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. 2019 Jul 23;7(7):CD004477.
doi: 10.1002/14651858.CD004477.pub3.

Pharmacological agents for adults with acute respiratory distress syndrome

Sharon R Lewis  1 , Michael W Pritchard, Carmel M Thomas, Andrew F Smith
Affiliations

Pharmacological agents for adults with acute respiratory distress syndrome

Sharon R Lewis et al. Cochrane Database Syst Rev. .

Abstract

Background: Acute respiratory distress syndrome (ARDS) is a life-threatening condition caused by direct or indirect injury to the lungs. Despite improvements in clinical management (for example, lung protection strategies), mortality in this patient group is at approximately 40%. This is an update of a previous version of this review, last published in 2004.

Objectives: To evaluate the effectiveness of pharmacological agents in adults with ARDS on mortality, mechanical ventilation, and fitness to return to work at 12 months.

Search methods: We searched CENTRAL, MEDLINE, Embase, and CINAHL on 10 December 2018. We searched clinical trials registers and grey literature, and handsearched reference lists of included studies and related reviews.

Selection criteria: We included randomized controlled trials (RCTs) comparing pharmacological agents with control (placebo or standard therapy) to treat adults with established ARDS. We excluded trials of nitric oxide, inhaled prostacyclins, partial liquid ventilation, neuromuscular blocking agents, fluid and nutritional interventions and medical oxygen. We excluded studies published earlier than 2000, because of changes to lung protection strategies for people with ARDS since this date.

Data collection and analysis: Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE.

Main results: We included 48 RCTs with 6299 participants who had ARDS; two included only participants with mild ARDS (also called acute lung injury). Most studies included causes of ARDS that were both direct and indirect injuries. We noted differences between studies, for example the time of administration or the size of dose, and because of unclear reporting we were uncertain whether all studies had used equivalent lung protection strategies.We included five types of agents as the primary comparisons in the review: corticosteroids, surfactants, N-acetylcysteine, statins, and beta-agonists. We included 15 additional agents (sivelestat, mesenchymal stem cells, ulinastatin, anisodimine, angiotensin-converting enzyme (ACE) inhibitor, recombinant human ACE2 (palifermin), AP301, granulocyte-macrophage colony stimulating factor (GM-CSF), levosimendan, prostacyclins, lisofylline, ketaconazole, nitroglycerins, L-2-oxothiazolidine-4-carboxylic acid (OTZ), and penehyclidine hydrochloride).We used GRADE to downgrade outcomes for imprecision (because of few studies and few participants), for study limitations (e.g. high risks of bias) and for inconsistency (e.g. differences between study data).Corticosteroids versus placebo or standard therapyCorticosteroids may reduce all-cause mortality within three months by 86 per 1000 patients (with as many as 161 fewer to 19 more deaths); however, the 95% confidence interval (CI) includes the possibility of both increased and reduced deaths (risk ratio (RR) 0.77, 95% CI 0.57 to 1.05; 6 studies, 574 participants; low-certainty evidence). Due to the very low-certainty evidence, we are uncertain whether corticosteroids make little or no difference to late all-cause mortality (later than three months) (RR 0.99, 95% CI 0.64 to 1.52; 1 study, 180 participants), or to the duration of mechanical ventilation (mean difference (MD) -4.30, 95% CI -9.72 to 1.12; 3 studies, 277 participants). We found that ventilator-free days up to day 28 (VFD) may be improved with corticosteroids (MD 4.09, 95% CI 1.74 to 6.44; 4 studies, 494 participants; low-certainty evidence). No studies reported adverse events leading to discontinuation of study medication, or fitness to return to work at 12 months (FTR).Surfactants versus placebo or standard therapyWe are uncertain whether surfactants make little or no difference to early mortality (RR 1.08, 95% CI 0.91 to 1.29; 9 studies, 1338 participants), or whether they reduce late all-cause mortality (RR 1.28, 95% CI 1.01 to 1.61; 1 study, 418 participants). Similarly, we are uncertain whether surfactants reduce the duration of mechanical ventilation (MD -2.50, 95% CI -4.95 to -0.05; 1 study, 16 participants), make little or no difference to VFD (MD -0.39, 95% CI -2.49 to 1.72; 2 studies, 344 participants), or to adverse events leading to discontinuation of study medication (RR 0.50, 95% CI 0.17 to 1.44; 2 studies, 88 participants). We are uncertain of these effects because we assessed them as very low-certainty. No studies reported FTR.N-aceytylcysteine versus placeboWe are uncertain whether N-acetylcysteine makes little or no difference to early mortality, because we assessed this as very low-certainty evidence (RR 0.64, 95% CI 0.32 to 1.30; 1 study, 36 participants). No studies reported late all-cause mortality, duration of mechanical ventilation, VFD, adverse events leading to study drug discontinuation, or FTR.Statins versus placeboStatins probably make little or no difference to early mortality (RR 0.99, 95% CI 0.78 to 1.26; 3 studies, 1344 participants; moderate-certainty evidence) or to VFD (MD 0.40, 95% CI -0.71 to 1.52; 3 studies, 1342 participants; moderate-certainty evidence). Statins may make little or no difference to duration of mechanical ventilation (MD 2.70, 95% CI -3.55 to 8.95; 1 study, 60 participants; low-certainty evidence). We could not include data for adverse events leading to study drug discontinuation in one study because it was unclearly reported. No studies reported late all-cause mortality or FTR.Beta-agonists versus placebo controlBeta-blockers probably slightly increase early mortality by 40 per 1000 patients (with as many as 119 more or 25 fewer deaths); however, the 95% CI includes the possibility of an increase as well as a reduction in mortality (RR 1.14, 95% CI 0.91 to 1.42; 3 studies, 646 participants; moderate-certainty evidence). Due to the very low-certainty evidence, we are uncertain whether beta-agonists increase VFD (MD -2.20, 95% CI -3.68 to -0.71; 3 studies, 646 participants), or make little or no difference to adverse events leading to study drug discontinuation (one study reported little or no difference between groups, and one study reported more events in the beta-agonist group). No studies reported late all-cause mortality, duration of mechanical ventilation, or FTR.

