EBQ:CORTICUS Trial

Complete Journal Club Article

Sprung CL, et al. "Hydrocortisone therapy for patients with septic shock". New England Journal of Medicine. 2008. 358(2):111-24.
PubMed Full text PDF

Clinical Question

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

Conclusion

Hydrocortisone increase the speed to shock reversal.

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.

Current Guidelines

2012 Surviving Sepsis Campaign Guidelines for Steroid Use

• Do not use IV hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability. Otherwise intravenous hydrocortisone alone at a dose of 200 mg per day (grade 2C)
• Do not use ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone (grade 2B).
• Tapering off hydrocortisone when vasopressors are no longer required is not needed (grade 2D).
• Do not use corticosteroids for the treatment of sepsis in the absence of shock (grade 1D).
• When hydrocortisone is given, use continuous flow (grade 2D)

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

Primary Outcomes

28-day mortality

Hydrocortisone 34% vs. placebo 32% (P=0.51)

Secondary Outcomes

Reversal of shock

Hydrocortisone 76% vs. placebo 70.4% (P=0.41)

Time to reversal of shock

Hydrocortisone 3.3 vs. placebo 5.8 days (P<0.001)

Subgroup analysis

Responsive to corticotropin

28-day mortality

Hydrocortisone 39% vs. placebo 36% (P=0.69)

Reversal of shock

Hydrocortisone 94.7% vs. placebo 76.5% (P=0.13)

Time to reversal of shock

Hydrocortisone 2.8 vs. placebo 5.8 days (P<0.001)

Non-responsive to corticotropin

28-day mortality

Hydrocortisone 29% vs. placebo 29% (P=1.00)

Reversal of shock

Hydrocortisone 79.7% vs. placebo 74.2% (P=0.18)

Time to reversal of shock

Hydrocortisone 3.9 vs. placebo 6.0 days (P=0.06)

Further Discussion

• 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

Eu- ropean 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