New England Journal of Medicine MARCH 01, 2018

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock

Djillali Annane, Agnès Renault, Christian Brun-Buisson, et al.

Bottom Line

In this randomized, double-blind, placebo-controlled trial, the administration of hydrocortisone plus fludrocortisone for 7 days significantly reduced 90-day all-cause mortality in patients with septic shock compared to placebo.

Key Findings

1. The primary outcome of 90-day all-cause mortality was significantly lower in the treatment group compared to the placebo group (43.0% vs. 49.1%; relative risk 0.88; 95% confidence interval 0.78 to 0.99; P=0.03).

2. Treatment with hydrocortisone plus fludrocortisone was associated with faster hemodynamic recovery, characterized by more vasopressor-free days at day 28 (mean 17.8 vs. 15.0 days; P<0.001).

3. Organ-failure–free days at day 28 were also significantly higher in the treatment arm (mean 14.8 vs. 13.6 days; P=0.003).

4. Hyperglycemia was more frequent in the steroid group (4.3 vs. 3.4 days with blood glucose ≥150 mg/dL; P<0.001), but there were no significant differences in the rates of serious adverse events such as gastrointestinal bleeding or secondary infections.

Study Design

Design

RCT

Double-Blind

Sample

1,241

Patients

Duration

180 days

Median

Setting

Multicenter, France

Population Adult patients with persistent septic shock (requiring vasopressors for ≥6 hours) admitted to the ICU.

Intervention Hydrocortisone (50 mg IV every 6 hours) plus fludrocortisone (50 mcg orally once daily) for 7 days.

Comparator Matching placebo for 7 days.

Outcome All-cause mortality at 90 days.

Study Limitations

• The trial was originally designed as a 2×2 factorial study including drotrecogin alfa (activated), which was withdrawn from the market, leading to modifications in the trial design and structure.

• The trial experienced two suspensions during the study period, introducing complexity to the trial conduct.

• The absolute mortality reduction of 6.1% resulted in a fragility index of 3, meaning the statistical significance is sensitive to small changes in event counts.

• The trial cannot definitively isolate the independent contribution of fludrocortisone, as the intervention always included both glucocorticoid and mineralocorticoid components.

Clinical Significance

The APROCCHSS trial provides evidence that a 7-day regimen of low-dose hydrocortisone plus fludrocortisone can reduce mortality and accelerate shock reversal in patients with septic shock, helping to resolve long-standing debates regarding the utility of corticosteroids in this population.

Historical Context

The role of corticosteroids in septic shock has been controversial for decades, with conflicting results from previous major trials like CORTICUS and ADRENAL, which raised questions about the efficacy and necessity of mineralocorticoid co-therapy and the relevance of adrenal insufficiency testing.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the physiologic rationale for adding fludrocortisone to a glucocorticoid like hydrocortisone in the management of septic shock, and how does this address the concept of Critical Illness-Related Corticosteroid Insufficiency (CIRCI)?

Key Response

Hydrocortisone provides the primary anti-inflammatory (glucocorticoid) effect, while fludrocortisone provides potent mineralocorticoid activity. In septic shock, CIRCI can involve both cortisol and aldosterone deficiency. Mineralocorticoids help maintain intravascular volume by promoting sodium and water retention and increasing vascular sensitivity to catecholamines, which theoretically helps reverse refractory vasodilation.

Resident

In clinical practice, the APROCCHSS and ADRENAL trials are often compared. Which specific subset of septic shock patients seen in the APROCCHSS trial appeared to derive a mortality benefit, and how does this influence your decision on when to initiate steroids?

Key Response

APROCCHSS enrolled a 'sicker' population—patients with septic shock for at least 6 hours on high-dose vasopressors (norepinephrine equivalent of ≥0.25 μg/kg/min). Unlike ADRENAL, which showed no mortality benefit in a broader population, APROCCHSS suggests that the hydrocortisone-fludrocortisone combination should be prioritized in patients with severe, refractory shock rather than early or mild sepsis.

Fellow

The APROCCHSS trial utilized a 7-day fixed-dose regimen without a taper. Considering the potential for 'rebound' hemodynamic instability, how do these results challenge traditional endocrine management of CIRCI and the necessity of tapering protocols in the ICU?

