235
Views
5
CrossRef citations to date
0
Altmetric
Review

Treatment for acute respiratory distress syndrome in adults: a narrative review of phase 2 and 3 trials

ORCID Icon, ORCID Icon, ORCID Icon &
Pages 187-209 | Received 01 Apr 2022, Accepted 21 Jul 2022, Published online: 28 Jul 2022

References

  • Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788.
  • Shaw TD, McAuley DF, O’Kane CM. Emerging drugs for treating the acute respiratory distress syndrome. Expert Opin Emerg Drugs. 2019;24(1):29–41.
  • Bos LDJ, Artigas A, Constantin J-M, et al., Precision medicine in acute respiratory distress syndrome: workshop report and recommendations for future research. Eur Respir Rev. 2021;30(159):200317.
  • Goligher EC, Ranieri VM, Slutsky AS. Is severe COVID-19 pneumonia a typical or atypical form of ARDS? And does it matter? Intensive Care Med. 2021;47(1):83–85.
  • Rezoagli E, Fumagalli R, Bellani G. Definition and epidemiology of acute respiratory distress syndrome. Ann Transl Med. 2017;5(14):282.
  • Laffey JG, Bellani G, Pham T, et al. Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study. Intensive Care Med. 2016;42(12):1865–1876.
  • Brower R, Matthay M, Morris A, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301–1308.
  • Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004;351:327–336.
  • Amato MBP, Meade MO, Slutsky AS, et al. driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372(8):747–755.
  • Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome. JAMA. 2010;303(9):865.
  • Sakr Y, Vincent J-L, Reinhart K, et al. High tidal volume and positive fluid balance are associated with worse outcome in acute lung injury. Chest. 2005;128(5):3098–3108.
  • Matthay MA, McAuley DF, Ware LB. Clinical trials in acute respiratory distress syndrome: challenges and opportunities. Lancet Respir Med. 2017;5(6):524–534.
  • Cochi SE, Kempker JA, Annangi S, et al. Mortality trends of acute respiratory distress syndrome in the United States from 1999-2013. Ann Am Thorac Soc. 2016;13(10):1742–1751.
  • Sweeney RM, McAuley DF. Acute respiratory distress syndrome. Lancet. 2016;388(10058):2416–2430.
  • Battaglini D, Sottano M, Ball L, et al. Ten golden rules for individualized mechanical ventilation in acute respiratory distress syndrome. J Intensive Med. 2021;1(1):42–51.
  • Slutsky AS. History of mechanical ventilation. from vesalius to ventilator-induced lung injury. Am J Respir Crit Care Med. 2015;191(10):1106–1115.
  • Walkey AJ, Goligher EC, Del Sorbo L, et al. Low tidal volume versus non–volume-limited strategies for patients with acute respiratory distress syndrome. A systematic review and meta-analysis. Ann Am Thorac Soc. 2017;14(Supplement_4):S271–S279.
  • Goligher EC, Kavanagh BP, Rubenfeld GD, et al. Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome. A secondary analysis of the LOVS and express trials. Am J Respir Crit Care Med. 2014;190(1):70–76.
  • Mercat A, Richard J-CM, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome. JAMA. 2008;299(6):646.
  • 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. JAMA. 2008;299(6):637.
  • Ball L, Serpa Neto A, Trifiletti V, et al. Effects of higher PEEP and recruitment manoeuvres on mortality in patients with ARDS: a systematic review, meta-analysis, meta-regression and trial sequential analysis of randomized controlled trials. Intensive Care Med Exp. 2020;8(S1):39.
  • Cavalcanti AB, Suzumura ÉA, Laranjeira LN, et al. Effect of lung recruitment and titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on mortality in patients with acute respiratory distress syndrome. JAMA. 2017;318(14):1335.
  • Hodgson CL, Cooper DJ, Arabi Y, et al. Maximal recruitment open lung ventilation in acute respiratory distress syndrome (PHARLAP). A Phase II, multicenter randomized controlled clinical trial. Am J Respir Crit Care Med. 2019;200(11):1363–1372.
  • Papazian L, Aubron C, Brochard L, et al. Formal guidelines: management of acute respiratory distress syndrome. Ann Intensive Care. 2019;9(1):69.
  • Dianti J, Tisminetzky M, Ferreyro BL, et al. Association of PEEP and lung recruitment selection strategies with mortality in acute respiratory distress syndrome: a systematic review and network meta-analysis. Am J Respir Crit Care Med. 2022;205(11):1300–1310.
  • Amato MBP, Barbas CSV, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338(6):347–354.
  • Aoyama H, Pettenuzzo T, Aoyama K, et al. Association of driving pressure with mortality among ventilated patients with acute respiratory distress syndrome. Crit Care Med. 2018;46(2):300–306.
