Electronic Suplementary Material

-SUPPLEMENTAL DATA FILE-

A quantile analysis of plateau and driving pressures: Effects on mortality in patients with the Acute Respiratory Distress Syndrome receiving lung protective ventilation

Running title: Plateau & driving pressures in ARDS outcome

Jesús Villar, MD, PhD, FCCM1,2; Carmen Martín-Rodríguez, MD3; Ana M. Domínguez- Berrot, MD4; Lorena Fernández, MD5; Carlos Ferrando, MD, PhD6; Juan A. Soler, MD, PhD7; Ana M. Díaz-Lamas, MD8; Elena González-Higueras, MD, PhD9; Leonor Nogales, MD10; Alfonso Ambrós, MD, PhD3; Demetrio Carriedo, MD, PhD4; Mónica Hernández, MD11; Domingo Martínez, MD12; Jesús Blanco, MD, PhD5; Javier Belda, MD, PhD6; Dácil Parrilla, MD13; Fernando Suárez-Sipmann, MD, PhD1,14; Concepción Tarancón, MD15; Juan M. Mora-Ordoñez, MD16; Lluís Blanch, MD, PhD1,17; Lina Pérez-Méndez, MD, PhD1,18; Rosa L. Fernández, MSc1,2; Robert M. Kacmarek, PhD, RTT19,20; for the Spanish Initiative for Epidemiology, Stratification and Therapies of ARDS (SIESTA) Network*

From (1) CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; (2) Research Unit, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canaria, Spain; (3) Intensive Care Unit, Hospital General de Ciudad Real, Ciudad Real, Spain; (4) Intensive Care Unit, Complejo Asistencial Universitario de León, León, Spain; (5) Intensive Care Unit, Hospital Universitario Río Hortega, Valladolid, Spain; (6) Department of Anesthesiology, Hospital Clínico Universitario, Valencia, Spain; (7) Intensive Care Unit, Hospital Universitario Morales Meseguer, Murcia, Spain; (8) Intensive Care Unit, Hospital Universitario A Coruña, Coruña, Spain; (9) Intensive Care Unit, Hospital Virgen de La Luz, Cuenca, Spain; (10) Intensive Care Unit, Hospital Clínico Universitario, Valladolid, Spain; (11) Intensive Care Unit, Hospital Universitario La Paz, Madrid, Spain; (12) Intensive Care Unit, Hospital Universitario Virgen de Arrixaca, Murcia, Spain; (13) Intensive Care Unit, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain; (14) Department of Surgical Sciences, Anesthesiology & Critical Care, Hedenstierna Laboratory, Uppsala University Hospital, Uppsala, Sweden; (15) Intensive Care Unit, Hospital Virgen de la Concha, Zamora, Spain; (16) Intensive Care Unit, Hospital Universitario Carlos Haya, Málaga, Spain; (17) Critical Care Center, Corporació Sanitaria Parc Taulí, Sabadell, Spain; (18) Research Unit, Hospital Universitario NS de Candelaria, Santa Cruz de Tenerife, Spain; (19) Department of Respiratory Care, Massachusetts General Hospital, Boston, Massachusetts, USA (20) Department of Anesthesia, Harvard University, Boston, Massachusetts, USA. * Additional investigators from the SIESTA Network are listed in the Appendix.

1 Corresponding author: Dr. Jesús Villar, Multidisciplinary Organ Disfunction Evaluation Research Network, Hospital Universitario Dr. Negrin, Barranco de la Ballena s/n, 4th floor, South wing. 35019 Las Palmas de Gran Canaria. SPAIN. Phone: (+34) 928449413; e-mail: [email protected]

2 SUPPLEMENTARY RESULTS

TABLE S1. Distribution of 478 ARDS patients by tertiles of tidal volume (VT) at 24 h after ARDS onset and the associated hospital mortality. VT is expressed in ml/kg predicted body weight.

≤6.5 ml/kg >6.5 – <7.5 ml/kg ≥7.5 ml/kg P No. of patients 123 178 177 Deaths, n (%) 60 (48.7%) 68 (38.2%) 74 (41.8%) 0.186

PEEP, cmH2O 11 ± 3 11 ± 2 11 ± 2 1 Plateau pressure, 28 ± 5 27 ± 5 27 ± 5 0.162

cmH2O Driving Pressure, 16 ± 5 16 ± 5 16 ± 5 1

TABLE S2. Distribution of 478 patients by tertiles of applied positive end-expiratory pressure

(PEEP) at 24 h after ARDS onset and their associated hospital mortality. PEEP levels are expressed in cmH2O. PBW: predicted body weight; VT: tidal volume.

