Hydrocortisone + Fludrocortisone in Septic Shock – APROCCHSS Trial

April 3, 2018

Written by Alex Chen, MD

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In patients with septic shock requiring rather high vasopressor doses for 6 hours, those treated with hydrocortisone + fludrocortisone had a lower 90-day mortality compared to placebo (43% vs 49.1%, NNT 17). They also had significantly more vasopressor-free and organ-failure free days, in addition to having a shorter time to weaning from vasopressors and mechanical ventilation.

Why does this matter?
Steroids in septic shock is still a controversial topic. The ADRENAL trial came out earlier this year and did not show mortality benefit; however, this was utilizing a hydrocortisone infusion only. A previous trial by Annane et al. showed mortality benefit with steroids in an adjusted analysis of RCT data on patients in refractory septic shock. This trial hopes to resolve this discrepancy.

“A steroid APROCCHSS a septic patient at the bar…”
This was a randomized placebo-controlled trial that took place in 34 ICUs across France evaluating 1241 patients. They originally had a 2×2 factorial design but simplified the study to 2 groups (hydrocortisone 50mg IV q6h + fludrocortisone 50mcg qd vs placebo) once drotrecogin alfa (Xigris) was removed from the market.  The primary outcome, 90 day all-cause mortality, was lower in the combined steroid group: 43% vs 49.1% (RR 0.88 (95%CI 0.78-0.99, p = 0.03).  Josh Farkas has an outstanding post on EMCrit discussing this trial and points out that the fragility index was only 3, meaning if only 3 patients had changed status from the intervention/control groups, the results would not have been statistically significant.  Interestingly, at the 28-day mark, the results were not statistically significant for mortality (p=0.06).

Importantly, they also demonstrated that the intervention group had a shorter time to weaning from vasopressors and mechanical ventilation. These secondary endpoints were similar to the ADRENAL trial. There was no significant difference in adverse events other than hyperglycemia in the intervention group. Overall, these patients were sicker and received steroids earlier compared to the ADRENAL trial, which may explain the differences in mortality. Therefore, my practice will be to utilize bolus dose steroids in refractory septic shock as there seems to be little downside and some potential benefit.

Source
Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.  N Engl J Med. 2018 Mar 1;378(9):809-818. doi: 10.1056/NEJMoa1705716.

Reviewed by Thomas Davis and Clay Smith