Populations
Thirty-one mechanically ventilated patients with COVID-19-related ARDS were included in the study. Patients were mostly male (26/31, 84%), and the most common comorbidities were hypertension (17/31, 42%) and chronic kidney disease (8/31, 26%). Thirteen patients (43%) were successfully weaned within 28-days and the mean length of stay in ICU was 31 [25–42] days. Hospital mortality was 35% (11 non-survivors). Non-survivors were older (68 ± 6 vs 61 ± 6; p value = 0.05) than survivors whereas other baseline characteristics were not significantly different (Table 1).
Table 1
Baseline characteristics and values of markers of lung injury in survivor vs non survivors.
Variables | Survivors (n = 20) | Non survivors (n = 11) | p value |
Age, years | 61 ± 6 | 68 ± 6 | 0.05 |
Male, sex, no. % | 17 (85) | 9 (82) | 0.59 |
BMI, Kg/m2 | 27.8 ± 4.1 | 28.9 ± 3.2 | 0.41 |
SAPS II at ICU admission | 27 [21–38] | 31 [21–37] | 0.55 |
SOFA score at ICU admission | 4 [2–5] | 5 [3–6] | 0.23 |
Length of ICU stay (days) | 31 [25–43] | 24 [16–31] | 0.04 |
Comorbidities | | | |
Hypertension, no. (%) | 9 (45) | 8 (73) | 0.13 |
Dyslipidemia, no. (%) | 4 (20) | 1 (9) | 0.40 |
Former smoker, no. (%) | 4 (20) | 6 (54) | 0.06 |
Diabetes, no. (%) | 4 (20) | 1 (9) | 0.40 |
COPD, no. (%) | 2 (5) | 2 (18) | 0.45 |
Chronic kidney disease, no. (%) | 3 (15) | 5 (45) | 0.08 |
Laboratory data at inclusion | | | |
White blood cells, x103/L | 9.8 [7.5–12.9] | 10.2 [8.8–12.7] | 0.85 |
Lymphocytes, x 103/L | 965 [640–1167] | 680 [560–980] | 0.18 |
Haemoglobin, g/dL | 12.1 ± 1.8 | 13.1 ± 1.1 | 0.11 |
Platelets count, x103/L | 286 [265–386] | 286 [195–332] | 0.43 |
apTT, seconds | 39 ± 5 | 37 ± 5 | 0.34 |
INR | 1.1 ± 0.1 | 1.1 ± 0.1 | 0.35 |
Fibrinogenm mg/dL | 708 [655–888] | 786 [532–862] | 0.87 |
D-dimer, mcg/mL | 31 [14–42] | 36 [19–57] | 0.31 |
IL-6, pg/mL | 84 [17–149] | 60 [37–145] | 0.73 |
Respiratory variables at admission | | | |
PaO2/ FiO2 ratio | 183 [124–264] | 116 [81–184] | 0.045 |
PaCO2, mmHg | 48 [36–56] | 48 [41–69] | 0.40 |
VT/PDW, mL | 6.0 ± 0.5 | 6.0 ± 0.5 | 0.96 |
Driving Pressure, cmH2O | 9 [8–11] | 8 [7–14] | 0.79 |
Compliance Respiratory System | 57 [36–78] | 60 [51–64] | 0.95 |
Plateau pressure, cmH2O | 18 [15–21] | 21 [18–23] | 0.11 |
PEEP setting (cmH2O) | 12 [9–12] | 10 [8–11] | 0.07 |
P-value: for the comparison between survivors vs non survivors cases. Data are reported as number (percentage), mean ± standard deviation or median [interquartile range] as appropriate. BMI: body mass index. COPD: chronic obstructive disease. |
At ICU admission, the PaO2/FiO2 ratio was higher in survivors (183 [126–264]) compared to non- survivors (116 [81–184]); p value = 0.04), while there were no differences in other PaCO2 or respiratory mechanics variable (Table 1). D-dimer levels did not differ at ICU admission between survivors and non-survivors (31 [14–42] vs 36 [19–57], p = 0.31) but there was an increase over time in non-survivors (p = 0.006 for two-sample Kolmogorov-Smirnov; Figure S1).
Biomarkers
In COVID-19-related ARDS Ang-2 was higher in non-survivors than in survivors at ICU admission (p = 0.04), and decreased similarly over time in the two groups (p = 0.17 for two-sample Kolmogorov-Smirnov analysis) (Fig. 1, Fig. 2, Table S1). The area under the receiver operating characteristic curve (AUROC) of Ang-2 at ICU admission for hospital mortality was 0.650. ICAM-1 values were higher in non-survivors than survivors (p = 0.03 at ICU admission, Fig. 1), and repeated measure analysis showed more significant decrease from T1 to T3 in survivors compared to non-survivors (p = 0.03 for two-sample Kolmogorov-Smirnov analysis) (Fig. 2, Table S1) The AUROC of ICAM-1 for hospital mortality at ICU admission was 0.717. The ICAM-1 plasma level at ICU admission was inversely correlated with the worsening of respiratory system compliance over time (r=-0.470; p = 0.03). VCAM-1 levels at T1 were higher in non-survivors than in survivors, though not statistically significantly (p = 0.06) (Fig. 1). We did not find differences in P-selectin or E-selectin plasma levels at ICU admission or during ICU stay between survivors and non-survivors.
