Background
Methods
Study setting
Study design
Experimental arm (i.e., ULP group)
Control arm (i.e., LP group)
Measurements
Primary and secondary outcomes
Sample size and statistical analysis
Results
Patients
Variable | Ultra-lung-protective group | Lung-protective group | ||
---|---|---|---|---|
N | n (%)* | N | n (%)* | |
Age, years, median (IQR) | 20 | 56 (41–65) | 18 | 57 (48–61) |
Male sex, | 20 | 13 (65) | 18 | 12 (67) |
Body mass index, kg/m2, median (IQR) | 20 | 28 (25–33) | 18 | 31 (27–36) |
SAPS 2 at admission, median (IQR) | 20 | 41 (35–49) | 18 | 45 (32–56) |
SOFA score at inclusion, median (IQR) | 20 | 8 (4–11) | 18 | 8 (5–9) |
Cause of ARDS | ||||
COVID-19 | 20 | 10 (50) | 18 | 9 (50) |
Non COVID-19 CAP | 20 | 7 (35) | 18 | 5 (28) |
Aspiration | 20 | 2 (10) | 18 | 3 (17) |
Lung contusion | 20 | 1 (5) | 18 | 0 (0) |
Extra-pulmonary sepsis | 20 | 0 | 18 | 1 (5) |
Comorbidity | ||||
Ischemic cardiomyopathy | 20 | 1 (5) | 18 | 0 (0) |
Diabetes | 20 | 5 (25) | 18 | 2 (11) |
Chronic renal insufficiency | 20 | 0 (0) | 18 | 1 (5) |
Chronic respiratory disease | 20 | 3 (15) | 18 | 2 (11) |
Immunocompromised | 20 | 1 (5) | 18 | 1 (5) |
Before ECMO, median (IQR) | ||||
Duration of mechanical ventilation, days | 20 | 8 (6–12) | 18 | 4 (1–12) |
Vasopressors | 20 | 10 (50) | 18 | 8 (44) |
Renal replacement therapy | 20 | 0 (0) | 18 | 1 (5) |
Rescue therapy
pre-ECMO | ||||
Any | 20 | 20 (100) | 18 | 18 (100) |
Continuous infusion of NMB | 20 | 18 (90) | 18 | 17 (94) |
Prone position | 20 | 17 (85) | 18 | 16 (89) |
Inhaled nitric oxide | 20 | 10 (50) | 18 | 10 (55) |
Almitrine infusion | 20 | 2 (10) | 18 | 2 (11) |
Respiratory mechanics at ECMO cannulation, median (IQR) | ||||
FiO2, % | 19 | 100 (100–100) | 18 | 100 (100–100) |
PEEP, cm H2O | 16 | 14 (10–15) | 15 | 14 (12–15) |
Tidal volume, mL/PBW | 15 | 5.6 (5.4–6.1) | 15 | 6.5 (5.9–6.9) |
Respiratory rate, breaths/min | 14 | 30 (27–30) | 15 | 26 (24–30) |
Minute ventilation, L/min | 14 | 11.6 (9.7–13.1) | 13 | 10.1 (9.3–12.1) |
Plateau pressure, cm H2O | 14 | 30 (28–32) | 12 | 31 (25–33) |
Peak pressure, cmH2O | 12 | 38 (37–45) | 6 | 39 (37–41) |
Driving pressure, cm H2O | 14 | 16 (14–19) | 12 | 17 (13–20) |
RS compliance, mL/cm H2O | 14 | 21 (19–29) | 12 | 24 (18–34) |
Mechanical power, J/min | 11 | 35 (25–43) | 6 | 28 (25–33) |
Ventilatory ratio | 12 | 2.6 (2.4–3.1) | 10 | 2.5 (1.93.5) |
Last blood gas values pre-ECMO, median (IQR) | ||||
