Table 1.
Randomized trials in ARDS with death as a reported study outcome.
| Ref. | Randomized comparison |
Number of patients randomi zed (interven tion / control) |
Number of deaths (interven tion / control) |
Terminat ed early |
Mortalit y at |
Calculated OR (95% CI) |
Calculated RR (95% CI) |
Adjusted HR (95% CI) |
Surviv al benefit # |
|---|---|---|---|---|---|---|---|---|---|
| MV strategies and respiratory care | |||||||||
| S1 | Prone vs. supine positioning |
237/229 | 38/75 | No | 28 d* | 0.39 (0.25- 0.61) |
0.49 (0.34- 0.69) |
By SOFA: 0.42 (0.26-0.66) |
+ |
| S2 | Lower tidal volume with extracorporeal CO2 removal vs. protective MV |
40/39 | 7/6 | No | Hospital | 1.17 (0.35- 3.84) |
1.14 (0.42- 3.08) |
NA | |
| S3 | HFOV vs. control ventilation |
275/273 | 129/96 | Yes (futility) |
Hospital * |
1.63 (1.16- 2.3) |
1.33 (1.09- 1.64) |
NA | − |
| S4 | HFOV vs. usual ventilatory care |
398/397 | 166/163 | No | 30 d* | 1.03 (0.77- 1.36) |
1.02 (0.86- 1.20) |
By several variables: 1.03 (0.75-1.40) |
|
| S5 | NIPPV vs. control (high concentration O2 therapy) |
21/19 | 1/5 | Yes (slow recruitm ent) |
Hospital § |
0.14 (0.01- 1.33) |
0.18 (0.02- 1.41) |
NA | |
| S6 | Recruitment maneuver | 55/55 | 16/24 | No | ICU to28 d* |
0.53 (0.24- 1.17) |
0.67 (0.4- 1.11) |
NA | |
| S7 | Airway pressure release ventilation vs. low tidal volume ventilation. |
31/32 | 2/2 | No | 5 d& | 1.03 (0.14- 7.84) |
1.03 (0.14- 6.80) |
NA | . |
| S8 | Referral for ECMO vs. conventional MV |
90/90 | 33/45 | Yes | 6 m | 0.58 (0.32- 1.05) |
0.73 (0.52- 1.03) |
NA | |
| S9 | Prone vs. supine positioning |
168/174 | 52/57 | No | 28 d* | 0.92 (0.58- 1.45) |
0.95 (0.69- 1.29) |
NA | |
| S10 | Decremental PEEP titration following Alveolar recruitment maneuver or a table- based PEEP |
30/27 | 14/15 | No | 60 d§ | 0.70 (0.25- 1.99) |
0.84 (0.5 – 1.40) |
NA | |
| S11 | PEEP guided by esophageal pressure vs. ARDS network recommendations |
30/31 | 8/14 | Yes (effect at interim analysis) |
6 m§ | 0.44 (0.15- 1.29) |
0.59 (0.29- 1.20) |
By APACHE II score was 0.52 (0.22-1.25) |
|
| S12 | Prone vs. supine positioning |
21/19 | 8/10 | Yes (low enrollme nt) |
60 d* | 0.55 (0.16- 1.95) |
0.72 (0.36- 1.45) |
NA | |
| S13 | High vs. moderate PEEP |
385/382 | 107/119 | No | 28 d* | 0.85 (0.62- 1.16) |
0.89 (0.72- 1.11)) |
NA | |
| S14 | Open-lung ventilation vs. low-tidal-volume ventilation |
475/508 | 173/205 | No | Hospital at 28 d* |
0.85 (0.65- 1.1) |
0.90 (0.77- 1.06) |
By several variables: 0.97 (0.84-1.12) |
|
| S15 | High PEEP and low tidal volume vs. low PEEP and higher tidal volume |
50/45 | 16/24 | Yes (mortalit y benefit) |
ICU* | 0.41 (0.18- 0.95) |
0.60 (0.37- 0.98) |
NA | + |
| S16 | Prone vs. supine positioning |
76/60 | 33/35 | Yes (decreas e in enrollme nt) |
ICU* | 0.55 (0.28- 1.09) |
0.74 (0.53- 1.04) |
By several variables: 0.40 (0.17-0.61) |
+ |
| S17 | PLV vs. conventional ventilation |
