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Arch Dis Child. 2007 July; 92(7): 653.
PMCID: PMC2083758

Steroids in septic shock: the confusion continues

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 7 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 and Carcillo, fig 1). Furthermore, these levels are roughly consistent with those achieved following doses of hydrocortisone of 50 mg/kg (Aneja and Carcillo, fig 2).1 Unfortunately, figure 1 of Aneja and Carcillo'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 vs 74 μg/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 vs 39 μg/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‐survivors3,4; 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 et al 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 should not 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!

Footnotes

Competing interests: None declared.

References

1. Aneja R, Carcillo J A. What is the rationale for hydrocortisone treatment in children with infection‐related adrenal insufficiency and septic shock? Arch Dis Child 2007. 92165–169.169 [PMC free article] [PubMed]
2. Riordan F A, Thomson A P, Ratcliffe J M. et al Admission cortisol and adrenocorticotrophic hormone levels in children with meningococcal disease: evidence of adrenal insufficiency? Crit Care Med 1999. 272257–2261.2261 [PubMed]
3. Hatherill M, Tibby S M, Hilliard T. et al Adrenal insufficiency in septic shock. Arch Dis Child 1999. 8051–55.55 [PMC free article] [PubMed]
4. Sarthi M, Lodha R, Vivekanandhan S. et al Adrenal status in children with septic shock using low‐dose stimulation test. Pediatr Crit Care Med 2007. 823–28.28 [PubMed]
5. Pizarro C F, Troster E J, Damiani D. et al Absolute and relative adrenal insufficiency in children with septic shock. Crit Care Med 2005. 33855–859.859 [PubMed]
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. 288862–871.871 [PubMed]
7. Joosten K F, de Kleijn E D, Westerterp M. et al Endocrine and metabolic responses in children with meningoccocal sepsis: striking differences between survivors and nonsurvivors. J Clin Endocrinol Metab 2000. 853746–3753.3753 [PubMed]
8. De Kleijn E D, Joosten K F, 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. 21330–336.336 [PubMed]
9. den Brinker M, Joosten K F, 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. 905110–5117.5117 [PubMed]
10. Hamrahian A H, Oseni T S, Arafah B M. Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004. 3501629–1638.1638 [PubMed]
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. 321184–1190.1190 [PubMed]

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