1 LUNG PROTECTIVE VENTILATION WITH LOW TIDAL VOLUMES AND THE OCCURRENCE OF PULMONARY COMPLICATIONS IN PATIENTS WITHOUT ARDS: a systematic review and individual patient data metaanalysis SUPPLEMENTARY APPENDIX Ary Serpa Neto MD MSc, Fabienne D Simonis MD, Carmen SV Barbas MD PhD, Michelle Biehl MD, Rogier M Determann MD PhD, Jonathan Elmer MD, Gilberto Friedman MD PhD, Ognjen Gajic MD, Joshua N Goldstein MD PhD, Rita Linko MD PhD, Roselaine Pinheiro de Oliveira MD PhD, Sugantha Sundar MD, Daniel Talmor MD PhD, Esther K Wolthuis MD PhD, Marcelo Gama de Abreu MD PhD, Paolo Pelosi MD PhD, Marcus J Schultz MD PhD
2 EXAMPLE OF DATASHEET USED FOR DATA COLLECTION PIN AUTHOR DAY GENDER AGE RISK OF DEATH DIAGNOSTIC PBW VENTILATORY MODE TV TV (PBW) PEEP PPEAK PPLATO RR P/F PH PACO2 Patient 1 Determann 1 Male 52 23% Sepsis 61 Pressure Control 364 5.96 5 23 18 21 301 7.42 43.9 Patient 1 Determann 2 Male 52 23% Sepsis 61 Pressure Control 401 6.57 8 22 20 22 299 7.39 44.0 Patient 1 Determann 3 Male 52 23% Sepsis 61 Pressure Control 399 6.54 6 22 19 23 303 7.37 44.1 PIN AUTHOR DAY GENDER AGE RISK OF DIAGNOSTIC FOLLOW- UP DEATH PNEUMONIA ARDS DURATION OF MV ICU LOS HOSPITAL LOS DEATH (DAYS) Patient 1 Determann 1 Male 52 23% Sepsis 23 Yes No Yes 20 19 23
3 APPENDIX 1 Appendix Figure 1 Literature search strategy.
4 APPENDIX 2 Appendix Table 2 Characteristics of the included studies Study, year N Protective Conservative Diagnosis of Diagnosis of Calculation of Jadad Design V T N V T N ARDS Pneumonia PBW Score Wolthuis, 2007 36 8 23 10 13 OBS AECC criteria scored As in ARMA Yilmaz, 2007 375 8 163 11 212 OBS AECC criteria scored As in ARMA Linko, 2009 853 8 412 10 441 OBS AECC criteria Diverse criteria * As in ARMA Determann, 2010 150 6 76 10 74 RCT AECC criteria Diverse criteria * As in ARMA 3 de Oliveira, 2010 20 6 10 12 10 RCT scored scored As in ARMA 3 Sundar, 2011 53 6 24 10 29 RCT scored scored As in ARMA 3 Elmer, 2013 697 8 210 10 487 OBS Berlin definition Diverse criteria * As in ARMA V T : Tidal volume (ml/kg predicted body weight); RCT: Randomized controlled trial; OBS: Observational; ARDS: acute respiratory distress syndrome; AECC criteria: American-European Consensus Conference criteria for ARDS; PBW: predicted body weight, ARMA: the Respiratory Management of Acute Lung Injury and Acute Respiratory Distress Syndrome trial, published in 2000 [NEJM 2000; 342:1301] *Based on new infiltrates on chest radiographs, clinical signs of infection, and/or positive sputum cultures.
5 APPENDIX 3 Appendix Table 3 Scientific quality of included studies Allocation Study, year Concealment Wolthuis, 2007 Yilmaz, 2007 Linko, 2009 Determann, 2010 Sealed envelopes Baseline Similarity Illness severity: similar (APACHE II) Pulmonary injury: modestly favors controls (PaO 2 /FiO 2 ) Age: similar Illness severity: similar (APACHE III) Pulmonary injury: modestly favors treatment (PaO 2 /FiO 2 ) Age: similar Illness severity: similar (APACHE II, SOFA) Pulmonary injury: similar (LIS, PaO 2 /FiO 2 ) Age: similar Illness severity: similar (APACHE II) Age: similar Illness severity: similar (STSMS) Early Stopping a Yes, Benefit, a priori rules Lost to Follow-up Sealed de Oliveira, 2010 envelopes Block Sundar, 2011 randomization Elmer, 2013 NS: not specified; V T : tidal volume; STSMS: society of thoracic surgeons mortality score; PORI: preoperative risk index a : Early termination for benefit or futility and the presence of an explicit a priori stopping rules Intention-to- Treat Analysis 2 (1.3%) Yes No 1 (4.7%) NS No 1.3% Yes
6 APPENDIX 4 Appendix Figure 4 Distribution of tidal volume in A) overall cohort, and in B) conventional (black bars) or protective (gray bars) arms of randomized controlled trials. The thick lines correspond to the cut-offs used in the study.