107/204 | 16/46 | No | 28 d§ | 0.60 (0.32- 1.13) |
0.66 (0.39- 1.11) |
NA | |
| S18 | HFOV vs. conventional ventilation |
24/37 | 8/16 | Yes (slow recruitm ent) |
30 d* | 1.52 (0.52- 4.44) |
1.3 (0.66- 2.55) |
By several variables: 1.15 (0.43-3.1) |
|
| S19 | Prone vs. supine positioning positioning |
413/378 | 134/119 | No | 28 d* | 1.05 (0.78- 1.41) |
1.03 (0.84- 1.26) |
NA | |
| S20 | Higher vs. lower PEEP | 276/273 | 76/68 | Yes (futility) |
Hospital at 60 d* |
1.15 (0.78- 1.68) |
1.11 (0.83- 1.46) |
By several variables: 0.88 (0.6-1.29) |
|
| S21 | APRV or SIMV | 30/28 | 5/5 | Yes (futility) |
28 d& | 0.92 (0.24- 3.59) |
0.93 (0.30- 2.88) |
NA | |
| S22 | HFOV vs. conventional ventilation |
75/73 | 28/38 | No | 30 d* | 0.55 (0.28- 1.08) |
0.72 (0.50- 1.03) |
NA | |
| S23 | PLV vs. conventional MV |
65/25 | 27/9 | No | 28 d§ | 1.26 (0.49- 3.28) |
1.15 (0.64- 2.1) |
NA | |
| S24 | Prone vs. supine positioning |
152/152 | 95/89 | Yes (slow recruitm ent) |
6 m* | 1.18 (0.74- 1.87) |
1.07 (0.89- 1.28) |
NA | |
| S25 | APRV with spontaneous breathing vs. controlled MV |
15/15 | 3/4 | No | NA& | 0.69 (0.12- 3.79) |
0.75 (0.20- 2.79) |
NA | |
| S26 | Prone positioning vs. continuous rotation |
12/14 | 7/9 | No | NA& | 0.78 (0.16- 3.8) |
0.9 (0.49- 1.68) |
NA | |
| S27 | PCV vs. VCV | 37 / 42 | 19 / 33 | No | Hospital * |
0.29 (0.11- 0.77) |
0.65 (0.46- 0.93) |
NA | + |
| S28 | Lower vs. traditional tidal volumes |
432/429 | 134/171 | Yes (lower mortality ) |
Hospital up to 6 m* |
0.68 (0.51- 0.90) |
0.78 (0.65- 0.93) |
NA | + |
| S29 | Computerized decision support for MV vs. not |
100/100 | 36/32 | No | Hospital * |
1.2 (0.67- 2.15) |
1.13 (0.76- 1.66) |
NA | |
| S30 | Reduced vs. traditional tidal volume MV. |
26/26 | 13/12 | Yes (futility) |
Hospital & |
1.17 (0.39- 3.47) |
1.08 (0.62- 1.91) |
NA | |
| S31 | Lung protective MV vs. control |
18/19 | 7/11 | No | 28 d& | 0.46 (0.12- 1.72) |
0.67 (0.34- 1.35) |
NA | |
| S32 | Reduced vs. traditional tidal volume (≥ 10 mL/kg) |
58/58 | 27/22 | Yes (futility) |
60 d* | 1.43 (0.68- 2.99) |
1.23 (0.80- 1.89) |
NA | |
| S33 | Pressure- and volume- limited MV or conventional MV |
60/60 | 30/28 | No | Hospital * |
1.14 (0.56- 2.34) |
1.07 (0.74- 1.55) |
NA | |
| S34 | Protective MV vs. conventional MV |
29/24 | 11/17 | Yes (surviva l benefit) |
28 d* | 0.25 (0.08-0.80) |
0.54 (0.31- 0.91) |
APACHE II score: 0.19 (0.08–0.47) |
+ |
| S35 | MV with “open lung approach” with low distending pressures vs. conventional approach |
15/13 | 5/7 | No | Hospital § |
0.43 (0.09- 1.98) |
0.62 (0.26- 1.48) |
NA | |
| S36 | PCV vs. VCV | 16/11 | 9/7 | No | 25 d& | 0.73 (0.15- 3.55) |
0.88 (0.47- 1.65) |
NA | |
| S37 | Extracorporeal CO2 removal vs. continuous positive pressure MV |
21 / 19 | 14 / 11 | Yes | 30 d* | 1.45 (0.40- 5.26) |
1.15 (0.71- 1.88) |
NA | |
| S38 | HFOV vs. conventional MV |
52/48 | 10/10 | No | Hospital & |
