CORTICUS

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

Among critically ill patients in septic shock, does low-dose hydrocortisone therapy improve survival?

Bottom Line

Hydrocortisone hastens the reversal of shock but does not confer a survival benefit among patients with septic shock.

Major Points

Prior studies, such as the smaller Annane Trial (2002), had suggested a survival benefit associated with the administration of hydrocortisone and fludrocortisone in patients with septic shock and relative adrenal insufficiency (cortisol rise <9 mcg/dL after ACTH stimulation test). As a result, corticosteroids remained standard of care for decades among such patients. Subsequent studies failed to duplicate the benefits seen in the Annane Trial and even suggested infection-related harm associated with routine corticosteroid use. Thus the role of corticosteroids in septic shock remained unclear.

The Corticosteroid Therapy of Septic Shock (CORTICUS) trial randomized 499 patients with septic shock to receive hydrocortisone or placebo. 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.

The study's outcomes sharply contrasted those of the smaller but well designed Annane Trial. These differences are probably due to 1) the Annane Trial's population generally being more critically ill at study entry, 2) having a markedly higher mortality rate in the placebo group, and 3) enrollment occurring within 8 hours (vs. 72 hours in CORTICUS). Although the Annane Trial used hydrocortisone plus the pure mineralocorticoid fludrocortisone (while CORTICUS used hydrocortisone alone), the addition of fludrocortisone probably did not have a meaningful effect given that hydrocortisone doses of ≥200 mg/day maximally activate the mineralocorticoid receptor. Furthermore, a subsequent 2013 study by Boonen et al.[1] has called into question our current understanding of steroid metabolism during critical illness as they found a reduction of mediators of cortisol degradation in ICU patients. As such, conventional plasma measurements of the hormone may be inaccurate.

Overall, the utility of steroids in septic shock patients remains controversial.[2] Based on CORTICUS and selected other studies, corticosteroids should not be routinely used in adult patients with septic shock. Nevertheless, there may be a benefit among selected patients.

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[3]

  • If adequate fluid resuscitation and vasopressor therapy can restore hemodynamics, suggest against using IV hydrocortisone (weak recommendation, low quality of evidence)
    • If above isn't achievable, suggest hydrocortisone 200 mg IV qday (weak recommendation, low quality of evidence)

Design

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

Population

Inclusion Criteria

  • Patients 18 years and older
  • All patients hospitalized in ICU
  • Septic shock within prior 72h (defined by systolic BP <90 despite adequate fluid replacement or need for vasopressors >1h) and hypoperfusion or organ dysfunction attributable to sepsis

Exclusion Criteria

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

Baseline Characteristics

From the hydrocortisone group

  • Demographics: Age 63 years, female sex 34%, White race 94%
  • PMH: HTN 35%, CAD 15%, HF 4%, COPD 11%, cancer 19%, DM 20%, CRF 9%
  • Admission type: Medical 32%, emergency surgery 55%, elective surgery 12%

Interventions

  • Randomly assigned to a group:
    • Hydrocortisone - Hydrocortisone 50 mg IV was administered q6h for 5 days, q12h for 3 days, q24 for 3 days, then stopped
    • Placebo - Administered with the same frequency as above
  • 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 increase >9 mcg/dL [>248 nmol/L]) or non-responsive to ACTH (cortisol increase ≤9 mcg/dL [≤248 nmol/L])

Outcomes

Comparisons are 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)

Etomidate exposure

28-day mortality
Etomidate: 45% vs. 40% (P not reported)
No etomidate: 31% vs. 29% (P=0.03)
Non-responders
Etomidate 60% vs. no etomidate 43% (P=0.004)

Adverse Events

New sepsis or septic shock
OR 1.37; 95% CI 1.05-1.79; NNH 26
New shock
6% vs. 2% (OR 2.78; 95% CI 1.02-7.58; NNH 25)
Hyperglycemia
85% vs. 72% (OR 1.18; 95% CI 1.07-1.31; NNH 8)
Hypernatremia
29% vs. 18% (OR 1.59; 95% CI 1.13-2.22; NNH 9)

Criticisms

  • Trial likely underpowered, did not power calculation requiring enrollment of 800.
  • The authors note that they did not perform neuromuscular-specific analysis to test for the development of myopathy among subjects.
  • There were 12 patients missing from the ITT analysis.
  • Patient population was less ill than patients enrolled in prior trials of corticosteroids in shock.
  • Post-hoc analysis showed appropriate antibiotics in 72% vs. 78%, outcomes reported as NSS; this means that one-quarter of patients did not receive appropriate antibiotics.[4]
  • Inclusion criteria of 72 hours may have missed the optimal window of opportunity.

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.

Further Reading

  1. Boonen E et al. "Reduced cortisol metabolism during critical illness." The New England Journal of Medicine. 2013;368:1477-1488.
  2. Concurrent editorial
  3. Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.
  4. NEJM Letters to the Editor