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Intensive Care Medicine

, Volume 42, Issue 5, pp 829–840 | Cite as

Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients’ data from four randomized trials and trial-level meta-analysis of the updated literature

  • G. Umberto MeduriEmail author
  • Lisa Bridges
  • Mei-Chiung Shih
  • Paul E. Marik
  • Reed A. C. Siemieniuk
  • Mehmet Kocak
Systematic Review

Abstract

Purpose

To investigate the effect of prolonged glucocorticoid treatment for patients with acute respiratory distress syndrome (ARDS).

Methods

We conducted two sets of intention-to-treat analyses: (1) a primary analysis of individual patients’ data (IPD) of four randomized controlled trials (RCTs) which investigated methylprednisolone treatment (n = 322) and (2) a trial-level meta-analysis incorporating four additional RCTs which investigated hydrocortisone treatment in early ARDS (n = 297). We standardized definitions to derive outcomes in all datasets. The primary outcome for the IPD analysis was time to achieving unassisted breathing (UAB) by study day 28. Secondary outcomes included mechanical ventilation (MV) and intensive care unit (ICU)-free days, hospital mortality, and time to hospital mortality by day 28.

Results

By study day 28, compared to the placebo group, the methylprednisolone group had fewer patients who died before achieving UAB (12 vs. 29 %; p < 0.001) and more patients who achieved UAB (80 vs. 50 %; p < 0.001). In the methylprednisolone group, time to achieving UAB was shorter [hazard ratio 2.59, 95 % confidence interval (CI) 1.95–3.43; p < 0.001], and hospital mortality was decreased (20 vs. 33 %; p = 0.006), leading to increased MV (13.3 ± 11.8 vs. 7.6 ± 5.7; p < 0.001) and ICU-free days (10.8 ± 0.71 vs. 6.4 ± 0.85; p < 0.001). In those patients randomized before day 14 of ARDS onset, the trial-level meta-analysis indicated decreased hospital mortality (36 vs. 49 %; risk ratio 0.76, 95 % CI 0.59–0.98, I 2 = 17 %, p = 0.035; moderate certainty). Treatment was not associated with increased risk for infections (risk ratio 0.77, 95 % CI 0.56–1.08, I 2 = 26 %; p = 0.13; moderate certainty).

Conclusions

Prolonged methylprednisolone treatment accelerates the resolution of ARDS, improving a broad spectrum of interrelated clinical outcomes and decreasing hospital mortality and healthcare utilization.

Keywords

Adult respiratory distress syndrome Glucocorticoid treatment Mechanical ventilation Survival 

Notes

Acknowledgments

The NHLBI ARDS network graciously provided and assisted with the ARDSnet02 Dataset on the “Efficacy of Corticosteroids as Rescue Therapy for the Late Phase of Acute Respiratory Distress Syndrome (LaSRS)”. Dr. Nasef Rezk (Mansoura University, Egypt) graciously provided unpublished data of his publication. Dr. Jeff Zuber (Memphis Veterans Affairs Medical Center) for assistance in organizing the IPD files.

Compliance with ethical standards

Conflicts of interest

The authors have no competing interests to declare or any real or perceived financial interest in any product or commodity mentioned in this paper.

Funding

This material is the result of work supported with the resources and use of facilities at the Memphis VA Medical Center. The contents of this commentary do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. Funding for the respective trials was disclosed in the original publications. None of the sponsors had any role in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, the preparation, review, or approval of the report, or the decision to submit the manuscript for publication. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Supplementary material

134_2015_4095_MOESM1_ESM.doc (1.9 mb)
Supplementary material 1 (DOC 1993 kb)