  • Mahmoud O. Mechanical power is associated with increased mortality and worsened oxygenation in ARDS. Chest. 2020;158(4):A679.
  • Serpa Neto A, Deliberato RO, Johnson AEW, et al. Mechanical power of ventilation is associated with mortality in critically ill patients: an analysis of patients in two observational cohorts. Intensive Care Med. 2018;44(11):1914–1922.
  • Grieco DL, Costa ELV, Nolan JP. The importance of ventilator settings and respiratory mechanics in patients resuscitated from cardiac arrest. Intensive Care Med. 2022;48(8):1056–1058.
  • Robba C, Badenes R, Battaglini D, et al. Ventilatory settings in the initial 72 h and their association with outcome in out-of-hospital cardiac arrest patients: a preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) tr. Intensive Care Med. 2022;48(8):1024–1038.
  • Murray MJ, DeBlock H, Erstad B, et al. Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med. 2016;44(11):2079–2103.
  • Guérin C, Reignier J, Richard J-C, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368(23):2159–2168.
  • Moss M, Huang D, Brower R, et al. Early neuromuscular blockade in the acute respiratory distress syndrome. N Engl J Med. 2019;380:1997–2008.
  • Alhazzani W, Alshahrani M, Jaeschke R, et al. Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials. Crit Care. 2013;17(2):R43.
  • Atn H, Patolia S, Guervilly C. Neuromuscular blockade in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials. J Intensive Care. 2020;8(1):12.
  • Wiedemann H, Wheeler A, Bernard G, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354:2564–2575.
  • Carvalho NC, Güldner A, Beda A, et al. Higher levels of spontaneous breathing reduce lung injury in experimental moderate acute respiratory distress syndrome. Crit Care Med. 2014;42(11):e702–e715.
  • Chanques G, Constantin J-M, Devlin JW, et al. Analgesia and sedation in patients with ARDS. Intensive Care Med. 2020;46(12):2342–2356.
  • Tarazan N, Alshehri M, Sharif S, et al. Neuromuscular blocking agents in acute respiratory distress syndrome: updated systematic review and meta-analysis of randomized trials. Intensive Care Med Exp. 2020;8(1):61.
  • Papazian L, Forel J-M, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107–1116.
  • Fanelli V, Morita Y, Cappello P, et al. Neuromuscular blocking agent cisatracurium attenuates lung injury by inhibition of nicotinic acetylcholine receptor-α1. Anesthesiology. 2016;124(1):132–140.
  • Forel J-M, Roch A, Marin V, et al. Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2006;34(11):2749–2757.
  • Alhazzani W, Belley-Cote E, Møller MH, et al. Neuromuscular blockade in patients with ARDS: a rapid practice guideline. Intensive Care Med. 2020;46(11):1977–1986.
  • Maca J, Jor O, Holub M, et al. Past and present ARDS mortality rates: a systematic review. Respir Care. 2017;62(1):113–122.
  • Fröhlich S, Murphy N, Boylan JF. ARDS: progress unlikely with non-biological definition. Br J Anaesth. 2013;111(5):696–699.
  • Boucher PE, Taplin J, Clement F. The Cost of ARDS. Chest. 2021;S0012-3692:03829.
  • Bice T, Cox C, Carson S. Cost and health care utilization in ARDS—different from other critical illness? Semin Respir Crit Care Med. 2013;34(4):529–536.
  • Biehl M, Ahmed A, Kashyap R, et al. The incremental burden of acute respiratory distress syndrome: long-term follow-up of a population-based nested case-control study. Mayo Clin Proc. 2018;93(4):445–452.
  • Hussey PS, Schneider EC, Rudin RS, et al. Continuity and the costs of care for chronic disease. JAMA Intern Med. 2014;174(5):742.
  • Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. N Engl J Med. 2017;377(6):562–572.
  • Rocco PRM, Negri EM, Kurtz PM, et al. Lung tissue mechanics and extracellular matrix remodeling in acute lung injury. Am J Respir Crit Care Med. 2001;164(6):1067–1071.
  • Pelosi P, Rocco PR. Effects of mechanical ventilation on the extracellular matrix. Intensive Care Med. 2008;34(4):631–639.
  • Aublanc M, Perinel S, Guérin C. Acute respiratory distress syndrome mimics. Curr Opin Crit Care. 2017;23(1):24–29.
  • Pelosi P, D’Onofrio D, Chiumello D, et al. Pulmonary and extrapulmonary acute respiratory distress syndrome are different. Eur Respir J. 2003;22(Supplement 42):48s–56s.
  • Gibelin A, Parrot A, Maitre B, et al. Acute respiratory distress syndrome mimickers lacking common risk factors of the Berlin definition. Intensive Care Med. 2016;42(2):164–172.
