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• Response to Dr Tibby's letter : Steroids in septic shock: the confusion continues
  Rajesh Aneja
  Published on: 22 March 2016
• Steroids in septic shock: the confusion continues
  Shane M Tibby
  Published on: 22 March 2016

• Published on: 22 March 2016

  Response to Dr Tibby's letter : Steroids in septic shock: the confusion continues

  • Rajesh Aneja, Physician
  • Other Contributors:
    • Joseph Carcillo

  Dear Editor,

  We thank Dr. Tibby, admire his work, and believe that his findings have saved the lives of many children with septic shock. We wish to be more clear on two opinions presented in our review. First, we do not recommend hydrocortisone therapy for relative adrenal insufficiency (basal cortisol > 18 mg/dL but ACTH response increment < 9 mg/dL), we only recommend further study. Second, we do recommen...

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  Dear Editor,

  We thank Dr. Tibby, admire his work, and believe that his findings have saved the lives of many children with septic shock. We wish to be more clear on two opinions presented in our review. First, we do not recommend hydrocortisone therapy for relative adrenal insufficiency (basal cortisol > 18 mg/dL but ACTH response increment < 9 mg/dL), we only recommend further study. Second, we do recommend hydrocortisone for patients with dopamine resistant shock and classical adrenal insufficiency (central HPA axis failure = basal cortisol level < 5 mg/dL, peripheral adrenal failure = peak level after ACTH < 18 mg/dL). As to hydrocortisone dosage, the classical literature has cited a treatment range between 2 mg/kg/day to 50 mg/kg/day. This low end dosage achieves cortisol levels seen in healthy patients undergoing routine surgical procedures, and the high end dosage attains circulating levels similar to those reported in septic shock survivors with the highest cortisol levels. We recommend titrating dosage according to patient hemodynamic response. For clinicians without ready access to cortisol levels, we recommend treatment based on the presence of risk factors. For example, purpura fulminans is a risk factor for adrenal failure, whereas chronic prior steroid exposure is a risk factor for hypothalamic-pituitary-adrenal axis failure.

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  Conflict of Interest:
  None declared.

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• Published on: 22 March 2016

  Steroids in septic shock: the confusion continues

  • Shane M Tibby, Consultant in paediatric intensive care

  Dear Editor,

  Aneja and Carcillo’s review of adrenal insufficiency and the rationale for steroid use in sepsis is both concise and timely.1 Although they acknowledge that further studies are needed in paediatrics before recommending a seven day course of hydrocortisone in catecholamine resistant septic shock, they suggest that the logic for this therapy is “compelling”; recommending a bolus of hydrocortisone fol...

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  Dear Editor,

  Aneja and Carcillo’s review of adrenal insufficiency and the rationale for steroid use in sepsis is both concise and timely.1 Although they acknowledge that further studies are needed in paediatrics before recommending a seven day course of hydrocortisone in catecholamine resistant septic shock, they suggest that the logic for this therapy is “compelling”; recommending a bolus of hydrocortisone followed by an infusion of up to 50 mg/kg/day in states of sepsis-induced relative adrenal insufficiency.

  This compelling logic is incorporated within their statement that, among children with septic shock, survivors exhibit dramatically increased plasma levels of cortisol compared to non-survivors (Aneja, figure 1); furthermore these levels are roughly consistent with those achieved following doses of hydrocortisone of 50 mg/kg (Aneja, figure 2).1 Unfortunately figure 1 of Aneja’s paper is very misleading, for two reasons. First, the data used for the septic categories within this graph come from one paediatric paper only, published in 1999.2 Second, the apparent dramatic difference between survivors and non-survivors (186 versus 74 microgram/dL, shown as dots on the graph) represents the upper limit of the range; thus this large discrepancy could have been due to one or two outliers. Indeed comparison of the median values between survivors and non-survivors (the solid lines) provides a more modest difference (45 versus 39 microgram/dL), and falls far short of that attained following administration of 50 mg/kg of hydrocortisone. There have been many paediatric papers published since then, with the majority showing no consistent differences between survivors and non-survivors;3,4 indeed the authors’ own paper in 2005 reached the same conclusion.5

  The waters are further muddied by the use of etomidate, which produces an iatrogenic state of adrenal insufficiency.6 This is illustrated beautifully by three papers from the Netherlands. In 2000 and 2002, Joosten et al reported lower cortisol levels among non-survivors of meningococcal sepsis (although reported as two papers, the patient group in the earlier paper appeared to be largely a subset of the latter).7,8 The same authors re-analysed these and more contemporary data, and showed that the apparent differences in both cortisol levels, and also the ratio of ACTH to cortisol, are dramatically attenuated when etomidate use is factored in.9

  Interpretation of previous papers on this subject is further obscured by the fact that all have measured total, rather than biologically active free cortisol. Hamrahian showed that the concept of relative adrenal insufficiency in the critically ill disappears when free cortisol is measured.10 This is further supported by work from Morel and colleagues, who were unable to differentiate between apparent “responders” and “non- responders” to steroids on the basis of any tests of adrenal function.11

  The question of steroid benefit in catecholamine resistant septic shock remains largely unanswered. Annane’s trial needs to be repeated in paediatrics, but this time we shouldn’t use etomidate and we should measure free cortisol. Until such a time, I will probably continue to use steroids, largely because I’m too nervous not to!

  References:

  1. Aneja R, Carcillo JA. What is the rationale for hydrocortisone treatment in children with infection-related adrenal insufficiency and septic shock? Arch Dis Child 2007;92:165-169

  2. Riordan FA, Thomson AP, Ratcliffe JM, et al. Admission cortisol and adrenocorticotrophic hormone levels in children with meningococcal disease: evidence of adrenal insufficiency? Crit Care Med 1999;27:2257–2261

  3. Hatherill M, Tibby SM, Hilliard T, et al. Adrenal insufficiency in septic shock. Arch Dis Child 1999;80:51–55

  4. Sarthi M, Lodha R, Vivekanandhan S, Arora NK. Adrenal status in children with septic shock using low-dose stimulation test. Pediatr Crit Care Med 2007;8:23-28

  5. Pizarro CF, Troster EJ, Damiani D, et al. Absolute and relative adrenal insufficiency in children with septic shock. Crit Care Med 2005;33:855–859

  6. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862–871

  7. Joosten KF, de Kleijn ED, Westerterp M, et al. Endocrine and metabolic responses in children with meningoccocal sepsis: striking differences between survivors and nonsurvivors. J Clin Endocrinol Metab 2000;85:3746–3753

  8. De Kleijn ED, Joosten KF, Van Rijn B, et al. Low serum cortisol in combination with high adrenocorticotrophic hormone concentrations are associated with poor outcome in children with severe meningococcal disease. Pediatr Infect Dis J 2002;21:330–336

  9. den Brinker M, Joosten KF, Liem O, et al. Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality. J Clin Endocrinol Metab. 2005;90:5110-5117

  10. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004;350:1629-1638

  11. Morel J, Venet C, Donati Y, et al. Adrenal axis function does not appear to be associated with hemodynamic improvement in septic shock patients systematically receiving glucocorticoid therapy. Intensive Care Med 2006;32:1184-1190

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  Conflict of Interest:
  None declared.

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