Authors' conclusions: We found insufficient evidence to determine with certainty whether corticosteroids, surfactants, N-acetylcysteine, statins, or beta-agonists were effective at reducing mortality in people with ARDS, or duration of mechanical ventilation, or increasing ventilator-free days. Three studies awaiting classification may alter the conclusions of this review. As the potential long-term consequences of ARDS are important to survivors, future research should incorporate a longer follow-up to measure the impacts on quality of life.

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Conflict of interest statement

Sharon R Lewis: none known Michael W Pritchard: none known Carmel M Thomas: none known Andrew F Smith: none known

Figures

1
1
Flow diagram for searches conducted since publication of the last version of the Review up to 10 December 2018
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for included studies in which outcome data is reported. Blank spaces in tables indicate that study authors did not report review outcomes.
1.1
1.1. Analysis
Comparison 1 Corticosteroids versus control, Outcome 1 Early mortality.
1.2
1.2. Analysis
Comparison 1 Corticosteroids versus control, Outcome 2 Duration of mechanical ventilation.
1.3
1.3. Analysis
Comparison 1 Corticosteroids versus control, Outcome 3 Ventilator‐free days up to day 28.
2.1
2.1. Analysis
Comparison 2 Surfactant versus control, Outcome 1 Early mortality.
2.2
2.2. Analysis
Comparison 2 Surfactant versus control, Outcome 2 Ventilator‐free days up to day 28.
2.3
2.3. Analysis
Comparison 2 Surfactant versus control, Outcome 3 Adverse events.
3.1
3.1. Analysis
Comparison 3 Statins versus control, Outcome 1 Early mortality.
3.2
3.2. Analysis
Comparison 3 Statins versus control, Outcome 2 Ventilator‐free days up to day 28.
4.1
4.1. Analysis
Comparison 4 Beta‐agonist versus control, Outcome 1 Early mortality.
4.2
4.2. Analysis
Comparison 4 Beta‐agonist versus control, Outcome 2 Ventilator‐free days up to day 28.
4.3
4.3. Analysis
Comparison 4 Beta‐agonist versus control, Outcome 3 Adverse events.
5.1
5.1. Analysis
Comparison 5 Other pharmacological agents versus control, Outcome 1 Early mortality.
5.2
5.2. Analysis
Comparison 5 Other pharmacological agents versus control, Outcome 2 Late mortality.
5.3
5.3. Analysis
Comparison 5 Other pharmacological agents versus control, Outcome 3 Duration of mechanical ventilation.
5.4
5.4. Analysis
Comparison 5 Other pharmacological agents versus control, Outcome 4 Ventilator‐free days up to day 28.
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References