  • Calfee CS, Delucchi K, Parsons PE, et al. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med. 2014;2(8):611–620.
  • Famous KR, Delucchi K, Ware LB, et al. Acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy. Am J Respir Crit Care Med. 2017;195(3):331–338.
  • Sinha P, Delucchi KL, Thompson BT, et al. Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study. Intensive Care Med. 2018;44(11):1859–1869.
  • Calfee CS, Delucchi KL, Sinha P, et al. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir Med. 2018;6(9):691–698.
  • Delucchi K, Famous KR, Ware LB, et al. Stability of ARDS subphenotypes over time in two randomised controlled trials. Thorax. 2018;73(5):439–445.
  • Pelosi P, Ball L, Barbas CSV, et al., Personalized mechanical ventilation in acute respiratory distress syndrome. Crit Care. 2021;25(1):250.
  • Ball L, Silva PL, Rocco PRM, et al. A critical approach to personalised medicine in ARDS. Lancet Respir Med. 2020;8(3):218–219.
  • Reilly J, Calfee C, Christie J. Acute respiratory distress syndrome phenotypes. Semin Respir Crit Care Med. 2019;40(1):019–030.
  • Wilson JG, Calfee CS. ARDS subphenotypes: understanding a heterogeneous syndrome. Crit Care. 2020;24(1):102.
  • García-Laorden MI, Lorente JA, Flores C, et al. Biomarkers for the acute respiratory distress syndrome: how to make the diagnosis more precise. Ann Transl Med. 2017;5(14):283.
  • Acosta-Herrera M, Pino-Yanes M, Perez-Mendez L, et al. Assessing the quality of studies supporting genetic susceptibility and outcomes of ARDS. Front Genet. 2014;5:20.
  • Christie JD, Wurfel MM, Feng R, et al. Genome wide association identifies PPFIA1 as a candidate gene for acute lung injury risk following major trauma. checkley W, editor. PLoS One. 2012;7(1):e28268.
  • Cobb JP, O’Keefe GE. Injury research in the genomic era. Lancet. 2004;363(9426):2076–2083.
  • Villar J, Maca-Meyer N, Pérez-Méndez L, et al. Bench-to-bedside review: understanding genetic predisposition to sepsis. Crit Care. 2004;8(3):180–189.
  • Cardinal-Fernández P, Ferruelo A, El-Assar M, et al. Genetic predisposition to acute respiratory distress syndrome in patients with severe sepsis. Shock. 2013;39(3):255–260.
  • Shyamsundar M, McAuley DF, Ingram RJ, et al. Keratinocyte growth factor promotes epithelial survival and resolution in a human model of lung injury. Am J Respir Crit Care Med. 2014;189(12):1520–1529.
  • McAuley DF, Cross LM, Hamid U, et al. Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Respir Med. 2017;5(6):484–491.
  • Matthay MA, Calfee CS, Zhuo H, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Respir Med. 2019;7(2):154–162.
  • Sinha P, Delucchi KL, McAuley DF, et al., Development and validation of parsimonious algorithms to classify acute respiratory distress syndrome phenotypes: a secondary analysis of randomised controlled trials. Lancet Respir Med. 2020;8(3):247–257.
  • Horie S, McNicholas B, Rezoagli E, et al., Emerging pharmacological therapies for ARDS: COVID-19 and beyond. Intensive Care Med. 2020;46(12):2265–2283.
  • Lin P, Zhao Y, Li X, et al. Decreased mortality in acute respiratory distress syndrome patients treated with corticosteroids: an updated meta-analysis of randomized clinical trials with trial sequential analysis. Crit Care. 2021;25(1):122.
  • Bernard G, Luce J, Sprung C, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Eng J Med. 1987;317(25):1565–1570.
  • Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome. JAMA. 1998;280(2):159.
  • Annane D, Sébille V, Bellissant E. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Crit Care Med. 2006;34(1):22–30.
  • Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS. Chest. 2007;131(4):954–963.
  • Liu L, Li J, Huang Y, et al. The effect of stress dose glucocorticoid on patients with acute respiratory distress syndrome combined with critical illness-related corticosteroid insufficiency. Zhonghua nei ke za zhi. 2012;51(8):599–603.
  • Zhao W, Wan S, Gu D, et al. Therapeutic effect of glucocorticoid inhalation for pulmonary fibrosis in ARDS patients. Jie Fang Jun Yi Xue Za Zhi. 2014;39:741–745.
  • Tongyoo S, Permpikul C, Mongkolpun W, et al. Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial. Crit Care. 2016;20(1):329.
  • Mohamed H, Meguid MA. Effect of nebulized budesonide on respiratory mechanics and oxygenation in acute lung injury/acute respiratory distress syndrome: randomized controlled study. Saudi J Anaesth. 2017;11(1):9.
