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Steroids in late ARDS?

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Expanded Abstract

Citation

Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, Thompson BT, Ancukiewicz M: Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006, 354:1671–1684 [1].

Background

Persistent acute respiratory distress syndrome (ARDS) is characterized by excessive fibroproliferation, ongoing inflammation, prolonged mechanical ventilation, and a substantial risk of death. Because previous reports suggested that corticosteroids may improve survival, the study authors performed a multicenter, randomized controlled trial of corticosteroids in patients with persistent ARDS.

Methods

Objective

To determine if low dose corticosteroids would improve survival among patients with persistent ARDS.

Design

Multicenter randomized controlled trial.

Setting

25 hospitals in the United States that were part of the ARDS Clinical Trials Network.

Subjects

180 mechanically ventilated patients with ARDS of at least seven days duration.

Intervention

Subjects were randomized to either intravenous methylprednisolone (steroid group) or placebo in a double-blind fashion. Those in the steroid group received 2 mg/kg loading dose followed by 0.5 mg/kg every 6 hours for 14 days, 0.5 mg/kg every 12 hours for 7 days, and then tapering of the dose over 2–4 days.

Measurements and main results

The primary end point was mortality at 60 days. Secondary end points included the number of ventilator-free days and organ-failure-free days, biochemical markers of inflammation and fibroproliferation, and infectious complications. At 60 days, the hospital mortality rate was 28.6 percent in the placebo group (95 percent confidence interval, 20.3 to 38.6 percent) and 29.2 percent in the methylprednisolone group (95 percent confidence interval, 20.8 to 39.4 percent; P = 1.0); at 180 days, the rates were 31.9 percent (95 percent confidence interval, 23.2 to 42.0 percent) and 31.5 percent (95 percent confidence interval, 22.8 to 41.7 percent; P = 1.0), respectively. Methylprednisolone was associated with significantly increased 60- and 180-day mortality rates among patients enrolled at least 14 days after the onset of ARDS. Methylprednisolone increased the number of ventilator-free and shock-free days during the first 28 days in association with an improvement in oxygenation, respiratory-system compliance, and blood pressure with fewer days of vasopressor therapy. As compared with placebo, methylprednisolone did not increase the rate of infectious complications but was associated with a higher rate of neuromuscular weakness.

Conclusion

These results do not support the routine use of methylprednisolone for persistent ARDS despite the improvement in cardiopulmonary physiology. In addition, starting methylprednisolone therapy more than two weeks after the onset of ARDS may increase the risk of death. (ClinicalTrials.gov number, NCT00295269.)

Commentary

ARDS is a condition characterized by excessive and protracted inflammation. The lung inflammation observed in ARDS can be precipitated by diverse disease processes, including both intrapulmonary ones (such as, infection or aspiration) and extrapulmonary ones (such as, shock or extensive trauma). In the early (<7 days) stages of ARDS, an exudative inflammation is thought to predominate. In later stages (>7 days), a fibroproliferative phase may develop. Each of these two inflammatory phases has been considered potentially amenable to the anti-inflammatory effects of corticosteroid (steroid) therapy.

Short courses of high doses of steroids in ARDS are not beneficial [2, 3]. More recently, it has been suggested that lower doses of steroid (1–2 mg/kg/day) for a more prolonged period might benefit the lung while reducing the potential for systemic side-effects. Recent data from a retrospective subgroup analysis of a clinical trial [4] and a small (n = 91) prospective clinical trial [5] suggest that such an approach may improve outcomes, including mortality, in early ARDS. In late ARDS, initial observational studies also suggested benefit [6, 7]. Subsequently, in 1998, Meduri and colleagues reported dramatically lower ICU (0% vs 62%, p = 0.002) and hospital (12% vs 62%, p = 0.03) mortality in a small (n = 24) randomized study of low dose steroids in patients who had severe ARDS for 7 days [8].