7 APPENDIX 5 Appendix Table 5 Down and Black checklist for non-randomized controlled trials 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Wolthuis, 2007 Y Y Y Y N Y Y Y N Y N UTD Y N N N N Y Y Y Y Y UTD N Y UTD UTD Yilmaz, 2007 Y Y Y Y N Y Y Y N Y N UTD Y N N N N Y Y Y Y Y UTD N Y UTD UTD Linko, 2009 Y Y Y Y N Y Y Y N Y Y UTD Y N N Y N Y Y Y Y Y UTD N Y UTD UTD Elmer, 2013 Y Y Y Y N Y Y Y N Y Y UTD Y N N N N Y Y Y Y Y UTD N Y UTD UTD
8 APPENDIX 6 Appendix Table 6 Respiratory parameters during the first five days of ventilation ǁ Parameters Less than or equal to 7 ml/kg PBW Day 1 Day 3 Day 5 Equal to or Less than Greater Equal to or Less than Greater greater or equal to than 7 and greater or equal to than 7 and than 10 7 ml/kg less than 10 than 10 7 ml/kg less than 10 ml/kg PBW PBW ml/kg PBW ml/kg PBW PBW ml/kg PBW Greater than 7 and less than 10 ml/kg PBW Equal to or greater than 10 ml/kg PBW Tidal Volume (ml/kg PBW) 6.4 (6.1 6.7) 8.9 (8.4 9.4) 11.1 (10.5 12.2) 6.8 (6.3 7.2) 9.0 (8.5 9.6) 11.4 (10.5 12.5) 7.1 (6.4 7.6) 9.0 (8.5 9.5) 11.4 (10.6 12.5) 720 754 710 501 673 531 278 301 265 Plateau pressure (cmh 2 O) 18.0 (15.0 21.0) 19.0 (16.0 23.0) 20.5 (17.0 25.0) 16.0 (14.0 18.0) 18.0 (17.0 19.7) 19.0 (17.0 23.0) 15.5 (15.0 17.2) 16.2 (13.7 17.2) 19.0 (16.0 22.0) 301 384 227 *, 101 124 117 98 101 71 α Peak inspiratory pressure (cmh 2 O) 22.0 (18.0 27.0) 23.0 (20.0 27.0) 25.0 (21.0 28.0) 20.0 (18.0 23.0) 20.0 (17.2 24.0) 21.0 (19.5 25.0) 20.0 (18.0 22.0) 22.0 (19.0 23.0) 23.2 (20.0 27.0) 539 647 471,α 501 651 522,α 201 256 207 Respiratory rate (breaths/min) 16.0 (13.0 20.0) 14.0 (12.0 16.0) 13.0 (12.0 15.0) 15.0 (12.2 18.0) 14.0 (12.0 16.0) 13.0 (12.0 16.0) 16.0 (12.0 19.0) 14.0 (12.0 17.5) 13.0 (10.0 16.0) 589 717 598 495 664 524 221 254 198 Minute-Ventilation (liters/min) 7.5 (6.2 9.1) 8.0 (6.6 9.6) 8.8 (7.2 10.8) 7.2 (6.4 8.8) 8.4 (7.0 9.8) 8.5 (7.2 10.8) 7.2 (5.7 9.0) 7.4 (7.4 9.5) 8.7 (7.7 11.0) 589 717 598 495 664 524 221 254 198 PEEP (cmh 2 O) 5.0 (5.0 8.0) 5.0 (5.0 6.0) 5.0 (5.0 6.0) 5.0 (5.0 5.0) 5.0 (5.0 5.0) 5.0 (5.0 5.0) 5.0 (5.0 5.0) 5.0 (5.0 5.0) 5.0 (5.0 5.0) 701 720 699 498 669 524 221 253 207 PaO 2 / FiO 2 299 (259 354) 291 (264 361) 295 (281 358) 265 (239 326) 279 (211 327) 255 (221 327) 277 (228 361) 270 (211 342) 260 (205 349) 590 698 612 467 501 467 123 109 153 PaCO 2 (mmhg) 42.0 (36.0 47.0) 38.0 (34.0 43.0) 36.0 (31.0 42.0) 40.0 (35.5 42.0) 38.0 (34.3 42.5) 39.0 (35.0 43.0) 39.0 (35.0 43.5) 40.0 (36.0 44.0) 39.0 (35.0 43.0) 566 679 563 431 497 411 101 109 150 Arterial ph 7.38 (7.32 7.43) 7.40 (7.35 7.45) 7.42 (7.37 7.47) 7.43 (7.40 7.45) 7.43 (7.40 7.46) 7.42 (7.40 7.45) 7.45 (7.42 7.47) 