EBQ:CORTICUS Trial: Difference between revisions

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 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 ^[1]. 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)^[2]

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

The Annane Trial's population was more critically ill
The Annane Trial’s enrollment occurring within 8 hours (vs. 72 hours in CORTICUS).
The Annane Trial used hydrocortisone plus the pure mineralocorticoid fludrocortisone and CORTICUS only used hydrocortisone
In 2013 Boonen et al^[3] 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.

CME

Sources

↑ Annane D, et al. "Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock". Journal of the American Medical Association. 2002. 288(7):862-871
↑ Surviving Sepsis Campaign 2012 guidelines
↑ Boonen E et al. "Reduced cortisol metabolism during critical illness." The New England Journal of Medicine. 2013;368:1477-1488.

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

@@ Line 129: / Line 129: @@
 -neither of the above
-{Regarding hydrocortisone therapy for patients with septic shock, which of the following statements is true?
+{Regarding the use of hydrocortisone in septic shock patients, which of the following was found?
-|type="[]"}
+|type="()"}
+-mortality was significantly reduced in patients who received steroids
+-mortality was only reduced in patients who had a positive corticotropin test
+-mortality was only reduced in patients who had a negative corticotropin test
++shock was reversed more quickly in the steroid group, when compared to the placebo group
+||Sprung CL et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358: 111-124. In summary, the use of hydrocortisone did not decrease mortality in a general population of patients with septic shock, even though the drug hastened reversal of shock. This lack of improvement may be related to an increased incidence of superinfection and new septic episodes. No benefit was seen in a subgroup of patients who had had no response to corticotropin, as was shown previously for patients with severe septic shock. This finding may be related to methodologic issues surrounding the accurate diagnosis of adrenal insufficiency in critically ill patients or to a decreased prognostic importance of this phenomenon in less severe shock. On the basis of these findings, hydrocortisone cannot be recommended as general adjuvant therapy for septic shock (vasopressor responsive), nor can corticotropin testing be recommended to determine which patients should receive hydrocortisone therapy. Hydrocortisone may have a role among patients who are treated early after the onset of septic shock who remain hypotensive despite the administration of high-dose vasopressors (vasopressor unresponsive).
+-there were fewer episodes of superinfection in the steroid group
--hydrocortisone improved survival in patients with septic shock who did not have a response to corticotropin
--hydrocortisone hastened reversal of shock in patients with septic shock who did not have a response to corticotropin
-+hydrocortisone increased the incidence of superinfection
-||Sprung CL et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358:111-124. In this multicenter, randomized, double-blind, placebo-controlled trial, of the 499 patients in the study, 233 (46.7%) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2% in the hydrocortisone group and 36.1% in the placebo group, P=0.69) or between those who had a response to corticotropin (28.8% in the hydrocortisone group and 28.7% in the placebo group, P=1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (P=0.51). In the hydrocortisone group, shock was reversed more quickly than in the placebo group. However, there were more episodes of superinfection, including new sepsis and septic shock. Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed.
-+hydrocortisone hastened the reversal of shock in patients in whom shock was reversed
--hydrocortisone improved survival in patients with septic shock only if they had a response to corticotropin
 </quiz>

	hydrocortisone improved survival in patients with septic shock who did not have a response to corticotropin
	hydrocortisone hastened reversal of shock in patients with septic shock who did not have a response to corticotropin
	hydrocortisone increased the incidence of superinfection
	hydrocortisone hastened the reversal of shock in patients in whom shock was reversed
	hydrocortisone improved survival in patients with septic shock only if they had a response to corticotropin

	a single dose of etomidate inhibited the metabolism of corticosteroids for 24 hours in patients who were critically ill
	an association between etomidate and the likelihood of adrenal hyporesponsiveness was found
	both of the above
	neither of the above

	mortality was significantly reduced in patients who received steroids
	mortality was only reduced in patients who had a positive corticotropin test
	mortality was only reduced in patients who had a negative corticotropin test
	shock was reversed more quickly in the steroid group, when compared to the placebo group
	there were fewer episodes of superinfection in the steroid group