Supplementary Online Content Writing Group for The Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators. Effect of lung recruitment and titrated positive end-expiratory pressure (peep) vs low peep on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA. doi:10.1001/jama.2017.14171 eAppendix. Supplemental Methods eTable 1. Lung recruitment maneuver and titrated positive end-expiratory pressure levels eTable 2. Respiratory variables during the first seven days of treatment eTable 3. Fluid balance, weight gain and co-interventions during the first seven days of treatment eFigure. Breath stacking in patients ventilating with low tidal volume This supplementary material has been provided by the authors to give readers additional information about their work. eAppendix. Supplemental Methods Changes in Study Outcomes Length of ICU stay was not originally defined as a study outcome in our protocol. It was introduced as a secondary outcome in the statistical analysis plan and in the ClinicalTrials.gov registry, before the database was locked and data analyzed. All other exploratory outcomes were introduced in our statistical analysis plan and in the ClinicalTrials.gov, although they were not originally presented in our study protocol. Other exploratory outcomes were: death with refractory hypoxemia within 7 days; death with refractory acidosis within 7 days; death with barotrauma within 7 days; cardiorespiratory arrest on day 1; need of commencement/increase of vasopressors or hypotension (MAP<65mmHg) within 1 hour after randomization; refractory hypoxemia (PaO2 < 55mmHg) within 1h after randomization; severe acidosis (pH <7.10) within 1h after randomization. We included these exploratory outcomes for two reasons: 1) they were closely followed by the independent data monitoring committee; 2) they represented potential adverse events of recruitment maneuvers and high positive end-expiratory pressures. Note Regarding the Statistical Analysis Plan and Statistical Analysis The statistical analysis plan was submitted for publication on May 19, 2017.1 The paper was accepted on June 1, 2017. The database was locked and statistical analyses started on June 28, 2017. © 2017 American Medical Association. All rights reserved. Reference 1. Damiani LP, Berwanger O, Paisani D, et al. Statistical analysis plan for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART). A randomized controlled trial. Rev Bras Ter Intensiva. 2017;29(2):142-153. © 2017 American Medical Association. All rights reserved. eTable 1 - Lung Recruitment Maneuver and Titrated PEEP Levels Characteristic Lung Recruitment Maneuver with PEEP Titration Group (n=501) Maximum alveolar recruitment maneuver, No. of events(%) Completed (PEEP = 45 cmH2O) 200 (39.9) Completed (PEEP = 35 cmH2O) 202 (40.3) Interrupted at PEEP = 45 cmH2O 28 (5.6) Interrupted at PEEP = 35 cmH2O 31 (6.2) Interrupted at PEEP = 30 cmH2O 2 (0.4) Interrupted at PEEP = 25 cmH2O 14 (2.8) Interrupted at other PEEP levels Not attempted Neuromuscular blocking agent immediately before alveolar recruitment maneuver, No. of events(%) a Volemia optimized before alveolar recruitment, No. of events (%) 3 (0.6) 21 (4.2) 470 (94.0) 341 (89.7) Reason for interrupting alveolar recruitment maneuver, No. of events (%) Heart rate <60bpm or >150bpm Mean blood pressure <65mmHg or systolic blood pressure <90mmHg SpO2 <88% for longer than 30s Other Titrated PEEP, mean (SD), cmH2O Recruitment maneuver repeated immediately after PEEP titration (on day 0), No. of events (%) Recruitment maneuver repeated on days 1 to 7 – No./total No. (%) 2/78 (2.6) 57/78 (73.1) 16/78 (20.5) 3/78 (3.8) 16.8 (3.8) 393 (78.4) No 314 (62.7) Once 95 (19.0) Twice 46 (9.2) Three or more times 46 (9.2) PEEP denotes positive end expiratory pressure. SpO2 denotes peripheral oxygen saturation. a Volemia is considered optimized when fluids are administered before recruitment maneuver