Fludricortisone combination vs. hydrocortisone alone in septic shock

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Bosch NA, et al. "Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone Among Patients With Septic Shock". JAMA Internal Medicine. 2023. 183(5):451-459.
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Clinical Question

In adult patients with septic shock receiving norepinephrine, what does adding fludricortisone to hydrocortisone as compared to hydrocortisone alone for in hospital death or discharge to hospice.

Bottom Line

The addition of fludricortisone to hydrocortisone lowered the adjusted absolute risk of mortality.

Major Points

There currently are no large, randomized trials comparing hydrocortisone alone to the addition of fludricortisone in septic shock. The surviving sepsis guidelines recommends adding IV hydrocortisone. Some of the prevailing logic is that hydrocortisone at 200mg/day should have adequate mineralocorticoid activity and the addition of fludricortisone would not add much benefit. Trials such as the Annane Trial or APROCCHSS showed benefit with the addition of fludricortisone whereas the CORTICUS, HYPRESS, and ADRENAL trials did not add fludricortisone. This retrospective registry trial sought to clarify the addition of fludricortisone to hydrocortisone in septic shock.

The authors analyzed registry data from 88 275 patients hospitalized with septic shock, received norepinephrine hemodynamic support, and were treated with hydrocortisone-fludrocortisone (n=2280) compared to hydrocortisone alone (n=85 995) within 3 days of hospitalization. For their primary outcome of in-hospital mortality or ICU discharge to hospice, the combination therapy demonstrated 47.2% mortality whereas the hydrocortisone alone had 50.8% (adjusted risk difference -3.7%, P < 0.001). They tested multiple sensitivity analyses where this finding remained robust. They also found the addition of fludricortisone led to more ventilator-free and hospital-free days. They did not detect any difference in adverse events such as blood transfusion (negative control outcome), hypernatremia, or health care associated infection between groups.

Mineralocorticoid equivalents may be an over simplification of steroid action in the body. Keeping in mind that the definition is based on measuring sodium-retention, hydrocortisone is cleaved at mineralocorticoid sites.[1] Keeping this in mind, that may explain why trials with the addition of fludricortisone demonstrate their benefit. This trial did have some potential critiques, the first being that it is a retrospective, observational, registry trial. The registry lacked some granularity in timing of drug administration down to calendar day or doses to offer clinical comparisons. This paper is hypothesis generating and will need to be tested with a large, randomized trial.


Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021, adapted[2]

  • If adequate fluid resuscitation and addition of vasopressor therapy unable to restore hemodynamic stability add IV hydrocortisone, 200 mg/day (Weak, moderate-quality evidence)


  • Multicenter, retrospective, cohort study
  • N=88 275
    • Fludricortisone-Hydrocortisone (n=2280)
    • Hydrocortisone (n=85 995)
  • Setting: Various sites in USA
  • Enrollment: 2016-2020
  • Median follow-up: 6 days (IQR 2-13)
  • Analysis: Intention-to-treat
  • Primary Outcome: Composite of hospital death or discharge to hospice


Inclusion Criteria

  • Premier Healthcare Database
  • Admitted to ICU or intermediate care unit
  • Septic shock (identified by ICD-10 code at admission)
  • received norepinephrine
  • began hydrocortisone within 3 days of hospital admission

Exclusion Criteria

  • younger than 18 years old
  • had alternative indication for fludricortisone (primary adrenal insufficiency, orthostatic hypotension, and congenital adrenal hyperplasia)

Baseline Characteristics

Hydrocortisone Group displayed

  • Demographics: median age 67 years, 49% female
  • Vasopressor use: 6.6% dopamine, 20.9% epinephrine, 24.9% phenylephrine, 52.4% vasopressin
  • Acute organ dysfunction: 42.5% respiratory, 30.4% hematologic, 12.8% hepatic, 70.3% renal
  • Concurrent medical conditions: 36.8% Heart Failure, 7.5% connective tissue disorder, 37.6% pneumonia, 9.7% major surgery,
  • Health Insurance type: 14.5% commercial, 10% Medicaid, 65.8% Medicare, 3.1% self-pay, 2.6% other


  • Fludricortisone given on the same calendar day as hydrocortisone
  • hydrocortisone alone


Comparisons are Fludricortisone-Hydrocortisone vs. Hydrocortisone alone.

Primary Outcomes

Died in hospital or discharged to hospice
47.2% vs. 50.8% (adjusted absolute risk difference of −3.7%, 95% CI −4.2% to −3.1%) P < 0.001; E-value, 1.37

Secondary Outcomes

Duration of therapy
3 days (IRQ 1-4) vs. 3 days (IRQ 2-6)
In-Hospital Death
39.3% vs. 42.7% (adjusted risk difference −3.7%, 95% CI−4.2% to −3.3%)
Vasopressor-free Days
13.8 vs. 12.9 (adjusted mean difference 0.9, 95% CI 0.8-1.1) P < 0.001
Hospital-free days
8.7 vs. 8.4 (adjusted mean difference 0.7, 95% CI 0.6-0.8) P < 0.001

Sensitivity Analysis

Primary analysis, met inclusion criteria on hospital Day 1
43% vs. 48.7% (adjusted risk difference -5.7, 95% CI -5.8 to -4.6) P < 0.001
Primary analysis, met inclusion criteria on hospital day 2 or 3 with covariates ascertained on the day before treatment assignment
50.8% vs. 53.2% (adjusted risk difference -2.2, 95% CI -3.2 to -1.3) P < 0.001
Primary analysis, excluding 2020
45.8% vs. 49.7% (adjusted risk difference -4, 95% CI -4.6 to -3.5) P < 0.001

Adverse Events

Blood transfusion (negative control outcome)
28.3% vs. 29.9% (adjusted risk difference -0.3, 95% CI -0.8 to 0.1) P = 0.12
Incident Hypernatremia
11.4% vs. 11.3%
Health care associated infection
1.4% vs. 1.0%


  • Retrospective, observational review
  • Selection bias: Premier Healthcare Database includes a non-random sample from voluntary hospital participants
  • Database did not include health care datapoints so comparisons such as vasopressor doses or severity index (e.g. SOFA or APACHE II) could not be compared
  • Timepoints in the database was only as precise as calendar day and time to receipt in hours may have impacted outcomes


  • National Institutes of Health (NIH) National Centerfor Advancing Translational Sciences (NCATS) grant number 1KL2TR001411 and 1UL1TR001430
  • Boston University Chobanian & Avedisian School of Medicine Department of Medicine Career Investment Award.

Further Reading