0.9 (0.34- 2.41) |
0.92 (0.42- 2.02) |
NA | |
| S39 | ECMO vs. conventional MV |
42/48 | 38/44 | Yes | 68 d* | 0.86 (0.20- 3.69) |
0.99 (0.97- 1.12) |
NA | |
| Enteral or parenteral therapies | |||||||||
| S40 | IV infusion of GMCSF vs. pl |
64/66 | 11/15 | No | 28 d§ | 0.71 (0.30- 1.68) |
0.76 (0.38- 1.52) |
NA | |
| S41 | Simvastatin PO or placebo |
30/30 | 11/11 | No | 14 d& | 1 (0.35- 2.86) |
1 (0.51- 1.94) |
NA | |
| S42 | Cisatracurium besylate IV vs. pl |
178/162 | 56/66 | No | 90 d* | 0.67 (0.43- 1.04) |
0.77 (0.58- 1.03) |
By several variables: 0.68 (0.48-0.98) |
+ |
| S43 | Ginger extract vs. pl | 16/16 | 3/2 | No | MICU stay to 21 d§ |
1.62 (0.23- 11.26) |
1.5 (0.29- 7.81) |
NA | |
| S44 | Inactivated recombinant factor VIIa IV vs. pl |
144/70 | 36/15 | Yes (higher mortality) |
28 d§ | 1.22 (0.61- 2.42) |
1.17 (0.69- 1.98) |
NA | |
| S45 | Activated protein C IV infusion or placebo |
37/38 | 5/5 | No | 60 d§ | 1.03 (0.27- 3.91) |
1.03 (0.32- 3.26) |
NA | |
| S46 | Oxothiazolidine IV vs. pl |
101/114 | 30/18 | Yes (higher mortality) |
30 d§ | 2.25 (1.16- 4.36) |
1.88 (1.12- 3.16) |
NA | - |
| S47 | Methylprednisone IV vs. pl |
63/28 | 15/12 | No | Hospital § |
0.42 (0.16- 1.07) |
0.56 (0.30- 1.03) |
NA | |
| S48 | Conservative vs. liberal strategy of fluid management |
503/497 | 128/14 1 |
No | Hospital to 60 d* |
0.86 (0.65- 1.14) |
0.9 (0.73- 1.1) |
NA | |
| S49 | Methylprednisolone IV vs. pl |
89/91 | 26/26 | No | Hospital at 60-d* |
1.03 (0.54- 1.97) |
1..02 (0.65- 1.62) |
NA | |
| S50 | Salbutamol IV vs. pl | 19/21 | 11/14 | No | 7 d§ | 0.69 (0.19- 2.49) |
0.87 (0.53- 1.42) |
NA | |
| S51 | Furosemide IV with or without albumin |
20/20 | 7/9 | No | 30 d§ | 0.66 (0.18- 2.35) |
0.78 (0.36- 1.68) |
NA | |
| S52 | Sivelest at sodium IV infusion vs. pl |
12/12 | 3/3 | No | 30 d§ | 1 (0.16- 6.35) |
1 (0.25- 4.00) |
NA | |
| S53 | Sivelestat sodium IV infusion vs. pl |
241/246 | 64/64 | Yes (trend to worsen mortality) |
28 d* | 1.03 (0.69- 1.54) |
1.05 (0.78- 1.41) |
NA | |
| S54 | Cisatracurium IV vs. pl | 28/28 | 10/17 | No | 28 d§ | 0.36 (0.12- 1.06) |
0.59 (0.33- 1.05) |
NA | |
| S55 | Lisofylline IV vs. pl | 116/119 | 37/29 | Yes (futility) |
28 d* | 1.45 (0.82- 2.58) |
1.31 (0.87- 1.98) |
NA | |
| S56 | Liposomal PGE1 IV infusion vs. pl |
70/32 | 21/9 | Yes (futility) |
28 d* | 1.1 (0.43- 2.76) |
1.07 (0.55- 2.06) |
NA | |
| S57 | Ketoconazole (enteral) vs. pl |
117/117 | 41/40 | Yes (futility) |
Hospital at 6 m* |
1.04 (0.61- 1.78) |
1.03 (0.72- 1.46) |
NA | |
| S58 | IV infusion of NAC vs. NAC with rutin vs. pl |
12/12/12 | 5/4/7 | No | 30 d& | 0.36 (0.07- 1.88)& |
0.57 (0.23- 1.45)& |
NA | |
| S59 | Liposomal PGE1 IV infusion vs. pl |
177/171 | 57/50 | No | 28 d§ | 1.14 (0.73- 1.81) |
1.10 (0.8- 1.51) |
NA | |
| S60 | Atrial Natriuretic peptide IV infusion vs. pl |
20/20 | 3/6 | No | NA& | 0.41 (0.09- 1.95) |
0.50 (0.14- 1.73) |
NA | |
