Lung recruitability is better estimated according to the ......Figure E1 Total lung tissue (A) and...

Lung recruitability is better estimated according to the Berlin Definition of Acute Respiratory Distress Syndrome at standard 5 cmH2O rather than clinical positive end-expiratory pressure:

a retrospective cohort study

Pietro Caironi, Eleonora Carlesso, Massimo Cressoni, Davide Chiumello, Onner Moerer, Chiara Chiurazzi, Matteo Brioni, Nicola Bottino, Marco Lazzerini, Guillermo Bugedo,

Michael Quintel, V. Marco Ranieri, and Luciano Gattinoni

SUPPLEMENT DIGITAL CONTENT 1

Caironi et al., Supplement Digital Content 1, page 2

Additional Methods Study population We retrospectively analyzed patients affected by Acute Lung Injury or ARDS according to the American-European Consensus Conference (AECC) criteria (1), which have been previously enrolled between 2003 and 2012 in four clinical trials (2-4) (one of which still ongoing, NCT00759590), in four university hospitals in Italy, Germany and Chile. Each study was conducted according to the 1975 Declaration of Helsinki (as revised in 2008), and approved by the Institutional Review Board of the Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy, as a coordinating center (approval numbers #2005-1060, #2006-208, #2008-1351, #2008-2184, respectively), as well as by the Institutional Review Board of each institutions involved. For each trial, written informed consent was obtained according to the national regulations of the participating institutions (consent was delayed in Italy after the patients had recovered from sedation, obtained from a legal representative in Germany, and obtained from the next of kin in Chile). CT-scan analysis Patients underwent whole lung CT-scanning both at 5 cmH2O PEEP and at 45 cmH2O end-inspiratory airway pressure, during an end-expiratory and end-inspiratory pause, respectively. The procedure to perform the quantitative analysis of each single CT-scan image was performed for the overall study population at the Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy. Each single CT-slice was considered for the subsequent analysis as a region of interest. The outline of the lungs was manually drawn in each CT section excluding the hilar vessels, the main bronchi, and pleural effusions. Before quantitative analysis was performed, the accuracy of each single countered images was assessed by a radiologist (M.L., from the from the Dipartimento di Radiologia, Fondazione IRCCS – Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena di Milano), blinded as to the patient, the airway pressure applied, and the classification of ARDS severity according to the Berlin definition. Each segmented cross-sectional image was processed with a custom-designed software package (2;5). For each lung region of interest obtained from this procedure, we first computed the frequency distribution of the CT numbers, expressed in Hounsfield Unit (HU), ranging from +1000 HU (bone) to –1000 HU (air), with water CT number equal to 0 HU. The CT number, measured in Hounsefield units gives the attenuation of x-rays (µ) normalized for the density of water. X-ray attenuation in biological tissue is linearly related to density.

CT number (HU) = 1000 * (µ – µwater) / µwater Assuming that lung parenchyma has a density equal to the water and that the lung is composed by two compartments (air with a CT number of –1000 and lung parenchyma with a CT number of 0) it is possible to compute in each voxel the relative proportion of air and tissue:

CT / –1000 = Vgas / (Vgas + Vtissue) where Vgas is gas volume (ml) and Vtissue is the tissue volume (g or ml). As the gas fraction equals CT / –1000, the tissue fraction will be 1 – CT / –1000. Multiplying gas fraction and tissue fraction for the voxel volume it is possible to compute gas volume and tissue volume. The following variables were computed:


1) total lung tissue weight, assuming the specific lung weight equal to 1; 2) non aerated lung tissue weight, including lung regions with voxels characterized by a

density between –100 and +100 HU; 3) poorly aerated lung tissue weight, including lung regions with voxels characterized by a

density between –100 and –500 HU; 4) normally aerated lung tissue weight, including lung regions with voxels characterized by a

density between –500 and –900 HU; 5) hyperinflated lung tissue weight, including lung regions with voxels characterized by a

density between –900 and –1000 HU; 6) recruitable lung tissue, defined as the difference between non aerated lung tissue weight at 5

cmH2O PEEP and at 45 cmH2O airway pressure, denoting the amount of collapsed lung regaining aeration from 5 cmH2O to 45 cmH2O airway pressure;

