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Figures
- Figure 1:
Selection of randomized controlled trials (RCTs) for the meta-analysis. ARDS = acute respiratory distress syndrome.
- Figure 2:
Effect of prone positioning during mechanical ventilation on all-cause mortality among patients with acute respiratory distress syndrome in trials that used protective lung ventilation (tidal volume < 8 mL/kg) and in trials that did not mandate protective ventilation. Risk ratios less than 1.0 indicate a decreased risk of death with prone positioning. *Mortality data differed from the original publication after verification by the primary investigator. The test for subgroup interaction is statistically significant (p = 0.05). CI = confidence interval, RR = risk ratio.
- Figure 3:
Effect of prone positioning during mechanical ventilation on all-cause mortality according to prespecified patient-level and trial-level subgroups. Risk ratios less than 1.0 indicate a decreased risk of death with prone positioning. *Severe hypoxemia = ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) < 100 mm Hg; moderate = Pao2/Fio2 ratio 100–199 mm Hg; mild = Pao2/Fio2 ratio 200–299 mm Hg. CI = 95% confidence interval, RR = risk ratio. Baseline Pao2/Fio2 ratios were unavailable for 10 patients in 3 trials. (17), (34), (35)
Tables
- Table 1:
Characteristics of randomized controlled trials included in the systematic review*
Study Patient characteristics at baseline Details of prone positioning Protective lung ventilation† mandated No. of patients Enrolment criteria Mean Pao2/Fio2 ratio, mm Hg Mean PEEP, cm H2O Mean Fio2, % Duration of ARDS before enrolment Mean duration Criteria for discontinuation Guérin et al., (17) 2013 474 ARDS‡ with Pao2/Fio2 ratio < 150 mm Hg, PEEP ≥ 5 cm H2O and Fio2 ≥ 60% after stabilization period of 12–24 h 100 10 79 < 36 h 17 h daily for 4 d PaO2/Fio2 ratio ≥ 150 mm Hg, PEEP ≤ 10 cm H2O and Fio2 ≤ 0.6 Yes Taccone et al., (14) 2009 344 ARDS‡ with PEEP ≥ 5 cm H2O 113 10 72 < 72 h 18 h daily for 8.3 d Fio2 ≤ 40% and PEEP ≤ 10 cm H2O Yes Fernandez et al., (34) 2008 42 ARDS‡ 118 11 85 < 48 h 18 h daily§ Pao2/Fio2 ratio > 250 mm Hg and PEEP ≤ 8 cm H2O for 12 h Yes Chan et al., (35) 2007 22 ARDS‡ secondary to community-acquired pneumonia 109 13 88 < 72 h 24 h daily for 4.4 d Spo2 > 90%, Fio2 < 60% for > 24 h (after 72 h) Yes Mancebo et al., (36) 2006 142 ARDS‡ with infiltrates in 4 quadrants on chest radiograph 105 7 82 < 48 h 17 h daily for 10.1 d Fio2 ≤ 45% and PEEP ≤ 5 cm H2O No Curley et al., (37) 2005 102 children (age 2 wk–18 yr) Acute lung injury or ARDS‡ 100 9 60 < 48 h 18 h daily for 4 d Spontaneous breathing and O2 index < 6 Yes Voggenreiter et al., (38) 2005 40 Acute lung injury (duration ≥ 24 h) or ARDS‡ (duration ≥ 8 h) with PEEP ≥ 5 cm H2O 221 11.5 49 < 48 h 11 h daily for 7 d Pao2/Fio2 ratio > 300 mm Hg for 48 h Yes Guérin et al., (16) 2004 802 Hypoxemic acute respiratory failure (n = 413 with acute lung injury or ARDS‡) 152 8 66 > 12–24 h 9 h daily for 4.1 d Clinical improvement¶ No Beuret et al., (39) 2002 53 Coma, intubation required (n = 7 with acute lung injury or ARDS‡) 326 (238 in pts with acute lung injury or ARDS) NR NR < 24 h 4 h daily for 6.0 d Able to sit in chair No Watanabe et al., (40) 2002 16 Pao2/Fio2 ratio < 200 mm Hg, PEEP > 5 cm H2O 5 d after esophagectomy 166** NR NR Not prespecified 6 h daily for 4 d Not applicable No Gattinoni et al., (15) 2001 304 Acute lung injury or ARDS‡ with PEEP ≥ 5 cm H2O 127 10 73 Not prespecified 7 h daily for 4.7 d None No Note: ARDS = acute respiratory distress syndrome, Fio2 = fractional concentration of inspired oxygen, NR = not reported, Pao2 = partial pressure of arterial oxygen, PEEP = positive end-expiratory pressure.
↵* Additional details about the study characteristics are available in Appendix 3 (www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.140081/-/DC1).
↵† Tidal volume < 8 mL/kg of predicted body weight.
↵‡ Defined according to the criteria of the American–European Consensus Conference. (18)
↵§ Average over first 2 d only; average number of days that prone positioning was used was not available.
↵¶ Defined by 1 major criterion (improvement in Pao2/Fio2 ratio ≥ 30% relative to value at randomization, with Fio2 ≤ 60%) and at least 1 minor criterion (PEEP ≤ 8 cm H2O, no sepsis, cause of acute respiratory failure under control [stable or signs of improvement on chest radiograph, and < 3 organ dysfunctions, including lung dysfunction]).
↵** Prone group only (baseline ratio in supine group not reported).