| S61 | Prolonged Methylprednisolone (IV/PO) vs. pl |
16/8 | 0/5 | Yes (lower mortality) |
ICU at 32 d* |
0.02 (0.00- 0.44) |
0.05 (0.00- 0.78) |
NA | + |
| S62 | IV infusion of NAC vs. pl |
22/20 | 7/5 | No | ICU* | 1.40 (0.36- 5.41) |
1.27 (0.48- 3.37) |
NA | |
| S63 | IV infusion of NAC vs. procysteine vs. pl |
14/17/15 | 5/6/6 | No | 30 d§ | 0.83 (0.19- 3.75)‡ |
0.89 (0.35- 2.28)‡ |
NA | |
| S64 | IV infusion of Liposomal prostaglandin E1 vs. pl |
17/8 | 1/2 | No | 28 d* | 0.19 (0.01- 2.47) |
0.24 (0.02- 2.23) |
NA | |
| S65 | Human monoclonal antiendotoxin antibody (HA-1A) vs. pl |
30/33 | 15/23 | No | 28 d§ | 0.43 (0.16- 1.22) |
0.72 (0.47- 1.09) |
NA | |
| S66 | NAC IV vs. pl | 32/29 | 7/10 | No | 1 m* | 0.53 (0.17- 1.66) |
0.63 (0.28- 1.45) |
NA | |
| S67 | NAC IV vs. pl | 32/34 | 17/17 | No | 60 d& | 1.13 (0.43- 2.98) |
1.06 (0.67- 1.7) |
NA | |
| S68 | PGE1 IV infusion vs. pl | 72/74 | 42/37 | No | 30 d& | 1.40 (0.73- 2.69) |
1.17 (0.86- 1.57) |
NA | |
| S69 | PGE1 IV infusion vs. pl | 50/50 | 30/24 | Yes (futility) |
30 d* | 1.63 (0.74- 3.59) |
1.25 (0.87- 1.8) |
NA | |
| S70 | IV high dose methylprednisolone vs. pl |
50/49 | 30/31 | Yes (futility) |
45 d* | 0.87 (0.39- 1.96) |
0.95 (0.69- 1.29) |
NA | |
| Inhaled / intratracheal medications | |||||||||
| S71 | Aerosolized β2- adrenergic receptor agonists vs. pl |
152/130 | 35/23 | Yes (futility) |
Hospital to 60 d§ |
1.39 (0.77- 2.51) |
1.30 (0.81- 2.08) |
By baseline covariates: 1.27 (0.68-2.38) |
|
| S72 | Intratracheal recombinant surfactant protein C-based surfactant vs. pl |
419/424 | 95/101 | Yes (futility) |
28 d* | 0.94 (0.68- 1.29) |
0.95 (0.74- 1.22) |
NA | |
| S73 | Intratracheal exogenous natural surfactant vs. usual care |
208/210 | 60/51 | Yes (futility) |
28 d* | 1.26 (0.82- 1.95) |
1.19 (0.86- 1.64) |
NA | |
| S74 | Intratracheal protein C– based recombinant surfactant vs. usual care |
224/224 | 72/81 | No | 28 d§ | 0.84 (0.57- 1.24) |
0.89 (0.68- 1.15) |
NA | |
| S75 | Inhaled NO vs. pl | 192/193 | 44/39 | No | 28 d§ | 1.17 (0.72- 1.91) |
1.13 (0.77- 1.66) |
NA | |
| S76 | Intratracheal recombinant protein C– based surfactant vs. control |
27/13 | 7/5 | No | 28 d§ | 0.56 (0.14- 2.29) |
0.67 (0.26- 1.72) |
NA | |
| S77 | MV with and without inhaled NO |
15/15 | 8/7 | No | 30 d& | 1.30 (0.31- 5.48) |
1.14 (0.56- 2.35) |
NA | |
| S78 | Inhaled NO vs. pl | 93/87 | 41/35 | Yes (slow enrollmen t) |
30 d§ | 1.17 (0.65- 2.12) |
1.10 (0.78- 1.55) |
NA | |
| S79 | Inhaled NO vs. usual care |
15/15 | 9/8 | No | 30 d* | 1.31 (0.31- 5.58) |
1.13 (0.6- 2.11) |
NA | |
| S80 | Inhaled NO vs. usual care |
20/20 | 11/9 | No | Hospital & |
1.49 (0.43- 5.19) |
1.22 (0.65- 2.29) |
NA | |
| S81 | Inhaled NO vs. pl (nitrogen gas) |
120/57 | 35/17 | No | 28 d§ | 0.97 (0.49- 1.93) |
0.98 (0.60- 1.59) |
NA | |
| S82 | Bovine surfactant by endotracheal instillation vs. pl |
43/16 | 10/7 | No | 28 d* | 0.39 (0.12- 1.31) |
