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Annane D, et al. "Hydrocortisone plus Fludrocortisone for Adults with Septic Shock". N Engl J Med. 2018. 378(9):809-818.
PubMedFull text

Clinical Question

In adult patients admitted to critical care, does low dose hydrocortisone plus fludrocortisone for 7 days affect mortality at 90 days. (original question included activated protein C)

Bottom Line

From the same lead author as Annane Trial, this trial again showed a benefit in mortality at 90 days with low dose steroids, but this was not replicated outside of France in the CORTICUS, HYPRESS, and ADRENAL trials.

Major Points

Multiple RCTs have investigated the potential role for steroid therapy in patients with septic shock. The Annane Trial in 2002 with 299 patients demonstrated a short-term mortality benefit with IV hydrocortisone and fludrocortisone among patients with evidence of adrenal insufficiency on ACTH stimulation testing. CORTICUS with 499 patients in 2008 investigated hydrocortisone in patients with and without adrenal insufficiency and found a faster reversal of shock but no benefit in either subgroup with suggestion of increased infection rates in patients receiving hydrocortisone. HYPRESS in 2016 with 380 patients showed no difference in mortality but showed decrease time to reversal of shock. In the same edition of the journal but selected to be epublished ahead of print, the ADRENAL trial included 3800, demonstrated no difference in 90 day mortality.

Published in 2018, the Hydrocortisone plus Fludrocortisone for Adults with Septic Shock, was the reporting of the steroid vs. placebo parallel arms of the Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial.[1] After withdrawal of activated protein C from the market, that arm was suspended and analyzed to show no statistical difference with activated protein C on mortality nor interaction with the low-dose steroids. From the same lead author as the original Annane Trial in 2002, this trial closely replicated the first trial in intervention and outcomes. The authors opted to again use a combination of hydrocortisone 60mg IV bolus every 6 hours and fludrocortisone 50 mcg via nasogastric tube for 7 days, in contrast to CORTICUS and subsequent trials that did not show affect of the addition of fludrocortisone in the French ICU population.[2] Randomizing 1241 patients over a seven year span (with two hiatus) this trial showed an absolute risk reduction of 6% in mortality at 90 days, NNT 16. This is in stark contrast to several other major trials. It also a demonstrated faster reversal of shock and organ failure which aligned with other trials.

The 2016 Surviving Sepsis Campaign severe sepsis and septic shock[3] suggests using IV hydrocortisone if hemodynamics cannot be stabilized using fluids and vasopressors. This recommendation was made before the release of ADRENAL and this trial and may lead to re-evaluation of this recommendation. The seemingly contradictory findings of this trial may be attributed to the difference in severity of illness of the patients found in this trial with high mortality and severity scores as compared to other trials, as well as the use of a minerocorticoid. The findings of the trial may support the use of steroids in patients that are continuing to fail despite adequate fluid resuscitation and vasopressor support. Meta-analysis of these findings may better aid in interpretation and application at the bedside.


As of March 2018, no guidelines have been published that reflect the results of this trial.


  • Multicenter, double-blind, 2-by-2 factorial, randomized trial
  • N=1241
    • Hydrocortisone plus Fludrocortisone (n = 614)
    • Placebo (n=627)
  • Setting: 34 centres
  • Enrollment: 2 Sept 2008 - 23 Dec 2015
    • two halts: 25 Oct 2011 to 12 May 2012; 22 Jul 2014 to 7 Oct 2014
  • Mean follow-up: 180 days
  • Analysis: intention to treat
  • Primary Outcome: 90-day all-cause mortality


Inclusion Criteria

  • admitted to the ICU < 7 days
  • indisputable or probable septic shock < 24 hours
    • presence of a clinically or microbiologically documented infection
    • SOFA[4] score of 3-4 for ≥ 2 organ systems for ≥ 6 consecutive hours
    • receipt of vasopressor therapy (norepinephrine, epinephrine, or any other vasopressor at a dose of ≥ 0.25 mcg/kg/min or ≥ 1 mg per hour) for ≥ 6 hours to maintain SBP ≥ 90 mm Hg or MAP ≥ 65 mm Hg