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Walmrath 2000 {published data only}
    1. Walmrath D, Vaal JB, Bruining HA, Kilian JG, Papazian L, Hohlfeld J, et al. Treatment of ARDS with a recombinant SP‐C (rSP‐C) based synthetic surfactant. American Journal of Respiratory and Critical Care Medicine 2000;161:A379.
Willson 2015 {published data only}
    1. Willson DF, Truwit JD, Conaway MR, Traul CS, Egan EE. The adult calfactant in acute respiratory distress syndrome trial. Chest 2015;148(2):356‐64. [PUBMED: 25855884] - PubMed
Wirtz 2017 {published data only}
    1. Wirtz H, Hasenclever D, Schwabe K, Jaschinski U, Weyland A, Kuhnt E, et al. ACE inhibitor for lung protection during mechanical ventilation for acute lung injury‐results of the double‐blind, placebo controlled, randomised ACEmeVent pilot study. American Journal of Respiratory and Critical Care Medicine. Conference: American Thoracic Society International Conference, ATS 2017. United states 2017;195:no pagination. [Embase: 617707751]
Zhao 2014 {published data only}
    1. Zhao WB, Wan SX, Gu DF, Shi B. Therapeutic effect of glucocorticoid inhalation for pulmonary fibrosis in ARDS patients. Medical Journal of Chinese People's Liberation Army 2014;39(9):741‐5. [EMBASE: 2014842327]
Zheng 2014 {published data only}
    1. Zheng G, Huang L, Tong H, Shu Q, Hu Y, Ge M, et al. Treatment of acute respiratory distress syndrome with allogeneic adipose‐derived mesenchymal stem cells: a randomized, placebo‐controlled pilot study. American Journal of Respiratory and Critical Care Medicine. Conference: American Thoracic Society International Conference, ATS 2014;189:no pagination. - PMC - PubMed
    1. Zheng G, Huang L, Tong H, Shu Q, Hu Y, Ge M, et al. Treatment of acute respiratory distress syndrome with allogeneic adipose‐derived mesenchymal stem cells: a randomized, placebo‐controlled pilot study. Respiratory Research 2014;15(1):39. [PUBMED: 24708472] - PMC - PubMed

