Should We Add Fludrocortisone to Hydrocortisone for Treatment of Septic Shock?

May 2, 2023

Written by Millie Cosse

Spoon Feed
Patients with septic shock on norepinephrine who were treated with fludrocortisone and hydrocortisone had an associated reduction of in-hospital death or discharge to hospice compared to those treated with hydrocortisone alone.

Why does this matter?
Surviving sepsis guidelines currently include a weak recommendation to add glucocorticoids to the treatment regimen for sepsis ¹. Currently, no studies with sufficient power have compared hydrocortisone to hydrocortisone-fludrocortisone combination therapy in the treatment of septic shock.

The more mineralocorticoid, the merrier
This retrospective cohort study used observational data from the Premier Healthcare Database to emulate a target trial. They analyzed data from 88,275 patients hospitalized with septic shock who were receiving a norepinephrine infusion and were treated with hydrocortisone or hydrocortisone-fludrocortisone combination treatment within 3 days of hospitalization. 85,995 (97.4%) were treated with hydrocortisone alone, and 2,280 (2.6%) were treated with combination hydrocortisone-fludrocortisone. Among patients who received hydrocortisone-fludrocortisone, 1,076 (47.2%) died or were discharged to hospice compared with 43,669 (50.8%) for those who received hydrocortisone alone. Vasopressor-free days and hospital-free days were also higher among patients who received combination therapy.

My take: A small mortality benefit for hydrocortisone-fludrocortisone treatment in septic shock was demonstrated by the APROCCHSS trial in 2018 ², and the consistent benefit of combination therapy in this study is encouraging. Additionally, these results suggest a number needed to treat of 28 to prevent death, which would be a big deal for such a prevalent condition. Although there are weaknesses and risk of confounding in this retrospective, target trial emulation strategy, I’ll certainly consider adding fludrocortisone when treating septic shock from now on.

Source
Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone Among Patients With Septic Shock. JAMA Intern Med. 2023 Mar 27:e230258. doi: 10.1001/jamainternmed.2023.0258. Epub ahead of print.

Editor’s note: Target trial emulation is helpful if adjustments are made for the most influential confounders. I think they did that in this study. The adjusted risk difference, -3.7% and corresponding NNT 28, are estimates. Only a very large RCT could give causal certainty. With the low downside risk to adding fludrocortisone, I agree with Dr. Cosse; this seems reasonable. ~Clay Smith

Works Cited

1. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49(11):e1063-e1143. doi:10.1097/ CCM.0000000000005337
2. Annane D, Renault A, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.  N Engl J Med. 2018 Mar 1;378(9):809-818. doi: 10.1056/NEJMoa1705716.