The ADRENAL Trial: Are steroids for septic shock dead?

BACKGROUND

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Do steroids help patients with septic shock? Despite its simplicity, this question has proven difficult to answer. The answer is complicated by several elements of the details - what steroid are you using? At what dose? Infusion or a bolus dosing? As you can see, this simple, black and white question quickly gets complicated and shaded grey.

Several studies have attempted to answer the question. The initial trial to recommend steroids for septic shock was by Schumer in 1976.[1] This methodologically flawed combination retrospective-prospective study showed an absolute difference in mortality of ~28% in both the prospective and retrospective study arms. From there, several other studies and meta-analyses have challenged their use, showing either no benefit or harm.[2,3] As a resident I remember reading CORTICUS [4] and thinking “steroids don’t seem to save lives, but they do seem to reverse shock, which ‘aint so bad.” So the idea of using steroids in refractory shock cases seemed to make sense to me.

THE CURRENT STUDY

Enter the ADRENAL trial, published in the New England Journal of Medicine in 2018.[5]

Design: Multicenter, double-blind, parallel-group, randomized, controlled trial involving 3,658 patients.

Population: Patients greater than 18 years old with mechanical ventilation, documented or strong suspicion for infection with 2+ SIRS criteria and who had been on vasopressors/ionotopes for >4 hours.

Exclusion: Patients receiving steroids (for some reason other than septic shock) or etomidate, were considered likely to die from preexisting condition within 90 days, had cerebral malaria, had strongyloids or met inclusion criteria for >24 hours.

Intervention: Hydrocortisone 200 mg infusion over 24 hours for maximum of 7 days or until ICU discharge (no taper).

Comparison: Placebo.

Primary Outcome: Death from any cause at 90 days from randomization

Secondary Outcome(s): Death from any cause at 28 days, time to resolution of shock, recurrence of shock, length of ICU stay, frequency and duration of mechanical ventilation, frequency and duration of treatment with renal replacement therapy (RRT), incidence of fungemia or bacteremia, and receipt of blood transfusion in the ICU.

Authors’ Conclusions: “Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo.”

Our Conclusions: A continuous infusion of hydrocortisone decreased length of shock and mechanical ventilation, but did not decrease mortality.

To hear our analysis, critiques, and takehome points, please listen to the podcast below:

References:

1.      Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg. 1976 Sep;184(3):333-41.

2.      Lefering R, Neugebauer EA. Steroid controversy in sepsis and septic shock: a meta-analysis. Crit Care Med. 1995 Jul;23(7):1294-303.

3.      Cronin L, et al. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med. 1995 Aug;23(8):1430-9.

4.      Sprung CL, et al; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24. doi: 10.1056/NEJMoa071366.

5. Venkatesh B, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018 Mar 1;378(9):797-808.