Based on the promising results in late ARDS, the ARDS Clinical Trials Network conducted the current study, which was a multicenter randomized trial of low dose steroids in 180 patients with ARDS of at least 7 days duration [1]. In this study, the steroid treated group received intravenous methylprednisolone (2 mg/kg/day) for 14 days. The dose was then decreased to 1 mg/kg/day for 7 more days, and then tapered to zero over 2–4 days. Steroid treated subjects had significantly reduced lung inflammation, improved oxygenation, better respiratory-system compliance, and more ventilator-free and shock-free days during the first 28 days. However, 60 and 180 day mortality rates in each group were almost identical (29.2% vs. 28.6% and 31.5% vs. 31.9%, steroids vs. placebo). There were no differences in infectious complications, but there was a higher rate of neuromuscular weakness in the steroid group. In the subset of patients enrolled at least 14 days after the onset of ARDS, steroids were associated with significantly worse 60 and 180 day mortality. Yet, in those enrolled between 7 and 13 days of ARDS onset, mortality was non-significantly lower with steroids.

Although this was a large and well conducted study, a number of criticisms have been raised. The study was conducted over a period of time when there were substantial changes in ICU practice, including low tidal volume ventilation, tight blood glucose control, and steroids for refractory septic shock. Even so, the authors did not find an interaction between period of time or baseline tidal volume and outcome, suggesting that secular trends did not obscure a beneficial steroid effect. The study had a large number of exclusion criteria, which resulted in only 5% of otherwise eligible patients being enrolled. While this could affect the generalizability of the study, it is not uncommon in ICU-based clinical trials. The methylprednisolone was tapered relatively quickly (over 2–4 days), which might have led to rebound pulmonary inflammation [9]. This premise is supported by greater reintubation rates in steroid treated subjects (22% vs. 7%), though neuromyopathy could also be responsible for this latter finding. The treatment group contained a disproportionate number of females, and females have previously been shown to be less responsive to corticosteroid therapy [10], perhaps because of a greater capacity to metabolize methylprednisolone compared to males [11]. However, the interactions between gender, treatment assignment, and outcome were not significant.

It is perhaps surprising that while steroids had beneficial short-term effects, such as reduced inflammation and improved physiologic measures, this did not translate into improved mortality. Yet the literature is full of examples where short-term effects and surrogate endpoints fail to predict long-term clinical outcomes [12] (table).

Such disparate findings do not indicate a failed clinical trial. In fact, protocol dictates that after in vivo biology has been demonstrated and efficacy inferred by improvements in surrogate measures, definitive studies should seek evidence of benefit using end points that measure important, patient-centered outcomes, including intermediate and longer term survival [21]. Clearly, the authors of the current study followed the established paradigm. Their findings should serve to remind us that while we may be eager to embrace the latest treatment advances, we should always maintain a skeptic's eye.

Recommendation

Prolonged low dose corticosteroids are not beneficial for the treatment of late ARDS and may be harmful for patients when initiated more than 14 days after the onset of ARDS. There may be a window of opportunity for further study of low dose steroids in late ARDS in patients who are within 7–13 days of disease onset. This distinction, however, is somewhat arbitrary and the optimum time to intervene might be better guided by as yet unidentified measures of pulmonary and systemic immune status.

Table 1 Surrogate vs. clinical outcomes

References

  1. Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, Thompson BT, Ancukiewicz M: Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006, 354: 1671-1684. 10.1056/NEJMoa051693

    Article  CAS  PubMed  Google Scholar 

  2. Bernard GR, Luce JM, Sprung CL, Rinaldo JE, Tate RM, Sibbald WJ, Kariman K, Higgins S, Bradley R, Metz CA: High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med 1987, 317: 1565-1570.

    Article  CAS  PubMed  Google Scholar 

  3. Luce JM, Montgomery AB, Marks JD, Turner J, Metz CA, Murray JF: Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am Rev Respir Dis 1988, 138: 62-68.