  • Rezk NA, Ibrahim AM. Effects of methyl prednisolone in early ARDS. Egypt J Chest Dis Tuberc. 2013;62(1):167–172.
  • Villar J, Ferrando C, Martínez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267–276.
  • Steinberg K, Hudson L, Goodman R, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354:1671–1684.
  • Weg J, Balk R, Tharratt R, et al. Safety and potential efficacy of an aerosolized surfactant in human sepsis-induced adult respiratory distress syndrome. JAMA. 1994;272(18):1433–1438.
  • Anzueto A, Baughman RP, Guntupalli KK, et al. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. N Engl J Med. 1996;334(22):1417–1422.
  • Gregory TJ, Steinberg KP, Spragg R, et al. Bovine surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 1997;155(4):1309–1315.
  • Kesecioglu J, Schultz M, Lundberg D, et al. Treatment of acute lung injury (ALI/ARDS) with surfactant. Am J Respir Crit Care Med. 2001;163:A819.
  • Walmrath D, Grimminger F, Pappert D, et al. Bronchoscopic administration of bovine natural surfactant in ARDS and septic shock: impact on gas exchange and haemodynamics. Eur Respir J. 2002;19(5):805–810.
  • Spragg RG, Lewis JF, Wurst W, et al. Treatment of acute respiratory distress syndrome with recombinant surfactant protein C surfactant. Am J Respir Crit Care Med. 2003;167(11):1562–1566.
  • Spragg RG, Lewis JF, Walmrath H-D, et al. Effect of recombinant surfactant protein C–based surfactant on the acute respiratory distress syndrome. N Engl J Med. 2004;351(9):884–892.
  • Tsangaris I, Galiatsou E, Kostanti E, et al. The effect of exogenous surfactant in patients with lung contusions and acute lung injury. Intensive Care Med. 2007;33(5):851.
  • 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(10):989–994.
  • Spragg RG, Taut FJH, Lewis JF, et al. Recombinant surfactant protein C–based surfactant for patients with severe direct lung injury. Am J Respir Crit Care Med. 2011;183(8):1055–1061.
  • Lewis SR, Pritchard MW, Thomas CM, et al. Pharmacological agents for adults with acute respiratory distress syndrome. Cochrane Database Syst Rev. 2019;7:CD004477.
  • Griffiths MJD, McAuley DF, Perkins GD, et al. Guidelines on the management of acute respiratory distress syndrome. BMJ Open Respir Res. 2019;6(1):e000420.
  • Bellingan G, Maksimow M, Howell DC, et al. The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study. Lancet Respir Med. 2014;2(2):98–107.
  • Ranieri VM, Pettilä V, Karvonen MK, et al. Effect of intravenous interferon β-1a on death and days free from mechanical ventilation among patients with moderate to severe acute respiratory distress syndrome. JAMA. 2020;323(8):725.
  • Amrein K, Schnedl C, Holl A, et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency. JAMA. 2014;312(15):1520.
  • Parekh D, Dancer RCA, Scott A, et al. Vitamin D to prevent lung injury following esophagectomy—a randomized, placebo-controlled trial*. Crit Care Med. 2018;46(12):e1128–e1135.
  • Ginde A, Brower R, Caterino J, et al. Early high-dose Vitamin D 3 for critically Ill, Vitamin D–deficient patients. N Engl J Med. 2019;381:2529–2540.
  • Teafatiller T, Agrawal S, De Robles G, et al. Vitamin C enhances antiviral functions of lung epithelial cells. Biomolecules. 2021;11(8):1148.
  • Fowler AA, Truwit JD, Hite RD, et al. Effect of Vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure. JAMA. 2019;322(13):1261.
  • Kor DJ, Carter RE, Park PK, et al. Effect of aspirin on development of ARDS in at-risk patients presenting to the emergency department. JAMA. 2016;315(22):2406.
  • Hamid U, Krasnodembskaya A, Fitzgerald M, et al. Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS. Thorax. 2017;72(11):971–980.
  • Zhang Y, Ding S, Li C, et al. Effects of N-acetylcysteine treatment in acute respiratory distress syndrome: a meta-analysis. Exp Ther Med. 2017;14(4):2863–2868.
  • Suter PM, Domenighetti G, Schaller M-D, et al. N-Acetylcysteine enhances recovery from acute lung injury in man. Chest. 1994;105(1):190–194.
  • Bernard GR, Wheeler AP, Arons MM, et al. A Trial of antioxidants N-acetylcysteine and procysteine in ARDS. Chest. 1997;112(1):164–172.
  • Domenighetti G, Suter PM, Schaller M-D, et al. Treatment with N-acetylcysteine during acute respiratory distress syndrome: a randomized, double-blind, placebo-controlled clinical study. J Crit Care. 1997;12(4):177–182.
