 4/26 vs 25/25; tracheotomy: 2/26 vs 5/25; ECCO2R duration (days): 5.4 ± 4 vs iMV duration (days): 27 ± 43	pH: 7.24 ± 0.05 to 7.41 ± 0.06 vs 7.23 ± 0.13 to 7.39 ± 0.06; PaCO2 (mmHg): 86 ± 21 to 53 ± 10 vs 82 ± 24 to 52 ± 13;	(ECCO2R) Major bleeding: 6/26; minor bleeding: 5/26; (control) ventilator associated pneumonia: 8/25; hemodynamic instability with catecholamine administration requirement: 3/26 vs 16/25
Braune et al. [23]	28-day: 4/25 (16%) vs 3/25 (12%); 90-day: 7/25 (28%) vs 7/25 (28%); hospital: 6/25 (24%) vs 3/25 (12%)	ICU: 28.9 (8.0, 100.0) vs 24.0 (2.0, 66.0); hospital: 36.9 (9.0, 100.0) vs 37.0 (12.0, 248.0)	14/25 avoided intubation vs 0/21 avoided intubation; iMV duration (days): 8.3 (0, 60.0) vs 13.7 (1.0, 52.0); tracheotomy: 9/25 (36%) vs 15/25 (60%)	ECCO2R: pH: 7.26 (7.15, 7.33) to 7.42 (7.34, 7.48); PaCO2 (mmHg): 82.0 (68.0, 94.0) to 52.0 (44.0, 66.0); RR: 25 (24, 34) to 20 (15, 23)	Major adverse events: 14 vs 2; minor adverse events: 11 vs 10 Major bleeding: 11/25 vs 2/25; minor bleeding: 10/25 vs 10/25
Del Sorbo et al. [24]	Hospital: 2/25 (8%) vs 8/21 (35%)	ICU: 8 (7, 10) vs 12 (6, 15); hospital: 24 (21, 28) vs 22 (13, 36)	3/25 requiring intubation vs 7/21 requiring intubation	pH: 7.27 (7.25, 7.28) to 7.34 (7.32, 7.39) vs 7.28 (7.23, 7.30) to 7.28 (7.17, 7.30); PaCO2 (mmHg): 88.0 (67.0, 96.0) to 63.0 (52.0, 84.0) vs 82.0 (76.0, 89.0) to 80.0 (66.0, 104.5); P/F ratio: 168 (133, 210) to 178 (131, 203) vs 176 (152, 233) to 235 (212, 262); RR (breaths/min): 32 (29, 35) to 22 (18, 24) vs 30 (28, 32) to 27 (25, 31)	13 patients (52%) experienced adverse events related to ECCO2R: mechanical events (9); patient-related events (4)
Kluge et al. [25] and Braune et al. [42]	28-day: 5/21 (24%) vs 4/21 (19%); 6-month: 7/21 (33%) vs 7/21 (33%)	ICU: 15 (4, 137) vs 30 (4, 66); hospital: 23 (4, 137) vs 42 (4, 248); (COPD) ICU: 11 (4, 23) vs 35 (4, 66); hospital: 17 (4, 43) vs 51 (4, 248);	19/21 avoided intubation vs 0/21 avoided intubation; duration of PECLA support (days): 9 (1, 116), duration of MV (days): 21 (1, 47); tracheotomy: 2/21 (10%) vs 14/21 (67%)	ECCO2R: pH: 7.28 (7.10, 7.41) to 7.44 (7.27, 7.56); PaCO2 (mmHg): 84.0 (54.2, 131.0) to 52.1 (33.0, 70.1); PaO2 (mmHg): 84.1 (67.2, 158.4) to 80.0 (57.3, 153.2); P/F ratio: 208 (153, 396) to 209 (134, 570); RR: 27 (15, 36) to 21 (11, 32)	ECCO2R: 2 major bleeding and 7 minor bleeding
İnal et al. [26]	28-day: 24/75 (32%) vs 133/320 (42%); ARDS: 7/26 (27%) vs 39/113 (35%); COPD: 17/49 (35%) vs 94/207 (45%)	ICU: 17 (7, 28) vs 26 (5, 45); ARDS: 15 (7, 23) vs 29 (13, 52); COPD: 17 (7, 19) vs 21 (5, 37)	iMV duration (days): 11 (8, 19) vs 14 (7, 22); ARDS: 10 (8, 17) vs 15 (9, 25); COPD: 11 (7, 18) vs 15 (8, 21)	pH: 7.156 ± 0.07 to 7.339 ± 0.05 vs 7.184 ± 0.02 to 7.265 ± 0.09; PaCO2 (mmHg): 81 ± 21 to 53 ± 9 vs 77 ± 19 to 71 ± 16; PaO2 (mmHg): 61 ± 6 to 82 ± 8 vs 59 ± 7 to 71 ± 9; ECCO2R: P/F ratio: 89 ± 11 to 150 ± 53	No severe adverse effects related to procedure were mentioned

iMV: invasive mechanic ventilation; COPD: chronic obstructive pulmonary disease; ARDS: acute respiratory distress syndrome; ICU: intensive care unit; ECCO₂R: extracorporeal carbon dioxide removal; VFD: ventilator-free day; CPPV: conventional positive pressure ventilation.