References to studies excluded from this review

Abraham 1996 {published data only}
    1. Abraham E, Park YC, Covington P, Conrad SA, Schwartz M. Liposomal prostaglandin E1 in acute respiratory distress syndrome: a placebo‐controlled, randomized, double‐blind, multicenter clinical trial. Critical Care Medicine 1996;24(1):10‐5. [PUBMED: 8565513] - PubMed
Abraham 1999 {published data only}
    1. Abraham E, Baughman R, Fletcher E, Heard S, Lamberti J, Levy H, et al. Liposomal prostaglandin E1 (TLC C‐53) in acute respiratory distress syndrome: a controlled, randomized, double‐blind, multicenter clinical trial. TLC C‐53 ARDS Study Group. Critical Care Medicine 1999;27(8):1478‐85. [PUBMED: 10470753] - PubMed
Annane 2006 {published data only}
    1. Annane D, Sebille V, Bellissant E. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Critical Care Medicine 2006;34(1):22‐30. [PUBMED: 16374152] - PubMed
Anzueto 1996 {published data only}
    1. Anzueto A, Baughman RP, Guntupalli KK, Weg JG, Wiedemann HP, Raventos AA, et al. Aerosolized surfactant in adults with sepsis‐induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group. New England Journal of Medicine 1996;334(22):1417‐21. [PUBMED: 8618579] - PubMed
Ardizzoia 1993 {published data only}
    1. Ardizzoia A, Lissoni P, Tancini G, Paolorossi F, Crispino S, Villa S, et al. Respiratory distress syndrome in patients with advanced cancer treated with pentoxifylline: a randomized study. Support Care in Cancer 1993;1(6):331‐3. [PUBMED: 8156252] - PubMed
Bastin 2010 {published data only}
    1. Bastin AJ, Lagan AL, Mumby S, Quinlan GJ, Griffiths MJD. Effect of N‐acetylcysteine in preventing inflammation after lung resection and one‐lung ventilation. A randomised controlled trial. American Journal of Respiratory and Critical Care Medicine 2010;181(1):no pagination.
Bastin 2016 {published data only}
    1. Bastin AJ, Davies N, Lim E, Quinlan GJ, Griffiths MJ. Systemic inflammation and oxidative stress post‐lung resection: Effect of pretreatment with N‐acetylcysteine. Respirology 2016;21(1):180‐7. [PUBMED: 26503312] - PubMed
Bernard 1987 {published data only}
    1. Bernard GR, Luce JM, Sprung CL, Rinaldo JE, Tate RM, Sibbald WJ, et al. High‐dose corticosteroids in patients with the adult respiratory distress syndrome. New England Journal of Medicine 1987;317(25):1565‐70. [PUBMED: 3317054] - PubMed
Bernard 1997 {published data only}
    1. Bernard GR, Wheeler AP, Arons MM, Morris PE, Paz HL, Russell JA, et al. A trial of antioxidants N‐acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group. Chest 1997;112(1):164‐72. [PUBMED: 9228372] - PubMed
Bernard 1999 {published data only}
    1. Bernard GR, Wheeler AP, Naum CC, Morris PE, Nelson L, Schein R, et al. A placebo‐controlled, randomized trial of IL‐10 in acute lung injury (ALI). Chest. 1999; Vol. 116, issue 4 Suppl 2:206S.
Bone 1989 {published data only}
    1. Bone RC, Slotman G, Maunder R, Silverman H, Hyers TM, Kerstein MD, et al. Randomized double‐blind, multicenter study of prostaglandin E1 in patients with the adult respiratory distress syndrome. Prostaglandin E1 Study Group. Chest 1989;96(1):114‐9. [PUBMED: 2661155] - PubMed
    1. Slotman GJ, Kerstein MD, Bone RC, Silverman H, Maunder R, Hyers TM, et al. The effects of prostaglandin E1 on non‐pulmonary organ function during clinical acute respiratory failure. The Prostaglandin E1 Study Group. Journal of Trauma 1992;32(4):480‐8. [PUBMED: 1569622] - PubMed
Confalonieri 2005 {published data only}
    1. Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, et al. Hydrocortisone infusion for severe community‐acquired pneumonia: a preliminary randomized study. American Journal of Respiratory and Critical Care Medicine 2005;171(3):242‐8. [PUBMED: 15557131] - PubMed
Cornet 2014 {published data only}
    1. Cornet AD, Groeneveld AB, Hofstra JJ, Vlaar AP, Tuinman PR, Lingen A, et al. Recombinant human activated protein C in the treatment of acute respiratory distress syndrome: a randomized clinical trial. PLOS One 2014;9(3):e90983. [PUBMED: 24632673] - PMC - PubMed