7.43 (7.39 7.46) 7.44 (7.40 7.46) 566 679 563 431 497 411 96 100 151 ǁ Data presented as median (Interquartile Range). The number of patients refers to those who were receiving ventilation and for whom data were available. PBW: predicted body weight; PEEP: positive end-expiratory pressure; PaO 2 : partial pressure of oxygen; FiO 2 : inspired fraction of oxygen; PaCO 2 : partial pressure of carbon dioxide a: p-value for time-group interaction with generalized linear models including the time (day 1, day 3, and day 5) as within-factor variable and the group (less than or
equal to 7, Greater than 7 and less than 10 and equal to or greaher than 10 ml/kg PBW) as between-factor variable * p < 0.05 for less than or equal to 7 ml/kg PBW compared to greater than 7 and less than 10 ml/kg PBW p < 0.05 for less than or equal to 7 ml/kg PBW compared to equal to or greater than 10 ml/kg PBW α p < 0.05 for greater than 7 and less than 10 ml/kg PBW compared to equal to or greater than 10 ml/kg PBW 9
10 APPENDIX 7 Appendix Figure 7 Individual and pooled pulmonary complications incidence rates.
11 APPENDIX 8 Appendix Table 8 Baseline characteristics of the patients according to initial diagnosis ǁ Variables Trauma or Post-Operative (n = 473) Neurological (n = 717) Others (n = 995) Greater than Equal to or Less than or Greater than Equal to or Less than or Greater 7 and less greater than equal to 7 7 and less greater than equal to 7 than 7 and than 10 (n = 10 (n = 133) ml/kg PBW than 10 (n = 10 (n = 233) ml/kg PBW less than 10 154) (n = 195) 289) (n = 338) (n = 311) Less than or equal to 7 ml/kg PBW (n = 186) Equal to or greater than 10 (n = 346) Age, years 68.64 ± 11.14 65.00 ± 12.82 71.40 ± 7.73 68.34 ± 14.45 67.42 ± 13.76 66.53 ± 15.33 59.03 ± 16.98 61.13 ± 16.38 62.35 ± 16.49 Gender, female 77 (41.2) 24 (36.8) 59 (44.4) 68 (34.9) 127 (44.1) 125 (53.7) 66 (19.4) 121 (39) 150 (43.5) PBW, kg 64.74 ± 9.67 65.22 ± 10.29 58.35 ± 9.78 70.23 ± 10.08 64.12 ± 9.51 58.82 ± 11.26 69.97 ± 9.44 65.12 ± 10.13 62.21 ± 11.55 APACHE II 24.00 ± 10.90 16.20 ± 4.89 20.57 ± 9.19 19.32 ± 6.47 20.42 ± 6.06 20.03 ± 6.21 22.64 ± 8.73 23.25 ± 8.92 23.15 ± 11.55 PaO 2 / FiO 2 229.0 ± 99.3 266.8 ± 94.9 289.7 ± 94.5 315.3 ± 186.8 290.6 ± 130.3 302.8 ± 148.6 261.9 ± 123.7 266.7 ± 122.0 265.3 ± 120.1 Initial diagnosis Post-surgery Cardiac arrest Traumatic brain injury Sepsis Trauma Stroke or Hemorrhage Status epilepticus Other 79 (42.5) 107 (57.5) 74 (48) 80 (52) 65 (48.9) 68 (51.1) 40 (20.5) 154 (79) 1 (0.5) 35 (12.1) 252 (87.2) 2 (0.7) 32 (13.7) 198 (85) 3 (1.3) 80 (23.7) 193 (57.1) 65 (19.2) 77 (24.7) 176 (56.6) 58 (18.7) 78 (22.5) 194 (56.1) 74 (21.4) Type of