Figure 2. Forest plot for overall mortality within RCTs targeted patients with ARF secondary to ARDS or acute hypoxic respiratory failure.

Figure 3. Forest plot for overall mortality within studies targeted patients with ARF secondary to COPD.

Table 3. Subgroup analysis of mortality in patients with ARF secondary to COPD.

	No. of studies	RR (95% CI)	P	I^2
Overall	6	0.80 (0.58, 1.11)	0.19	0.0%
28-day mortality	4	0.88 (0.60, 1.30)	0.53	0.0%
90-day mortality	3	0.93 (0.49, 1.75)	0.82	0.0%
≥6-month mortality	1	/	/	/
ICU mortality	2	1.02 (0.07, 15.73)	0.99	66.8%
Hospital mortality	3	0.99 (0.25, 4.01)	0.99	57.4%
Modality of AV-ECCO2R	1	/	/	/
Modality of VV-ECCO2R	5	0.78 (0.55, 1.10)	0.16	0.0%
Mean age (years) ≤60	1	/	/	/
Mean age (years) >60	5	0.78 (0.55, 1.10)	0.16	0.0%

ARF: acute respiratory failure; COPD: chronic obstructive pulmonary disease; ICU: intensive care unit; ECCO₂R: extracorporeal carbon dioxide removal.

Table 4. Subgroup analysis of outcomes based on the severity of P/F ratio.

Group	Mortality				Length of ICU stay (days)				Length of hospital stay (days)
	RCTs		Observational studies		RCTs		Observational studies		RCTs		Observational studies
	Statistic (RR) (95%CI)	P	Statistic (RR) (95%CI)	P	Statistic (WMD) (95%CI)	P	Statistic (WMD) (95%CI)	P	Statistic (WMD) (95%CI)	P	Statistic (WMD) (95%CI)	P
All	1.05 (0.83, 1.32)	0.70	0.77 (0.55, 1.08)	0.13	1.57 (-0.73, 3.87)	0.18	−4.25 (-6.62, −1.87)	0.01	4.44 (0.62, 8.25)	0.02	−0.40 (-7.50, 6.71)	0.91
Severity of P/F ratio
P/F ratio <150	1.04 (0.82, 1.32)	0.73	/	/	0.94 (-1.46, 3.34)	0.44	/	/	3.56 (-0.48, 7.60)	0.08	/	/
P/F ratio >150	/	/	0.74 (0.42, 1.32)	0.31			−4.16 (-7.13, −1.20)	0.01	/	/	1.79 (-5.70, 9.28)	0.64
Group	Intubation rate				Tracheotomy rate				Mechanical ventilation days (d)
	RCTs		Observational studies		RCTs		Observational studies		RCTs		Observational studies
	Statistic (RR) (95%CI)	P	Statistic (RR) (95%CI)	P	Statistic (RR) (95%CI)	P	Statistic (RR) (95%CI)	P	Statistic (SMD) (95%CI)	P	Statistic (SMD) (95%CI)	P
All	/	/	0.37 (0.24, 0.58)	0.01	/	/	0.48 (0.27, 0.85)	0.01	/	/	−0.43 (-0.66, -0.21)	0.01
Severity of P/F ratio
P/F ratio <150	/	/	/	/	/	/	/	/	/	/	/	/
P/F ratio >150	/	/	0.42 (0.26, 0.70)	0.01	/	/	0.45 (0.14, 1.45)	0.18	/	/	−0.16 (-0.58, 0.26)	0.47

Table 5. Ongoing randomized clinical trials on ECCO₂R therapy for patients with ARF.

Status	NCT	Study	Target population
Active, recruiting	NCT04842344	A prospective randomized controlled trial of extracorporeal carbon dioxide removal (ECCO2R) in the treatment of acute exacerbation of chronic obstructive pulmonary disease with severe hypercapnia	COPD
Active, recruiting	NCT03255057	A prospective, multi-center, randomized, controlled, pivotal trial to validate the safety and efficacy of the Hemolung® respiratory assist system for COPD patients experiencing an acute exacerbation requiring ventilatory support	COPD
Active, recruiting	NCT03525691	Enhanced lung protective ventilation with extracorporeal CO2 removal during acute respiratory distress syndrome	ARDS
Not yet recruiting	NCT04582799	Extracorporeal carbon dioxide removal for acute decompensation of chronic obstructive pulmonary disease: A randomized clinical trial (The ORION Study)	COPD
Not yet recruiting	NCT04147104	ECCO2R to facilitate early liberation from mechanical ventilation inpatients with COPD acute exacerbation	COPD
Not yet recruiting	NCT03584295	A multicenter randomized-controlled trial of extracorporeal CO2 removal to facilitate early extubation compared to invasive mechanical ventilation in patients with severe acute exacerbation of COPD (X-COPD)	COPD
Not yet recruiting	NCT04903262	Strategy of ultra-protective lung ventilation with extracorporeal CO2 removal for new-onset moderate ARDS: A prospective multicenter randomized clinical trial	ARDS

ECCO₂R: extracorporeal carbon dioxide removal; COPD: chronic obstructive pulmonary disease; ARDS: acute respiratory distress syndrome.

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Data availability statement

All data generated or analyzed during this study are included in this article and its supplementary information files.