    1. Cornet AD, Hofstra JJ, Vlaar AP, Tuinman PR, Levi M, Girbes AR, et al. Activated protein C attenuates pulmonary coagulopathy in patients with acute respiratory distress syndrome. Journal of Thrombosis and Haemostasis 2013;11(5):894‐901. [PUBMED: 23433188] - PMC - PubMed
Domenighetti 1997 {published data only}
    1. Domenighetti G, Suter PM, Schaller MD, Ritz R, Perret C. Treatment with N‐acetylcysteine during acute respiratory distress syndrome: a randomized, double‐blind, placebo‐controlled clinical study. Journal of Critical Care 1997;12(4):177‐82. [PUBMED: 9459113] - PubMed
Forel 2006 {published data only}
    1. Forel JM, Roch A, Marin V, Michelet P, Demory D, Blache JL, et al. Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Critical Care Medicine 2006;34(11):2749‐57. [PUBMED: 16932229] - PubMed
Gainnier 2004 {published data only}
    1. Gainnier M, Roch A, Forel JM, Thirion X, Arnal JM, Donati S, et al. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Critical Care Medicine 2004;32(1):113‐9. [PUBMED: 14707568] - PubMed
Gottlieb 1994 {published data only}
    1. Gottlieb JE, Elmer M, Steiner R. Efficacy of intravenous ICI 200,880, a neutrophil elastase inhibitor, in the treatment of adult respiratory distress syndrome (ARDS). Chest 1994;106(Suppl 2):67S.
Gregory 1997 {published data only}
    1. Gregory TJ, Steinberg KP, Spragg R, Gadek JE, Hyers TM, Longmore WJ, et al. Bovine surfactant therapy for patients with acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 1997;155(4):1309‐15. [PUBMED: 9105072] - PubMed
Holcroft 1986 {published data only}
    1. Holcroft JW, Vassar MJ, Weber CJ. Prostaglandin E1 and survival in patients with the adult respiratory distress syndrome. A prospective trial. Annals of Surgery 1986;203(4):371‐8. [PUBMED: 3516085] - PMC - PubMed
    1. Holcroft JW, Vassar MJ, Weber CJ. Prostaglandin E1 and survival in patients with the adult respiratory distress syndrome. A prospective trial. Seminars in Respiratory Medicine 1986;7(5):40‐7. - PMC - PubMed
Hua 2013 {published data only}
    1. Hua F, Wang X, Zhu L. Terlipressin decreases vascular endothelial growth factor expression and improves oxygenation in patients with acute respiratory distress syndrome and shock. Journal of Emergency Medicine 2013;44(2):434‐9. [PUBMED: 22921855] - PMC - PubMed
Jepsen 1992 {published data only}
    1. Jepsen S, Herlevsen P, Knudsen P, Bud MI, Klausen NO. Antioxidant treatment with N‐acetylcysteine during adult respiratory distress syndrome: a prospective, randomized, placebo‐controlled study. Critical Care Medicine 1992;20(7):918‐23. [PUBMED: 1617983] - PubMed
Liu 2008 {published data only}
    1. Liu KD, Levitt J, Zhuo H, Kallet RH, Brady S, Steingrub J, et al. Randomized clinical trial of activated protein C for the treatment of acute lung injury. American Journal of Respiratory and Critical Care Medicine 2008;178(6):618‐23. [PUBMED: 18565951] - PMC - PubMed
Markart 2007 {published data only}
    1. Markart P, Ruppert C, Wygrecka M, Colaris T, Dahal B, Walmrath D, et al. Patients with ARDS show improvement but not normalisation of alveolar surface activity with surfactant treatment: putative role of neutral lipids. Thorax 2007;62(7):588‐94. [PUBMED: 17287298] - PMC - PubMed
Meduri 1998 {published data only}
    1. Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA 1998;280(2):159‐65. [PUBMED: 9669790] - PubMed
Papazian 2010 {published data only}
    1. Papazian L, Forel JM, Gacouin A, Penot‐Ragon C, Perrin G, Loundou A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. New England Journal of Medicine 2010;363(12):1107‐16. [PUBMED: 20843245] - PubMed
    1. Papazian L, Forel JM, Gacouin A, Perrin G, Jaber S, Arnal JM, et al. Systematic two‐day muscle relaxants course in the early phase of severe acute respiratory distress syndrome. A multicenter randomized controlled trial. Intensive Care Medicine 2009;35:S6. [Embase: 70190221]
    1. Papazian L, Forel JM, Morange S, Barrau K, Penot‐Ragon C. Interest of a 48 h systematic paralysis at the early phase, in patients presenting with ARDS. The ACURASYS study. Protocol presentation [Interet d'une curarisation systematique precoce de 48 heures sur le pronostic des patients presentant un syndrome de detresse respiratoire aigue. Etude ACURASYS. Presentation du protocole]. Reanimation 2007;16(1):88‐95.
