Glucocorticoids for ARDS

Abstract

A RDS 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 im-pact 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 trials 5– 8 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 understand-ing 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. 9 –16 Glucocorticoids modulate almost all steps of the inflammatory process through genomic and non-genomic actions. In patients with ARDS, moderate doses of glucocorticoids were associated with a pro-gressive increase in glucocorticoid receptor-medi-ated activities leading to significant reductions in nuclear factor-␬B DNA binding and transcription of tumor necrosis factor and interleukin-1␤. 10 Thereby, prolonged glucocorticoid treatment decreased both lung and circulating levels of various proinflamma-tory mediators at both early and late phases of the disease. 10 –16 In animal models of acute lung injury, early administration of glucocorticoids showed pro-tective effects on lung parenchyma with mainte-nance of tissue impedance and extracellular matrix. 15 In five randomized trials 11–14,16 of patients with acute lung injury or ARDS, prolonged treatment with glucocorticoids in moderate doses consistently im-proved gas exchange, lung injury score, and dramat-ically shortened duration of mechanical ventilation. Glucocorticoid treatment prevented the dissemina-tion of inflammation to extrapulmonary organs and decreased the prevalence of cardiovascular dysfunc-tion. 6 –10,12 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 or-gan failure should become a standard of care for ARDS patients. The effect of prolonged glucocorti-coid treatment on survival in ARDS remains contro-versial. In patients treated for persistent ARDS, ie, glucocorticoids were initiated after day 7 from the disease onset, one single-center randomized trial 11 showed dramatic increase in survival rate, whereas a recent multicenter trial 13 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 neuro-muscular blocking agent were the most important. The current study by Meduri et al 14 in this issue of CHEST (see page 954) is the first multicenter ran-domized, placebo-controlled trial focusing on early and prolonged (2 weeks at full dose then tapered off Ͼ 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 parame-ters and on ARDS complications, and suggested that this treatment improved short-term and long-term survival. The potential survival benefit was in keep-ing with a recently published post hoc analysis 12 of a randomized trial of low-dose glucocorticoids for CHEST