In the overall study population, RAGE decreased significantly during the study period (60.9 [18.8–274.4] at T1, 30.6 [13.4–90.7] at T2, and 20.5 [12.2–41.6] at T3; p value T3 vs T1 < 0.001). RAGE did not differ between survivors and non-survivors at ICU admission (p = 0.34), (Fig. 1, Fig. 2) and had similar decrease overtime. (p = 0.71 for two-sample Kolmogorov-Smirnov analysis) (Table S1).
Gas exchange and respiratory mechanics
Measures of gas exchange and respiratory mechanics during the study period are reported in Table 2. At ICU admission, the PaO2/FiO2 ratio was significantly higher in survivors than in non-survivors (p = 0.04), and the PaO2/FiO2 ratio increased more in survivors than in non-survivors from T1 to T3 (p = 0.001 for two-sample Kolmogorov-Smirnov analysis) (Table 2). PaCO2 values did not differ at ICU admission between survivors and non-survivors (p = 0.40), but the PaCO2 increased over time more in non-survivors than in survivors (p = 0.001 for two-sample Kolmogorov-Smirnov analysis from T1 to T3). Finally, the respiratory system compliance and the plateau pressure did not significantly differ among the two groups.
Table 2
Gas exchange and respiratory mechanics in mechanically ventilated COVID-19 ICU patients.
| T1 n = 31 | T2 n = 26 | T3 n = 20 | p- value for inter-group trend | p value for group trend comparison |
PaO2/FIO2 | | | | | |
Survivor | 183 [124–264] | 215 [165–304] | 251 [204–355] | 0.08 | 0.001 |
Non survivor | 116 [81–184] | 104 [77–147] | 144 [94–193] | 0.84 |
PaCO2 | | | | | |
Survivor | 48 [36–56] | 45 [38–67] | 41 [35–55] | 0.22 | 0.001 |
Non survivor | 48 [41–69] | 63 [50–71] | 64 [54–83] | 0.02 |
Driving Pressure | | | | | |
Survivor | 9 [8–11] | 8 [7–11] | 8 [6–8] | 0.31 | 0.10 |
Non survivor | 8 [7–14] | 10 [9–12] | 10 [9–12] | 0.57 |
Static compliance | | | | | |
Survivor | 57 [36–78] | 71 [41–80] | 60 [49–79] | 0.07 | 0.35 |
Non survivor | 60 [51–64] | 41 [24–54] | 46 [40–64] | 0.23 |
PEEP | | | | | |
Survivor | 12 [9–12] | 8 [6–11] | 8 [6–10] | 0.36 | 0.03 |
Non survivor | 10 [8–11] | 14 [9–17] | 10 [9–13] | 0.93 |
Plateau | | | | | |
Survivor | 18 [15–21] | 17 [14–22] | 15 [12–17] | 0.25 | 0.07 |
Non survivor | 21 [18–23] | 22 [19–31] | 21 [16–23] | 0.84 |
Data are reported as median [interquartile range] |
Comparison between COVID-19-related ARDS and classical ARDS
All the biomarkers analyzed differed significantly between COVID-19-related ARDS and classical ARDS at ICU admission (Table 3). In detail, Ang-2, ICAM-1 and E-selectin were higher in COVID-19 related ARDS (all p < 0.001 for group comparison), whereas RAGE and P-selectin levels were higher in classical ARDS. A comparison of clinical characteristics between classical ARDS and COVID-19-related ARDS patients is shown in Table S2. Patients with classical ARDS had higher hemoglobin and lower D-Dimer and international normalized ratio (INR) when compared to COVID-19 patients (Table S2). Regarding respiratory mechanics, patients with classical ARDS had higher driving pressure, lower respiratory system compliance, and were ventilated with higher PEEP levels (Table S2).
Table 3
Comparison of markers of endothelial and epithelial dysfunction between patients with COVID-19-related ARDS and classical ARDS
Biomarker | Covid-19-related ARDS (n = 31) | Classical ARDS (n = 10) | p value |
RAGE, pg/mL | 60 [18–274] | 789 [440–1021] | < 0.001 |
ICAM-1, ng/mL | 1093 [575–1515] | 75.7 [63.1–89.6] | < 0.001 |
VCAM-1, ng/mL | 1093 [575–1515] | 739 [439–1021] | 0.019 |
Ang-2, pg-mL | 3909 [1658–6348] | 1045 [627–1654] | < 0.001 |
P-selectin, ng/mL | 93 [50–145] | 750 [631–1103] | < 0.001 |
E-selectin, ng/mL | 24.9 [19.2–42.5] | 3.3 [2.4–5.7] | < 0.001 |
Data are reported as median [interquartile range]. |