The Role of Steroids in ARDSA review of the evidence

Alex Yartsev 11/2010

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.

Briefly, on the pathology of ARDSThere 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.

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,

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

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

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)

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 unresolvingacute respiratory distress syndrome. A randomized controlled trial. JAMA 280:159–165Meduri GU, (2007) Methylprednisolone infusion in early severe ARDS: results of a randomizedcontrolled trial. Chest 131:954–963Steinberg KP, (2006) Efficacy and safety of corticosteroids for persistent acute respiratorydistress syndrome. N Engl J Med 354:1671–1684

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

Meduri G.U et al Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature 2008 Intensive Care Medicine Volume 34, Number 1, 61-69

Gianfranco Umberto Meduri

ARDS network trial

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

Evidence for benefit

Evidence for minimal benefit

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?

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?

No Further Questions, Please

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 Medicine Volume 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

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