Fludrocortisone for Septic Shock: Current Evidence
The combination of hydrocortisone plus fludrocortisone reduces 90-day mortality in adults with septic shock compared to placebo, with a 12% lower risk of death compared to hydrocortisone alone, though this recommendation is based primarily on indirect evidence. 1, 2
Primary Evidence for Combination Therapy
The landmark APROCCHSS trial (2018) demonstrated that hydrocortisone 50 mg IV every 6 hours plus fludrocortisone 50 μg daily via nasogastric tube for 7 days reduced 90-day mortality from 49.1% to 43.0% (relative risk 0.88, P=0.03) in 1,241 adults with septic shock. 1 This represents an absolute mortality reduction of 6.1% and a number needed to treat of approximately 16 patients. 1
The combination therapy also improved secondary outcomes: vasopressor-free days increased from 15 to 17 days (P<0.001), organ-failure-free days increased from 12 to 14 days (P=0.003), and mortality was significantly lower at ICU discharge (35.4% vs 41.0%), hospital discharge (39.0% vs 45.3%), and 180 days (46.6% vs 52.5%). 1
Network Meta-Analysis Findings
A 2024 Bayesian network meta-analysis of 17 trials (7,688 patients) confirmed that fludrocortisone plus hydrocortisone had the highest probability of reducing mortality among all interventions studied. 2 The analysis showed:
- Fludrocortisone plus hydrocortisone: RR 0.85 (95% CrI 0.72-0.99) versus placebo, with 98.3% probability of superiority and moderate-certainty evidence 2
- Hydrocortisone alone: RR 0.97 (95% CrI 0.87-1.07) versus placebo, with only 73.1% probability of superiority and low-certainty evidence 2
- Direct comparison: Fludrocortisone plus hydrocortisone showed 12% lower mortality risk versus hydrocortisone alone (RR 0.88,95% CrI 0.74-1.03), with 94.2% probability of superiority 2
Critical Limitation: Scarcity of Direct Evidence
A major caveat is that only two trials directly compared fludrocortisone plus hydrocortisone versus hydrocortisone alone, meaning the network meta-analysis relied primarily on indirect comparisons. 2 This introduces uncertainty despite the statistical findings. The heterogeneity of included trials and varying definitions of septic shock across studies further complicate interpretation. 2
Historical Context and Earlier Evidence
The 2002 Annane trial first demonstrated benefit of combination therapy in 229 "non-responders" to corticotropin testing, showing reduced 28-day mortality (53% vs 63%, hazard ratio 0.67, P=0.02) and faster vasopressor withdrawal (57% vs 40%, P=0.001). 3 However, this trial's reliance on ACTH stimulation testing is now considered outdated, as current guidelines do not recommend using this test to guide treatment decisions. 4
Pharmacokinetic Concerns
Fludrocortisone absorption in septic shock is highly unreliable. A 2016 pharmacokinetic study found that one-third of septic shock patients had undetectable plasma fludrocortisone concentrations after a 50 μg oral dose. 5 Among those with detectable levels, there was massive inter-individual variability (98% for lag time, 49% for clearance), and the plasma half-life was only 1.35 hours—much shorter than expected. 5 Illness severity significantly increased both the lag time before absorption and drug clearance. 5
This pharmacokinetic data raises serious questions about whether fludrocortisone is reliably absorbed via nasogastric tube in critically ill patients with septic shock, potentially explaining why some trials showed no benefit.
Current Guideline Recommendations
The 2017 SCCM/ESICM guidelines suggest using low-dose IV hydrocortisone <400 mg/day for at least 3 days in adults with septic shock unresponsive to fluids and moderate-to-high dose vasopressors (>0.1 μg/kg/min norepinephrine equivalent). 6 However, these guidelines were published before the APROCCHSS trial results and do not make a definitive recommendation regarding fludrocortisone addition. 6
The 2018 BMJ rapid recommendation acknowledges the question "Does the addition of fludrocortisone improve outcomes?" as a key research gap requiring further investigation. 6
Practical Implementation
If using fludrocortisone in septic shock, the evidence-based regimen is:
- Hydrocortisone 50 mg IV bolus every 6 hours (or 200 mg/24 hours continuous infusion) 1, 7
- Fludrocortisone 50 μg tablet via nasogastric tube once daily 1
- Continue for 7 days, then taper when vasopressors are discontinued 1, 7
- Initiate only when shock remains refractory despite adequate fluid resuscitation AND moderate-to-high dose vasopressors 7, 4
Monitoring and Adverse Effects
The primary adverse effect is hyperglycemia, which occurred more frequently with combination therapy but did not increase rates of superinfection or gastrointestinal bleeding. 1, 7 Hypernatremia may also occur and requires monitoring. 7, 4
Common Pitfalls to Avoid
- Do not use corticosteroids in sepsis without shock—no mortality benefit has been demonstrated and potential harm exists 7, 4
- Do not use high-dose, short-course regimens (>400 mg/day for <3 days)—these show no benefit and potential harm 6, 7
- Do not rely on ACTH stimulation testing to determine which patients should receive treatment—clinical criteria (vasopressor-refractory shock) should guide decisions 4
- Do not stop abruptly—taper over 6-14 days when vasopressors are discontinued to avoid rebound inflammation 7, 4
- Recognize unreliable absorption—enteral fludrocortisone may not be absorbed in one-third of patients 5
Unresolved Questions
The role of fludrocortisone remains genuinely controversial. While the APROCCHSS trial and network meta-analysis suggest benefit, the reliance on indirect evidence, pharmacokinetic concerns about absorption, and lack of head-to-head trials comparing combination therapy versus hydrocortisone alone mean definitive conclusions cannot yet be drawn. 2, 5 The ongoing ADRENAL trial results (3,800 patients) may provide additional clarity, though this trial studied hydrocortisone alone without fludrocortisone. 6
In clinical practice, given the moderate-certainty evidence of mortality benefit, the low cost, and acceptable safety profile, adding fludrocortisone 50 μg daily to hydrocortisone in adults with vasopressor-dependent septic shock is reasonable, while acknowledging the limitations of current evidence. 1, 2