pH | 14 | 7.27 (7.21–7.33) | 14 | 7.24 (7.18–7.37) |
PaO2:FiO2, mm Hg | 18 | 74 (55–106) | 17 | 83 (72–94) |
PaCO2, mm Hg | 11 | 68 (55–72) | 11 | 59 (50–71) |
Lactates, mmol/L | 14 | 1.8 (1.0–2.5) | 13 | 1.5 (1.1–2.0) |
ECMO configuration | ||||
Femoral–jugular | 20 | 14 (70) | 18 | 16 (89) |
Femoral–femoral | 20 | 6 (30) | 18 | 2 (11) |
Respiratory mechanics and ventilator settings at baseline (T0) | ||||
FiO2, % | 16 | 100 (77–100) | 17 | 100
(50–100) |
PEEP, cm H2O | 18 | 13 (12–15) | 16 | 14 (12–15) |
Tidal volume, mL/PBW | 18 | 2.6 (1.9–3.8) | 18 | 3.5 (2.8–4.2) |
Respiratory rate, breaths/min | 18 | 13 (10–15) | 18 | 15 (11–21) |
Minute ventilation, L/min | 17 | 2.2 (1.4–3.0) | 15 | 3.1 (2.2–6.1) |
Plateau pressure, cm H2O | 16 | 24 (21–25) | 15 | 25 (24–27) |
Peak airway pressure, cmH2O | 14 | 28 (24–30) | 14 | 29 (24–36) |
Driving pressure, cm H2O | 18 | 10 (7–15) | 14 | 11 (9–15) |
RS compliance, mL/cm H2O | 18 | 17 (14–21) | 14 | 21 (13–35) |
Mechanical power, J/min | 13 | 2.7 (1.7–3.9) | 12 | 3.9 (2.9–5.6) |
ECMO settings | ||||
ECMO blood flow L/min | 18 | 4 (3.7–5.0) | 18 | 4.6 (3.9–5.2) |
Sweep gas flow, L/min | 18 | 4 (3–5) | 18 | 3.5 (3–5) |
Membrane FmO2, % | 20 | 100 (100–100) | 18 | 100 (100–100) |
Arterial blood gas | ||||
pH | 17 | 7.40 (7.36–7.44) | 18 | 7.40 (7.34–7.45) |
PaO2, mmHg | 17 | 82 (69–115) | 18 | 97 (73–118) |
PaCO2, mmHg | 17 | 49 (40–56) | 18 | 43 (37–51) |
Plasma bicarbonate, mmol/L | 17 | 30 (25–33) | 18 | 27 (22–31) |
SaO2, % | 17 | 98 (96–99) | 18 | 99 (97–99) |
Lactates, mmol/L | 16 | 1.7 (1.2–3.2) | 18 | 1.5 (1.0–3.1) |
Respiratory mechanics, ventilator, and ECMO settings in each group
During the first 48 h of the study (protocol timeline)
Variable | T0 | H+24 h | H+48 h | ||||||
---|---|---|---|---|---|---|---|---|---|
Ultra-lung-protective group | Lung-protective group | p value | Ultra-lung-protective group | Lung-protective group | p value | Ultra-lung-protective group | Lung-protective group | p value | |
Ventilatory mode ACV/APRV/PSV, n (%) | 19 (95)/1 (5)/0 (0) | 13 (72)/5 (28)/0 (0) | 0.055 | 19 (95)/1 (5)/0 (0) | 13 (72)/5 (28)/0 (0) | 0.055 | 17 (85)/3 (20)/ 0 (0) | 12 (67)/ 6 (33)/ 0 (0) | 0.18 |
No. of patients | 20 | 18 | 20 | 18 | 20 | 18 | |||
Tidal volume (mL/PBW) | 2.6 (1.9–3.8) | 3.5 (2.8–4.2) | 0.04 | 1.8 (1.7–2.0) | 2.9 (2.4–3.9) | < 0.001 | 1.9 (1.6–2.0) | 3.3 (2.4–3.8) | 0.001 |
No. of patients | 18 | 18 | 19 | 18 | 20 | 18 | |||