  • Ortolani O, Conti A, De Gaudio AR, et al. Protective effects of N-acetylcisteine and rutin on the lipid peroxidation of the lung epithelium during the adult respiratory distress syndrome. Shock. 2000;13(1):14–18.
  • Soltan-Sharifi MS, Mojtahedzadeh M, Najafi A, et al. Improvement by N-acetylcysteine of acute respiratory distress syndrome through increasing intracellular glutathione, and extracellular thiol molecules and anti-oxidant power: evidence for underlying toxicological mechanisms. Hum Exp Toxicol. 2007;26(9):697–703.
  • Moradi M, Mojtahedzadeh M, Mandegari A, et al. The role of glutathione-S-transferase polymorphisms on clinical outcome of ALI/ARDS patient treated with N-acetylcysteine. Respir Med. 2009;103(3):434–441.
  • Najafi A, Mojtahedzadeh M, Mahmoodpoor A, et al. Clinical research Effect of N-acetylcysteine on microalbuminuria in patients with acute respiratory distress syndrome. Arch Med Sci. 2009;5:408–414.
  • Bassford CR, Thickett DR, Perkins GD. The rise and fall of β-agonists in the treatment of ARDS. Crit Care. 2012;16(2):208.
  • Wright PE, Carmichael LC, Bernard GR. Effect of bronchodilators on lung mechanics in the Acute Respiratory Distress Syndrome (ARDS). Chest. 1994;106(5):1517–1523.
  • Perkins GD, McAuley DF, Thickett DR, et al. The β-Agonist Lung Injury Trial (BALTI). Am J Respir Crit Care Med. 2006;173(3):281–287.
  • Matthay M, Brower R, Carson S, et al. Randomized, placebo-controlled clinical trial of an aerosolized β 2 -agonist for treatment of acute lung injury. Am J Respir Crit Care Med. 2011;184:561–568.
  • Gates S, Perkins G, Lamb S, et al. Beta-Agonist Lung injury TrIal-2 (BALTI-2): a multicentre, randomised, double-blind, placebo-controlled trial and economic evaluation of intravenous infusion of salbutamol versus placebo in patients with acute respiratory distress syndrome. Health Technol Assess (Rockv). 2013;17:1–87.
  • Festic E, Carr GE, Cartin-Ceba R, et al. Randomized clinical trial of a combination of an inhaled corticosteroid and beta agonist in patients at risk of developing the acute respiratory distress syndrome. Crit Care Med. 2017;45(5):798–805.
  • Miyazaki Y, Inoue T, Kyi M, et al. Effects of a neutrophil elastase inhibitor (ONO-5046) on acute pulmonary injury induced by Tumor Necrosis Factor Alpha (TNF α) and activated neutrophils in isolated perfused rabbit lungs. Am J Respir Crit Care Med. 1998;157(1):89–94.
  • Tamakuma S, Ogawa M, Aikawa N, et al. Relationship between neutrophil elastase and acute lung injury in humans. Pulm Pharmacol Ther. 2004;17(5):271–279.
  • Kadoi Y, Hinohara H, Kunimoto F, et al. Pilot study of the effects of ONO-5046 in patients with acute respiratory distress syndrome. Anesth Analg. 2004;99(3):872–877.
  • Zeiher BG, Artigas A, Vincent J-L, et al. Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study. Crit Care Med. 2004;32:1695–1702.
  • Endo S, Sato N, Yaegashi Y, et al. Sivelestat sodium hydrate improves septic acute lung injury by reducing alveolar dysfunction. Res Commun Mol Pathol Pharmacol. 2006;119(1–6):53–65.
  • Ryugo M, Sawa Y, Takano H, et al. Effect of a polymorphonuclear elastase inhibitor (Sivelestat Sodium) on acute lung injury after cardiopulmonary bypass: findings of a double-blind randomized study. Surg Today. 2006;36(4):321–326.
  • Pu S, Wang D, Liu D, et al. Effect of sivelestat sodium in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of randomized controlled trials. BMC Pulm Med. 2017;17(1):148.
  • Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome. Crit Care Med. 1998;26(1):15–23.
  • Adhikari NKJ, Dellinger RP, Lundin S, et al. Inhaled nitric oxide does not reduce mortality in patients with acute respiratory distress syndrome regardless of severity. Crit Care Med. 2014;42(2):404–412.
  • Michael J, Barton R, Saffle J, et al. Inhaled nitric oxide versus conventional therapy. Am J Respir Crit Care Med. 1998;157(5):1372–1380.
  • Troncy E, Collet J, Shapiro S, et al. Inhaled nitric oxide in acute respiratory distress syndrome. Am J Respir Crit Care Med. 1998;157(5):1483–1488.