Presneill 2002 {published data only}
    1. Presneill JJ, Harris T, Stewart AG, Cade JF, Wilson JW. A randomized phase II trial of granulocyte‐macrophage colony‐stimulating factor therapy in severe sepsis with respiratory dysfunction. American Journal of Respiratory and Critical Care Medicine 2002;166(2):138‐43. [PUBMED: 12119223] - PubMed
Reines 1985 {published data only}
    1. Reines HD, Halushka PV, Olanoff LS, Hunt PS. Dazoxiben in human sepsis and adult respiratory distress syndrome. Clinical Pharmacology and Therapeutics 1985;37(4):391‐5. [PUBMED: 3979000] - PubMed
Reines 1992 {published data only}
    1. Reines HD, Sliverman H, Hurst J, Warren J, Williams J, Rotello L, et al. Effects of two concentrations of nebulized surfactant (Exosurf) in sepsis‐induced adult respiratory distress syndrome (ARDS). Critical Care Medicine 1992;20(4 Suppl):S61.
    1. Wiedermann H, Baughman R, DeBoisblanc B, Schuster D, Caldwell E, Weg J, et al. A multicenter trial in human sepsis‐induced ARDS of an aerosolized synthetic surfactant (Exosurf). American Review of Respiratory Disease 1992;145(4 part 2):A184.
Rossignon 1990 {published data only}
    1. Rossignon MD, Khayat D, Royer C, Rouby JJ, Jacquillat C, Viars P. Functional and metabolic activity of polymorphonuclear leukocytes from patients with adult respiratory distress syndrome: results of a randomized double‐blind placebo‐controlled study on the activity of prostaglandin E1. Anesthesiology 1990;72(2):276‐81. [PUBMED: 2405741] - PubMed
Shoemaker 1986 {published data only}
    1. Shoemaker WC. Effectiveness of prostaglandin E1 in adult respiratory distress syndrome. Progress in Clinical and Biological Research 1987;236A:361‐81. [PUBMED: 3615440] - PubMed
    1. Shoemaker WC, Appel PL. Effects of prostaglandin E1 in adult respiratory distress syndrome. Surgery 1986;99(3):275‐83. [PUBMED: 3513357] - PubMed
Shyamsundar 2010 {published data only}
    1. Shyamsundar M, O'Kane CM, Calfee C, McKeown ST, Taggart C, Matthay MA, et al. KGF enhances pulmonary production of proepithelial repair factors in a human in vivo model of acute lung injur y. Thorax 2010;65:A47. [Embase: 70325792]
Steinberg 1990 {published data only}
    1. Steinberg SM, Rodriguez JL, Bitzer LG, Rhee JW, Kelley KA, Flint LM. Indomethacin treatment of human adult respiratory distress syndrome. Circulatory Shock 1990;30(4):375‐84. [PUBMED: 2350875] - PubMed
Suter 1994 {published data only}
    1. Suter PM, Domenighetti G, Schaller MD, Laverriere MC, Ritz R, Perret C. N‐acetylcysteine enhances recovery from acute lung injury in man. A randomized, double‐blind, placebo‐controlled clinical study. Chest 1994;105(1):190‐4. [PUBMED: 8272731] - PubMed
Tuxen 1987 {published data only}
    1. Tuxen DV, Wilson JW, Cade JF. Prevention of lower respiratory herpes simplex virus infection with acyclovir in patients with the adult respiratory distress syndrome. American Review of Respiratory Distress 1987;136(2):402‐5. [PUBMED: 3039882] - PubMed
Vincent 2009 {published data only}
    1. Vincent JL, Artigas A, Petersen LC, Meyer C. A multicenter, randomized, double‐blind, placebo‐controlled, dose‐escalation trial assessing safety and efficacy of active site inactivated recombinant factor VIIa in subjects with acute lung injury or acute respiratory distress syndrome. Critical Care Medicine 2009;37(6):1874‐80. [PUBMED: 19384216] - PubMed
Weg 1994 {published data only}
    1. Doig C, Weg JG. Aerosolized surfactant in sepsis‐induced adult respiratory distress syndrome. JAMA 1995;273(16):1259‐60. [PUBMED: 7715036] - PubMed
    1. Weg JG, Balk RA, Tharratt RS, Jenkinson SG, Shah JB, Zaccardelli D, et al. Safety and potential efficacy of an aerosolized surfactant in human sepsis‐induced adult respiratory distress syndrome. JAMA 1994;272(18):1433‐8. [PUBMED: 7933425] - PubMed
Weigelt 1985 {published data only}
    1. Weigelt JA, Norcross JF, Borman KR, Snyder WH 3rd. Early steroid therapy for respiratory failure. Archives of Surgery 1985;120(5):536‐40. [PUBMED: 3885915] - PubMed