ventilation, VC 165 (88.9) 87 (56.3) 106 (80) 124 (63.8) 155 (53.6) 104 (44.7) 202 (59.9) 191 (61.3) 201 (58.2) Tidal volume, ml/kg PBW Day 01 Day 03 Day 05 6.25 ± 0.47 5.88 ± 0.23 6.39 ± 0.12 9.31 ± 0.59 8.80 ± 0.66 8.83 ± 0.29 10.51 ± 0.63 12.97 ± 1.21 11.23 ± 1.52 7.11 ± 0.73 7.11 ± 0.73 6.97 ± 0.79 9.00 ± 0.57 9.02 ± 0.59 9.00 ± 0.58 11.56 ± 1.67 11.73 ± 1.61 11.72 ± 1.48 6.76 ± 0.90 6.40 ± 1.54 6.48 ± 1.44 8.90 ± 0.56 9.02 ± 0.84 9.05 ± 0.76 11.60 ± 1.60 12.93 ± 4.24 13.56 ± 2.07 Plateau pressure, cmh 2 O Day 01 17.29 ± 3.73 20.44 ± 4.30 20.72 ± 5.29 17.36 ± 5.83 17.25 ± 3.25 20.00 ± 2.68 18.63 ± 5.28 20.46 ± 5.24 21.39 ± 5.85
12 Day 03 Day 05 16.00 ± 1.00 17.12 ± 2.78 17.00 ± 1.21 19.21 ± 3.43 21.12 ± 3.43 21.01 ± 2.34 16.72 ± 4.23 16.38 ± 2.99 18.04 ± 2.38 15.52 ± 3.44 19.62 ± 3.49 19.00 ± 3.24 PEEP, cmh 2 O Day 01 9.05 ± 16.24 7.94 ± 4.58 6.25 ± 2.47 5.27 ± 1.22 5.16 ± 0.86 5.16 ± 0.86 Day 03 7.50 ± 3.53 9.50 ± 3.92 9.66 ± 0.57 5.13 ± 0.77 5.15 ± 0.69 5.12 ± 0.76 Day 05 6.78 ± 1.23 8.50 ± 3.53 6.80 ± 1.92 5.18 ± 0.86 5.24 ± 1.00 5.16 ± 0.82 ǁ Plus-minus values are mean ± SD and other values are n (%) Comparisons were made using analysis of variance (ANOVA) PBW: predicted body weight; RCT: randomized controlled trial; VC: volume controlled; PEEP: positive end-expiratory pressure; 17.52 ± 1.29 18.92 ± 3.41 6.95 ± 2.70 5.50 ± 0.70 5.25 ± 0.50 21.55 ± 4.32 22.23 ± 4.32 6.60 ± 2.41 8.33 ± 4.08 6.00 ± 0.00 24.32 ± 4.32 24.01 ± 3.21 6.21 ± 1.99 8.17 ± 7.07 10.33 ± 3.21
13 APPENDIX 9 Appendix Table 9 Primary and secondary outcomes according to initial diagnosis Trauma or Post-Operative (n = 473) Neurological (n = 717) Others (n = 995) Variables Pulmonary Complications ARDS Pneumonia Adjusted OR** (95% CI) * p 0.99 (0.71 1.34) 0.81 (0.65 1.04) 1.21 (0.87 3.21) 0.831 0.090 0.451 Adjusted OR (95% CI) * p 0.80 (0.75 2.22) 0.99 (0.87 1.54) 1.09 (0.72 2.21) 0.777 0.431 0.321 Adjusted OR** (95% CI) * p 0.84 (0.55 1.30) 0.65 (0.40 1.05) 1.64 (0.91 2.94) 0.431 0.078 0.100 Adjusted OR (95% CI) * p 0.88 (0.60 1.28) 0.88 (0.59 1.33) 1.17 (0.68 2.03) 0.505 0.553 0.567 Adjusted OR** (95% CI) * p 0.68 (0.47 0.96) 0.40 (0.26 0.63) 1.50 (0.90 2.52) 0.031 < 0.01 0.121 Adjusted OR (95% CI) * p 0.83 (0.59 1.16) 0.47 (0.31 0.71) 1.35 (0.82 2.22) In-Hospital Mortality 1.17 (0.55 2.21) 0.721 0.89 (0.55 3.01) 0.657 1.07 (0.70 1.62) 0.759 1.06 (0.73 1.55) 0.749 0.94 (0.67 1.31) 0.725 0.83 (0.60 1.15) 0.274 * Adjusted by: age, risk of death, baseline PaO 2 / FiO 2, baseline ph ** 7 ml/kg PBW vs. 10 ml/kg PBW 8 to 9 ml/kg PBW vs. 10 ml/kg PBW ARDS: acute respiratory distress syndrome; RR: odds ratio; CI: confidence interval; 0.829 < 0.01 0.237