College Answer

ARDS  – ARDS part of the sepsis inflammatory response, fibroprolifeartive pahse associated with laying down of collagen, hence use of steroids to reduce the extent of these processes.
Lines of evidence: a) Meduri study (JAMA) cross over trial showed a reduction in lung injury score and improved mortality (small sample). (Candidates not expected to name authors, if they do get bonus marks)

b) Recent Meduri study : Reduction in LIS, length of stay and duration of IPPV

c) Recent ARDS net study:  the use of steroids was not associated with any benefit and there was an increased incidence of reintubation. Improves oxygenation faster, more ventilator and shock free days, but higher complications such as weakness, reintubation – no mortality advantage

Septic shock –
• one of the most controversial areas,
• Basis thought to be relative adrenal insufficiency (RAI)
• Basis of RAI diagnosis questionable, -doubts about validity of using plasma cortisol and the synacthen test.
• Shown to be of benefit in meningitis

• In septic shock – high dose steroids (30 mg/Kg) clearly increase mortality
• Low  dose  steroids  improve  shock  reversal  –   only  one  RCT  study  showed improvement (ANNANE) but study limitations- trial design, use of etomidate
• A     recent  multicentre-study  (CORTICUS)  demonstrated  a  lack  of  benefit  with steroids, although the study was underpowered.

Discussion

This old issue is easy to scoff at from the enlightened position we now occupy, but the pendulum of expert opinion keeps swinging.

Let us consider this answer from such a position.

As far as ARDS goes, steroids have long been viewed as harmful. The discussion of pharmacological management for ARDS goes into this in greater detail.

Steroids in sepsis have also seen their heyday come and go, and now have been degraded to the position of ancillary therapies in vasopressor-refractory shock, to treat some imaginary spectre of relative cortisol deficiency. Everybody now agrees that high dose steroids increase mortality, and that though the evidence for steroids in sepsis is pretty weak, nobody should ever die of sepsis without having tasted some steroids.

To finish with this would be pretty superficial. In general, thecomplicated issue of steroids in sepsisis dealt with in some detail in a dedicated chapter on this topic, nested within the greater discussion of the management of shock. This discussion is also relevant to the topic of relative adrenal insufficiencywhich is an endocrine curiosity found in severe disease states. The question of using steroids in refractory shock states is answered in the discussion of Question 12 from the second paper of 2000.

In brief, a list of acceptable indications is as follows:

• Adrenal insufficiency
  • Due to primary hypoadrenalism
  • Due to withdrawal of chronic exogenous corticosteroids
  • Due to relative insufficiency during critical illness
• Severe septic shock
  • If the shock state is refractory to vasopressors and fluid resuscitation
• Shock states due to autoimmune inflammatory disease
  • Severe vasculitis with widespread SIRS
  • Severe autoimmune myocarditis with cardiogenic shock

Anyway, the above is time-wasting gibberish. The college asks us to outline the evidence and current controversies. Thus:

Steroids and sepsis

Evidence

2002 French study:

• Significant improvement in mortality among 300 septic patients, from 70% to 58%.
• Severely shocked patients, 1.1μg/kg/min (75ml/hr) of noradrenaline.

2008 CORTICUS trial:

• No mortality difference associated with the use of steroids.
• Moderately shocked patients, only 0.5μg/kg/min (35ml/hr) of noradrenaline.

2009 meta-analysis:

• 17 trials; conclusion: there is a small mortality benefit.

The same analysis, excluding all but 6 well-designed trials:

• Conclusion: steroids did not improve survival

2013 Surviving Sepsis Guidelines:

• Grade 2B recommendation in favour of steroids, provided they are reserved for those patients who are refractory to fluids and vasopressors.
• Rationale: survival only seems to be improved in patients whose mortality from sepsis is likely to be over 60%.

Current controversies

• Disagreement regarding the dose of steroids: is 200mg of hydrocortisone too much?
• Disagreement regarding the timing of steroids: if one waits for shock to become "vasopressor-refractory", one risks damage o organ systems which might theoretically have been prevented if steroids were given earlier
• Disagreement regarding the early identification of patients who may benefit: the short synacthen test and random cortisol levels do not seem to identify those patients whose survival chances are likely to improve as the result of steroids
• Contempt of Surviving Sepsis guidelines: though a good literature search, some have argued that their interpretation of the evidence has been immature and superficial. Nowithstanding the corporate whoring, and the questionable use of an international guidelines statement to sell Edwards Life Sciences ScvO₂ monitoring products.

Steroids and ARDS

Evidence

• Animal models predict benefit from steroids in ARDS.
• Human trials among early ARDS patients did not demonstrate any benefit (and suggested that there may be an increase in infectious complications).
• Human trials among late "fibroproliferative" ARDS patients demonstrated good evidence of harm rather than benefit, with greater incidence of muscular weakness.
• 2009 meta-analysis concluded that there might be some trend towards a mortality benefit, but without good quality evidence
• Another 2009 meta-analysis found a trend towards a small decrease in all-cause mortality in the group who received the lowest doses of steroids.

Current controversies

• ARDS is aetiologically heterogeneous, and trials of ARDS as an undifferentiated group may obscure the subgroup-specific benefit (eg. ARDS due to pulmonary sepsis end up in the same intervention group as ARDS due to autoimmune pneumonitis).
• Increased mortality due to weakness-associated complications may obscure increased survival due to improved respiratory function
• Increased weakness may confuse studies which look for decreased ventilator time; a steroid-weakened patient with improved lungs will take longer to wean, similarly to a non-weakned patient with ARDS-damaged lungs
• ARDS and severe sepsis frequently co-exist, and severe sepsis frequently receives "stress dose" steroids, with an observed improvement in mortality and decreased duration of shock.