APROCCHSS

Published

Annane D, et al. "Hydrocortisone plus Fludrocortisone for Adults with Septic Shock". The New England Journal of Medicine. 2018. 378(9):809-818.
PubMed • Full text • PDF

Clinical Question

In adult patients with septic shock, does low-dose hydrocortisone plus fludrocortisone for 7 days affect overall survival at 90 days?

Bottom Line

Among patients with septic shock, low-dose hydrocortisone plus fludrocortisone improved 90-day overall survival compared to placebo. (The trial's parallel study of drotrecogin alfa versus placebo was abandoned after the drug was withdrawn from the market.)

Major Points

Multiple RCTs have investigated the potential role for steroid therapy in patients with septic shock with some studies suggesting a survival benefit (eg, the Annane Trial) and others demonstrating no such benefit (eg, CORTICUS, HYPRESS, and ADRENAL). With uncertainty about the role of steroids for patients with septic shock, the authors of the present study redesigned a trial to add to the evidence.

Published in 2018, the Recombinant Human Activated Protein C and Low Dose of Hydrocortisone and Fludrocortisone in Adult Septic Shock (APROCCHSS) study studied over 1,200 patients with septic shock admitted to the ICU. Patients were randomized in a 2×2 factorial design to activated protein C (APC; drotrecogin alfa) or placebo, or hydrocortisone plus fludrocortisone or placebo. Once activated protein C was removed from the market, the APC arm was discontinued. The steroid regimen consisted of 7 days of hydrocortisone 60 mg IV every 6 hours and fludrocortisone 50 mcg via nasogastric tube. The steroid group showed an advantage compared to placebo in terms of the study's primary endpoint, overall survival at 90 days (43% vs. 49.1%; RR 0.88; P=0.03), as well as in secondary endpoints including time to reversal of septic shock and resolution of organ failure.

The survival advantage observed in this study is consistent with that seen in the Annane Trial but is discordant with other trials such as CORTICUS, and may be explained in part by differences in baseline severity of illness in patients across studies. For example, patients enrolled in APROCCHSS had higher disease illness severity scores compared to those in other studies, and these more severely ill patients may stand to benefit the most from adjunctive therapies such as steroids. Additionally, APROCCHSS used combination hydrocortisone plus the mineralocorticoid fludrocortisone, whereas other trials like CORTICUS used only hydrocortisone, which may have led to a difference in efficacy between steroid regimens used across trials.

Regardless of the discrepant results across studies, the cumulative trial data suggest that if steroids do in fact improve survival in septic shock, the effect is modest at best. This idea is supported by multiple meta-analyses of trials evaluating steroids in patients with septic shock. The clearest role for steroids in septic shock appears to be in patients failing to improve despite adequate fluid resuscitation and vasopressor support, and this is supported by the 2016 Surviving Sepsis Campaign guidelines which were issued before APROCCHSS was published but which remain relevant today.

Guidelines

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

Design

• Multicenter, double-blind, 2×2 factorial, randomized trial
• N=1,241 patients with septic shock
  • Hydrocortisone plus fludrocortisone (n=614)
  • Placebo (n=627)
• Setting: 34 centres in France
• Enrollment: 2008-2015
• Mean follow-up: 180 days
• Analysis: Intention to treat
• Primary Outcome: 90-day overall survival

Population

Inclusion Criteria

• Admitted to the ICU for <7 days
• Septic shock lasting <24 h
  • Documented infection
  • SOFA score of 3-4 for ≥2 organ systems for ≥6 consecutive hours
  • Receipt of vasopressor therapy for ≥6 h to maintain SBP ≥90 mm Hg or MAP ≥65 mm Hg

Exclusion Criteria

• High risk of bleeding
• Pregnancy or lactation
• Underlying conditions that could affect short-term survival
• Known hypersensitivity to drotrecogin alfa (activated)
• Previous treatment with corticosteroids

Baseline Characteristics

From the placebo group.

• Demographics: 32% female, mean age 66 years, admission from medicine ward 81%
• Sepsis severity: mean SAPS II score 56, mean SOFA score 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, norepinepherine n=552, mechanical ventilation 91%, renal replacement therapy 28%

Interventions

Patients randomized in a 2×2 factorial design:

• Hydrocortisone 50mg IV every 6 hours and fludrocortisone 50 mcg NG daily (or matching placebo) for 7 days without taper
• Activated protein C 24 mcg/kg/h for 96 h (or matching placebo) (This arm was discontinued following withdrawal of the product from the market.)

Outcomes

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)

Criticisms

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

Funding

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