    Article  CAS  PubMed  Google Scholar 

  4. Annane D, Sebille V, Bellissant E, Ger-Inf-05 Study Group: Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Crit Care Med 2006, 34: 22-30. 10.1097/01.CCM.0000194723.78632.62

    Article  CAS  PubMed  Google Scholar 

  5. Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, Gibson M, Umberger R: Methylprednisolone Infusion in Early Severe ARDS*Results of a Randomized Controlled Trial. Chest 2007, 131: 954-963. 10.1378/chest.06-2100

    Article  CAS  PubMed  Google Scholar 

  6. Biffl WL, Moore FA, Moore EE, Haenel JB, McIntyre RC Jr, Burch JM: Are corticosteroids salvage therapy for refractory acute respiratory distress syndrome? Am J Surg 1995, 170: 591-595. 10.1016/S0002-9610(99)80022-1

    Article  CAS  PubMed  Google Scholar 

  7. Keel JB, Hauser M, Stocker R, Baumann PC, Speich R: Established acute respiratory distress syndrome: benefit of corticosteroid rescue therapy. Respiration 1998, 65: 258-264. 10.1159/000029273

    Article  CAS  PubMed  Google Scholar 

  8. Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, Tolley EA: Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA 1998, 280: 159-165. 10.1001/jama.280.2.159

    Article  CAS  PubMed  Google Scholar 

  9. Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk HD, Doecke WD, Falke KJ, Gerlach H: 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 2003, 167: 512-520. 10.1164/rccm.200205-446OC

    Article  PubMed  Google Scholar 

  10. Keel JB, Hauser M, Stocker R, Baumann PC, Speich R: Established acute respiratory distress syndrome: benefit of corticosteroid rescue therapy. Respiration 1998, 65: 258-264. 10.1159/000029273

    Article  CAS  PubMed  Google Scholar 

  11. Lew KH, Ludwig EA, Milad MA, Donovan K, Middleton E Jr, Ferry JJ, Jusko WJ: Gender-based effects on methylprednisolone pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 1993, 54: 402-414.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Fleming TR, DeMets DL: Surrogate end points in clinical trials: are we being misled? Ann Intern Med 1996, 125: 605-613.

    Article  CAS  PubMed  Google Scholar 

  13. Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ: Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 1999, 341: 785-792. 10.1056/NEJM199909093411102

    Article  CAS  PubMed  Google Scholar 

  14. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML: Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med 1991, 325: 1468-1475.

    Article  CAS  PubMed  Google Scholar 

  15. DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant RC, Wright R: A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med 1989, 320: 677-683.

    Article  CAS  PubMed  Google Scholar 

  16. Effects of encainide, flecainide, imipramine and moricizine on ventricular arrhythmias during the year after acute myocardial infarction: the CAPS. The Cardiac Arrhythmia Pilot Study (CAPS) Investigators Am J Cardiol 1988, 61: 501-509. 10.1016/0002-9149(88)90754-0

  17. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators N Engl J Med 1989, 321: 406-412.

  18. Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E: A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 1999, 340: 409-417. 10.1056/NEJM199902113400601

    Article  CAS  PubMed  Google Scholar 

  19. Griffiths MJ, Evans TW: Inhaled nitric oxide therapy in adults. N Engl J Med 2005, 353: 2683-2695. 10.1056/NEJMra051884

    Article  CAS  PubMed  Google Scholar 

  20. Spragg RG, Lewis JF, Walmrath HD, Johannigman J, Bellingan G, Laterre PF, Witte MC, Richards GA, Rippin G, Rathgeb F, Hafner D, Taut FJ, Seeger W: Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. N Engl J Med 2004, 351: 884-892. 10.1056/NEJMoa033181

    Article  CAS  PubMed  Google Scholar 

  21. Marshall JC, Vincent JL, Guyatt G, Angus DC, Abraham E, Bernard G, Bombardier C, Calandra T, Jorgensen HS, Sylvester R, Boers M: Outcome measures for clinical research in sepsis: a report of the 2nd Cambridge Colloquium of the International Sepsis Forum. Crit Care Med 2005, 33: 1708-1716. 10.1097/01.CCM.0000174478.70338.03

    Article  PubMed  Google Scholar 

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Wajanaponsan, N., Reade, M.C. & Milbrandt, E.B. Steroids in late ARDS?. Crit Care 11, 310 (2007). https://doi.org/10.1186/cc5954

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