PEEP<10 PEEP=10 PEEP 11-15 PEEP>15 p-value No. patients 27 285 142 24 Deaths, n (%) 11 (40.7) 104 (36.5) 75 (52.8) 12 (50) 0.012

PaO2/FiO2, mmHg 170±68 181±80 132±59 133±59 <0.000

1 VT, ml/kg PBW 7.1±1.0 7.1±1.0 6.9±1.0 6.8±1.0 0.160

3 TABLE S3. Quantiles of plateau and driving pressures in 478 patients with ARDS of the derivation cohort and their associated hospital mortality*. Relative risk (RR) and 95% confidence intervals (CI) of each quantile is calculated in relation to the overall 42.2% hospital mortality as the reference (assumed to be 1). CI: confidence interval; DP: driving pressure; N: number of cases; Pplat: plateau pressure; RR: relative risk.

Pplat N Mortality RR (95% CI) DP N Mortality RR (95% CI)

cmH2O % cmH2O % 16 13 23.1 0.55 (0.21-1.48) 6 15 26.7 0.63 (0.27-1.47) 18 14 28.6 0.68 (0.30-1.55) 8 19 26.3 0.62 (0.29-1.33) 20 22 22.7 0.54 (0.25-1.17) 9 12 25.0 0.59 (0.22-1.58) 21 13 23.1 0.55 (0.21-1.48) 10 19 21.1 0.50 (0.21-1.20) 22 13 23.1 0.55 (0.21-1.48) 11 18 16.7 0.40 (0.14-1.11) 23 21 23.8 0.56 (0.26-1.21) 12 14 28.6 0.68 (0.29-1.55) 24 25 28.0 0.66 (0.35-1.25) 13 13 30.8 0.73 (0.32-1.65) 25 34 29.4 0.70 (0.41-1.18) 14 46 32.6 0.77 (0.50-1.18) 26 29 27.6 0.65 (0.36-1.18) 15 47 34.0 0.81 (0.53-1.21) 27 22 18.2 0.43 (0.18-1.05) 16 39 35.9 0.85 (0.55-1.30) 28 50 24.0 0.57 (0.34-0.94) 17 25 36-0 0.85 (0.50-1.45) 29 28 42.8 1.01 (0.65-1.57) 18 48 37.5 0.88 (0.61-1.29) 30 66 60.6 1.44 (1-15-1.79) 19 28 53.6 1.27 (0.88-1.82) 31 18 66.7 1.58 (1.12-2.22) 20 53 62.3 1.47 (1.17-1-89) 32 34 70.6 1.67 (1.31-2.13) 21 17 70.6 1.67 (1.21-2.31) 33 14 71.4 1.69 (1.19-2.39) 22 17 64.7 1.53 (1.06-2.21) 34 11 72.7 1.72 (1.18-2.51) 23 10 70.0 1.66 (1.09-2.51) 36 23 91.3 2.16 (1.83-2.55) 26 19 89.5 2.12 (1.76-2.55)

(*) For the purpose of reporting mortality associated with each quantile of plateau and driving pressure, only those quantiles with ≥10 patients were considered.

4 TABLE S4. Cross-tabulated interaction between the values of plateau pressure and driving pressure in the derivation cohort of 478 patients with ARDS. CI: confidence of intervals, DP: driving pressure, N: number of cases, Pplat: plateau pressure, RR: relative risk.