7) consolidated lung tissue, defined as non aerated lung tissue weight at 45 cmH2O airway pressure, denoting the non aerated lung tissue at 5 cmH2O which remained non aerated even after the application of 45 cmH2O airway pressure;

8) potentially recruitable lung, defined as the recruitable tissue expressed as a percentage of the total lung tissue weight.

Physiological respiratory and hemodynamic variables The following respiratory physiological variables were computed, when appropriate, for each patient, at clinical PEEP, as well as at 5 and 15 cmH2O PEEP. Intrapulmonary right-to-left shunt was computed as follows:

Shunt = (CcO2 – CvO2) / (CcO2 – CaO2) where CcO2 is the capillary oxygen content (ml/dl), CaO2 is the arterial oxygen content (ml/dl) and CvO2 is the central venous oxygen content taken from central venous catheter (ml/dl). The capillary oxygen content (CcO2) was computed as follows:

CcO2 = (PAO2 * 0.003) + Hb * 1 * 1.39 where PAO2 is the alveolar partial pressure of oxygen (computed as PAO2 = (760 – 47) * FiO2/100 – (PaCO2)) and Hb is the blood concentration of hemoglobin (mg/dL); we assume that capillary hemoglobin is fully saturated, being all patients ventilated at high FiO2. The arterial content (CaO2) was computed as follows:

CaO2 = (PaO2 * 0.003) + Hb * SaO2 * 1.39 where PaO2 is the arterial partial pressure of oxygen and SaO2 is the fraction of arterial hemoglobin which is saturated. The venous oxygen content (CvO2) was computed as follows:

CvO2 = (PvO2 * 0.003) + Hb * SvO2 * 1.39 where PvO2 is the central venous partial pressure of oxygen and SvO2 is the fraction of central venous hemoglobin which is saturated. The arterial partial pressure of carbon dioxide (PaCO2), the end tidal partial pressure of carbon dioxide (EtCO2) and the expired CO2 in one minute (PECO2) were measured by means of


continuous expiratory air sampling (CO2SMO PLUS 8100; Novametrix Medical System Inc., Wallingford, CT). The physiologic (Vd/Vt physiol) and the alveolar dead spaces fraction (Vd/Vt alveolar) were computed according to standard formulas, as follows:

Vd/Vt physiol = (PaCO2 – PECO2) / PaCO2,

Vd/Vt alveolar = (PaCO2 – EtCO2) / PaCO2 where PECO2 is the mixed expired partial pressure of carbon dioxide, and EtCO2 is the end tidal partial pressure of carbon dioxide. Minute ventilation, peak pressure, inspiratory plateau pressure and mean airway pressure were recorded. Respiratory system elastance (Ers) and lung elastance (EL) were also computed as follows:

Ers = (airway plateau pressure – PEEP) / VT

EL= ((airway plateau pressure – PEEP) – (esophageal plateau pressure – esophageal end-expiratory pressure)) / VT

where VT is the tidal volume applied.


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Figure E1 Total lung tissue (A) and potential for lung recruitment (B) in patients with mild, moderate and severe ARDS classified by applying the Berlin definition at clinical PEEP. Data of total lung tissue are expressed as median value, inter-quartile range, and 5° and 95° percentile range; data of potential for lung recruitment are expressed as dot-density graph, solid line representing median values of each group. The potential for lung recruitment denotes the amount of non-aerated lung tissue at 5 cmH2O PEEP regaining aeration at 45 cmH2O airway pressure, and was expressed as percentage of the total lung tissue weight. In patients with severe ARDS, total lung tissue (P = 0.004) and the potential for lung recruitment (P = 0.003, one-way ANOVA for all) were significantly greater than those in patients with either mild or moderate ARDS. Of note, no difference was observed between patients with either mild or moderate ARDS (* P < 0.05 vs. patients with mild ARDS, † P < 0.05 vs. patients with moderate ARDS).


