Addition of fludrocortisone to hydrocortisone is beneficial in management of septic shock

1. Patients treated for septic shock with fludrocortisone and hydrocortisone were less likely to die or be discharged to hospice care than patients treated with hydrocortisone alone.

2. The absolute risk of death or discharge to hospice was 3.7% lower in patients receiving combined steroid treatment.

Level of Evidence Rating: 2 (Good)

Study Rundown: Septic shock is a severe manifestation of bacteremia characterized by cardiovascular dysfunction requiring vasopressor medications to maintain hemodynamic stability. Treatment guidelines suggest the addition of corticosteroids for patients who require ongoing vasopressor support, with hydrocortisone most frequently used. The present study sought to compare hydrocortisone alone versus in combination with fludrocortisone in patients treated for septic shock.

88,275 patients were included in total, with 97.4% falling in the hydrocortisone-only (control arm) and 2.6% (2,280) patients receiving combination therapy. The primary outcome occurred in 47.2% of patients in the fludrocortisone-hydrocortisone group and 50.8% of patients in the hydrocortisone only group; this difference was statistically significant. The in-hospital death rate was 39.3% in the combination group and 42.7% in the hydrocortisone-only group. Patients in the experimental group also had more vasopressor-free days in hospital (0.9 vs. 0.7 days). Finally, rates of hypernatremia and hospital-acquired infections were similar between groups.

This study utilized population-level data to simulate a head-to-head trial, determining that combination treatment with fludrocortisone and hydrocortisone is superior in treating septic shock compared to hydrocortisone alone. A major strength of this study includes the plausibility of these findings, as previous studies have noted a trend towards improved outcomes with combination steroid therapy. However, these results are limited by the inability to control for confounding factors and the paucity of some important clinical data due to the retrospective nature of the study design. Further study in this area is needed to describe the clinical applicability of these findings.

Click here to read this study in JAMA Internal Medicine

Click to read an accompanying editorial in JAMA Internal Medicine

Relevant reading: What is the role of steroids for septic shock in 2021?

In-Depth [retrospective cohort]: A retrospective cohort study was conducted in the United States to emulate a target trial. Adult patients diagnosed with septic shock admitted to an intensive or intermediate care unit received norepinephrine and hydrocortisone therapy within three days of admission. Patients were included in the trial arm (fludrocortisone and hydrocortisone) only if they began treatment with both agents on the same day. Patient data were obtained through the Premier Healthcare Database (2016-2020), including approximately ¼ inpatients nationally. The primary outcome was a composite of death or discharge to a hospice.

Patients were treated for a median duration of 3 days in each group. The median (interquartile range) daily dose of hydrocortisone was 225mg (200-300) in the combination group and 200mg (100-300) in the hydrocortisone-only group. The addition of fludrocortisone to hydrocortisone was associated with an adjusted absolute risk difference of -3.7% (95% confidence interval -4.2% to -3.1%) for the primary outcome of death or discharge to hospice. The in-hospital death rate was 39.3%  (adjusted risk difference, −3.7%; 95% confidence interval −4.2% to −3.3%) in the combination group and 42.7% in the hydrocortisone-only group. Patients in the experimental group also had more vasopressor-free days in hospital (0.9 [0.8-1.1] vs. 0.7 [0.6-0.8] days).

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