EBQ:CORTICUS Trial

Clinical Question

Does low-dose hydrocortisone therapy improve survival in patients with septic shock?

Conclusion

Hydrocortisone increase the speed to shock reversal but does not have a mortality benefit in patients with septic shock.

Major Points

This trial was performed to address the suggestion that there was a survival benefit with hydrocortisone and fludrocortisone administration to patients in septic shock with insufficiency . The Annane Trial caused epiric corticosteroid administration to be the standard of care in patients with sepsis and resumed adrenal insufficiency.

The Corticosteroid Therapy of Septic Shock (CORTICUS) trial randomized 499 patients with septic shock to hydrocortisone or placebo administration. Prior to treatment, all patients received an ACTH stimulation test and were classified as responders (cortisol rise >9 mcg/dL) or non-responders (cortisol rise ≤9 mcg/dL).

In contrast to the Annane Trial, CORTICUS demonstrated that hydrocortisone does not improve survival in patients with septic shock, regardless of response to ACTH. While there was no survival benefit, hydrocortisone conferred a more rapid reversal of shock in all subgroups studied.

2012 Guidelines

Surviving Sepsis Campaign guidelines for severe sepsis and septic shock (2012)

• Recommend against using hydrocortisone IV to treat adult septic shock if fluid resuscitation and vasopressor therapy reverse shock.
• Hydrocortisone 200 mg IV daily may be used at that point (grade 2C)
• *Recommend against ACTH stimulation test in adults with septic shock (grade 2B)
• *Recommend against using hydrocortisone when vasopressors aren't required (grade 2D)
  • Recommend against using corticosteroids in sepsis without shock (grade 1D)

Design

• Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
• N=499
  • Hydrocortisone (n=251)
  • Placebo (n=248)
• Mean follow-up: 28 days

Inclusion Criteria

• Patients 18 years and older
• All patients hospitalized in ICU
• Septic shock (SBP<90 with 20cc/kg fluid replacement or vasopressors need for >1hr) or organ dysfunction attributable to sepsis

Exclusion Criteria

• Life expectancy <24h
• Immunosuppression
• Underlying disease with poor prognosis
• Treatment with long-term corticosteroids within past 6 months or short-term corticosteroids within past 4 weeks

Interventions

• Sixty minutes prior to administration of study drug, a high-dose (250mcg) ACTH-stimulation test was performed in all patients
• Patients were classified as responsive (cortisol >9 mcg/dL) or non-responsive to ACTH (cortisol ≤9 mcg/dL)
• Lastly patients were randomized to hydrocortisone 50mg or placebo IV q 6 hrs, tapered over a 6-day period

Outcome

Hydrocortisone vs. placebo.

Primary Outcomes

28-day mortality

34% vs. 32% (P=0.51)

Secondary Outcomes

Reversal of shock

76% vs. 70.4% (P=0.41)

Time to reversal of shock

3.3 vs. 5.8 days (P<0.001)

Other outcomes were not statistically different: length of stay, reversal of organ failure, rates of new infection, hypernatremia, hyperglycemia.

Subgroup analysis

Responsive to corticotropin

28-day mortality

39% vs. 36% (P=0.69)

Reversal of shock

94.7% vs. 76.5% (P=0.13)

Time to reversal of shock

2.8 vs. 5.8 days (P<0.001)

Non-responsive to corticotropin

28-day mortality

29% vs. 29% (P=1.00)

Reversal of shock

79.7% vs. 74.2% (P=0.18)

Time to reversal of shock

3.9 vs. 6.0 days (P=0.06)

Criticisms

• The authors note that they did not each their goal enrollment of 800 patients.

• The CORTICUS trial questioned the outcome of the Annane Trial. Differences in the conclusions between the two trials may be due to

1. The Annane Trial's population was more critically ill
2. The Annane Trial’s enrollment occurring within 8 hours (vs. 72 hours in CORTICUS).
3. The Annane Trial used hydrocortisone plus the pure mineralocorticoid fludrocortisone and CORTICUS only used hydrocortisone
4. In 2013 Boonen et al in the NEJM questioned conventional plasma measurements of the cortisone during critical illness since there was a reduction in mediators of cortisol degradation in ICU patients. The ACTH stimulation test may be an inaccurate measurement of adrenal insufficiency during critical illness.

Funding

Supported by the European Commission, the European Society of Intensive Care Medicine, the European Critical Care Research Network, the International Sepsis Forum, and the Gorham Foundation. Roche Diagnostics provided the Elecsys cortisol immunoassay.

Sources

• [Sprung CL, et al. "Hydrocortisone therapy for patients with septic shock". New England Journal of Medicine. 2008. 358(2):111-24. CORTICUS Trial]

• NEJM Letters to the Editor
• Concurrent editorial