if dynamic signs of fluid responsiveness are present (such as pulse pressure variation >13%) or central venous pressure < 10cmH2O. © 2017 American Medical Association. All rights reserved. eTable 2 - Respiratory Variables During the First Seven Days of Treatment Variable Tidal volume, mean (95% CI), mL/kg of predicted body weight No. of patients 1hour Day 1 Day 3 Day 7 Lung Recruitment Maneuver with PEEP Titration Group Control Group P Value Lung Recruitment Maneuver with PEEP Titration Group Control Group P Value Lung Recruitment Maneuver with PEEP Titration Group Control Group P Value Lung Recruitment Maneuver with PEEP Titration Group Control Group P Value 5.4 (5.3 to 5.5) 5.5 (5.5 to 5.6) 0.004 5.6 (5.5 to 5.7) 5.7 (5.7 to 5.8) 0.006 5.8 (5.6 to 5.9) 5.8 (5.8 to 5.9) 0.20 6.1 (6.0 to 6.3) 6.2 (6.0 to 6.3) 0.67 500 507 482 490 418 431 296 325 Tidal volume > 6.5 mL/kg of predicted body weight, No. of events / total No. (%) PEEP, mean (95% CI), cmH2O No. of patients 30/500 (6.0) 36/507 (7.1) 0.56 54/482 (11.2) 49/490 (10) 0.61 64/418 (15.3) 66/431 (15.3) >0.99 78/296 (26.4) 85/324 (26.2) >0.99 16.4 (16.0 to 16.7) 499 13.0 (12.7 to 13.3) 507 <0.001 16.2 (15.9 to 16.6) 481 12.0 (11.7 to 12.3) 490 <0.001 14.2 (13.8 to 14.6) 418 10.5 (10.2 to 10.9) 432 <0.001 11.6 (11.2 to 12.1) 296 9.6 (9.3 to 10.0) 326 <0.001 Plateau pressure, mean (95% CI), cmH2O 27.9 (27.5 to 28.3) 25.9 (25.5 to 26.3) <0.001 27.9 (27.5 to 28.3) 25.4 (25.0 to 25.9) <0.001 26.3 (25.8 to 26.9) 24.0 (23.5 to 24.6) <0.001 24.1 (23.4 to 24.8) 23.2 (22.5 to 23.8) 0.05 498 503 478 488 417 431 294 325 80/498 (16.1) 45/503 (8.9) 0.001 83/478 (17.4) 52/488 (10.7) 0.004 55/417 (13.2) 37/431 (8.6) 0.04 22/294 (7.5) 25/325 (7.7) >0.99 11.5 (11.1 to 11.8) 13.0 (12.6 to 13.3) <0.001 11.7 (11.3 to 12.1) 13.5 (13.1 to 13.8) <0.001 12.1 (11.7 to 12.5) 13.5 (13.1 to 13.9) <0.001 12.5 (12.0 to 12.9) 13.6 (13.1 to 14.1) 0.001 478 488 417 431 294 325 0.001 32.8 (31.5 to 34.1) 29.7 (28.4 to 31.0) 0.001 34.0 (31.9 to 36.2) 31.3 (29.5 to 33.1) 0.06 34.5 (32.5 to 36.5) 32.4 (30.5 to 34.3) 478 488 417 431 294 325 30.4 (29.9 to 30.9) 29.1 (28.5 to 29.6) 29.2 (28.7 to 29.8) 28.0 (27.4 to 28.6) 25.9 (25.1 to 26.8) 26.4 (25.7 to 27.1) 482 490 418 434 296 326 <0.001 No. of patients Plateau pressure > 30 cmH2O, No. of events / total No. (%) Driving pressure, mean (95% CI), cmH2O No. of patients 498 503 32.5 (31.3 to 33.8) 29.6 (28.4 to 30.7) 498 503 29.7 (29.1 to 30.2) 28.1 (27.5 to 28.7) 500 508 184.1 (175.3 to 192.9) 496 142.3 (137.3 to 147.4) 506 <0.001 221.9 (213.5 to 230.4) 481 164.7 (158.5 to 170.9) 489 <0.001 241.4 (231.3 to 251.5) 418 184.2 (176.5 to 191.9) 434 <0.001 262.7 (250.0 to 275.4) 340 215.1 (204.8 to 225.4) 376 PaCO2, mean (95% CI), mmHg No. of patients 59.7 (57.7 to 61.6) 496 55.9 (54.1 to 57.7) 506 0.006 52.3 (50.9 to 53.7) 481 51.4 (49.9 to 53.0) 489 0.42 49.5 (48.3 to 50.8) 418 49.5 (48.0 to 51.0) 434 0.99 45.9 (44.6 to 47.3) 340 46.6 (45.4 to 47.9) 376 0.43 Arterial pH, mean (95% CI), 7.23 (7.22 to 7.25) 7.26 (7.25 to 7.27) 0.007 7.29 (7.28 to 7.30) 7.30 (7.29 to 7.31) 0.15 7.34 (7.33 to 7.35) 7.34 (7.34 to 7.35) 0.41 7.39 (7.38 to 7.40) 7.38 (7.37 to 7.39) 0.59 Respiratory system static compliance, mean (95% CI),, mL/cmH2O No. of patients Respiratory rate, mean (95% CI), breaths/min No. of patients PaO2:FIO2, mean (95% CI) No. of patients <0.001 © 2017 American Medical Association. All rights reserved. 