The Role of Steroids in ARDS

1. The Role of Steroids in ARDS A review of the evidence Alex Yartsev 11/2010

2. Briefly, on the definition of ARDS • Acute severe hypoxic respiratory failure with bilateral diffuse alveolar damage • Lots of different criteria: 1994 AECC consensus, the LIS score, the Delphi definition… • It has to be acute • PaO2 to FiO2 ratio of <200 • PEEP > 10 • bilaterality • ABSENCE of left ventricular failure Bersen A.D, the Acute Respiratory Distress Syndrome (ARDS) Ch 29 in Ohs Intensive Care Manual, 6th ed.

3. Briefly, on the pathology of ARDS There is diffuse alveolar damage; • Alveolar-capillary barrier is damaged • Thus, there is pulmonary oedema • There is a complex inflammatory infiltrate • Neutrophils play some role? a major role?... • but neutropenic patients gets ARDS as well… • There is surfactant dysfunction • Surfactant keep alveoli from collapsing • Sequence of events depends on what is causing the ARDS: is the cause pulmonary or extrapulmonary? Bersen A.D, the Acute Respiratory Distress Syndrome (ARDS) Ch 29 in Ohs Intensive Care Manual, 6th ed.

4. Briefly, on the pathogenesis of ARDS • The lung is a filter for the whole body’s blood • Circulating or local inflammatory mediators • Either way, something damages the endothelium first • The endothelium becomes leaky when it is inflamed • The endothelium expresses adhesion molecules, attracts neutrophils • Neutrophils / macrophages amplify lung damage • They also secrete mediators which cause pulmonary vasoconstriction and thus worsening hypoxia • Leaky inflamed endothelium ceases to produce surfactant, and surfactant is also lost because the leak through the capillary wall is bi-directional Orfanos SE et al, Pulmonary endothelium in acute lung injury: from basic science to the critically ill Applied Physiology in Intensive Care Medicine 2009, Part 2, 215-227,

5. Resolution of ARDS • Pulmonary oedema resolves (type 2 cells pump Na+ back into the vessels) • About 5 days after onset, some repair takes place • There is a balance between repair and fibrosis • Occasionally, fibrosis dominates • This is fibrosing alveolitis

6. In summary • The causes of ARDS are inflammatory • The immune system does most of the damage • Recovery of alveolar function is impaired by the inappropriate fibrosis process

7. Why would steroids work? • Inhibit the extravasation of leucocytes (inhibit leucocyte adhesion molecules from interacting with endothelial cell adhesion molecules; this raises the WCC ) • Increase the migration of lymphocytes to the lymphoid tissues (and out of the bloodstream) • Inhibit the function of macrophages and antigen-presenting cells • Inhibit phagocytosis by macrophages • Inhibit production of TNF-alpha and interleukin-1 • Inhibit expression of cyclooxygenase-2: Thus, inhibit the synthesis of prostaglandins • Inhibit synthesis of antibodies (in large doses)

8. What harm could they do? • More risk of neuromuscular weakness • When yoused together with neuromuscular blocking agents, LOTS more risk of neuromuscular weakness • Blunted febrile response = iatrogenic sepsis goes unrecognised Meduri GU, (1998) Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome. A randomized controlled trial. JAMA 280:159–165 Meduri GU, (2007) Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest 131:954–963 Steinberg KP, (2006) Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 354:1671–1684

9. Evidence for steroids in ARDS • Meduri et al published a meta-analysis (2008) • n = 518; all trials retrieved from Cochrane • Reduction in RR of death: 0.84 (0.78 if treated before day 14) - Reduced length of ICU stay and decreased number of ventilated days Gianfranco Umberto Meduri Meduri G.U et al Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature 2008 Intensive Care MedicineVolume 34, Number 1, 61-69

10. ARDS network trial Steinberg KP, (2006) Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 354:1671–1684

11. Evidence for benefit

12. Evidence for minimal benefit

13. And even if there was some benefit… • When would you administer the steroids? • How long is an effective course? • Is there a difference in pulmonary vs extrapulmonary causes of ARDS? • Is there an improvement in long term lung function?

14. And even if there was some benefit… • When would you administer the steroids? • How long is an effective course? • Is there a difference in pulmonary vs extrapulmonary causes of ARDS? • Is there an improvement in long term lung function?

15. No Further Questions, Please

16. References • Bersen A.D, the Acute Respiratory Distress Syndrome (ARDS) Ch 29 in Ohs Intensive Care Manual, 6th ed. • Orfanos SE et al, Pulmonary endothelium in acute lung injury: from basic science to the critically ill Applied Physiology in Intensive Care Medicine 2009, Part 2, 215-227, • Meduri G.U et al Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature 2008 Intensive Care MedicineVolume 34, Number 1, 61-69 • Steinberg KP, (2006) Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 354:1671–1684