Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature
To compare the design and results of randomized trials investigating prolonged glucocorticoid treatment (≥ 7 days) in patients with acute lung injury–acute respiratory distress syndrome (ALI–ARDS), and review factors affecting response to therapy, including the role of secondary prevention.
Trials were retrieved from the Cochrane Central Register of Controlled Trials (CENTRAL). Two investigators collected data on study characteristics, treatment intervention, and outcomes. The methodological quality of trials was determined and data were analyzed with Review Manager 4.2.3.
Measurements and results
Five selected trials (n = 518) consistently reported significant improvement in gas exchange, reduction in markers of inflammation, and decreased duration of mechanical ventilation and intensive care unit stay (all p < 0.05). Two early small clinical trials showed marked reductions in the relative risk (RR) of death with glucocorticoid therapy (RR = 0.14, 95% CI 0.04–0.53; p = 0.004, I2 = 0%). Three subsequent larger trials, when combined, although nominally beneficial, did not reproduce the marked reductions observed in the earlier trials (RR = 0.84; 95% CI 0.68–1.03; p = 0.09, I2 = 9.1%), but achieved a distinct reduction in the RR of death in the larger subgroup of patients (n = 400) treated before day 14 of ARDS [82/214 (38%) vs. 98/186 (52.5%), RR = 0.78; 95% CI 0.64–0.96; p = 0.02, I2 = 0%].
Prolonged glucocorticoid treatment substantially and significantly improves meaningful patient-centered outcome variables, and has a distinct survival benefit when initiated before day 14 of ARDS.
KeywordsAcute respiratory distress syndrome Glucocorticoid treatment Duration of mechanical ventilation Mortality
- 1.Meduri GU, Muthiah MP, Carratu P, Eltorky M, Chrousos GP (2005) Nuclear factor-kappaB- and glucocorticoid receptor alpha-mediated mechanisms in the regulation of systemic and pulmonary inflammation during sepsis and acute respiratory distress syndrome. Evidence for inflammation-induced target tissue resistance to glucocorticoids. Neuroimmunomodulation 12:321–338PubMedCrossRefGoogle Scholar
- 4.Sinclair S, Bijoy J, Golden E, Carratu P, Umberger R, Meduri GU (2006) Interleukin-8 and soluble intercellular adhesion molecule-1 during acute respiratory distress syndrome and in response to prolonged methylprednisolone treatment. Minerva Pneumol 45:93–104Google Scholar
- 5.Bone RC, Maunder R, Slotman G, Silverman H, Hyers TM, Kerstein MD, Ursprung JJ (1989) An early test of survival in patients with the adult respiratory distress syndrome. The PaO2/FiO2 ratio and its differential response to conventional therapy. Prostaglandin E1 Study Group. Chest 96:849–851PubMedCrossRefGoogle Scholar
- 8.Meduri GU, Tolley EA, Chrousos GP, Stentz F (2002) Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome. Evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids. Am J Respir Crit Care Med 165:983–991PubMedGoogle Scholar
- 20.Keh D BT, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk HD, Doecke WD, Falke KJ, Gerlach H (2003) Immunologic and hemodynamic effects of “low-dose” hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med 167:512–520PubMedCrossRefGoogle Scholar
- 21.Yates CR, Vysokanov A, Mukherjee A, Ludden TM, Tolley EA, Meduri GU, Dalton JT (2001) Time-variant increase in methylprednisolone clearance in patients with acute respiratory distress syndrome: A population pharmocokinetic study. J Clin Pharmacol 41:1–10Google Scholar
- 42.Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E (2002) Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288:862–871PubMedCrossRefGoogle Scholar