eTable 1. Trial characteristics of randomized controlled trials (trials are listed based on date of publication from earliest to latest)
Author, Year of Publication (Reference)
ARDSNet Center
Geographic Location
Single vs.
Multicenter (Multi.)
ALI or ARDS Study Population
Investigational
Treatment Reported Exclusion Criteria
Post- Randomization
Ventilation Protocol Used
Survival Assessment Time points
Gainnier et al, 20041
No Europe Multi. ARDS NMBA
Age < 18 y
Enrollment in another trial Prior medical conditions
Low long-term predicted survival
Patients receiving NMBA within 2 week before inclusion
ARDSNet Protocol
28 d 60 d ICU
Wheeler et al,
20062 Yes North
America Multi. ALI
ARDS PAC
Presence of a PAC after the onset of ALI Presence of ALI >48 h
Prior medical conditions
ARDSNet
Protocol 60 d Tsangaris et al,
20073 No Europe Single ARDS Surfactant Prior medical conditions None specified 28 d
Meade et al, 20084
No
North America,
Asia, Australia
Multi. ALI
ARDS
Lung open ventilation strategy
Prior medical conditions
Anticipated duration of mechanical ventilation
<48 h Pregnancy
Low long-term predicted survival Enrollment in another trial
Target: 6 mL/kg PBW
28 d ICU Hospital
Mercat et al, 20085
No
Europe Multi. ALI
ARDS
Lung recruitment
Age <18 y Pregnancy
Enrollment in another trial Prior medical conditions
Anticipated duration of mechanical ventilation
<48 h
Low long-term predicted survival
Target: 6 mL/kg PBW
28 d 60 d Hospital
Fernandez et al,
20086 No Europe Multi. ARDS Prone
positioning
Prior medical conditions Enrollment in another trial
Target: 6-8
mL/kg PBW 60 d
Talmor et al,
20087 No North
America Single ALI
ARDS
Esophageal pressure monitoring
Prior medical conditions ARDSNet
Protocol
28 d 180 d
Liu et al, 20088 Yes North
America Multi. ALI
ARDS
Activated Protein C
Presence of ALI >72 h
Presence of sepsis with APACHE II score ≥25 Prior medical conditions
Inability to obtain consent Low long-term predicted survival
ARDSNet
Protocol 60 d
Kesecioglu et al,
20099 No Europe,
North America
Multi. ALI
ARDS Surfactant
Prior medical conditions
Need for mechanical >48 h with 1 month inclusion
MAP < 50 mmHg in spite of fluid and/or vasoactive drugs
Target: 6-8
mL/kg PBW 180 d
PaO2 < 75 with FiO2=1.0 and not responding to PEEP
Low long-term predicted survival Known or suspected hypersensitivity to investigational products
Treatment with investigational drugs with 4 weeks
Enrollment in another trial
Previous randomization in this trial
Known or suspected not to be able to comply Pregnant or breastfeeding
Taccone et al,
200910 No Europe Multi. ARDS Prone
positioning
Age <16 y
Diagnosis of ARDS >72 h Prior medical conditions
None specified
28 d 180 d
ICU
Huh et al, 200911 No Asia Single ARDS Decremental
PEEP Prior medical conditions ARDSNet
Protocol
28 d 60 d ICU
Xi et al, 201012 No Asia Multi. ARDS Recruitment
maneuver
Prior medical conditions Pregnancy
Enrollment in another trial
Target: 6-8 mL/kg PBW
28 d ICU Hospital
Papazian et al,
201013 No Europe Multi. ARDS Neuromuscular
blockade
Age<18 y
Inability to obtain consent Pregnancy
Enrollment in another trial Prior medical conditions
Expected duration mechanical ventilation <48 h Low long-term predicted survival
Target: 6-8 mL/kg PBW
28 d ICU Hospital
Stapleton et al,
201114 Yes North
America Multi. ALI
ARDS Fish Oil
ALI ≥48 h
Low long-term predicted survival Pregnancy
Prior medical conditions Current confounding treatments
ARDSNet
Protocol Hospital
Mentzelopoulos et al, 201115
No Europe Single ARDS HFO-TGI
Significant air leak
Significant hemodynamic instability Prior medical conditions
Pregnancy
Enrollment in another trial Hemodynamic instability
Target: 6
mL/kg PBW Hospital
Craig et al, 201116
No Europe Single ALI
ARDS Simvastatin
Creatine kinase > 10 times ULN Liver transaminases > 3 times ULN Prior medical conditions
Current treatment with any lipid lowering agent Contraindication to enteral drug administration Age < 18 y
Pregnancy
Enrollment in another trial
None specified ICU Hospital
Low long-term predicted survival Declined consent
Matthay et al,
201117 Yes North
America Multi. ALI
ARDS Albuterol
Prior medical conditions Inability to obtain consent Low long-term predicted survival
ARDSNet Protocol
60 d 90 d
Mentzelopoulos
et al, 201218 No Europe Multi. ARDS HFO-TGI
Significant air leak
Significant hemodynamic instability Prior medical conditions
Inability to wean from prone positioning or iNO Pregnancy or morbidly obese
Enrollment in another trial
Target: 6 mL/kg PBW
Not specified
Gao Smith et al,
