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Adrenocortical Insufficiency and Steroids

Created: 16/5/2007

Adrenocortical Insufficiency and Steroids

Dr Andy Walden PhD MRCP
Advance trainee Intensive Care Medicine

Focus on adrenocortical insufficiency in the critically ill

Interest in the use of steroids in the critically ill has been around for many years. The first large randomised, controlled study was performed in 1987. This study demonstrated that septic patients given high doses of methylprednisolone had a worse outcome, predominantly due to increased incidence of further infections. In the 1990s there was a renewed interest in the use of steroids on the ICU following the discovery that up to 75% of critically ill patients demonstrate adrenal dysfunction when tested with a formal short adrenocorticotropic hormone (ACTH) test. Moreover, further research suggested that replacement of the corticosteroids could result in reversal of hyperdynamic septic shock. Corticosteroid replacement is thought to achieve this by mediating both suppression of inflammatory response and upregulation of catecholamine receptors. Interestingly, the doses of steroids used in these latter studies were much lower and similar to the doses prescribed for physiological replacement of adrenal insufficiency. Well-described adverse effects of steroids that may delay recovery from critical illness include the development and reactivation of infection, hyperglycaemia, bone catabolism, psychosis and critical illness polyneuropathy.

Focus on low dose adrenocortical hormone replacement in the critically ill

In a paper published in 2002, Annane and colleagues used replacement doses of hydrocortisone and fludrocortisone in a randomised, controlled, double-blinded study of patients in septic shock. Patients had a synthetic ACTH test performed and were classified as either ‘responders’ if an adequate response was seen, or ‘non-responders’ if the response was inadequate. As a result of their analysis, Annane and his co-workers reported a significant reduction in mortality in the non-responders from 63% to 53% (RR 0.83), with a number needed to treat of 7. There appeared to be no significant difference in the responders but the effect on all patients still showed a positive outcome benefit with a number needed to treat of 8. The time to recovery of septic shock was also reduced in the steroid-treated group. The recommendation was that all septic patients should have a synthetic ACTH test and be commenced on steroids, and these should be continued for 7-11 days pending the result of the test. There were no differences in adverse effects possibly related to steroids. The authors, however, made no comment on the incidence of critical illness polyneuropathy and myopathy.

Criticism of this paper centred on a number of issues. At interim analysis, the use of the induction agent sodium etomidate within the previous 6 hours was used as an exclusion criterion. A single dose of etomidate can inhibit adrenal synthesis of corticosteroids for more than 24 hours through its inhibition of the enzyme 11β-hydroxylase. However, the original paper did not report the number of patients recruited to the trial that had received etomidate. It transpired that 72 patients had received etomidate within 12 hours of enrolment. Moreover, 68 of the 72 patients were ‘non-responders’. The authors’ justification was that their original rationale was to investigate the effect of steroid replacement in non-responders in sepsis, regardless of the cause. The validity of this statistical approach has also been questioned, because a single-tailed test was used in the original statistical analysis, based on the assumption of two smaller trials that it would be unlikely for there to be a deleterious effect from the steroids. In an editorial in the British Journal of Anaesthesia, the result of this study was interpreted as: “appropriate treatment of iatrogenic etomidate-induced adrenal suppression improves outcome in patients with septic shock”. In the same editorial, the authors concluded that, at present, the scientific evidence was insufficient to render corticosteroids a “standard of care” for patients with septic shock.

Following the criticism of his study, Annane performed a meta-analysis of all trials of steroids in sepsis. The analysis of the trials that had been performed after 1992 (when a consensus was reached on the definition of sepsis and a recognition of adrenocortical insufficiency in sepsis) suggested a mortality benefit from low-dose, long courses of steroids, and that steroids resulted in quicker resolution of septic shock.

Focus on steroid trials in progress

The results of the corticosteroid in septic shock (CORTICUS) trial are awaited. This is a randomised, multicentre, double-blinded clinical trial. The primary outcome is 28-day mortality of non-responder patients treated with hydrocortisone. The classification between non-responders and responders was identical to the cut-off in the Annane paper, and the treatment doses of hydrocortisone are the same. The preliminary data were presented at the 2006 European Society of Intensive Care Medicine, and suggested that there is no difference in mortality between steroids and placebo in the non-responders.

Key learning points

  • A proportion of patients in septic shock have adrenal insufficiency
  • There is clear evidence of a deleterious effect of high-dose steroids in sepsis
  • There are concerns as to the true benefit of low-dose steroid replacement in sepsis
  • Further insight into the role of steroids in sepsis may be given by the results of the CORTICUS study.


Key references

Bone RC, Fisher CJ, Clemmer TP, Slotman, GJ, Metz, CA, Balk, RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987; 317: 653-658.

Bouachour G, Tirot P, Gouello JP, Mathieu E, Vincent JF, Alquier P. Adrenocortical function during septic shock. Intensive Care Med 1995; 21: 57-62.

Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, Hemmer B, Hummel T, Lenhart A, Heyduck M, Stoll C, Peter K. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 1999; 27: 723-732.

Annane D, Sebille V, Charpentier C, Bollaert P-E, Francois B, Korach J-M, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288: 862-871.

Annane D, Bellisant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ 2004; 329: 480.

Bloomfield R, Noble DW. Corticosteroids for septic shock-a standard of care? Br J Anaesth 2004; 93: 178-180.

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