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At 5 cmH2O PEEPAt 15 cmH2O PEEP


Figure E2 Potential for lung recruitment (A), total lung tissue (B) and non-aerated lung tissue (C) in patients with mild, moderate and severe ARDS classified by applying the Berlin definition either at 5 or 15 clinical PEEP. Data are expressed as median value, inter-quartile range, and 5° and 95° percentile range. The potential for lung recruitment denotes the amount of non-aerated lung tissue at 5 cmH2O PEEP regaining aeration at 45 cmH2O airway pressure, and was expressed as percentage of the total lung tissue weight. In patients with severe ARDS, the potential for lung recruitment, the total lung tissue and the non-aerated lung tissue weights were significantly greater than those in patients with either mild or moderate ARDS only when applying ARDS definition at 5 cmH2O PEEP (P<0.05 for all). In contrast, no differences were observed between patients with mild, moderate or severe ARDS when applying the ARDS Berlin definition at 15 cmH2O PEEP (* P < 0.05 vs. patients with mild ARDS, † P < 0.05 vs. patients with moderate ARDS).


Variation of ARDS classification when applying the Berlin definition at clinical and 15 cmH2O PEEP In Figure E2 we show the effects of changing PEEP from clinical values to standard 15 cmH2O in each individual patient classified at clinical PEEP within the mild (panel A), moderate (panel B) and severe ARDS subgroups (panel C). Out of the 51 patients assigned to mild ARDS at clinical PEEP (panel A), after the application of 15 cmH2O PEEP 10 patients lost the PaO2/FiO2 criteria for ARDS, 33 patients remained as assigned to mild ARDS, and 8 patients were re-assigned to moderate ARDS (35% change). Out of the 76 patients assigned to moderate ARDS at clinical PEEP (panel B), after the application of 15 cmH2O PEEP 15 patients were re-assigned to mild ARDS, 3 patients lost the PaO2/FiO2 criteria for ARDS, and one patient were re-assigned to severe ARDS (25% change). Finally, out of the 11 patients assigned to severe ARDS at clinical PEEP (panel C), at 15 cmH2O PEEP 3 patients were re-assigned to moderate ARDS, while 4 patients were re-assigned to mild ARDS (64% change). Of note, only 4 patients remained as assigned to severe ARDS.


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Figure E3 Effects of changing positive end-expiratory pressure (PEEP) from clinical value to a standard values of 15 cmH2O on PaO2/FiO2 in individual patients classified as affected by mild (A), moderate (B) and severe (C) ARDS at clinical PEEP. White dots represent PaO2/FiO2 values at clinical PEEP, black triangles represent PaO2/FiO2 values at 15 cmH2O. Dashed grey lines represent the different PaO2/FiO2 thresholds for ARDS classifications according to the Berlin definition. As shown, the change of PEEP from its clinical value to standard 15 cmH2O led to a wide re-classification of patients in each category of ARDS severity.


Table E1 – Respiratory Physiological Variables and Hemodynamics according to the Berlin Definition Applied at either Clinical, 5 or 15 cmH2O PEEP

Characteristic Classification ARDS Severity

P valuea Mild Moderate Severe

PaO2/FiO2 – mmHg Clinical 233 ±22 159 ±26b 79 ±13b,c <0.001

5 cmH2O 239 ±30 147 ±28b 73 ±14b,c <0.001 15 cmH2O (138) 241 ±29 161 ±26b 82 ±16b,c <0.001

Shunt – % of cardiac outputd Clinical ── ── ──

5 cmH2O (131) 0.35 ±0.08 0.46 ±0.10b 0.68 ±0.11b,c <0.001 15 cmH2O (129) 0.33 ±0.08 0.43 ±0.10b 0.64 ±0.11b,c <0.001

