As the authors say in their introduction, glucocorticoids have been in and out of favor as adjunctive treatment of patients in septic shock for over 40 years. Various trials have found results both favoring and discounting their utility – leading, finally, to this trial to end all trials: ADRENAL.
Of course, there’s hardly ever any such definitive thing in medicine – but this is as close as it comes. This multi-center, multi-country, blinded, placebo-controlled, randomized trial evaluated the use of hydrocortisone in critically ill patients on vasopressors in septic shock. Patients were randomized to receive either 200mg of hydrocortisone daily as continuous infusion, or placebo. The primary outcome was 90-day mortality, with multiple secondary outcomes regarding length of ICU stay, hemodynamics, and others.
With 3,800 patients enrolled, this trial – if any could ever say to do so – should be essentially the final word with regard to detecting any significant difference in outcomes. And the final answer is: choose your own adventure!
For the primary outcome, there was no statistically significance difference in mortality at 90 days – 27.9% in the hydrocortisone cohort, and 28.8% with placebo. Looking at secondary outcomes, the results here tended to favor hydrocortisone – a slightly faster resolution of shock, shorter ICU stays, and, oddly, decreased transfusion requirements. The purist would say: negative trial. The Bayesian would say: this doesn’t change my prior opinion. The answer is, probably, somewhere in between.
Effectively, when a massive trial fails to find a difference, there is still the possibility of there actually being a difference – but any magnitude of effect is likely to be quite small. “Small” in this case, looks to be on the order of numbers-needed-to-treat ranging from 20 to 200, depending on the outcome. To take this into context, the much lauded WOMAN trial celebrating tranexamic acid found only a 0.4% absolute reduction in death due to bleeding. Hydrocortisone, similarly, is inexpensive, displayed few serious adverse effects, and even a small advantage with regard to an outcome such as mortality ought to be considered valuable.
Thus, the choose your own adventure. I tend to feel this is a reasonable treatment adjunct, but, as far as moving the needle on outcomes, there are many other higher-yield clinical interventions to prioritize above hydrocortisone. The critically ill are complex, and there are many aspects to high-quality intensive clinical and nursing care that have a greater impact on ultimate outcomes. To spend much time engaged in debate regarding hydrocortisone should be done only to the extent it does not distract and detract from other, more important aspects of their care.
“Adjunctive Glucocorticoid Therapy in Patients with Septic Shock”
thank you sir.