0.001 0.003 0.14 0.43 No. of patients a 496 506 481 489 418 434 340 376 CI denotes confidence interval PEEP denotes positive end-expiratory pressure. PaO2 denotes partial pressure of arterial oxygen. PaCO2 denotes partial pressure of carbon dioxide. Driving pressure is the difference between plateau pressure and PEEP.. Respiratory system static compliance is the ratio of tidal volume to driving pressure © 2017 American Medical Association. All rights reserved. eTable 3. Fluid Balance, Weight Gain and Co-interventions During the First Seven Days of Treatment Lung Recruitment Maneuver with PEEP Titration Group (n=501) Control Group (n=509) Absolute Difference (95% CI) P Value 1,610 (756 – 2,669) [n=480] 1,128 (500 – 2,160) [n=408] 1,309 (580 – 2,568) [n=489] 1,093 (505 – 2,015) [n=429] 301.5 (80.6 to 495.9)ª 0.06 35.0 (-116.5 to 207.0)ª 0.70 1.0 (0.0 – 2.3) [n=89] 1.1 (-0.3 - 3.1) [n=79] -0.2 (-3.4 - 2.4) [n=68] 423 (84.4) 0.1 (0.0 – 2.0) [n=88] 1.3 (-0.9 - 3.2) [n=79] -0.7 (-5.4 - 3.8) [n=72] 422 (82.9) 0.9 (-0.1 to 1.1)ª 0.97 -0.2 (-1.5 to 1.2)ª 0.95 0.5 (-2.0 to 2.4)ª 0.91 1.5 (-3.2 to 6.3) 0.57 Days of vasopressor use, median (IQR) 3 (1 - 6) 3 (1 - 6) 0.0 (0.0 to 1.0)ª 0.60 Neuromuscular blockade, No. of events (%) 485 (96.8) 373 (73.3) 23.5 (19.2 to 27.9) <0.001 2 (1 - 4) 2 (0 - 4) 0.0 (0.0 to 1.0)ª 0.001 496 (99.0) 494 (97.1) 1.9 (0.0 to 3.9) 0.05 6 (3 - 7) 6 (3 - 7) 0.0 (-1.0 to 1.0)ª 0.95 422 (84.2) 426 (83.7) 0.5 (-4.2 to 5.3) 0.88 5 (2 - 7) 6 (2 - 7) 0.0 (-1.0 to 0.0)ª 0.35 Use of corticosteroid, No. of events (%) 281 (56.1) 279 (54.8) 1.3 (-5.1 to 7.6) 0.73 Days of corticosteroid, median (IQR) 2 (0 - 7) 1 (0 - 7) 1.0 (-1.0 to 2.0)ª 0.81 78 (15.6) 89 (17.5) -1.9 (-6.7 to 2.9) 0.46 76 (15.2) 82 (16.1) -0.9 (-5.6 to 3.7) 0.75 Inhaled nitric oxide 6 (1.2) 6 (1.2) 0.0 (-1.3 to 1.4) 0.99 High frequency oscillation 2 (0.4) 3 (0.6) -0.2 (-1.2 to 0.9) 0.99 Extracorporeal membrane oxygenation 5 (1.0) 5 (1.0) 0.0 (-1.2 to 1.3) 0.99 24-h fluid balance, median (IQR), mL Day 1 Day 3 Weight gain, median (IQR), kg Baseline to day 1 Baseline to day 3 Baseline to day 7 Use of vasopressors, No. of events (%) Days of neuromuscular blocker use, median (IQR) Sedative infusion, No. of events (%) Days of sedative infusion, median (IQR) Narcotic infusion, No. of events (%) Days of narcotic infusion, median (IQR) Rescue therapies, No. of events. (%) Prone position ª Confidence Interval estimated by bootstrapping method with 3,000 replicates. eFigure 1. Breath Stacking in Patients Ventilating with Low Tidal Volumes © 2017 American Medical Association. All rights reserved. © 2017 American Medical Association. All rights reserved. Patient enrolled and randomized to the experimental group (positive end-expiratory pressure [PEEP] titrated according to respiratory-system compliance after recruitment). Tidal volume was set at 6 mL/kg of predicted body-weight and PEEP set at 16cmH2O. The tracing shows 3 stacked breaths (red arrows). Breath stacking is a form of patient-ventilator dyssynchrony in which consecutive machine inspiratory cycles occur in close succession with incomplete exhalation between them, usually owing to inspiratory muscle effort early during the machine expiratory phase. The ventilator showed a tidal volume of 420 mL/Kg (6mL/kg of predicted body weight) and did not display extra tidal volumes, because of the resetting algorithm present in most mechanical ventilators in the market. When tidal volume was calculated by electrical impedance tomography, we could observe the stacked volume reaching 12 ml/kg and peak pressure of approximately 55 cmH2O. In additional patients monitored with electrical impedance tomography (submitted to similar protocol but not enrolled in this trial), we noticed that the resulting driving pressure during stacked breaths was much higher at high-PEEP: whereas the driving pressure during normal breaths was equivalent (at higher or lower PEEP levels), the driving pressure during stacked breaths was much higher at high-PEEP, because of the trespassing of elastic limits of the respiratory system. Paw denotes airway pressure. Min denotes minutes. ΔZ denotes electrical impedance. The black dashed line in the flow versus time tracing indicates a flow equal to zero. The red dashed line in the pressure versus time tracing indicates an airway pressure of 55cmH2O. © 2017 American Medical Association. All rights reserved.