Physiologic dead space – % of tidal volumed

Clinical ── ── ── 5 cmH2O (106) 0.52 ±0.10 0.59 ±0.11b 0.73 ±0.08b,c <0.001 15 cmH2O (104) 0.56 ±0.13 0.62 ±0.10b 0.79 ±0.06b <0.001

Alveolar dead space – % of tidal volumed

Clinical ── ── ── 5 cmH2O (128) 0.14 ±0.10 0.20 ±0.11 0.34 ±0.16b,c <0.001 15 cmH2O (128) 0.14 ±0.11 0.22 ±0.11b 0.45 ±0.12b,c <0.001

Normalized minute ventilation – l/min

Clinical 9.3 ±3.1 9.7 ±3.2 13.5 ±5.1b,c 0.01 5 cmH2O 9.2 ±2.5 9.9 ±3.6 12.5 ±2.8b,c <0.001

15 cmH2O (138) 10.1 ±4.4 10.4 ±2.9 14.9 ±4.4b 0.01

Tidal volume – ml/kg predicted body weight

Clinical 8.4 ±1.6 8.3 ±2.0 7.1 ±1.7 0.10 5 cmH2O 8.5 ±1.6 8.4 ±1.6 7.9 ±1.3 0.33

15 cmH2O (138) 8.4 ±1.4 8.3 ±1.7 7.6 ±0.8 0.45


Plateau pressure – cmH2Od Clinical (122) 23 ±4 25 ±4 27 ±5 0.03

5 cmH2O (111) 19 ±3 19 ±4 21 ±4 0.09 15 cmH2O (110) 29 ±4 30 ±4 31 ±2 0.16

Respiratory system elastance – cmH2O/ld

Clinical (122) 20.1 [16.3-26.5] 28.5 [21.9-32.2]b 33.3 [25.9-42.9]b <0.001 5 cmH2O 22.5 [18.8-29.0] 23.6 [19.5-30.9] 29.4 [25.7-33.3] 0.07

15 cmH2O (138) 23.7 [19.2-30.0] 26.9 [20.5-33.3] 34.8 [29.4-44.1] 0.09

Lung elastance – cmH2O/ld Clinical ── ── ──

5 cmH2O (77) 16.7 [12.4-20.7] 17.0 [13.6-22.3] 20.7 [14.8-26.8] 0.37 15 cmH2O (75) 17.5 [14.5-20.2] 17.4 [14.8-25.7] 20.1 [15.7-31.8] 0.75

Mean arterial pressure – mmHgd

Clinical (109) 88 ±10 81 ±14b 79 ±10 0.02 5 cmH2O (138) 85 ±13 82 ±13 80 ±16 0.34 15 cmH2O (137) 80 ±12 79 ±14 85 ±20 0.70

SvO2 – %d Clinical ── ── ──

5 cmH2O (132) 76 ±6 74 ±8 73 ±5 0.20 15 cmH2O (130) 77 ±7 74 ±8 77 ±5 0.21

Heart rate – b/mind Clinical (137) 90 ±18 87 ±21 91 ±19 0.62

5 cmH2O (138) 90 ±23 88 ±19 95 ±23 0.41 15 cmH2O (137) 88 ±18 88 ±21 98 ±23 0.55

a P values for continuous variables refer to one-way ANOVA with post-hoc all pairwise multiple comparison procedures (Bonferroni t-test) or Kruskal-Wallis one-way ANOVA on Ranks with post-hoc pairwise multiple comparison procedures (Dunn's Method), as appropriate; P values for categorical variables refer to chi-square test. b P < 0.05 vs. patients with mild ARDS; c P < 0.05 vs. patients with moderate ARDS. d Some values are missing for these variables (see table for details). Numbers in brackets refer to the actual sample size. Moreover, analyses at 15 cmH2O PEEP were performed excluding patients who lost PaO2/FiO2 criteria for ARDS definition (n = 13).


