ASSOCIATION BETWEEN TIDAL VOLUME SIZE, DURATION OF VENTILATION AND SEDATION NEEDS IN PATIENTS WITHOUT THE ACUTE RESPIRATORY DISTRESS SYNDROME: An individual patient data meta-analysis

ONLINE SUPPLEMENT DATA

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, Janneke Horn MD PhD, Nicole P Juffermans 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, Marcus J Schultz MD PhD; for the PROVENet investigators

APPENDIX 1

Appendix 1 Figure – Literature search strategy for analysis of duration of ventilation (left) and sedation needs (right).

APPENDIX 2

Appendix 2 Table – Characteristics of the included studies
Study, year / N / Protective / Conservative / Design / Diagnosis of ARDS / Sedation Protocol / Weaning Protocol / Jadad Score
VT / N / VT / N
Wolthuis, 2007 / 36 / 8 / 23 / 10 / 13 / OBS / AECC / Yes / NS / ---
Yilmaz, 2007 / 375 / 8 / 163 / 11 / 212 / OBS / AECC / NS / NS / ---
Linko, 2009 / 853 / 8 / 412 / 10 / 441 / OBS / AECC / NS / NS / ---
Determann, 2010 / 150 / 6 / 76 / 10 / 74 / RCT / AECC / Yes / Yes / 3
de Oliveira, 2010 / 20 / 6 / 10 / 12 / 10 / RCT / None* / NS / NS / 3
Sundar, 2011 / 53 / 6 / 24 / 10 / 29 / RCT / None* / NS / Yes / 3
Elmer, 2013 / 697 / 8 / 210 / 10 / 487 / OBS / Berlin / NS / NS / ---
VT: tidal volume (ml/kg predicted body weight); RCT: randomized controlled trial; OBS: observational; ARDS: acute respiratory distress syndrome; AECC: American-European Consensus Conference on ARDS; NS: not specified
*: did not report the incidence of ARDS

APPENDIX 3

Appendix 3 Table – Scientific quality of included studies
Study, year / Allocation Concealment / Baseline Similarity / Early Stoppinga / Lost to Follow-up / Intention-to-Treat Analysis
Wolthuis, 2007 / Not applicable / Illness severity: similar (APACHE II)
Pulmonary injury: modestly favors controls (PaO2/FiO2) / Not applicable / Not applicable / Not applicable
Yilmaz, 2007 / Not applicable / Age: similar
Illness severity: similar (APACHE III)
Pulmonary injury: modestly favors treatment (PaO2/FiO2) / Not applicable / Not applicable / Not applicable
Linko, 2009 / Not applicable / Not applicable / Not applicable / Not applicable / Not applicable
Determann, 2010 / Sealed envelopes / Age: similar
Illness severity: similar (APACHE II, SOFA)
Pulmonary injury: similar (LIS, PaO2/FiO2) / Yes, Benefit, a priori rules / 2 (1.3%) / Yes
de Oliveira, 2010 / Sealed envelopes / Age: similar
Illness severity: similar (APACHE II) / No / 1 (4.7%) / NS
Sundar, 2011 / Block randomization / Age: similar
Illness severity: similar (STSMS) / No / 1.3% / Yes
Elmer, 2013 / Not applicable / Not applicable / Not applicable / Not applicable / Not applicable
NS: not specified; VT: 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

APPENDIX 4

Appendix 4 Figure – Diagram of sedation protocol used in the study by Wolthuis et al and Determann et al.

