Article Identification

• Title: “Hydrocortisone plus Fludrocortisone for Adults with Septic Shock”
• Authors: Djillali Annane, Alain Renault, Christian Brun-Buisson, et al.
• Journal: The New England Journal of Medicine (2018); 378(9):809–818
• PMID: 29490185 | DOI: 10.1056/NEJMoa1705716

Quick Reference Summary

• In this multicenter, double-blind, randomized trial (N=1241), adult patients with septic shock who received hydrocortisone (50 mg IV every 6 hours) plus fludrocortisone (50 μg enterally once daily) for 7 days had a 90-day all-cause mortality of 43.0%, compared to 49.1% with placebo (absolute difference ~6%; relative risk 0.88 [95% CI, 0.78–0.99]; p=0.03).
• Patients also had significantly more vasopressor-free days (17 vs. 15 days; p<0.001) and organ-failure–free days (14 vs. 12 days; p=0.003), with no significant increase in serious adverse events except for higher rates of hyperglycemia.

Core Clinical Question

Among adults with persistent septic shock despite initial resuscitation, does adding hydrocortisone plus fludrocortisone to standard care reduce short- and long-term mortality compared to placebo? (Population: adults with septic shock; Intervention: hydrocortisone + fludrocortisone; Comparison: placebo; Outcome: 90-day mortality and secondary clinical outcomes.)

Background

• Disease or Condition Overview:
  • Septic shock is a life-threatening syndrome of circulatory, cellular, and metabolic dysfunction, usually requiring vasopressors to maintain adequate mean arterial pressure. Mortality historically has been as high as 40–50%.
• Prior Data on the Topic:
  • Earlier trials have evaluated low-dose corticosteroids (i.e., 200–300 mg/day hydrocortisone), with mixed results on mortality:
    • The Ger-Inf-05 trial showed survival benefit with hydrocortisone plus fludrocortisone. (JAMA. 2002;288(7):862–871. Referenced in systematic reviews.)
    • The CORTICUS trial found no significant overall mortality benefit with hydrocortisone alone. (N Engl J Med. 2008;358(2):111–124.)
• Current Standard of Care:
  • Mainstay of management involves early antibiotics, fluid resuscitation, and vasopressors. Corticosteroids are used variably in patients who remain hypotensive after appropriate resuscitation. No previous consensus existed on whether fludrocortisone adds benefit.
• Knowledge Gaps Addressed by This Study:
  • Uncertainty over the survival impact of combining fludrocortisone with hydrocortisone in septic shock.
  • Whether adding mineralocorticoid activity shortens shock duration or improves mortality.
• Study Rationale:
  • Preclinical and clinical data suggested synergy between glucocorticoid and mineralocorticoid effects in septic shock. This trial tested whether combination therapy would improve outcomes in vasopressor-dependent septic shock compared with placebo.

Methods Summary

• Study Design:
  • Prospective, multicenter, double-blind, randomized controlled trial originally planned with a 2×2 factorial design comparing (1) hydrocortisone plus fludrocortisone vs. placebo and (2) drotrecogin alfa (activated) vs. placebo.
  • After drotrecogin alfa (activated) was withdrawn from the market, the study continued effectively as a two-arm design (hydrocortisone-plus-fludrocortisone vs. placebo).
• Setting and Time Period:
  • Conducted across 34 ICUs in France.
  • Enrollment from September 2008 to June 2015.
• Population Characteristics:
  • Adults (≥18 years) with septic shock (per criteria) requiring vasopressors (≥0.25 μg/kg/min norepinephrine or equivalent) for ≥6 hours.
  • High baseline illness severity (mean norepinephrine ~1 μg/kg/min, high SAPS II, and high SOFA scores).
• Inclusion/Exclusion Criteria:
  • Included: Septic shock <24 hours, adequate fluid resuscitation, vasopressor-dependent.
  • Excluded: High bleeding risk, prior steroids, pregnancy, or other conditions complicating short-term survival.
• Intervention Details:
  • Hydrocortisone 50 mg IV every 6 hours + fludrocortisone 50 μg by NG tube once daily for 7 days, without taper.
• Control/Comparison:
  • Placebo for both hydrocortisone and fludrocortisone.
• Primary & Secondary Outcomes:
  • Primary: 90-day all-cause mortality.
  • Secondary: ICU, hospital, day 28, and day 180 mortality; vasopressor-free days; ventilator-free days; organ-failure–free days.
• Statistical Analysis:
  • Logistic regression for mortality outcomes.
  • Cox or Fine-Gray models for time-to-event endpoints (shock reversal, mechanical ventilation weaning).
  • Planned sample size: ~1280 patients for adequate precision of outcomes.
• Sample Size Calculations:
  • Powered (95%) to detect a 10% absolute reduction in 90-day mortality from an estimated 45–50% baseline.
• Ethics and Funding:
  • Funded by the French Ministry of Social Affairs and Health, with public sponsorship.
  • Approved by an independent ethics committee. Written informed consent obtained from patients or surrogates.