Table E2 – Clinical PEEP, Lung Functional Anatomy and Recruitability according to the Agreement or the Modification of ARDS Severity Class of the Berlin Definition Applied at either Clinical or 15 cmH2O PEEP

ARDS severity at clinical PEEP

Characteristic ARDS severity at 15 cmH2O PEEP

P valuea Non-ARDS Mild Moderate Severe

Mild ARDS (n = 52)

Patients – no. (%) 10 33 8 ── <0.001 Clinical PEEP – cmH2O 9.0 ±3.2b 11.4 ±2.7 13.8 ±3.3 ── 0.01 Total Lung Tissue – g 1246 [1115-1447] 1277 [1123-1471] 1771 [1247-2266] ── 0.06 Non-aerated Lung Tissue – g 436 [343-550] 405 [353-517] 575 [418-1389] ── 0.20 Recruitable Lung Tissue – gc 62 [35-172] 120 [53-209] ── 0.21 Potential for Lung Recruitment – %c

5 [3-17] 10 [4-16] 15 [7-24] ── 0.48

Moderate ARDS (n = 76)

Patients – no. (%) 3 15 57 1 <0.001 Clinical PEEP – cmH2O 9.0 ±5.3 10.5 ±2.4 11.2 ±2.7 15.0 ±0.0 0.30 Total Lung Tissue – g 1452 [1164-2107] 1374 [1119-1705] 1426 [1119-1664] 1751 [1751-1751] 0.75 Non-aerated Lung Tissue – g 336 [224-377] 449 [330-947] 566 [380-849] [1217 [1217-1217] 0.12 Recruitable Lung Tissue – gc 94 [70-326] 191 [88-306] 162 [88-288] 454 [454-454] 0.59 Potential for Lung Recruitment – %c

8 [5-15] 14 [7-16] 12 [8-19] 26 [26-26] 0.38

Severe ARDS (n = 11)

Patients – no. (%) ── 4 3 4 0.91 Clinical PEEP – cmH2O ── 9.3 ±3.0 8.0 ±3.6 13.3 ±4.7 0.31 Total Lung Tissue – g ── 1656 [1263-2156] 2183 [1488-3300] 1652 [1604-2469] 0.761 Non-aerated Lung Tissue – g ── 989 [553-1223] 1257 [647-1634] 1157 [846-1376] 0.79 Recruitable Lung Tissue – g ── 249 [180-626] 627 [87-634] 557 [404-734] 0.57 Potential for Lung Recruitment – %

── 19 [12-36] 19 [6-29] 25 [24-35] 0.45


Table E2 a P values for continuous variables refer to one-way ANOVA with post-hoc all pairwise multiple comparison procedures (Bonferroni t-test) or Kruskal-Wallis one-way ANOVA on Ranks with post-hoc pairwise multiple comparison procedures (Dunn's Method), as appropriate; P values for categorical variables refer to chi-square test (b P < 0.05 vs. patients moderate ARDS). c These values were available for 9 patients with mild ARDS at clinical PEEP who lost PaO2/FiO2 criteria for ARDS at 15 cmH2O PEEP, 32 patients with mild ARDS both at clinical and 15 cmH2O PEEP, 14 patients with moderate ARDS at clinical PEEP and mild ARDS at 15 cmH2O PEEP, and for 55 patients with moderate ARDS both at clinical and 15 cmH2O PEEP. Both total lung tissue and non-aerated lung tissue were assessed by CT-scanning performed at 5 cmH2O PEEP.


