Sepsis: Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL)

Question 1

ADRENAL Clinical Question

Answer 1

In patients with septic shock requiring ventilatory and vasopressor support, does a continuous week-long infusion of hydrocortisone 200 mg/day improve mortality at 90 days when compared to placebo?

Question 2

ADRENAL Bottom Line

Answer 2

In patients with septic shock on mechanical ventilation and receiving vasopressors, a week of hydrocortisone 200 mg/day did not reduce 90 day mortality but may be associated with time until reversal of shock, time to extubation, length of ICU stay, and blood transfusion.

Question 3

ADRENAL Design, n

Answer 3

Multicenter, double-blind, parallel-group, randomized, controlled trial, 1832

Question 4

ADRENAL Inclusion criteria

Answer 4

• Age ≥18 years
• Mechanical ventilation
• Strong clinical suspicion of infection
• ≥2 SIRS criteria
• Continuous vasopressors/inotropes for SBP >90mmHg or MAP >60mmHg for ≥4 hours

Question 5

ADRENAL Exclusion criteria

Answer 5

• Receiving systemic corticosteroids for indication other than septic shock
• Received etomidate
• Receiving amphotericin B for systemic fungal infection
• Documented cerebral malaria
• Documented strongyloides infection
• Life expectancy ≤90 days from pre-existing disease
• Treatment limitations in place (e.g., DNR)
• Met all inclusion criteria for longer than 24 hours

Question 6

ADRENAL Intervention

Answer 6

• Hydrocortisone - Continuous infusion of hydrocortisone 200 mg IV daily for 7 days or ICU discharge or death
• Placebo

Question 7

ADRENAL Primary outcome

Answer 7

90-day mortality

Question 8

ADRENAL Criticisms

Answer 8

• Adverse events were recorded based on clinical judgement and were not centrally adjudicated. -Similarly, appropriateness of antimicrobials was not centrally adjudicated.
• The trial excluded those who had received etomidate, an anesthetic with some adrenal suppression. This limits generalizability.
• Long-term neuromuscular weakness not assessed.
• Cost analysis not performed.
• ACTH stimulation testing was not performed.
• Prior trials used bolus doses of corticosteroids. Given importance of rapid reversal of shock, is unclear if a slower infusion may have delayed onset of action of the medication and, thus, attenuated any true association between the intervention and primary outcome. The authors note that they chose an infusion over bolus dosing because of theoretical safety benefits (lower hyperglycemia and impacts on the inflammatory response).