APPENDIX 5

Appendix 5 Table – Respiratory parameters during the first five days of treatment in patients included in the analysis of duration of ventilationǁ
Parameters / Day 01 / Day 03 / Day 05
≤ 6 ml/kg PBW / 6 – 10 ml/kg PBW / ≥ 10 ml/kg PBW / ≤ 6 ml/kg PBW / 6 – 10 ml/kg PBW / ≥ 10 ml/kg PBW / ≤ 6 ml/kg PBW / 6 – 10 ml/kg PBW / ≥ 10 ml/kg PBW
Tidal Volume (ml/kg PBW) / 5.6 ± 0.6 / 8.2 ± 1.0 / 11.5 ± 1.6 / 5.7 ± 0.6 / 8.3 ± 1.0 / 11.8 ± 1.7 / 5.5 ± 0.5 / 8.2 ± 1.0 / 11.7 ± 1.5
Peak inspiratory pressure (cmH2O) / 23.3 ± 6.1 / 23.6 ± 6.1 / 25.3 ± 6.1 / 19.3 ± 4.1 / 20.7 ± 4.6 / 22.6 ± 4.8 / 20.8 ± 3.7 / 21.4 ± 3.9 / 23.2 ± 4.6
Respiratory rate (breaths/min) / 20.4 ± 5.9 / 15.0 ± 4.2 / 13.5 ± 3.3 / 16.4 ± 4.4 / 15.3 ± 4.3 / 13.8 ± 3.9 / 19.3 ± 5.3 / 15.0 ± 4.6 / 13.1 ± 4.9
PEEP (cmH2O) / 6.9 ± 2.7 / 6.3 ± 3.6 / 5.9 ± 1.8 / 5.2 ± 1.1 / 5.3 ± 1.3 / 5.2 ± 1.2 / 5.1 ± 0.6 / 5.3 ± 1.1 / 5.3 ± 1.3
PaO2 / FiO2 / 260.2 ± 135.2 / 276.7 ± 132.3 / 278.6 ± 130.3 / 286.1 ± 88.8 / 259.2 ± 135.7 / 247.1 ± 125.9 / 290.2 ± 101.6 / 291.5 ± 110.0 / 282.7 ± 108.7
PaCO2 (mmHg) / 44.6 ± 16.1 / 40.0 ± 8.4 / 37.5 ± 16.5 / 41.1 ± 7.5 / 38.6 ± 7.4 / 39.3 ± 6.1 / 43.0 ± 9.1 / 39.1 ± 6.7 / 38.6 ± 5.3
Arterial pH / 7.34 ± 0.1 / 7.39 ± 0.09 / 7.41 ± 0.08 / 7.42 ± 0.03 / 7.42 ± 0.04 / 7.42 ± 0.05 / 7.44 ± 0.03 / 7.43 ± 0.04 / 7.43 ± 0.05
ǁ Plus-minus values are mean ± SD. 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; PaO2: partial pressure of oxygen; FiO2: inspired fraction of oxygen; PaCO2: partial pressure of carbon dioxide

APPENDIX 6

Appendix 6 Table – Number of patients receiving sedation, analgesia or neuromuscular blockade on days 1, 2, 3, and 5 of follow-up.
Drug / ≤ 6 ml/kg PBW
(n = 65) / 6 – 10 ml/kg PBW
(n = 58) / ≥ 10 ml/kg PBW
(n = 64) / p value*
Sedation**
Day 1
Day 2
Day 3
Day 5 / 48 (74.1)
17 (26.1)
22 (34.4)
26 (40.9) / 34 (58.0)
26 (45.5)
32 (54.8)
22 (38.1) / 38 (60.3)
19 (30.6)
34 (53.1)
36 (56.3) / 0.174
0.128
0.193
0.508
Analgesia**
Day 1
Day 2
Day 3
Day 5 / 41 (63.0)
21 (32.6)
18 (28.1)
15 (22.7) / 25 (44.0)
28(47.7)
35 (61.3)
25 (42.9) / 38 (60.3)
25 (38.8)
24 (37.5)
13 (20.0) / 0.109
0.338
0.023
0.229
NMB**
Day 1
Day 2
Day 3
Day 5 / 16 (25.0)
9 (13.5)
16 (25.0)
11 (17.5) / 11 (19.0)
5 (9.5)
11 (18.8)
10 (16.7) / 38 (60.0)
13 (20.0)
7 (11.1)
0 (0.00) / 0.069
0.518
0.806
0.130
Data presented as frequency (percentage).
NMB: neuromuscular blockade; CI: confidence interval
*: chi-square test
**: Sedation defined as use of any benzodiazepine, propofol or haloperidol. Analgesia defined as use of any opioid. Neuromuscular blockade defined as use of any neuromuscular blocking agent