201219 No Europe Multi. ARDS Salbutamol
Pregnancy
Concurrent confounding treatments Low long-term predicted survival Prior medical conditions
Enrollment in another trial
ARDSNet
Protocol 28 d
Rice et al, 201220
Yes
North
America Multi. ALI
ARDS Trophic feeding
Age <13 y Pregnancy
Prior medical conditions
Low long-term predicted survival Inability to obtain consent
Concurrent confounding treatments
ARDSNet
Protocol 60 d
Ferguson et al,
201321 No
North America,
South America,
Europe
Multi. ARDS HFOV
Prior medical conditions
Low long-term predicted survival Risk of intracranial hypertension Lack of commitment to life support
Expected duration mechanical ventilation <48 h Age < 16 y
Weight < 35kg or more than 1 kg per cm or height
Presence of ARDS >72 h Physicians declined enrollment Already receiving HFOV
Target: 6
mL/kg PBW Hospital
Young et al, 201322
No Europe Multi. ARDS HFOV
Mechanical ventilation > 7 d Age < 16 y
Weight < 35 kg
Enrollment in another trial
Lung disease characterized by airway narrowing or air trapping
Recent lung surgery
Target: 6-8
mL/kg PBW 30 d
ARDS – adult respiratory distress syndrome; ALI – acute lung injury; NMBA – neuromuscular blocking agent; HFO – high frequency oscillatory ventilation; TGI – tracheal gas insufflation; PEEP – positive end expiratory pressure; ULN – upper limit of normal; iNO – inhaled nitric oxide
References
1. Gainnier M, Roch A, Forel JM, et al. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Crit Care Med 2004;32:113-9.
2. Wheeler AP, Bernard GR, Thompson BT, et al. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006;354:2213-24.
3. Tsangaris I, Galiatsou E, Kostanti E, Nakos G. The effect of exogenous surfactant in patients with lung contusions and acute lung injury. Intensive Care Med 2007;33:851-5.
4. Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:637-45.
5. Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:646-55.
6. Fernandez R, Trenchs X, Klamburg J, et al. Prone positioning in acute respiratory distress syndrome: A multicenter randomized clinical trial. Intensive Care Med 2008;34:1487-91.
7. Talmor D, Sarge T, Malhotra A, et al. Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med 2008;359:2095-104.
8. Liu KD, Levitt J, Zhuo H, et al. Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med 2008;178:618-23.
9. Kesecioglu J, Beale R, Stewart TE, et al. Exogenous natural surfactant for treatment of acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2009;180:989-94.
10. Taccone P, Pesenti A, Latini R, et al. Prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial. JAMA 2009;302:1977-84.
11. Huh JW, Jung H, Choi HS, Hong SB, Lim CM, Koh Y. Efficacy of positive end-expiratory pressure titration after the alveolar recruitment manoeuvre in patients with acute respiratory distress syndrome. Crit Care 2009;13:R22.
12. Xi XM, Jiang L, Zhu B. Clinical efficacy and safety of recruitment maneuver in patients with acute respiratory distress syndrome using low tidal volume ventilation: a multicenter randomized controlled clinical trial. Chin Med J (Engl) 2010;123:3100-5.
13. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107-16.
14. Stapleton RD, Martin TR, Weiss NS, et al. A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury. Crit Care Med 2011;39:1655-62.
15. Mentzelopoulos SD, Theodoridou M, Malachias S, et al. Scanographic comparison of high frequency oscillation with versus without tracheal gas insufflation in acute respiratory distress syndrome. Intensive Care Med 2011;37:990-9.
16. Craig TR, Duffy MJ, Shyamsundar M, et al. A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study). Am J Respir Crit Care Med 2011;183:620-6.
17. Matthay MA, Brower RG, Carson S, et al. Randomized, placebo-controlled clinical trial of an aerosolized beta(2)-agonist for treatment of acute lung injury. Am J Respir Crit Care Med 2011;184:561-8.
18. Mentzelopoulos SD, Malachias S, Zintzaras E, et al. Intermittent recruitment with high-frequency oscillation/tracheal gas insufflation in acute respiratory distress syndrome. Eur Respir J 2012;39:635-47.
19. Gao Smith F, Perkins GD, Gates S, et al. Effect of intravenous beta-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet 2012;379:229-35.
20. Rice TW, Wheeler AP, Thompson BT, et al. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA 2012;307:795-803.
21. Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med 2013;368:795-805.
22. Young D, Lamb SE, Shah S, et al. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med 2013;368:806-13.