References

  1. 1.
    Meduri GU, Annane D, Chrousos GP, Marik PE, Sinclair SE (2009) Activation and regulation of systemic inflammation in ARDS: rationale for prolonged glucocorticoid therapy. Chest 136:1631–1643CrossRefPubMedGoogle Scholar
  2. 2.
    Meduri GU, Eltorky MA (2015) Understanding ARDS-associated fibroproliferation. Intensive Care Med 41:517–520CrossRefPubMedGoogle Scholar
  3. 3.
    Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS (2012) Acute respiratory distress syndrome: the Berlin definition. JAMA 307:2526–2533Google Scholar
  4. 4.
    Lamontagne F, Briel M, Guyatt GH, Cook DJ, Bhatnagar N, Meade M (2010) Corticosteroid therapy for acute lung injury, acute respiratory distress syndrome, and severe pneumonia: a meta-analysis of randomized controlled trials. J Crit Care 25:420–435CrossRefPubMedGoogle Scholar
  5. 5.
    Reade MC, Delaney A, Bailey MJ, Harrison DA, Yealy DM, Jones PG, Rowan KM, Bellomo R, Angus DC (2010) Prospective meta-analysis using individual patient data in intensive care medicine. Intensive Care Med 36:11–21CrossRefPubMedGoogle Scholar
  6. 6.
    Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, Gibson M, Umbergere R (2007) Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest 131:954–963CrossRefPubMedGoogle Scholar
  7. 7.
    Rezk N, Ibrahim A (2013) Effects of methylprednisolone in early ARDS. Egypt J Chest Dis Tuberc 62:167–172CrossRefGoogle Scholar
  8. 8.
    Meduri GU, Headley S, Golden E, Carson S, Umberger R, Kelso T, Tolley E (1998) Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome. A randomized control trial. JAMA 280:159–165CrossRefPubMedGoogle Scholar
  9. 9.
    Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, Thompson BT, Ancukiewicz M (2006) Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 354:1671–1684CrossRefPubMedGoogle Scholar
  10. 10.
    Meduri GU, Marik PE, Chrousos GP, Pastores SM, Arlt W, Beishuizen A, Bokhari F, Zaloga G, Annane D (2008) Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature. Intensive Care Med 34:61–69CrossRefPubMedGoogle Scholar
  11. 11.
    Confalonieri M, Urbino R, Potena A, Piattella M, Parigi P, Puccio G, Della Porta R, Giorgio C, Blasi F, Umberger R, Meduri GU (2005) Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med 171:242–248CrossRefPubMedGoogle Scholar
  12. 12.
    Annane D, Sébille V, Bellissant E; Ger-Inf-05 Study Group (2006) Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Crit Care Med 34(1):22–30CrossRefPubMedGoogle Scholar
  13. 13.
    Sabry NA, Omar EE-D (2011) Corticosteroids and ICU course of community acquired pneumonia in Egyptian settings. Pharmacol Pharm 2:73–81CrossRefGoogle Scholar
  14. 14.
    Liu L, Li J, Huang YZ, Liu SQ, Yang CS, Guo FM, Qiu HB, Yang Y (2012) 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 51:599–603PubMedGoogle Scholar
  15. 15.
    Vincent JL, de Mendonca A, Cantraine F, Moreno R, Takala J, Suter PM, Sprung CL, Colardyn F, Blecher S (1998) Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit Care Med 26:1793–1800CrossRefPubMedGoogle Scholar
  16. 16.
    Busse J, Guyatt G (2013) Modification of Cochrane tool to assess risk of bias in randomized trials. https://distillercer.com/wp-content/uploads/2014/02/Tool-to-Assess-Risk-of-Bias-in-Randomized-Controlled-Trials.docx
  17. 17.
    Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schunemann HJ (2008) GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 336:924–926CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Gray J (1998) A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141–1154CrossRefGoogle Scholar
  19. 19.
    Fine JP, Gray RJ (1999) A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94:496–509CrossRefGoogle Scholar
  20. 20.
    Therneau T (2000) Modeling survival data: extending the Cox model. Springer, New YorkCrossRefGoogle Scholar
  21. 21.
    Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339:b2535CrossRefGoogle Scholar
  22. 22.
    Tang B, Craig J, Eslick G, Seppelt I, McLean A (2009) Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care Med 37:1594–1603CrossRefPubMedGoogle Scholar
  23. 23.
    Bassler D, Briel M, Montori VM, Lane M, Glasziou P, Zhou Q, Heels-Ansdell D, Walter SD, Guyatt GH, Group S-S, Flynn DN, Elamin MB, Murad MH, Abu Elnour NO, Lampropulos JF, Sood A, Mullan RJ, Erwin PJ, Bankhead CR, Perera R, Ruiz Culebro C, You JJ, Mulla SM, Kaur J, Nerenberg KA, Schunemann H, Cook DJ, Lutz K, Ribic CM, Vale N, Malaga G, Akl EA, Ferreira-Gonzalez I, Alonso-Coello P, Urrutia G, Kunz R, Bucher HC, Nordmann AJ, Raatz H, da Silva SA, Tuche F, Strahm B, Djulbegovic B, Adhikari NK, Mills EJ, Gwadry-Sridhar F, Kirpalani H, Soares HP, Karanicolas PJ, Burns KE, Vandvik PO, Coto-Yglesias F, Chrispim PP, Ramsay T (2010) Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA 303:1180–1187CrossRefPubMedGoogle Scholar
  24. 24.
    Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, Fine J, Krichevsky A, Delude RL, Angus DC (2007) Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med 167:1655–1663CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Meduri GU, Headley S, Kohler G, Stentz F, Tolley E, Umberger R, Leeper K (1995) Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 107:1062–1073CrossRefPubMedGoogle Scholar