Study Adequate sequence generation Concealment of allocation Complete outcome reporting Complete outcome data Trial ended early (reason) Overall risk of bias* Guérin et al., (17) 2013 Yes Centralized, Web-based Yes Yes No Low Taccone et al., (14) 2009 Yes Central Yes No (mortality unknown for 1/175 in supine group, 1/169 in prone group) No Low Fernandez et al., (34) 2008 Yes Central Yes No (mortality unknown for 1/20 in supine group, 1/22 in prone group) Yes (slow enrolment) Low Chan et al., (35) 2007 Yes No (randomization table visible to person enrolling patients) Yes Yes Yes (slow enrolment) High† Mancebo et al., (36) 2006 Yes Sealed opaque envelopes Yes No (mortality unknown for 2/62 in supine group, 4/80 in prone group) Yes (slow enrolment) Unclear‡ Curley et al., (37) 2005 Yes Sealed opaque envelopes Yes Yes Yes (futility stopping rule) Low Voggenreiter et al., (38) 2005 Yes Central Yes Yes Yes (slow enrolment) Low Guérin et al., (16) 2004 Yes Sealed opaque envelopes Yes No (mortality unknown for 7/385 in supine group, 4/417 in prone group) No Unclear‡ Beuret et al., (39) 2002 Yes Sealed opaque envelopes Yes No (mortality unknown for 2/28 in supine group, 0/25 in prone group) Yes (slow enrolment) Unclear‡ Watanabe et al., (40) 2002 No (alternate allocation) No (alternate allocation) No mortality data NA NR High† Gattinoni et al., (15) 2001 Yes Central Yes Yes Yes (slow enrolment) Low Note: NA = not applicable, NR = not reported.
↵* The Cochrane risk-of-bias tool (22) was used to assess the risk of bias for each study. Low risk = bias, if present, is unlikely to alter the results seriously, unclear risk = bias raises some doubt about the results, high risk = bias may alter the results seriously.
↵† High risk of bias because of unconcealed allocation (35) or alternate allocation. (40)
↵‡ Unclear risk of bias because of multiple possible sources of plausible bias: protective lung ventilation not mandated in both study arms, (16), (36), (39) incomplete mortality data, (16), (36), (39) early study termination (36), (39) and excessive crossover from prone to supine group (> 40%). (16)
- Table 3:
Results of primary and sensitivity analyses for the effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome (ARDS)
Analysis* No. of trials No. of deaths, n/N Risk ratio (95% CI) I2 value, % Primary Trials mandating protective ventilation† 6 363/1016 0.74 (0.59–0.95) 29 Sensitivity Included all trials‡ 10 797/1869 0.86 (0.73–1.00) 42 Assumed patients lost to follow-up lived 6 363/1020 0.74 (0.59–0.95) 28 Assumed patients lost to follow-up died 6 366/1020 0.74 (0.59–0.94) 26 Excluded trial in which allocation was not concealed (35) 5 352/994 0.73 (0.55–0.98) 43 Excluded trial with pediatric population (37) 5 355/914 0.73 (0.56–0.96) 42 Included trial that used moderate tidal volume (< 10 mL/kg) (36) 7 438/1152 0.77 (0.65–0.91) 16 Fixed-effects model 6 363/1016 0.74 (0.63–0.87) 29 Note: CI = confidence interval.
↵* Random-effects models were used for all analyses except in the final sensitivity analysis.
↵† Tidal volume < 8 mL/kg of predicted or actual body weight.
↵‡ For the 2 trials that enrolled some patients without ARDS, (16), (39) we included only patients whose condition met the authors’ definition of ARDS; when the analysis was redone to include all patients in these trials, the risk ratio changed minimally (0.87, 95% CI 0.74–1.02; I2 = 48%).
- Table 4:
Physiologic, clinical and safety outcomes associated with prone positioning during mechanical ventilation
Outcome No. of patients or events Measure of effect* I2 value, % Oxygenation (Pao2/Fio2 ratio)† No. of patients Ratio of means (95% CI) Day 1 1283 1.36 (1.25–1.47) 49 Day 2 1171 1.29 (1.21–1.37) 27 Day 3 933 1.25 (1.18–1.31) 0 Clinical and safety outcomes No. of events, n/N Risk ratio (95% CI) Ventilator-associated pneumonia 368/1561 0.89 (0.71–1.13) 0 Pressure ulcers 818/1765 1.27 (1.16–1.40) 0 Obstruction of endotracheal tube 200/1847 1.60 (1.27–2.02) 0 Unplanned extubation or dislodgement of endotracheal tube‡ 211/2309 1.08 (0.78–1.48) 16 Unplanned removal of central or arterial lines 59/886 1.49 (0.42–5.27) 67 Dislodgement of thoracostomy tube 17/886 3.14 (1.02–9.69) 0 Pneumothorax 95/1663 0.84 (0.57–1.25) 0 Cardiac arrest 211/1527 0.73 (0.39–1.38) 76 Note: CI = confidence interval, Pao2/Fio2 ratio = ratio of partial pressure of arterial oxygen to fraction of inspired oxygen.
↵* Random-effects models were used for all analyses.
↵† We measured effect on oxygenation by comparing the mean Pao2/Fio2 ratio in the prone group to the closest available recorded measurement in the supine group. If more than one measurement was taken, we chose the measurement closest to the end of the session of prone positioning on that day.
↵‡ One trial (14) included all dislodgements of endotracheal tubes, not just unplanned extubations. When we excluded the results of this trial from the meta-analysis, the risk ratio for unplanned extubation was 0.86 (95% CI 0.62–1.20; I2 = 0%; 9 trials, 1471 patients, 129 events).
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