  • Lundin S, Mang H, Smithies M, et al. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. Intensive Care Med. 1999;25(9):911–919.
  • Paven D, Muret J, Beloucif S, et al. Inhaled nitric oxide, almitrine infusion, or their coadministration as a treatment of severe hypoxemic focal lung lesions. Anesthesiology. 1998;89(5):1157–1165.
  • Gebistorf F, Karam O, Wetterslev J, et al. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev. 2016;6:CD002787.
  • Gerlach H, Keh D, Semmerow A, et al. Dose–response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome. Am J Respir Crit Care Med. 2003;167(7):1008–1015.
  • Park KJ, Lee YJ, Oh YJ, et al. Combined effects of inhaled nitric oxide and a recruitment maneuver in patients with acute respiratory distress syndrome. Yonsei Med J. 2003;44(2):219.
  • Taylor RW, Zimmerman J, Dellinger R, et al. Low-dose inhaled nitric oxide in patients with acute lung injury a randomized controlled trial. JAMA. 2004;291(13):1603.
  • Perrin G, Roch A, Michelet P, et al. Inhaled nitric oxide does not prevent pulmonary edema after lung transplantation measured by lung water content. Chest. 2006;129(4):1024–1030.
  • Ford HJ, Anderson WH, Wendlandt B, et al. Randomized, placebo-controlled trial of inhaled treprostinil for patients at risk for acute respiratory distress syndrome. Ann Am Thorac Soc. 2021;18(4):641–647.
  • Walmrath D, Schneider T, Schermuly R, et al. Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. Am J Respir Crit Care Med. 1996;153(3):991–996.
  • Liu L, Hu S, Shuai T, et al. Clinical effect of alprostadil in patients with septic shock associated with acute respiratory distress syndrome. Plamj. 2017;42.
  • Vincent J-L, Brase R, Santman F, et al. A multi-centre, double-blind, placebo-controlled study of liposomal prostaglandin E1 (TLC C-53) in patients with acute respiratory distress syndrome. Intensive Care Med. 2001;27(10):1578–1583.
  • Gong MN, Thompson BT, Williams P, et al. Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion. Crit Care Med. 2005;33(6):1191–1198.
  • Iscimen R, Cartin-Ceba R, Yilmaz M, et al. Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study. Crit Care Med. 2008;36:1518–1522.
  • Honiden S, Gong MN. Diabetes, insulin, and development of acute lung injury. Crit Care Med. 2009;37(8):2455–2464.
  • Zhang X, Zhu Z, Jiao W, et al. Ulinastatin treatment for acute respiratory distress syndrome in China: a meta-analysis of randomized controlled trials. BMC Pulm Med. 2019;19(1):196.
  • Feng Y. Efficacy of statin therapy in patients with acute respiratory distress syndrome/acute lung injury: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2018;22(10):3190–3198.
  • 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;183:620–626.
  • McAuley DF, Laffey JG, O’Kane CM, et al. Simvastatin in the acute respiratory distress syndrome. N Engl J Med. 2014;371:1695–1703.
  • Truwit J, Bernard G, Steingrub J, et al. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med. 2014;370:2191–2200.
  • Chen Y, Luo J, Jiang D, et al. Effect of ulinastatin on acute lung injury induced by severe heat stroke and its mechanism. Cochrane Libr. 2017;42:301–306.
  • Ji M, Chen T, Wang B, et al. Effects of ulinastatin combined with mechanical ventilation on oxygen metabolism, inflammation and stress response and antioxidant capacity of ARDS. Exp Ther Med. 2018;15(6):4665–4670.
  • Grimaldi D, Durand A, Gleeson J, et al. Failure of statins in ARDS: the quest for the Holy Grail continues. Minerva Anestesiol. 2016;82(11):1230–1234.
  • Zheng G, Huang L, Tong H, et al. Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respir Res. 2014;15(1):39.
  • Wick KD, Leligdowicz A, Zhuo H, et al. Mesenchymal stromal cells reduce evidence of lung injury in patients with ARDS. JCI Insight. 2021;6(12):e1488983.
  • Bellingan G, Jacono F, Bannard-Smith J, et al. Safety and efficacy of multipotent adult progenitor cells in acute respiratory distress syndrome (MUST-ARDS): a multicentre, randomised, double-blind, placebo-controlled phase 1/2 trial. Intensive Care Med. 2022;48(1):36–44.
  • Schmid B, Kredel M, Ullrich R, et al. Safety and preliminary efficacy of sequential multiple ascending doses of solnatide to treat pulmonary permeability edema in patients with moderate-to-severe ARDS—a randomized, placebo-controlled, double-blind trial. Trials. 2021;22(1):643.
  • Dixon B, Smith RJ, Campbell DJ, et al. Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir Med. 2021;9(4):360–372.