Respiratory rate (breaths/min) | 13 (10–15) | 15 (11–21) | 0.34 | 10 (10–13) | 15 (12–20) | 0.003 | 10 (10–10) | 15 (11–22) | 0.001 |
No. of patients | 18 | 18 | 20 | 18 | 20 | 18 | |||
PEEP (cmH2O) | 13 (11–14) | 14 (12–15) | 0.38 | 13 (10–16) | 12 (12–15) | 0.73 | 12 (10–15) | 14 (12–14) | 0.23 |
No. of patients | 17 | 16 | 19 | 15 | 18 | 15 | |||
Plateau pressure (cmH2O) | 24 (21–25) | 25 (24–27) | 0.07 | 24 (20–24) | 24 (23–26) | 0.04 | 21 (18–23) | 24 (22–26) | 0.01 |
No. of patients | 17 | 15 | 19 | 15 | 19 | 15 | |||
Minute ventilation (L/min) | 2.2 (1.4–3.0) | 3.1 (2.2–6.1) | 0.03 | 1.3 (1.1–1.4) | 2.8 (2.1–5.1) | < 0.001 | 1.3 (1.1–1.5) | 2.8 (2.1–5.1) | 0.001 |
No. of patients | 18 | 18 | 19 | 18 | 20 | 18 | |||
Driving pressure (cmH2O) | 10 (7–15) | 11 (9–15) | 0.59 | 10 (7–15) | 10 (8–13) | 0.25 | 9 (6–11) | 10 (8–14) | 0.21 |
No. of patients | 17 | 14 | 19 | 13 | 18 | 13 | |||
Respiratory system compliance (mL/cmH2O) | 17 (14–21) | 21 (13–35) | 0.2 | 13 (10–19) | 19 (10–24) | 0.25 | 15 (11–22) | 20 (11–32) | 0.46 |
No. of patients | 17 | 14 | 19 | 13 | 18 | 13 | |||
PL. exp (cmH2O) | 3 (1–4) | 6 (4–6) | 0.07 | 3 (2–5) | − 2 (− 4 to + 5) | 0.2 | 2 (1–3) | 1.5 (− 2 to + 5) | 1 |
No. of patients | 7 | 3 | 11 | 8 | 8 | 8 | |||
Mechanical power (J/min) | 2.7 (1.7–3.9) | 3.9 (2.9–5.6) | 0.04 | 2.5 (2.0–2.6) | 5.3 (3.7–6.5) | < 0.001 | 2.4 (2.2–3.2) | 5.4 (3.3–6.5) | 0.003 |
No. of patients | 12 | 12 | 13 | 13 | 14 | 13 | |||
ECMO blood flow (L/min) | 4 (3.7–5.0) | 4.6 (3.9–5.2) | 0.31 | 4.5 (3.9–4.8) | 4.3 (3.6–5.0) | 0.63 | 4.4 (4.1–5.0) | 4.0 (3.5–5.1) | 0.18 |
No. of patients | 18 | 18 | 20 | 18 | 20 | 18 | |||
Sweep gas flow (L/min) | 4 (3–5) | 3.5 (3–5) | 0.91 | 5 (4–7) | 4 (3.5–6) | 0.34 | 6 (5–7) | 4.5 (3.5–6) | 0.04 |
No. of patients | 18 | 18 | 18 | 18 | 19 | 18 | |||
Membrane FmO2 (%) | 100 (100–100) | 100 (100–100) | 1 | 100 (100–100) | 100 (100–100) | 1 | 100 (100–100) | 100 (100–100) | 1 |
No. of patients | 20 | 18 | 20 | 18 | 20 | 18 | |||
pH | 7.40 (7.36–7.44) | 7.40 (7.34–7.45) | 0.88 | 7.41 (7.37–7.45) | 7.41 (7.36–7.45) | 0.72 | 7.37 (7.35–7.45) | 7.41 (7.34–7.44) | 0.85 |
No. of patients | 17 | 18 | 20 | 18 | 20 | 18 | |||
PaO2 (mmHg) | 82 (69–115) | 97 (73–118) | 0.71 | 82 (68–98) | 81 (69–104) | 0.88 | 75 (69–83) | 81 (68–92) | 0.48 |
No. of patients | 17 | 18 | 20 | 18 | 20 | 18 | |||