Table E3 – Lung Functional Anatomy, Recruitability, and ICU Mortality according to the Berlin Definiti on Applied at either Clinical or 5 cmH2O PEEP, and according to the Subgroup Analysis of Patients with Moderate ARDS

Characteristic Classification

ARDS Severity

P valuea Mild

Moderate Severe

Mild Severe

Patients – no. (%) Clinical 52 (37) 44 (32) 32 (23) 11 (78) ──

5 cmH2O 27 (19) 44 (32) 48 (35) 20 (14) ──

Clinical PEEP – cmH2O Clinical 11.3 ±3.1 11.3 ±3.2 10.7 ±2.2 10.4 ±4.2 0.79

5 cmH2O 9.9 ±2.2 10.7 ±2.7 11.1 ±3.1 13.3 ±3.4b,c,d 0.002

Total Lung Tissue – g

Clinical 1289 [1125-1496]

1346 [1131-1605]

1489 [1163-1958]

1686 [1501-2502]b,c,d

0.006

5 cmH2O 1219

[1075-1471] 1214

[1061-1440] 1498

[1289-1772]b,c

1893 [1577-2234]b,c,d <0.001

Hyperinflated Lung Tissue – g

Clinical 0.5 [0.1-2.1] 0.2 [0.0-6.3] 0.2 [0.0-1.9]b,c 0.2 [0.0-3.0]b 0.68 5 cmH2O 0.5 [0.0-2.1] 0.3 [0.1-1.9] 0.2 [0.0-8.0]b 0.3 [0.0-2.7]b 0.98

Normally aerated Lung Tissue – g

Clinical 400 [297-522] 379 [258-523] 275 [191-380]b,c 232 [124-503]b <0.001 5 cmH2O 455 [334-566] 387 [288-500] 290 [181-455]b 249 [188-420]b <0.001

Poorly aerated Lung Tissue – g

Clinical 389 [302-474] 402 [311-624] 364 [247-717] 524 [327-853] 0.20 5 cmH2O 336 [241-423] 355 [260-440] 492 [323-665]b,c 685 [337-868]b,c <0.001

Not-aerated Lung Tissue – g

Clinical 445 [350-580] 437 [328-615] 631 [474-863]b,c 1153 [661-1293]b,c <0.001

5 cmH2O 405 [336-503] 395 [317-532] 595 [427-901]b,c 961 [579-1376]b,c <0.001


Recruitable Lung Tissue – ge

Clinical 131 [52-219] 100 [70-265] 236 [150-336] 408 [184-706]b,c <0.001 5 cmH2O 62 [26-164] 102 [70-192] 223 [131-326] 431 [180-633]b,c <0.001

Potentially Recruitable Lung – %e

Clinical 10 [4-17] 9 [5-17] 16 [11-21] 23 [17-29]b,c <0.001 5 cmH2O 5 [2-12] 9 [6-16] 16 [8-21] 23 [12-30]b,c <0.001

Higher Potentially Recruitable Lung – no. (%)

Clinical 26 (53) 22 (51) 24 (80) 9 (82) 0.02 5 cmH2O 10 (40) 21 (51) 33 (70) 17 (85) 0.005

ICU Mortality – no. (%) Clinical 12 (23) 19 (43) 12 (38) 7 (64) 0.04

5 cmH2O 7 (26) 17 (39) 12 (25) 14 (70) 0.003

Table E3 Patients with moderate-mild and moderate-severe ARDS were obtained dividing patients with moderate ARDS according to the PaO2/FiO2 threshold value of 150 mmHg: patients with moderate-mild, with a PaO2/FiO2 between 150 and 199 mmHg, and those with moderate-severe ARDS, with a PaO2/FiO2 between 101 and 149 mmHg. a P values for continuous variables refer to one-way ANOVA with post-hoc all pairwise multiple comparison procedures (Bonferroni t-test) or Kruskal-Wallis one-way ANOVA on ranks with post-hoc pairwise multiple comparison procedures (Dunn's Method), as appropriate; P values for categorical variables refer to chi-square test (b P < 0.05 vs. patients with mild ARDS; c P < 0.05 vs. patients with moderate-mild ARDS; d P < 0.05 vs. patients with moderate-severe ARDS). e These values were available for 133 patients evaluated both at clinical PEEP (49 with mild, 43 with moderate-mild, 30 with moderate-severe, and 11 with severe ARDS) and at 5 cmH2O PEEP (25 with mild, 41 with moderate-mild, 47 with moderate-severe, and 20 with severe ARDS).


