Critically evaluate the use of adjunctive corticosteroid treatment in the management of septic shock.

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College answer

Rationale:

Long history of use

Potential mechanism of action includes:

Anti-inflammatory/anti- cytokine action Treatment of adrenal dysfunction

Vasopressor and inotrope- by beta -receptor upregulation sparing action

Advantages

Cheap, simple widely available

Disadvantages

Hyperglycaemia

Muscle weakness Increased infection risk Increased risk of GI bleed

Evidence

Several randomised trials with conflicting results

Annane (2002) and CORTICUS (2008) used short Synacthen test to stratify patients – divergent effects on mortality reported

Recent large scale trials:

ADRENAL – no effect on mortality but more rapid reversal of shock and more rapid wean of mechanical ventilation and ICU stay

APPROCCHS – Reduction in mortality and more rapid shock reversal and ventilator wean. Used fludrocortisone in addition to hydrocortisone – role of this is unclear.

Neither trial demonstrated clinically important side effects

Personal Use

Although effect on mortality still uncertain the evidence suggests patients are weaned from mechanical ventilation faster and discharged from ICU earlier. Given the good safety profile this may be enough rationale for use, and likely to have substantial cost benefits as well.

Discussion

This SAQ is essentially identical to Question 16 from the first paper of 2013, except it is worded slightly differently and we now have a few extra trials to mention.

Rationale

  • Introduction / definition:
    • A certain group of sepsis patients may benefit from the administration of steroids, with improvement in mortality.
  • Rationale: 
    It is probably not a very strong rationale to argue that something should be used because it has a "long history of use", mainly because scientifically, tradition is an idiot thing. However one could argue that 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%.
    • ADRENAL (Venkatesh et al, 2018): no mortality difference at 90 days, unless you're in Australia and New Zealand

    • APROCCHSS (Annane et al, 2018): 6% mortality reduction in the steroid group, but a very low fragility index.

  • 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.

References

References

LITFL have an excellent page, summarising the current literature on steroids in sepsis.

Scott, W. J. M. "THE INFLUENCE OF THE ADRENAL GLANDS ON RESISTANCE: II. THE TOXIC EFFECT OF KILLED BACTERIA IN ADRENALECTOMIZED RATS." The Journal of experimental medicine 39.3 (1924): 457.

Annane, Djillali, et al. "A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin." Jama 283.8 (2000): 1038-1045.

Cooper, Mark S., and Paul M. Stewart. "Corticosteroid insufficiency in acutely ill patients." New England Journal of Medicine 348.8 (2003): 727-734.

Kass, Edward H., and Maxwell Finland. "Adrenocortical hormones and the management of infection." Annual review of medicine 8.1 (1957): 1-18.

Robson, HUGH G., and L. E. Cluff. "Experimental pneumococcal and staphylococcal sepsis: effects of hydrocortisone and phenoxybenzamine upon mortality rates." Journal of Clinical Investigation 45.9 (1966): 1421.

SIBBALD, WILLIAM J., et al. "Variations in adrenocortical responsiveness during severe bacterial infections: unrecognized adrenocortical insufficiency in severe bacterial infections." Annals of surgery 186.1 (1977): 29-33.

Marik, Paul E., and Gary P. Zaloga. "Adrenal insufficiency during septic shock*." Critical care medicine 31.1 (2003): 141-145.

Cohen, Jeremy, et al. "Variability of cortisol assays can confound the diagnosis of adrenal insufficiency in the critically ill population." Intensive care medicine32.11 (2006): 1901-1905.

Annane, Djillali, et al. "Diagnosis of adrenal insufficiency in severe sepsis and septic shock." American journal of respiratory and critical care medicine 174.12 (2006): 1319-1326.

Kromah, Fatuma, et al. "Relative adrenal insufficiency in the critical care setting: debunking the classic myth." World journal of surgery 35.8 (2011): 1818-1823.

Siraux, Valérie, et al. "Relative adrenal insufficiency in patients with septic shock: comparison of low-dose and conventional corticotropin tests." CRITICAL CARE MEDICINE-BALTIMORE- 33.11 (2005): 2479.

Yaegashi, Makito, and Arthur J. Boujoukos. "The low-dose ACTH test in the ICU: Not ready for prime time." Critical Care 10.4 (2006): 313.

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.

Barnes, Peter J., and Michael Karin. "Nuclear factor-κB—a pivotal transcription factor in chronic inflammatory diseases." New England Journal of Medicine336.15 (1997): 1066-1071.

Kashiwabara, Moto, et al. "Surgical trauma-induced adrenal insufficiency is associated with postoperative inflammatory responses." Journal of Nippon Medical School 74.4 (2007): 274-283.

Ehrchen, Jan, et al. "Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes." Blood 109.3 (2007): 1265-1274.

Boyer, A., et al. "Glucocorticoid treatment in patients with septic shock: effects on vasopressor use and mortality." International journal of clinical pharmacology and therapeutics 44.7 (2006): 309-318.

Szabo, Csaba, et al. "Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo."Proceedings of the National Academy of Sciences 91.1 (1994): 271-275.

MACNICOL, MALCOLM F., ALAN H. GOLDBERG, and GEORGE HA CLOWES. "Depression of isolated heart muscle by bacterial endotoxin."Journal of Trauma and Acute Care Surgery 13.6 (1973): 554-558.

Romero-Bermejo, Francisco J., et al. "Sepsis-induced cardiomyopathy."Current cardiology reviews 7.3 (2011): 163.

Asfar, Pierre, Jan Tuckermann, and Peter Radermacher. "Steroids and Vasopressin in Septic Shock—Brother and Sister or Just Distant Cousins?*."Critical care medicine 42.6 (2014): 1531-1532.

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.

Schumer, William. "Steroids in the treatment of clinical septic shock." Annals of surgery 184.3 (1976): 333.

Weitzman, Stephen, and Stephen Berger. "Clinical trial design in studies of corticosteroids for bacterial infections." Annals of internal medicine 81.1 (1974): 36-42.

Bloch, Jack H. "Physiology and therapy of bacteremic shock: experimental and clinical observations." American Journal of Cardiology 12.5 (1963): 599-613.

Schumer, William, and Lloyd M. Nyhus. "The role of corticoids in the management of shock." Surgical Clinics of North America 49.1 (1969): 147-162.

Schumer, William. "Septic shock." JAMA 242.17 (1979): 1906-1907.

Blaisdell, F. W. "Controversy in shock research. Con: The role of steroids in septic shock." Circulatory shock 8.6 (1981): 673.

Schumer, W. "Controversy in shock research. Pro: The role of steroids in septic shock." Circulatory shock 8.6 (1981): 667.

Sprung, Charles L., et al. "The effects of high-dose corticosteroids in patients with septic shock: a prospective, controlled study." New England Journal of Medicine 311.18 (1984): 1137-1143.

Cohen, J., and M. P. Glauser. "Septic shock: treatment." The Lancet 338.8769 (1991): 736-739.

Zeni, Fabrice, Bradley Freeman, and Charles Natanson. "Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment." (1997): 1095-1100.

Briegel, Josef, et al. "Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study." Critical care medicine 27.4 (1999): 723-732.

Venkatesh, Balasubramanian, et al. "Adjunctive Glucocorticoid Therapy in Patients with Septic Shock." New England Journal of Medicine (2018).

Annane, Djillali, et al. "Hydrocortisone plus fludrocortisone for adults with septic shock." New England Journal of Medicine378.9 (2018): 809-818.