References to studies awaiting assessment

Hegazy 2016 {published data only}
    1. Hegazy S, Helmy T, Salah M. Role of nebivolol therapy in patients with severe acute respiratory distress syndrome. Critical Care Medicine 2016;44(12 Supplement 1):314.
NCT00879606 {published data only}
    1. NCT00879606. Efficacy and safety evaluation of ALT‐836 in patients with sepsis and acute lung injury/acute respiratory distress syndrome. www.clinicaltrials.gov/ct2/show/NCT00879606 (first received 10 April 2009).
RPCEC00000126 {published data only}
    1. RPCEC00000126. Evaluation of the effect and safety of SURFACEN in the treatment of acute respiratory distress syndrome in adults. rpcec.sld.cu/en/trials/RPCEC00000126‐En (first received 11 April 2012).

References to ongoing studies

ACTRN12612000418875 {published data only}
    1. ACTRN12612000418875. A multi‐centre randomised, placebo controlled trial of nebulised heparin in patients with or at risk of developing acute respiratory distress syndrome, to determine if nebulised heparin improves long term physical function. www.anzctr.org.au/ACTRN12612000418875.aspx (first received 6 April 2012).
ACTRN12615000373572 {published data only}
    1. ACTRN12615000373572. Effect of nebulized budesonide on respiratory mechanics and oxygenation in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). www.anzctr.org.au/ACTRN12615000373572.aspx (first received 13 January 2015).
Bellingan 2017 {published data only}
    1. Bellingan G, Brealey D, Mancebo J, Mercat A, Patroniti N, Pettila V, et al. Comparison of the efficacy and safety of FP‐1201‐lyo (intravenously administered recombinant human interferon beta‐1a) and placebo in the treatment of patients with moderate or severe acute respiratory distress syndrome: study protocol for a randomized controlled trial. Trials 2017;18(1):no pagination. - PMC - PubMed
ChiCTR1800014733 {published data only}
    1. ChiCTR1800014733. Clinical study of rhGM‐CSF in the treatment of pulmonary extraneous acute respiratory distress syndrome. www.chictr.org.cn/showproj.aspx?proj=25020 (first received 31 January 2018).
ChiCTR1800014998 {published data only}
    1. ChiCTR1800014998. Human umbilical cord derived mesenchymal stem cells therapy in acute respiratory distress syndrome: a pilot study. www.chictr.org.cn/showproj.aspx?proj=25576 (first received 27 February 2018).
EUCTR2012‐000775‐17 {published data only}
    1. EudraCT2012‐000775‐17. A comparative, randomised controlled trial for evaluating the efficacy of dexamethasone administration in the treatment of patients with the acute respiratory distress syndrome. www.clinicaltrialsregister.eu/ctr‐search/search?query=eudract_number:201... (first received 21 November 2012).
JPRN‐JapicCTI‐163320 {published data only}
    1. JPRN‐JapicCTI‐163320. A phase 3 clinical study to evaluate the efficacy and safety of intravenous MR11A8 in the treatment of patients with moderate or severe acute respiratory distress syndrome. www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI‐163320 (first received 19 July 2016).
NCT02326350 {published data only}