Exclusion Criteria

  • septic shock > 24 hours
  • high risk of bleeding (eg recent surgery, full anticoagulation, etc)
  • pregnancy or lactation
  • underlying conditions that could affect short-term survival
  • known hypersensitivity to drotrecogin alfa (activated)
  • previous treatment with corticosteroids

Baseline Characteristics

Placebo group displayed

  • Demographics: 68% male, mean age 66 years, admission from medicine ward 81%,
  • Sepsis severity: mean SAPS II[5] 56, mean SOFA 11
  • Infection: community acquired 76%, unknown site 3%, Lung 58%, Abdomen 11%, Urinary tract 18%, Positive blood culture 37%, Gram-positive 70%, Gram-negative 42%, adequate antimicrobial therapy 96%
  • Supportive therapy: Epinepherine n=58, dose 1.74 mcg/kg/min, Norepinepherine n=552, dose 1.14 mcg/kg/min, Mechanical ventilation 91%, Renal replacement therapy 28%


2x2 factorial design, patients randomized:

  • Hydrocortisone 50mg IV every 6 hours and fludrocortisone 50 mcg NG daily for 7 days without taper
  • Activated protein C 24 mcg/kg/h for 96 h[1] This arm discontinued follow withdrawal of the product from the market
  • Placebo (mannitol 133.6 mg IV, microsrystalline cellulose 50 mg, and 0.95 Abnormal Saline)


Comparisons are Placebo vs. Hydrocortisone plus Fludrocortisone.

Primary Outcomes

All cause mortality at 90 days
49% vs. 43% (RR 0.88; 95% CI 0.78-0.99; P=0.03)

Secondary Outcomes

All cause mortality at 28 days
39% vs. 34% (RR 0.87; 95% CI 0.75–1.01; P=0.06)
All cause mortality at ICU discharge
41% vs. 35% (RR 0.86; 95% CI 0.75–0.99; P=0.04)
All cause mortality at hospital discharge
45% vs. 39% (RR 0.86; 95% CI 0.76–0.98; P=0.02)
All cause mortality at 180 days
53% vs. 47% (RR 0.89; 95% CI 0.79–0.99; P=0.04)
Decision to withdraw care/active treatment at 90 days
9% vs. 10% (RR 1.07; 95% CI 0.77–1.49; P=0.69)
Vasopressor-free days at 28 days
Mean 15±11 vs. 17±11 (P<0.001)
Median(IRQ) 19(1–26) vs. 23(5–26)
Ventilator-free days at 28 days
Mean 10±11 vs. 11±11 (P=0.07)
Median(IRQ) 4(0–21) vs. 10(0–22)
Organ-failure-free days at 28 days
Mean 12±11 vs. 14±11 (P=0.003)
Median(IRQ) 12(0–24) vs. 19(0–25)

Adverse Events

There was no difference in serious adverse event, bleeding, rate or site of superinfection, new onset sepsis or septic shock, or neurologic sequelae

≥1 Episode of blood glucose levels ≥8.3 mmol/L [≥150 mg/dl] by day 7
83% vs. 89% (RR 1.07; 95% CI 1.03–1.12; P=0.002)
Days without blood glucose levels ≥8.3 mmol/L [≥150 mg/dl] by day 7
Mean 3.4±2.5 vs. 4.3±2.5 (P<0.001)
Median 3(1–6) vs. 5(2–6)


  • Additional treatments were harmonized using the Surviving Sepsis 2008[6] and results may be affected by shifting baseline bias.
  • Corticotropin stimulation performed and result not reported nor were non-responders analyzed


  • French Ministry of Health with the Program Hospitalier de Recherche Clinique

Further Reading

  1. 1.0 1.1 Annane D et al. Recombinant human activated protein C for adults with septic shock: a randomized controlled trial. Am. J. Respir. Crit. Care Med. 2013. 187:1091-7.
  2. Annane D et al. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA 2010. 303:341-8.
  3. Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.
  4. Vincent JL et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine. Crit. Care Med. 1998. 26:1793-800.
  5. Le Gall JR et al. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993. 270:2957-63.
  6. Dellinger RP et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit. Care Med. 2008. 36:296-327.