  • Christie JD, Vaslef S, Chang PK, et al. A randomized dose-escalation study of the safety and anti-inflammatory activity of the p38 mitogen-activated protein kinase inhibitor dilmapimod in severe trauma subjects at risk for acute respiratory distress syndrome. Crit Care Med. 2015;43(9):1859–1869.
  • Yang S, Dumitrescu TP. Population pharmacokinetics and pharmacodynamics modelling of dilmapimod in severe trauma subjects at risk for acute respiratory distress syndrome. Drugs R D. 2017;17(1):145–158.
  • Meng -S-S, Chang W, Lu Z-H, et al. Effect of surfactant administration on outcomes of adult patients in acute respiratory distress syndrome: a meta-analysis of randomized controlled trials. BMC Pulm Med. 2019;19(1):9.
  • Willson DF, Truwit JD, Conaway MR, et al. The adult calfactant in acute respiratory distress syndrome trial. Chest. 2015;148(2):356–364.
  • Barrese-Perez Y, Hidalgo-Sanchez A, Avila-Albuerne Y, et al. Pulmonary surfactant exogenous in adults with acute respiratory distress syndrome. Neumol Cir Torax. 2015;74:172–178.
  • Frossard JL, Saluja AK, Mach N, et al. In vivo evidence for the role of GM-CSF as a mediator in acute pancreatitis-associated lung injury. Am J Physiol Cell Mol Physiol. 2002;283(3):L541–L548.
  • Paine R, Standiford TJ, Dechert RE, et al. A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury. Crit Care Med. 2012;40(1):90–97.
  • Liu B, Yin Q, Chen Y-X, et al. Role of Presepsin (sCD14-ST) and the CURB65 scoring system in predicting severity and outcome of community-acquired pneumonia in an emergency department. Respir Med. 2014;108(8):1204–1213.
  • Khan A, Benthin C, Zeno B, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017;21(1):234.
  • Morelli A, Teboul J-L, Maggiore SM, et al. Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: a pilot study. Crit Care Med. 2006;34(9):2287–2293.
  • Ards Network Authors for the Ards Network T. The ARDS Network Authors for the ARDS network. Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome. JAMA. 2000;283(15):1995.
  • The ARDS Clinical Trials Network. Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome. Crit Care Med. 2002;30(1):1–6.
  • Granholm A, Munch MW, Myatra SN, et al. Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial. Intensive Care Med. 2022;48(1):45–55.
  • Russell L, Uhre KR, Lindgaard ALS, et al. Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia. JAMA. 2021;326(18):1807.
  • The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19 — preliminary Report. N Engl J Med. 2020;384(8):693–704.
  • The RECOVERY collaborative group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397:1637–1645.
  • REMAP-CAP investigators. Interleukin-6 receptor antagonists in critically Ill Patients with Covid-19. N Engl J Med. 2021;384(16):1491–1502.
  • Marconi VC, Ramanan AV, de Bono S, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021;9(12):1407–1418.
  • WHO. WHO Therapeutics and COVID-19: living guideline. 7 December. 2021.
  • Lamontagne F, Agoritsas T, Siemieniuk R, et al. A living WHO guideline on drugs to prevent covid-19. BMJ. 2021;372:526.
  • Bartoszko JJ, Siemieniuk RAC, Kum E, et al. Prophylaxis against covid-19: living systematic review and network meta-analysis. BMJ. 2021;373:949.
  • Guimarães PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with Covid-19 pneumonia. N Engl J Med. 2021;385(5):406–415.
  • Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med. 2021;384(9):795–807.
  • Ali K, Azher T, Baqi M, et al. Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial. Can Med Assoc J. 2022;194(7):E242–E251.
  • Lingas G, Néant N, Gaymard A, et al. Effect of remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial. J Antimicrob Chemother. 2022;77(5):1404–1412.
  • EMA. EMA recommends approval for use of Kineret in adults with COVID-19 [Internet]. European Medicines Agency Science & Medicine Health; 2021 [cited 2022 Jan 5]. Available from: https://www.ema.europa.eu/en/news/ema-recommends-approval-use-kineret-adults-covid-19
  • Kyriazopoulou E, Poulakou G, Milionis H, et al. Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial. Nat Med. 2021;27(10):1752–1760.
  • Tharaux P-L, Pialoux G, Pavot A, et al. Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial. Lancet Respir Med. 2021;9:295–304.
  • Caricchio R, Abbate A, Gordeev I, et al. Effect of canakinumab vs placebo on survival without invasive mechanical ventilation in patients hospitalized with severe COVID-19. JAMA. 2021;326(3):230.