  26. 26.
    Meduri GU, Kohler G, Headley S, Tolley E, Stentz F, Postlethwaite A (1995) Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome. Chest 108:1303–1314CrossRefPubMedGoogle Scholar
  27. 27.
    Meduri GU, Tolley EA, Chinn A, Stentz F, Postlethwaite A (1998) Procollagen types I and III aminoterminal propeptide levels during acute respiratory distress syndrome and in response to methylprednisolone treatment. Am J Respir Crit Care Med 158:1432–1441CrossRefPubMedGoogle Scholar
  28. 28.
    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 12:321–338CrossRefPubMedGoogle Scholar
  29. 29.
    Meduri GU, Headley S, Tolley E, Shelby M, Stentz F, Postlethwaite A (1995) Plasma and BAL cytokine response to corticosteroid rescue treatment in late ARDS. Chest 108:1315–1325CrossRefPubMedGoogle Scholar
  30. 30.
    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 165:983–991CrossRefPubMedGoogle Scholar
  31. 31.
    Sinclair SE, 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
  32. 32.
    Henzen C, Suter A, Lerch E, Urbinelli R, Schorno XH, Briner VA (2000) Suppression and recovery of adrenal response after short-term, high- dose glucocorticoid treatment. Lancet 355:542–545CrossRefPubMedGoogle Scholar
  33. 33.
    Pfizer (2009) Solu-medrol. Methylprednisolone sodium succinate product information. Pfizer, New York. Available at:http://labeling.pfizer.com/ShowLabeling.aspx?id=648
  34. 34.
    Nawab Q, Golden E, Confalonieri M, Umberger R, Meduri G (2011) Corticosteroid treatment in severe community-acquired pneumonia: duration of treatment affects control of systemic inflammation and clinical improvement. Intensive Care Med 37:1153–1554CrossRefGoogle Scholar
  35. 35.
    Meduri GU (2007) There is no illumination in speculation. Additional data in support of methylprednisolone treatment in ARDS. Chest 132:1097–1100CrossRefGoogle Scholar
  36. 36.
    Thompson BT, Ancukiewicz M, Hudson LD, Steinberg KP, Bernard GR (2007) Steroid treatment for persistent ARDS: a word of caution. Crit Care 11:425CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Marik PE, Pastores S, Annane D, Meduri G, Sprung C, Arlt W, Keh D, Briegel J, Beishuizen A, Dimopoulou I, Tsagarakis S, Singer M, Chrousos GP, Zaloga GP, Bokhari F, Vogeser M (2008) Clinical practice guidelines for the diagnosis and management of corticosteroid insufficiency in critical illness: recommendations of an international task force. Crit Care Med 36:1937–1949CrossRefPubMedGoogle Scholar
  38. 38.
    Siemieniuk RA, Meade MO, Alonso-Coello P, Briel M, Evaniew N, Prasad M, Alexander PE, Fei Y, Vandvik PO, Loeb M, Guyatt GH (2015) Corticosteroid therapy for patients hospitalized with community-acquired Pneumonia: A systematic review and meta-analysis. Ann Intern Med 163(7):519–528Google Scholar
  39. 39.
    Greos LS, Vichyanond P, Bloedow DC, Irvin CG, Larsen GL, Szefler SJ, Hill MR (1991) Methylprednisolone achieves greater concentrations in the lung than prednisolone. A pharmacokinetic analysis. Am Rev Respir Dis 144:586–592CrossRefPubMedGoogle Scholar
  40. 40.
    Jantz MA, Sahn SA (1999) Corticosteroids in acute respiratory failure. Am J Respir Crit Care Med 160:1079–1100CrossRefPubMedGoogle Scholar
  41. 41.
    Gupta L, James B (2012) Prone position and intravenous steroids for the management of severe ARDS. Thorax 67:A38CrossRefGoogle Scholar
  42. 42.
    Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Guerin C, Prat G, Morange S, Roch A, Investigators AS (2010) Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 363:1107–1116CrossRefPubMedGoogle Scholar
  43. 43.
    Dunser M, Hasibeder W, Rieger M, Mayr AJ (2004) Successful therapy of severe pneumonia-associated ARDS after pneumonectomy with ECMO and steroids. Ann Thorac Surg 78:335–337CrossRefPubMedGoogle Scholar
  44. 44.
    Gomez Manjarres D, Gay E (2015) A promising combination for treating blastomyces induced ARDS. Am J Respir Crit Care Med 191:A1690Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2015

Authors and Affiliations

  • G. Umberto Meduri
    • 1
    Email author
  • Lisa Bridges
    • 1
  • Mei-Chiung Shih
    • 2
    • 3
  • Paul E. Marik
    • 4
  • Reed A. C. Siemieniuk
    • 5
    • 6
  • Mehmet Kocak
    • 7
  1. 1.Division of Pulmonary, Critical Care and Sleep Medicine, Department of MedicineMemphis Veterans Affairs Medical Center (111)MemphisUSA
  2. 2.Department of Veterans AffairsCooperative Studies Program Coordinating CenterPalo AltoUSA
  3. 3.Department of Health Research and PolicyStanford UniversityStanfordUSA
  4. 4.Division of Pulmonary and Critical Care Medicine, Department of MedicineEastern Virginia Medical SchoolNorfolkUSA
  5. 5.Department of Clinical Epidemiology and BiostatisticsMcMaster UniversityHamiltonCanada
  6. 6.Department of MedicineUniversity of TorontoTorontoCanada
  7. 7.Department of Preventive MedicineUniversity of Tennessee Health Science CenterMemphisUSA

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