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Hospital Raymond Poincaré Garches, France
Dr. Annane is Professor in Medicine, Director of the General Intensive Care Unit, and Vice President of University of Versailles Saint Quentin en Yvelines.
Correspondence to: Djillali Annane, MD, PhD, service de reanimation, hospital Raymond Poincaré (AP-HP), University of Versailles SQY, 104 boulevard Raymond Poincaré, 92380 Garches, France; e-mail: Djillali.Annane{at}rpc.aphp.fr
ARDS places a significant burden on the health-care system, with an estimated prevalence of 7% of ICU admissions and an unacceptable hospital mortality rate of 50%.1 Pulmonary and systemic inflammation are the pathophysiologic hallmarks of this syndrome,2 and activation of the glucocorticoid receptor in pulmonary and circulating cells is an essential step in restoring homeostasis.3 While changing the ventilator settings to low tidal volume reduces systemic inflammation with a favorable impact on survival,4 a concomitant antiinflammatory pharmacologic intervention should lead to a more rapid resolution of ARDS and earlier extubation. Among the antiinflammatory drugs, glucocorticoids have been the most investigated treatment in ARDS. Early trials5678 demonstrated that, when administered at high dose (eg, 30 mg/kg of body weight [2,100 mg for a patient weighing 70 kg] of methylprednisolone [or equivalent] per day for approximately 24 h) to cure or to prevent ARDS, glucocorticoids provided no survival benefit and even may have favored life-threatening superinfections. In the last 20 years, significant advances have been made in understanding the complex molecular mechanisms of action of glucocorticoids, while accumulated clinical data on low-dose, prolonged glucocorticoid treatment (methylprednisolone, 1 mg/kg/d [70 mg for a patient weighing 70 kg], or equivalent) in ARDS has shown significant improvement in inflammation and lung physiology with a favorable benefit/risk profile.910111213141516 Glucocorticoids modulate almost all steps of the inflammatory process through genomic and nongenomic actions. In patients with ARDS, moderate doses of glucocorticoids were associated with a progressive increase in glucocorticoid receptor-mediated activities leading to significant reductions in nuclear factor-
B DNA binding and transcription of tumor necrosis factor and interleukin-1ß.10 Thereby, prolonged glucocorticoid treatment decreased both lung and circulating levels of various proinflammatory mediators at both early and late phases of the disease.10111213141516 In animal models of acute lung injury, early administration of glucocorticoids showed protective effects on lung parenchyma with maintenance of tissue impedance and extracellular matrix.15 In five randomized trials1112131416 of patients with acute lung injury or ARDS, prolonged treatment with glucocorticoids in moderate doses consistently improved gas exchange, lung injury score, and dramatically shortened duration of mechanical ventilation. Glucocorticoid treatment prevented the dissemination of inflammation to extrapulmonary organs and decreased the prevalence of cardiovascular dysfunction.67891012 Needless to say, that for many physicians, a treatment that reduces pulmonary and systemic inflammation, improves lung mechanics and gas exchange, and prevents progression of multiple organ failure should become a standard of care for ARDS patients. The effect of prolonged glucocorticoid treatment on survival in ARDS remains controversial. In patients treated for persistent ARDS, ie, glucocorticoids were initiated after day 7 from the disease onset, one single-center randomized trial11 showed dramatic increase in survival rate, whereas a recent multicenter trial13 did not show any evidence for a survival benefit, and even suggested that when glucocorticoids are administered very late after 2 weeks of progression of the disease, they may cause harm. There are significant differences in between-studies design that may account for this discrepancy in results on survival. Among them, too short of a period allowed to wean glucocorticoids in the ARDSnet trial,13 and concomitant use of a neuromuscular blocking agent were the most important. The current study by Meduri et al14 in this issue of CHEST (see page 954) is the first multicenter randomized, placebo-controlled trial focusing on early and prolonged (2 weeks at full dose then tapered off > 2 weeks) treatment with low- dose glucocorticoids (1 mg/kg per day [70 mg/d for a patient weighing 70 kg] of methylprednisolone). This study confirms the benefit from glucocorticoids on physiologic parameters and on ARDS complications, and suggested that this treatment improved short-term and long-term survival. The potential survival benefit was in keeping with a recently published post hoc analysis12 of a randomized trial of low-dose glucocorticoids for septic shock that included patients with ARDS and showed significant improvement in hospital and 1-year survival. Then, when data from these four randomized placebo-controlled trials on moderate dose of glucocorticoids for ARDS are pooled, accounting for 472 patients, the relative risk of short-term mortality was 0.81 (95% confidence interval, 0.66 to 0.99) in favor of treatment with glucocorticoids.11–19 Glucocorticoids may induce serious adverse events; among them, GI bleeding, superinfection, blunted febrile response, hyperglycemia, and muscle weakness deserve specific attention to be prevented. These drug-related adverse events should not discourage physicians from treating ARDS patients with glucocorticoids, similar to our approach with prolonged methylprednisone treatment in patients admitted to the ICU with acute exacerbation of asthma or COPD.
Moreover, in randomized controlled trials11121314 on moderate-dose glucocorticoids, this treatment was not associated with increased risks of bleeding or superinfection. Infection surveillance, as shown in this study, is essential to identify infection in the presence of a blunted febrile response.10 Tight glycemic control with insulin and avoidance of neuromuscular blocking agents are likely to minimize metabolic and neurologic complications. Short course with high-dose glucocorticoids (30 mg/kg [2,100 mg for a patient weighing 70 kg] of methylprenisolone for approximately 24 h) must not be administered to patients with ARDS. In contrast, it is this author’s opinion that patients with ARDS, regardless of the stage of the disease (except for patients with ARDS persisting for > 2 weeks), should be treated with prolonged, moderate-dose methylprednisolone as proposed by Meduri and colleagues.1114 Secondary measures implemented in this study to prevent complications associated with glucocorticoids are essential to achieve favorable results and should be an integral part of treatment.
Footnotes
The author has no conflict of interest to disclose.
References
B- and glucocorticoid receptor 
-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 2005;12,321-338[CrossRef][ISI][Medline]Related Article
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R. H. Savel, E. B. Goldstein, H. Lehman, Y. Kupfer, and D. Annane Methylprednisolone Infusion in Early Severe ARDS Chest, September 1, 2007; 132(3): 1096 - 1097. [Full Text] [PDF]
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