  • NIH. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines [Internet]. NIH COVID-19 Treat. Guidel; 2021 [cited 2022 Jan 5]. Available from: https://www.covid19treatmentguidelines.nih.gov/about-the-guidelines/whats-new
  • Bégin P, Callum J, Jamula E, et al. Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial. Nat Med. 2021;27:2012–2024.
  • Devos T, Van Thillo Q, Compernolle V, et al. Early high antibody titre convalescent plasma for hospitalised COVID-19 patients: dawn-plasma. Eur Respir J. 2022;59(2):2101724.
  • Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent plasma antibody levels and the risk of death from covid-19. N Engl J Med. 2021;384(11):1015–1027.
  • Janiaud P, Hemkens LG, Ioannidis JPA. Challenges and lessons learned from COVID-19 Trials: should we be doing clinical trials differently? Can J Cardiol. 2021;37(9):1353–1364.
  • Park JJH, Mogg R, Smith GE, et al. How COVID-19 has fundamentally changed clinical research in global health. Lancet Glob Heal. 2021;9(5):e711–e720.
  • Landoni G, Piemonti L, Monforte AD, et al. A multicenter phase 2 randomized controlled study on the efficacy and safety of reparixin in the treatment of hospitalized patients with COVID-19 pneumonia. Infect Dis Ther. 2022;26:1–16.
  • Laffey JG, Kavanagh BP. FIfty years of Research in ARDS.Insight into acute respiratory distress syndrome. From models to patients. Am J Respir Crit Care Med. 2017;196(1):18–28.
  • Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Eng J Med. 2006;354(17):1775–1786.
  • Samanta RJ, Summers C. Translational research in intensive care Unit: novel approaches for drug development and personalized medicine. Semin Respir Crit Care Med. 2019;40(5):687–698.
  • Calfee CS, Eisner MD, Ware LB, et al. Trauma-associated lung injury differs clinically and biologically from acute lung injury due to other clinical disorders*. Crit Care Med. 2007;35(10):2243–2250.
  • Luo L, Shaver CM, Zhao Z, et al. Clinical predictors of hospital mortality differ between direct and indirect ARDS. Chest. 2017;151(4):755–763.
  • Calfee CS, Janz DR, Bernard GR, et al. Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies. Chest. 2015;147(6):1539–1548.
  • Du M, Garcia JGN, Christie JD, et al. Integrative omics provide biological and clinical insights into acute respiratory distress syndrome. Intensive Care Med. 2021;47(7):761–771.
  • Battaglini D, Lopes-Pacheco M, Castro-Faria-Neto HC, et al. Laboratory biomarkers for diagnosis and prognosis in COVID-19. Front Immunol. 2022;13:857573.
  • Ware LB, Matthay MA, Mebazaa A. Designing an ARDS trial for 2020 and beyond: focus on enrichment strategies. Intensive Care Med. 2020;46(12):2153–2156.
  • Neto AS, Barbas CSV, Simonis FD, et al. Epidemiological characteristics, practice of ventilation, and clinical outcome in patients at risk of acute respiratory distress syndrome in intensive care units from 16 countries (PRoVENT): an international, multicentre, prospective study. Lancet Respir Med. 2016;4(11):882–893.
  • Wang CY, Calfee CS, Paul DW, et al. One-year mortality and predictors of death among hospital survivors of acute respiratory distress syndrome. Intensive Care Med. 2014;40(3):388–396.
  • Wilson JG, Liu KD, Zhuo H, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med. 2015;3(1):24–32.
  • Liu KD, Wilson JG, Zhuo H, et al. Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome. Ann Intensive Care. 2014;4(1):22.
  • Prescott HC, Calfee CS, Thompson BT, et al., Toward smarter lumping and smarter splitting: rethinking strategies for sepsis and acute respiratory distress syndrome clinical trial design. Am J Respir Crit Care Med. 2016;194(2):147–155.
  • Ware LB, Koyama T, Billheimer DD, et al. Prognostic and pathogenetic value of combining clinical and biochemical indices in patients with acute lung injury. Chest. 2010;137(2):288–296.
  • Mullard A. RECOVERY 1 year on: a rare success in the COVID-19 clinical trial landscape. Nat Rev Drug Discov. 2021;20(5):336–337.
  • Millar JE, Wildi K, Bartnikowski N, et al. Characterizing preclinical sub‐phenotypic models of acute respiratory distress syndrome: an experimental ovine study. Physiol Rep. 2021;9(19):e15048.
  • Zhai R, Bonda WLM, Matute-Bello G, et al. From preclinical to clinical models of acute respiratory distress syndrome. Signa Vitae. 2021;18:3–14.
  • Spagnolo F, Ghiorzo P, and Orgiano L, et al. BRAF-mutant melanoma: treatment approaches, resistance mechanisms, and diagnostic strategies. Onco Targets Ther. 2015;8:157–168.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.