PaCO2 (mmHg) | 49 (40–56) | 43 (37–51) | 0.23 | 47 (45–53) | 45 (41–53) | 0.41 | 48 (44–54) | 47 (43–57) | 0.67 |
No. of patients | 17 | 18 | 20 | 18 | 20 | 18 |
From day 3 to day 6
Biomarkers and surrogates of biotrauma
Primary outcome
Biomarker | Primary outcome | Sample | Technic of measure, unit | Ultra-lung-protective group | Lung-protective group | p value | ||
---|---|---|---|---|---|---|---|---|
N | N | |||||||
Interleukin-1 Beta | Yes | BAL | ELISA, pg/mL | 20 | 73 (5–548) | 18 | 71 (28–349) | 0.81 |
Interleukin-1 Beta | No | Serum | ELISA, pg/mL | 20 | 0.7 (0.3–0.8) | 18 | 0.4 (0.3–1) | 0.36 |
sRAGE | No | BAL | ELISA, pg/mL | 20 | 114 (50–2002) | 18 | 715 (395–2736) | 0.27 |
sRAGE | Yes | Plasma | ELISA, pg/mL | 20 | 831 ± 796 | 18 | 1249 ± 1541 | 0.86 |
Angiopoietin 2 | Yes | Plasma | Luminex, pg/mL | 20 | 10,735 ± 6356 | 18 | 8753 ± 4084 | 0.52 |
TNF receptor 1 | No | BAL | ELISA, pg/mL | 20 | 815 ± 593 | 18 | 792 ± 418 | 0.90 |
TNF receptor 1 | No | Plasma | ELISA, pg/mL | 20 | 5756 ± 3308 | 18 | 6425 ± 5106 | 0.86 |
TNF-alpha | No | BAL | Luminex, pg/mL | 20 | 5.6 (1.6–16.8) | 18 | 6.9 (1.9–32.6) | 0.86 |
TNF-alpha | No | Serum | Luminex, pg/mL | 20 | 32 ± 28 | 18 | 36 ± 30 | 0.70 |
Interleukin-1ra | No | BAL | Luminex, pg/mL | 20 | 4.9 (1–16.3) | 18 | 3.2 (2.1–7.9) | 0.94 |
Interleukin-6 | Yes | BAL | Luminex, pg/mL | 20 | 153 (52–935) | 18 | 256 (136–599) | 0.32 |
Interleukin-8 | No | Serum | Luminex, pg/mL | 20 | 47 (20–69) | 18 | 52 (27–204) | 0.55 |
Interleukin-8 | Yes | BAL | Luminex, pg/mL | 20 | 563 (165–8963) | 18 | 432 (156–1525) | 0.48 |
Interleukin-10 | No | Serum | Luminex, pg/mL | 20 | 38 ± 45 | 18 | 50 ± 67 | 0.52 |
Interleukin-10 | No | BAL | Luminex, pg/mL | 20 | 9.4 (2.6–32.5) | 18 | 7.1 (2.9–16.9) | 0.70 |
IP10 | No | BAL | Luminex, pg/mL | 19 | 214 (45–682) | 18 | 538 (144–1534) | 0.33 |
Procollagen 3 | No | BAL | ELISA, ng/mL | 20 | 2.6 (1–16.3) | 18 | 2.4 (1–13.4) | 0.92 |
MMP-9 | No | BAL | ELISA, ng/mL | 20 | 650 ± 737 | 18 | 683 ± 559 | 0.44 |
Surfactant protein D | Yes | BAL | ELISA, ng/mL | 20 | 2.5 (0.5–15.2) | 18 | 11.1 (0.3–66.6) | 0.58 |
Clara cell protein 16 | No | BAL | ELISA, ng/mL | 20 | 5635 ± 6617 | 18 | 4489 ± 5638 | 0.70 |
Clara cell protein 16 | No | Plasma | ELISA, ng/mL | 20 | 56 ± 37 | 18 | 58 ± 39 | 0.93 |
VEGF | No | Plasma | ELISA, pg/mL | 20 | 61 (20–78) | 18 | 60 (26–194) | 0.53 |
vWF antigen | No | BAL | ELISA, mU/mL | 20 | 1.8 (0.6–19.1) | 18 | 9.4 (0.4–25.1) | 0.59 |