Question 16

College Answer

Controversial unresolved topic, conflicting evidence.

Background:

In septic shock, cytokines may suppress the cortisol response to adrenocorticotropin hormone and in almost half of the patients this causes poor adrenal activity. Tissues possibly become resistant to corticosteroids because of fewer corticosteroid receptors or receptors with lower affinity.

Mechanism:

1. Treatment of deficiency - concept of CIRCI possibly associated with increased mortality
2. Pharmacological effects on immune system through nuclear factor kappa B
3. Up-regulation of receptors for vasopressors such as noradrenaline
4. A possible interaction with vasopressin treatment has been identified but this needs further research

Indications:

Concept of CIRCI unclear and use of short Synacthen test to determine who may benefit from steroids is controversial

Surviving Sepsis Campaign Guidelines 2012 reoommend 200mg hydrocortisone /24hr for septic shock only if fluid resuscitation and vasopressor therapy have been inadequate to restore haemodynamic stability (grade 2C). Further recommendations are not to use the short Synacthen test, to taper hydrocortisone when vasopressors are no longer required and not to use steroids in sepsis without shock

Clear role for steroids in patients who are overtly hypoadrenal (as opposed to CIRCI) and Waterhouse-Friderichsen Syndrome

Steroid treatment is recommended as early adjunctive treatment in bacterial meningitis but studies evaluating role of steroids in bacterial meningitis with septic shock are lacking and recommendations advise treatment as per septic shock

Consider additional supplementation in patients already on steroid therapy

Treatment effects:

The use of low-dose corticosteroids in septic shock significantly reduces shock duration. No improvement in mortality has been shown except for a possible reduction in 28-day mortality in the subgroup of patients who received a prolonged course (defined as more than 5 days) of low-dose corticosteroids.

Possible adverse effects include: impaired glucose control, increased fungal infection, myopathy and poor wound healing.

Studies using low-dose corticosteroids have not shown an increase in the risk of gastrointestinal bleeding, superinfection, or acquired neuromuscular weakness compared with placebo, but may not have been adequately powered to observe significant differences in side effects.

The use of corticosteroids may affect glucose metabolism and the need for insulin administration.

Discussion

Relative adrenal insufficiency and the use of corticosteroids in severe septic shock are treated with brief summaries in the Required reading section.

Steroids in shock generally are asked about in Question 12 from the second paper of 2000.

Evidence for steroids in sepsis, and controversies surrounding their use, are asked about in Question 22 from the first paper of 2008: "Outline the evidence for the role of glucocorticoids  in ARDS and septic shock and the current controversies surrounding their use in these conditions".

In brief:

• Introduction / definition:
  • A certain group of sepsis patients may benefit from the administration of steroids, with improvement in mortality.
• Rationale: 
  Steroids may produce the following beneficial actions in severe shock: 
  • Reversal of relative adrenal insufficiency
  • Reversal of inflammatory overactivity
  • Reprogramming of the immune response
  • Improved responsiveness of α-1 receptors (thus, decreased catecholamine requirements)
  • Correction of vasoplegia by deactivation of nitric oxide synthase
  • Improved cardiac tolerance of bacterial endotoxin
  • Improved retention of resuscitation fluid
• 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%.
• Advantages
  • Cardiovascular improvement (decreased vasopressor dose)
  • Decreased organ system dysfunction
  • Earlier withdrawal of vasopressor support
  • Possibly, decreased mortality in selected patients
• Disadvantages
  • Hyperglycaemia
  • Fluid retention
  • Possibly, increased risk of nosocomial infection
  • Steroid myopathy and delayed ventilator weaning
  • Increased risk of gastric ulceration
• Own practice:
  • practice according to the Surviving Sepsis guidelines, or local policy.

Surviving Sepsis Guidelines

Annane, Djillali, et al. "Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review." Jama 301.22 (2009): 2362-2375.

Sligl, Wendy I., et al. "Safety and efficacy of corticosteroids for the treatment of septic shock: A systematic review and meta-analysis." Clinical infectious diseases 49.1 (2009): 93-101.

Annane, Djillali. "Corticosteroids for severe sepsis: an evidence-based guide for physicians." Annals of intensive care 1.1 (2011): 1-7.

Sprung, Charles L., et al. "Hydrocortisone therapy for patients with septic shock." New England Journal of Medicine 358.2 (2008): 111.

Vassiliadi, Dimitra A., et al. "Longitudinal assessment of adrenocortical responses to low-dose ACTH in critically ill septic patients." Endocrine Abstracts (2013) 32 P26

Annane, Djillali, et al. "Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock." Jama 288.7 (2002): 862-871.