Combination of N Hospit Mortality RR (CI 95%) p-value

parameters al (%)

Deaths Pplat <30 and DP <19 284 72 25.3 1 Pplat <30 and DP ≥19 20 10 50.0 1.97 (1.22- P for trend 3.19) Pplat ≥30 and DP <19 46 32 69.5 2.74 (2.08- <0.000000

3.62) 1 Pplat ≥30 and DP ≥19 128 88 68.8 2.71 (2.15-

3.42) 478 202 42.2

DP <19 and Pplat <30 284 72 25.3 1 DP <19 and Pplat ≥30 46 32 69.5 2.74 (2.08- <0.0001 3.62) DP ≥19 and Pplat <30 20 10 50.0 1.97 (1.22-

3.19) 0.127 DP ≥19 and Pplat ≥30 128 88 68.8 2.71 (2.15-

5 TABLE S5. Quantiles of plateau and driving pressures in 300 patients with ARDS of the validation cohort and their associated hospital mortality*. Relative risk (RR) and 95% confidence intervals (CI) of each quantile is calculated in relation to the overall 42.3% hospital mortality as the reference (assumed to be 1). CI: confidence interval; DP: driving pressure; N: number of cases; Pplat: plateau pressure; RR: relative risk.

Pplat N Mortality RR (95% CI) DP N Mortality RR (95% CI)

cmH2O % cmH2O % 18 10 30.0 0.71 (0.27-1.84) 8 11 27.2 0.64 (0.24-1.71) 20 12 33.3 0.79 (0.35-1.77) 9 13 30.7 0.73 (0.32-1.66) 22 16 25.0 0.59 (0.25-1.39) 10 23 17.4 0.41 (0.17-1.01) 23 16 31.2 0.74 (0.35-1.54) 11 12 33.3 0.79 (0.35-1.77) 24 24 33.3 0.79 (0.35-1.77) 12 19 31.5 0.74 (0.38-1.46) 25 26 23.0 0.54 (0.27-1.11) 13 33 30.3 0.72 (0.42-1.22) 26 17 11.7 0.28 (0.08-1.03) 14 31 35.5 0.84 (0.51-1.37) 27 20 35.0 0.83 (0.45-1.52) 15 27 37.0 0.87 (0.53-1.46) 28 33 33.3 0.79 (0.48-1.30) 16 15 40.0 0.94 (0.50-1.78) 29 17 41.1 0.97 (0.54-1.74) 17 15 40.0 0.94 (0.50-1.78) 30 24 54.2 1.28 (0.87-1.89) 18 26 42.3 1.0 (0.63-1.59) 31 15 66.7 1.58 (1.08-2.31) 19 14 64.3 1.52 (1.01-2.29) 32 18 83.3 1.97 (1.54-2.52) 20 15 66.7 1.58 (1.08-2.31) 33 12 91.6 2.16 (1.74-2.69) 21 11 81.8 1.93 (1.42-2.63) 34 11 100 2.36 (2.07-2.70) 22 10 70.0 1.65 (1.08-2.53) 23 11 100 2.36 (2.07-2.70)

(*) For the purpose of reporting mortality associated with each quantile of plateau (Pplat) and driving (DP) pressure, only those quantiles with ≥10 patients were considered.

6 TABLE S6. Cross-tabulated interaction between the values of plateau pressure and driving pressure in the validation cohort of 300 patients with ARDS. CI: confidence of intervals, DP: driving pressure, N: number of cases, Pplat: plateu pressure, RR: relative risk.

Combination of N Hospit Mortality RR (CI 95%) p-value

parameters al (%)

Deaths Pplat <30 and DP <19 199 56 28.1 1 Pplat <30 and DP ≥19 11 5 45.4 1.61 (0.81- P for trend 3.20) Pplat ≥30 and DP <19 33 20 60.6 2.15 (1.51- <0.000000

3.07) 1 Pplat ≥30 and DP ≥19 57 46 80.7 2.87 (2.22-

3.70) 300 127 42.3

DP <19 and Pplat <30 199 56 28.1 1 DP <19 and Pplat ≥30 33 20 60.6 2.15 (1.51- <0.001 3.07) DP ≥19 and Pplat <30 11 5 45.4 1.61 (0.81-

3.20) 0.022 DP ≥19 and Pplat ≥30 57 46 80.7 2.87 (2.22-

7 FIGURE S1. Receiving operating curves for plateau pressure (Pplat) and driving pressure (DP) in 778 patients with moderate/severe acute respiratory distress syndrome. Area under the curve was 0.724 (95%CI: 0.686-0.761) for plateau pressure, and 0.704 (95%CI: 0.667-0.741) for driving

pressure (p<0.000001).

VI ITI Pplat

SE Reference line

1-SPECIFICITY (true negative fraction)