APROCCHSS -Hydrocortisone plus Fludrocortisone for Septic Shock
Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.
Annane D, Renault A, Brun-Buisson C, et al; CRICS-TRIGGERSEP Network.
N Engl J Med. 2018 Mar 1;378(9):809-818. [Full text]
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Summary By Lisa Crisalli
The utility of steroids in septic shock has been a question since at least the 1980, with competing results surrounding potential survival benefit. The primary author of the current study was involved in work published in 2002 which demonstrated a survival benefit; however, since CORTICUS [1] and more recently the ADRENAL [2] trial failed to support this finding. Similarly meta-analyses had shown conflicting results [3, 4]. In this context the authors of the APROCCHSS attempted to settle the debate, and though the results were positive for hydrocortisone, uncertainty for steroids in septic shock persists.
Patients and Intervention
A total of 1,241 patients with septic shock were enrolled in a 2-by-2 factorial design from 34 centers in France between 2008-2015. Patients were included if they had been admitted to the ICU for <7 days and were in shock no more than 24 hours. Septic shock was defined as a documented infection with a SOFA score of 3-4 for ≥2 organ systems for ≥6 consecutive hours and requiring vasopressor therapy for ≥6 h to maintain SBP ≥90 mm Hg or MAP ≥65 mm Hg.
Participants were randomized to one of three therapies: steroids (hydrocortisone + fludrocortisone), activated protein C (APC), a combination of all three drugs, or placebo. During the course of the trial APC was taken off the market, and the final data was compiled from two arms, either hydrocortisone + fludrocortisone, or placebo.
Patients were excluded if they had prior corticosteroid therapy or conditions affecting short-term survival, as well as those patients who were pregnant or lactating.
Safety monitoring included rates of serious adverse event, bleeding, superinfection, new onset sepsis or septic shock, neurologic sequelae or episodes of hyperglycemia ≥150 mg/dL.
Hydrocortisone was administered as a 50-mg IV bolus every 6 hours, and fludrocortisone was given as a 50-μg tablet once daily. There agents were administered for 7 days without tapering.
Outcomes
The primary outcome was 90-day overall mortality. There were multiple predefined secondary outcomes including all-cause mortality at 28 days, at 180 days, at ICU discharge, and at hospital discharge. Other secondary but important patient centered outcomes included vasopressor-free days at 28 days:, ventilator-free days at 28 days, and organ-failure-free days at 28 days.
Results
The primary outcome of 90-day overall mortality was reduced in the intervention group in which 264 of 614 (43.0%) patients had died compared to 308 of 627 (49.1%) deaths in the placebo group. This was significant with a relative risk of 0.88 (95% CI 0.78 to 0.99; P=0.03), and absolute risk reduction of 6.1% corresponding to a number needed to treat (NNT) of 17. However, this represented only a fragility index of 3, or that only 3 more events would have to occur in the intervention to negate the statistical significance observed.
Though multiple secondary outcomes were statistically significant at an α <0.05 level, many advocate for a lower threshold for secondary outcomes, to account for multiple comparisons (in which case only vasopressor-free and organ-failure-free days remains significant). Regardless of this it is notable that mortality at 28 days was NOT significantly different.
Secondary outcomes are summarized below:
| 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 | Median(d) 19 vs. 23 | P<0.001 |
| Ventilator-free days at 28 days | Median(d) 4 vs. 10 | P=0.07 |
| Organ-failure-free days at 28 days | Median(d) 12 vs. 19 | P=0.003 |
There was no difference in serious adverse event, bleeding, rate or site of superinfection, new onset sepsis or septic shock, or neurologic sequelae. There were risk to have blood glucose ≥150 mg/dL by day 7 (RR 1.07; 95% CI 1.03–1.12; P=0.002).
Discussion
Unlike CORTICUS [1] and ADRENAL [2], which did not identify a mortality benefit from hydrocortisone, APROCCHSS demonstrated a mortality benefit at 90 days and possibly 180 days but NOT 28 days. A notable difference in this trial was the focus on administering steroids earlier to patients with more severe disease (inclusion criteria including need for mechanical ventilation, vasopressor therapy, and SOFA score 3-4 in the setting of recent-onset of septic shock within the preceding 24 hours). In ADRENAL hydrocortisone was started at a median 20 ± 90 hours compared to all APROCCHSS receiving steroids within the first 24 hours. Fludrocortisone was also not given in ADRENAL but given that hydrocortisone has mineralocorticoid activity, this is likely not a significant difference. The dosing of hydrocortisone was different, with IV Q6 bolus dosing here and continuous drip dosing without a bolus in ADRENAL.
Overall, APROCCHSS findings suggest that hydrocortisone given early (<24 hr from shock onset) as bolus dosing (50 mg IV Q6) for the sickest septic shock patients, may offer mortality benefit, decrease vasopressor requirements and decrease duration of organ failure. This is supported by a 2019 update to the Cochrane systematic review that found “Moderate-certainty evidence indicates that corticosteroids probably reduce 28-day and hospital mortality among patients with sepsis. Corticosteroids result in large reductions in ICU and hospital length of stay (high-certainty evidence)” [3].
| F: Follow up | 180 days |
| R: Randomization | Yes |
| I: Intention to treat | Yes |
| S: Similar at baseline | Yes |
| B: Blinding | Yes |
| E: Equal treatment | Yes |
| S: Source (funding) | French Ministry of Health with the Program Hospitalier de Recherche Clinique |
- Sprung CL, Annane D, Keh D, et al.; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24.
- Venkatesh B, Finfer S, Cohen J, et al.; ADRENAL Trial Investigators and the Australian–New Zealand Intensive Care Society Clinical Trials Group. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):797-808.
- Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for treating sepsis. Cochrane Database Syst Rev. 2015 Dec 3;2015(12):CD002243. doi: 10.1002/14651858.CD002243.pub3. Update in: Cochrane Database Syst Rev. 2019 Dec 6;12:CD002243.
- Volbeda M, Wetterslev J, Gluud C, Zijlstra JG, van der Horst IC, Keus F. Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis. Intensive Care Med. 2015 Jul;41(7):1220-34.