APPENDIX 7

Appendix 7 Table – Doses of sedation, analgesia or neuromuscular blockade on days 1, 2, 3, and 5 of follow-up.
Drug / ≤ 6 ml/kg PBW
(n = 65) / 6 – 10 ml/kg PBW
(n = 58) / ≥ 10 ml/kg PBW
(n = 64) / p value*
Sedation**
Day 1
Day 2
Day 3
Day 5
Total¶ / 0.1 ± 0.2
0.2 ± 0.7
0.6 ± 0.2
0.3 ± 0.05
1.7 ± 3.5 / 0.2 ± 0.4
0.5 ± 0.9
0.8 ± 1.6
0.4 ± 0.8
2.5 ± 5.3 / 0.6 ± 1.1
0.7 ± 1.1
1.1 ± 1.1
0.5 ± 0.8
5.1 ± 7.5 / 0.285
0.212
0.016
0.247
0.074
Propofol*
Day 1
Day 2
Day 3
Day 5
Total¶ / 1.5 ± 1.8
14.0 ± 28.1
8.5 ± 16.9
3.4 ± 4.0
28.8 ± 40.9 / 16.6 ± 20.7
30.4 ± 46.1
18.4 ± 32.6
8.3 ± 23.3
105.7 ± 168.6 / 2.4 ± 3.9
2.6 ± 5.9
7.3 ± 17.5
0.1 ± 0.2
16.9 ± 23.4 / 0.365
0.101
0.172
0.550
0.422
Analgesia**
Day 1
Day 2
Day 3
Day 5
Total¶ / 0.2 ± 0.3
0.4 ± 0.6
0.2 ± 0.3
0.3 ± 0.5
1.3 ± 1.1 / 0.2 ± 0.3
0.4 ± 0.6
0.4 ± 0.6
0.1 ± 0.2
1.6 ± 2.6 / 0.5 ± 0.8
0.7 ± 0.9
0.7 ± 1.0
0.4 ± 0.6
4.4 ± 7.1 / 0.248
0.455
0.132
0.408
0.664
NMB**
Day 1
Day 2
Day 3
Day 5
Total¶ / 0.2 ± 0.3
0.1 ± 0.2
0.2 ± 0.4
0.7 ± 0.8
1.3 ± 0.3 / 0.2 ± 0.5
0.1 ± 0.3
0.2 ± 0.5
0.2 ± 0.6
0.9 ± 1.3 / 1.0 ± 1.0
0.1 ± 0.3
0.1 ± 0.3
0.0 ± 0.00
2.3 ± 2.5 / 0.046
0.529
0.809
0.146
0.248
Data presented as frequency (percentage).
NMB: neuromuscular blockade; CI: confidence interval
*: ANOVA
**: Benzodiazepines in mg/kg PBW of midazolam equivalents, propofol in mg/kg PBW, opioid in mg/kg PBW of morphine equivalent, and neuromuscular blocking agent in mg/kg PBW
¶: during all ICU stay

APPENDIX 8

Appendix 8 Figure – Dosages of sedation (a, in midazolam equivalents), analgesia (b, in morphine equivalents), and propofol (c). Boxes demonstrate the median and interquartile range, with adjacent values and outliers indicated by whiskers and dots, respectively. Groups: ≤ 6 ml/kg PBW (gray box), 6 – 10 ml/kg PBW (white box), and ≥ 10 ml/kg PBW (light gray box).