Table E4 – Respiratory Physiological Variables and Hemodynamics according to the Berlin Definition Applied at either Clinical or 5 cmH2O PEEP, and according to the Subgroup Analysis of Patients with Moderate ARDS

Characteristic Classification

ARDS Severity

P valuea Mild

Moderate Severe

Mild Severe

PaO2/FiO2 – mmHg Clinical 233 ±22 178 ±14b 132 ±12b,c 79 ±13b,c,d <0.001

5 cmH2O 239 ±30 172 ±14b 124 ±16b,c 73 ±14b,c,d <0.001

Shunt – % of cardiac outpute

Clinical ── ── ── ── 5 cmH2O (131) 0.35 ±0.08 0.41 ±0.10 0.50 ±0.08b,c 0.68 ±0.11b,c,d <0.001

Physiologic dead space – % of tidal volumee

Clinical ── ── ── ── 5 cmH2O (106) 0.52 ±0.10 0.56 ±0.11 0.61 ±0.11b,c 0.73 ±0.08b,c.d <0.001

Alveolar dead space – % of tidal volumee

Clinical ── ── ── ── 5 cmH2O (128) 0.14 ±0.10 0.15 ±0.09 0.24 ±0.10b,c 0.34 ±0.16b,c,d <0.001

Normalized minute ventilation – l/min

Clinical 9.3 ±3.1 9.4 ±2.8 10.0 ±3.7 13.5 ±5.1b,c 0.028 5 cmH2O 9.2 ±2.5 9.2 ±2.6 10.5 ±4.3 12.5 ±2.8b,c,d <0.001

Tidal volume – ml/kg predicted body weight

Clinical 8.4 ±1.6 8.4 ±2.0 8.1 ±2.0 7.1 ±1.7 0.17 5 cmH2O 8.5 ±1.6 8.7 ±1.8 8.2 ±1.3 7.9 ±1.3 0.37

Plateau pressure – cmH2Oe Clinical (122) 23 ±4 25 ±4 25 ±4 27 ±5 0.07

5 cmH2O (111) 19 ±3 19 ±4 20 ±4 21 ±4 0.05

Respiratory system elastance – cmH2O/le

Clinical (122) 20.1 [16.3-26.5] 27.3 [20.1-31.7] 30.0 [23.8-32.2]b 33.3 [25.9-42.9]b <0.001

5 cmH2O 22.5 [18.8-29.0] 22.3 [19.2-25.8] 27.2 [20.3-34.5]c 29.4 [25.7-33.3]c 0.003


Lung Elastance – cmH2O/le

Clinical ── ── ── ── 5 cmH2O (77) 16.7 [12.4-20.7] 17.4 [14.8-21.3] 15.6 [12.3-24.2] 20.7 [14.8-26.8] 0.55

Mean arterial pressure – mmHge

Clinical (109) 88 ±10 84 ±15 78 ±11 79 ±10 0.009 5 cmH2O (138) 85 ±13 83 ±13 82 ±13 80 ±16 0.47