0.53 (0.24- 1.16) |
NA | |
| S83 | Aerosolized synthetic surfactant or placebo. |
364/361 | 145/14 3 |
Yes (futility) |
30 d* | 1.01 (0.75- 1.36) |
1.01 (0.84- 1.20) |
NA | |
| S84 | Aerosolized surfactant for 12 vs. 24 hs vs. pl |
17/17/17 | 7/6/8 | No | 30 d* | 0.61 (0.15- 2.43)¶ |
0.75 (0.33- 1.7)¶ |
NA | |
| Nutritional support | |||||||||
| S85 | Trophic vs. full enteral feeding |
508/492 | 118/10 9 |
No | 60 d§ | 1.06 (0.79- 1.43) |
1.05 (0.83- 1.32) |
NA | |
| S86 | Inflammatory modulators vs. control diet |
143/129 | 38/21 | Yes (futility) |
60 d§ | 1.86 (1.02- 3.38) |
1.63 (1.01- 2.63) |
NA | |
| S87 | Inflammatory modulators vs. control diet |
71/61 | 11/11 | No | 28 d§ | 0.83 (0.33- 2.08) |
0.86 (0.40- 1.84) |
NA | |
| S88 | Inflammatory modulators vs. pl |
41/49 | 9/12 | No | 60 d& | 0.87 (0.32- 2.32) |
0.9 (0.42- 1.91) |
NA | |
| S89 | Inflammatory modulators vs. control diet |
46/49 | 20/17 | No | 14 d§ | 1.45 (0.63- 3.31) |
1.25 (0.76- 2.08) |
NA | |
| S90 | Enteral Inflammatory modulators vs. pl |
51/47 | 6/9 | No | 30 d& | 0.56 (0.18- 1.72) |
0.61 (0.24- 1.59) |
NA | |
| Hemodynamic monitoring and others | |||||||||
| S91 | PAOP vs. CVP | 513/488 | 141/12 8 |
No | Hospital at 60 d* |
1.07 (0.81- 1.41) |
1.05 (0.85- 1.29) |
NA | |
| S92 | PAC vs. no PAC | 335/341 | 199/20 8 |
No | 28 d* | 1.17 (0.72- 1.91) |
0.97 (0.86- 1.10) |
NA | |
| S93 | CAVH vs. pl | 9/6 | 4/5 | No | NA& | 0.16 (0.01- 1.98) |
0.53 (0.24- 1.20) |
NA | |
References are provided in the Reference Appendix of the supplemetal file.
Abbreviations: APACHE: Acute Physiology and Chronic Health Evaluation, APVR: airway pressure release ventilation, ARM: alveolar recruitment maneuvers, CI: confidence interval, d: day, ECMO: extracorporeal membrane oxygenation, HFOV: high-frequency oscillatory ventilation, HR: hazard ratio, ICU: intensive care unit, m: month, IV: intravenous, M: mortality, MV: mechanical ventilation, NA: not available, OR: odds ratio, PAC: pulmonary artery catheter, PCV: pressure-controlled ventilation, PEEP: positive end-expiratory pressure, PGE1: prostaglandin E1, pl: placebo, PLV: partial liquid ventilation, PO: by mouth, PPV: positive pressure ventilation, RR: relative risk, SIMV: synchronized intermittent ventilation, SOFA: Sequential Organ Failure Assessment score, VCV: volume-controlled ventilation, vs.:versus.
&
for the comparison of NAC with rutin versus placebo.
‡
NAC versus placebo.
¶
For the comparison between 24 hs aerosolized surfactant versus placebo.
*
mortality as the only or as part of primary outcome.
§
mortality as a secondary outcome. & mortality not as part of a prespecified primary or secondary outcome.
#
based on statistical significance (crude or adjusted ratios) a positive sign represents a beneficial effect, a negative sign a deleterious effect and an empty box the lack of difference in survival between the study groups.