    1. NCT02326350. Aspirin as a treatment for ARDS (STAR): a phase 2 randomised control trial. clinicaltrials.gov/ct2/show/NCT02326350 (first received 29 December 2014).
NCT02595060 {published data only}
    1. NCT02595060. GM‐CSF inhalation to improve host defense and pulmonary barrier restoration (GI‐HOPE). A randomized, double‐blind, parallel group, multicenter, phase II study. www.clinicaltrials.gov/ct2/show/NCT02595060 (first received 3 November 2015).
NCT02611609 {published data only}
    1. NCT02611609. A phase 1/2 study to assess the safety and efficacy of MultiStem® therapy in subjects with acute respiratory distress syndrome. clinicaltrials.gov/ct2/show/NCT02611609 (first received 23 November 2015).
NCT02895191 {published data only}
    1. NCT02895191. A randomized, blind, placebo‐controlled, parallel group, multi‐center study to evaluate the safety and dose response relationship of ulinastatin for acute respiratory distress syndrome (ARDS). clinicaltrials.gov/ct2/show/NCT02895191 (first received 9 September 2016).
NCT03017547 {published data only}
    1. NCT03017547. A phase 2, randomized, double‐blind, placebo‐controlled, preliminary efficacy study of IC14 in acute respiratory distress syndrome. clinicaltrials.gov/ct2/show/NCT03017547 (first received 11 January 2017).
NCT03042143 {published data only}
    1. NCT03042143. Repair of acute respiratory distress syndrome by stromal cell administration (REALIST): an open label dose escalation phase 1 trial followed by a randomized, double‐blind, placebo‐controlled phase 2 trial. clinicaltrials.gov/ct2/show/NCT03042143 (first received 3 February 2017).
NCT03202394 {published data only}
    1. NCT03202394. A phase IIa, placebo controlled, multicenter pilot study to evaluate the safety and efficacy of BIO‐11006 inhalation solution in patients with acute respiratory distress syndrome. clinicaltrials.gov/ct2/show/NCT03202394 (first received 28 June 2017).
NCT03346681 {published data only}
    1. NCT03346681. N‐acetylcysteine in early acute respiratory distress syndrome (NARDS). clinicaltrials.gov/show/NCT03346681 (first received 17 November 2017).
NCT03371498 {published data only}
    1. NCT03371498. Procollagen‐3 driven corticosteroids for persistent acute respiratory distress syndrome (ProCoCo). clinicaltrials.gov/ct2/show/nct03371498 (first received 13 December 2017).
NCT03608592 {published data only}
    1. NCT03608592. Human umbilical cord derived mesenchymal stem cells therapy in acute respiratory distress syndrome: a pilot study. clinicaltrials.gov/ct2/show/NCT03608592 (first received 1 August 2018).
Villar 2016 {published data only}
    1. NCT01731795. A comparative, randomised controlled trial for evaluating the efficacy of dexamethasone in the treatment of patients with acute respiratory distress syndrome. clinicaltrials.gov/ct2/show/NCT01731795 (first received 22 November 2012).
    1. Villar J, Belda J, Añón JM, Blanco J, Pérez‐Méndez L, Ferrando C, et al. Evaluating the efficacy of dexamethasone in the treatment of patients with persistent acute respiratory distress syndrome: Study protocol for a randomized controlled trial. Trials 2016 2016;17(342):no pagination. - PMC - PubMed

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