SvO2 – %e Clinical ── ── ── ──

5 cmH2O (132) 76 ±6 75 ±9 72 ±7 73 ±5 0.15

Heart rate – b/mine Clinical (137) 90 ±18 85 ±23 88 ±16 91 ±19 0.74

5 cmH2O (138) 90 ±23 90 ±19 86 ±19 95 ±23 0.45

Table E4. Patients with moderate-mild and moderate-severe ARDS were obtained dividing patients with moderate ARDS according to the PaO2/FiO2 threshold value of 150 mmHg: patients with moderate-mild, with a PaO2/FiO2 between 150 and 199 mmHg, and those with moderate-severe ARDS, with a PaO2/FiO2 between 101 and 149 mmHg. a P values for continuous variables refer to one-way ANOVA with post-hoc all pairwise multiple comparison procedures (Bonferroni t-test) or Kruskal-Wallis one-way ANOVA on ranks with post-hoc pairwise multiple comparison procedures (Dunn's Method), as appropriate; P values for categorical variables refer to chi-square test (b P<0.05 vs. patients with mild ARDS; c P<0.05 vs. patients with moderate-mild ARDS; d P<0.05 vs. patients with moderate-severe ARDS). e Some values are missing for these variables (see table for details). Numbers in brackets refer to the actual sample size.


Table E5 – Univariate and multivariable Cox models for ICU mortality after adjustments for clinical relevant variables and lung injury severity

Characteristics Univariate Multivariable

HR P valuea HR P valuea

Total Lung Tissue – g 1.00 (1.00-1.00) 0.66 1.00 (1.00-1.00) 0.07

Non-aerated Lung Tissue – % 1.01 (0.99-1.03) 0.29 1.02 (0.99-1.05) 0.28

Poorly aerated Lung Tissue – % 1.01 (0.99-1.03) 0.56 1.01 (0.98-1.03) 0.62

Normally aerated Lung Tissue – % 0.98 (0.96-1.00) 0.007 0.97 (0.94-1.00) 0.07

Hyperinflated Lung Tissue – % 1.14 (0.90-1.47) 0.27 1.15 (0.86-1.54) 0.34

Consolidated Lung Tissue – % 0.99 (0.96-1.01) 0.23 0.98 (0.95-1.01) 0.21

Potentially Recruitable Lung – % 1.04 (1.02-1.06) 0.002 1.05 (1.01-1.08) 0.006

PaO2/FiO2

at clinical PEEP – mmHg 1.00 (0.99-1.00) 0.05 1.00 (0.99-1.01) 0.72

PaO2/FiO2

at 5 cmH2O PEEP – mmHg 0.99 (0.99-1.00) 0.07 1.00 (0.99-1.00) 0.41

PaO2/FiO2

at 15 cmH2O PEEP – mmHg 1.00 (0.99-1.00) 0.03 1.00 (0.99-1.00) 0.17

Table E5. Data are presented as hazard ratio and 95% CI with increment of one unit for one point gram, percentage or mmHg, as appropriate. The following covariates, deemed a priori as clinically relevant, were considered in the multivariable models: SAPS II score, age, normalized minute ventilation, days of mechanical ventilation before the study, and the amount of non-aerated lung tissue. Data on survival time were available for 119 patients. ICU = Intensive Care Unit; HR = hazard ratio; PaO2 = arterial partial pressure of oxygen; FiO2 = inspiratory oxygen fraction; PEEP = positive end-expiratory pressure. a P values refer to Cox model analysis performed either as univariate or multivariable analysis.


References

1. Bernard GR, Artigas A, Brigham KL et al: The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am.J.Respir.Crit Care Med. 1994;149: 818-824

2. Gattinoni L, Caironi P, Cressoni M et al: Lung recruitment in patients with the acute respiratory distress syndrome. N.Engl.J.Med. 2006;354: 1775-1786

3. Chiumello D, Marino A, Cressoni M et al: Pleural effusion in patients with acute lung injury: a CT scan study. Crit Care Med. 2013;41: 935-944

4. Chiumello D, Cressoni M, Carlesso E et al: Bedside Selection of Positive End-Expiratory Pressure in Mild, Moderate, and Severe Acute Respiratory Distress Syndrome. Crit Care Med. 2013;

5. Gattinoni L, Caironi P, Pelosi P,Goodman LR: What has computed tomography taught us about the acute respiratory distress syndrome? American Journal of Respiratory and Critical Care Medicine 2001;164: 1701-1711

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