Detailed Results

• Participant Flow and Demographics:
  • N=1241 randomized (614 in hydrocortisone + fludrocortisone, 627 in placebo).
  • Baseline characteristics (SOFA ~11, SAPS II ~60, lactate ~6 mmol/L) balanced between groups.
• Primary Outcome: 90-Day Mortality:
  • Hydrocortisone-plus-fludrocortisone: 43.0% (264/614)
  • Placebo: 49.1% (308/627)
  • Absolute difference: ~6.1%
  • RR=0.88 (95% CI, 0.78–0.99), p=0.03
• Secondary Outcomes:
  • ICU mortality: 35.4% vs. 41.0% (p=0.04)
  • Hospital mortality: 39.0% vs. 45.3% (p=0.02)
  • Day-180 mortality: 46.6% vs. 52.5% (p=0.04)
  • Day-28 mortality (NS): 33.7% vs. 38.9% (p=0.06)
  • Vasopressor-free days to day 28: 17 vs. 15 days (p<0.001)
  • Organ-failure–free days to day 28: 14 vs. 12 days (p=0.003)
  • Ventilator-free days to day 28: 11 vs. 10 days (p=0.07)
• Adverse Events:
  • Serious adverse events by day 180: 53.1% vs. 58.0% (p=0.08)
  • Hyperglycemia more common with hydrocortisone-plus-fludrocortisone (p=0.002).
  • No significant increase in superinfection or GI bleeding.

Results Table

*To day 28; patients who died were assigned zero free days.

Authors' Conclusions

• The addition of hydrocortisone plus fludrocortisone, administered for 7 days, reduced 90-day all-cause mortality in adults with septic shock, and accelerated shock resolution without increasing serious adverse events (aside from more hyperglycemia).
• The authors suggest that low-dose glucocorticoid-plus-mineralocorticoid therapy should be considered in patients with persistent septic shock.

Critical Analysis

A. Strengths

• Randomized, double-blind, placebo-controlled design with multicenter involvement.
• Fairly large sample size (N=1241), with adequate power to detect differences in mortality.
• Well-defined inclusion criteria targeting patients with genuine persistent shock.
• Comprehensive outcome assessment spanning ICU, hospital, and 90-day to 180-day mortality.

B. Limitations

• Original 2×2 factorial design was interrupted by drotrecogin alfa withdrawal, potentially affecting full power for interactive analyses.
• Only a 7-day fixed course of corticosteroids was evaluated; impacts of tapering or longer therapy remain unknown.
• Conducted primarily in French ICUs; generalizability to different healthcare systems or patient populations may be limited.
• Although serious adverse events were not usually different, the single-center or regional approach might not capture broader real-world heterogeneity.
• Hyperglycemia was significantly higher in the treatment group, requiring close glucose monitoring.

C. Literature Context

• Previous Studies and Meta-Analyses:
  • CORTICUS (N Engl J Med. 2008;358(2):111–124) found no 28-day mortality improvement from hydrocortisone alone, though shock reversed more quickly.
  • ADRENAL (N Engl J Med. 2018;378(9):797–808) also showed no significant 90-day mortality benefit with hydrocortisone alone but faster shock resolution.
  • Ger-Inf-05 (JAMA. 2002;288(7):862–871, cited in reviews) found mortality benefit when combining hydrocortisone and fludrocortisone in septic shock.
  • Marik et al. (Chest. 2017;151(6):1229–1238.) proposed combining hydrocortisone with vitamin C and thiamine, but subsequent trials have reported inconsistent mortality results.
  • Pirracchio et al. (NEJM Evid. 2023;2(6):EVIDoa2300034) patient-level meta-analysis suggests that hydrocortisone plus fludrocortisone may reduce mortality compared to placebo, but hydrocortisone alone shows less clear benefit.
  • Lai et al. (Crit Care Med. 2024;52(4):e193–e202) similarly reported that combining fludrocortisone with hydrocortisone improved short-term survival, albeit with low to moderate certainty.
• Contrasting Methodological Quality:
  • The APROCCHSS trial’s large, randomized, double-blind design improves internal validity. In contrast, many older studies used smaller cohorts or lacked fludrocortisone.
  • Comparison to observational studies (Pharmacotherapy. 2023;43(8):787–794) indicates robust design likely explains the clearer mortality signal here.
• Comparisons with Guidelines:
  • Previous Surviving Sepsis Campaign guidelines have endorsed low-dose hydrocortisone for refractory septic shock but were inconclusive for adding fludrocortisone.
  • More recent data (2023–2025) increasingly support hydrocortisone plus fludrocortisone in vasopressor-dependent septic shock.
• This Trial’s Contribution:
  • Solidifies evidence that hydrocortisone plus fludrocortisone decreases mortality in severe septic shock.
  • Provides impetus for further guidance updates; it resolves some controversies left by earlier trials that used hydrocortisone alone.

Clinical Application

• Impact on Practice:
  • Proposes early use of low-dose hydrocortisone plus fludrocortisone in appropriate patients with persistent septic shock.
• Patient Populations:
  • Particularly suitable for patients failing initial resuscitation with ongoing vasopressor requirements.
• Implementation Considerations:
  • Clinicians need to balance potential benefits against risks such as hyperglycemia.
• Integration with Existing Evidence:
  • Aligns with evolving guidelines and provides more robust evidence favoring combination therapy.

How To Use This Info In Practice

Clinicians should consider early low-dose hydrocortisone plus fludrocortisone in patients with septic shock not responsive to initial fluid resuscitation and vasopressors. While this study supports improved survival, ongoing clinical judgment is needed to ensure appropriate patient selection (e.g., exclusion of those with minimal vasopressor requirements). Further large-scale studies and updates to international guidelines may continue refining recommendations, but in 2025, hydrocortisone plus fludrocortisone remains an evidence-based adjunct for septic shock management.