Key Response

Historically, many clinicians feared a rebound effect or adrenal crisis if steroids were stopped abruptly. However, APROCCHSS demonstrated a clear 90-day mortality benefit despite an abrupt 7-day stop. This suggests that the hemodynamic stabilization achieved by the combination therapy is durable and that prolonged tapers—which increase the risk of secondary infections and hyperglycemia—may be unnecessary for most septic shock patients.

Attending

Considering the conflicting results between APROCCHSS (mortality benefit) and ADRENAL (no mortality benefit), how do you integrate these findings into a teaching pearl regarding the 'mineralocorticoid gap' in standard hydrocortisone dosing?

Key Response

A key teaching point is that while 200mg of hydrocortisone has significant mineralocorticoid activity (equivalent to ~0.1mg of fludrocortisone), the APROCCHSS trial specifically added oral fludrocortisone and found a survival advantage. This raises the question of whether the benefit was due to the specific drug combination or the higher severity of the study population. In practice, adding fludrocortisone is a low-risk, high-reward intervention in the most hemodynamically unstable patients.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The APROCCHSS trial faced significant logistical challenges, including a trial interruption and a change in drug batches. How might these factors introduce 'noise' or bias into a Frequentist analysis, and would a Bayesian re-analysis of the probability of benefit provide more clarity for clinical adoption?

Key Response

Interruptions and batch changes can introduce secular trends and variability in drug potency. A Frequentist p-value of 0.03 is significant but potentially fragile. A Bayesian approach, using the ADRENAL trial or earlier meta-analyses as a prior, would help quantify the 'probability of a mortality reduction >0%,' which remains high for the APROCCHSS cohort but helps temper the absolute effect size when integrated with other negative trials.

Journal Editor

As a reviewer, what concerns would you raise regarding the external validity of APROCCHSS given the 7-year recruitment period (2008-2015) and the evolution of 'Standard of Care' in sepsis (e.g., the shift away from Early Goal-Directed Therapy) during that timeframe?

Key Response

A critical reviewer would flag that sepsis care evolved significantly over those 7 years (e.g., changes in fluid resuscitation volumes and vasopressor thresholds). If the 'placebo' group’s standard care in 2008 was different from 2015, it complicates the interpretation of the treatment effect. Additionally, the requirement for a 6-hour shock duration might exclude patients who are rapidly stabilized, potentially overestimating the benefit in a 'survivor-bias' cohort.

Guideline Committee

The 2021 Surviving Sepsis Campaign (SSC) guidelines provide a 'weak recommendation' with 'moderate quality of evidence' for using corticosteroids in septic shock. Does the inclusion of fludrocortisone in the APROCCHSS protocol justify a specific guideline update to mandate its use over hydrocortisone monotherapy?

Key Response

Currently, the SSC (Guideline 33) suggests IV hydrocortisone at 200mg/day for patients with ongoing vasopressor requirements (≥0.25 mcg/kg/min). While APROCCHSS showed mortality benefit with fludrocortisone, the ADRENAL trial (hydrocortisone alone) did not. Because the evidence is 'inconsistent' across trials, guidelines currently view fludrocortisone as optional. An update would require a meta-analysis specifically isolating the 'fludrocortisone effect' to determine if it adds value beyond high-dose hydrocortisone's baseline mineralocorticoid activity.

Clinical Landscape

Noteworthy Related Trials

2002

Annane et al. Trial

n = 300 · JAMA

Tested

Hydrocortisone 50mg every 6 hours plus Fludrocortisone 50mcg daily

Population

Patients with septic shock and relative adrenal insufficiency

Comparator

Placebo

Endpoint

28-day mortality

Key result: Corticosteroid therapy significantly improved survival in patients with septic shock and adrenal insufficiency.

2008

CORTICUS Trial

n = 499 · NEJM

Tested

Hydrocortisone 50mg every 6 hours

Population

Patients with septic shock

Comparator

Placebo

Endpoint

28-day mortality

Key result: Hydrocortisone therapy did not improve survival in patients with septic shock, though it did accelerate shock reversal.

2018

ADRENAL Trial

n = 3,658 · NEJM

Tested

Hydrocortisone 200mg continuous infusion

Population

Adults with septic shock

Comparator

Placebo

Endpoint

90-day mortality

Key result: Continuous hydrocortisone infusion did not result in lower 90-day mortality compared to placebo.

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