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  1. Steroid treatment in ARDS: a highly effective treatment.

    G. Umberto Meduri, University of Tennessee Health Science Center, Memphis, TN

    3 September 2007

    Steroid treatment in ARDS: a highly effective treatment.

    G. Umberto Meduri,1 MD, FCCP; Paul E. Marik,2 Stephen M. Pastores,3 MD; Djillali Annane,4 MD, PhD.

    Word count: 535

    1 University of Tennessee Health Science Center, Memphis, TN

    2 Thomas Jefferson University, Philadelphia, PA

    3 Memorial Sloan-Kettering Cancer Center, New York, NY

    4 Universite de Versailes Saint-Quentin en Yvelines, Garches, France

    The Journal club critique by Wajanaponsan and colleagues provides a partial picture of the literature on prolonged methylprednisolone treatment in acute respiratory distress syndrome (ARDS).1 Three randomized trials (N = 245) have investigated prolonged methylprednisolone treatment in early2 and unresolving ARDS.3,4 Two additional trials have also investigated prolonged hydrocortisone treatment in community-acquired pneumonia with early acute lung injury (ALI),5 and septic shock with early ARDS.6

    These trials (N = 518) consistently reported that prolonged glucocorticoid treatment was associated with significant improvement in PaO2:FiO2,2-6 and a significant reduction in markers of systemic inflammation,2-6 bronchoalveolar lavage neutrophilia,4,7 duration of mechanical ventilation,2-6 and intensive care unit stay.2-5 For studies that have investigated prolonged methylprednisolone treatment,2,3,4 the weighted mean difference in ventilator-free days to day 28 was 5.59 (3.49 - 7.68) days in favor of glucocorticoid treatment (P < 0.001).8 No other ventilatory or pharmacological intervention in ARDS has demonstrated a similar meaningful clinical response.

    Although the cited ARDS network trial4 reported substantial positive results for most secondary variables, the trial is portrayed as negative partly because of (1) increased mortality observed in the subgroup of patients randomized to methylprednisolone after day 14 of ARDS, and (2) increased rate of neuromuscular weakness. The small subgroup (N = 48), of patients randomized after day 14 of ARDS, however, had large imbalances in baseline characteristics for age, gender, pneumonia, trauma, serum creatinine, APACHE III, compliance, and lung injury score that likely accounted for the uncharacteristically low mortality in the control group (8% vs 36%; P = 0.035). When mortality was adjusted for baseline imbalances (Dr. Marek Ancukiewicz personal communication) significance was lost (P = 0.57). These findings directly challenge the conclusion of the ARDS network trial that “starting methylprednisolone therapy more than two weeks after the onset of ARDS may increase the risk of death”.

    When this uneven subgroup is removed, subgroup analysis for treatment initiation before day 14 of ARDS shows a significant reduction in mortality (35/144 (24%) vs. 40/101 (40%), RR = 0.62, 95% CI: 0.43 - 0.90; P = 0.01) with little heterogeneity across trials (Chi2 = 2.43, P = 0.30).8

    As Wajanaponsan and colleagues correctly point out, ICU-acquired paresis is a known independent predictor of prolonged weaning.9 However, among the 43 patients with identified weakness in the ARDS network trial, those randomized to methylprednisolone (N = 25) had a significant (P = 0.003) and sizable (11 days) reduction in duration of mechanical ventilation (Table 7, supplementary appendix).4 Of interest, criteria for serious events associated with myopathy or neuropathy were not defined in the text of the manuscript.

    Finally, glucocorticoid treatment has a strong benefit/risk ratio when it is applied in conjunction with measures proven to reduce morbidity associated with glucocorticoids.2,3 These measures include (i) intensive infections surveillance, (ii) avoidance of paralytic agents, and (iii) avoidance of rebound inflammation with premature discontinuation of treatment that may lead to physiological deterioration and re-intubation.2 The ARDS network trial did not include secondary prevention, a factor that likely increased morbidity and mortality in the treated group.

    The reviewed literature provides strong and consistent evidence that the correct use of this inexpensive and highly effective anti-inflammatory therapy accelerates resolution of ARDS and decreases duration of mechanical ventilation and ICU stay. Subgroup analyses for mortality are favorable, and a new confirmatory trial in early ALI-ARDS is under consideration.

    References

    1. Wajanaponsan N, Reade MC, Milbrandt EB. Steroids in late ARDS? Critical Care 2007;11:310

    2. Meduri GU, Golden E , Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest 2007;131:954-63.

    3. Meduri GU, Headley S, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome. A randomized controlled trial. JAMA 1998;280:159-65.

    4. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006;354(16):1671-84.

    5. Confalonieri M, Urbino R, Potena A, et al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med 2005;171(3):242-8.

    6. Annane D, Sebille 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.

    7. Sinclair S, Bijoy J, Golden E, Carratu P, Umberger R, GU M. Interleukin-8 and Soluble Intercellular Adhesion Molecule-1 during Acute Respiratory Distress Syndrome and in Response to Prolonged Methylprednisolone Treatment. Minerva Pneumologica 2006;45(2):93-104

    8. Meduri GU. There is no illumination in speculation. Additional data in support of methylprednisolone treatment in ARDS. Chest 2007;132:(in press)

    9. De Jonghe B, Bastuji-Garin S, Sharshar T, Outin H, Brochard L. Does ICU-acquired paresis lengthen weaning from mechanical ventilation? Intensive Care Med 2004;30(6):1117-21.

    Competing interests

    None

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