Reviving glucocorticoids to treat Sepsis?

EJRC Article Review

Certainly, one of the greatest calamities of the modern world is Sepsis, which, despite the great advances in medicine, still doesn’t have a specific pharmacological treatment. This could be explained by the nature of Sepsis, as a very complex pathological entity, capable of affecting multiple organs, often with the same devastating capacity. Given the lack of specific treatments, we do have many adjunctive therapies_[1] whose potential uses continue to be discussed, despite the lack of data demonstrating their clinical efficacy and effectiveness in patients with sepsis and septic shock. Of these therapies, the one that has been subjected to the most clinical trials is treatment with glucorticoids, which once again has been put into test in a recent clinical trial (ADRENAL)_[2], where this therapy still appears to be not enough to improve the mortality outcome at 90-days. However, Annane et al. revisits this hypothesis with a new approach in a newly-published randomised trial – APROCCHSS_[3].

In this multicentre, double-blind, randomised trial, authors evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin-alfa, the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day-28, day-180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure.

As we all know drotrecogin-alfa was withdrawn from the market. Nevertheless, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group).

A total of 34 centres participated in the trial, and 1241 patients were recruited from September 2008 to June 2015. Patients in ICU were eligible for inclusion in the trial if they had indisputable or probable septic shock less than 24 hours. The pre-specified vasopressor therapy (norepinephrine, epinephrine, or any other vasopressor at a dose of ≥0.25 μg per kilogram of body weight per minute or ≥1 mg per hour) for at least 6 hours to maintain a systolic blood pressure of at least 90 mm Hg or a mean blood pressure of at least 65 mm Hg. In the treatment group, hydrocortisone was administered as a 50-mg intravenous bolus every 6 hours, and fludrocortisone was given as a 50-μg tablet through a nasogastric tube once, daily for 7 days without tapering.

Among the 1241-patients included in the trial, the 90-day mortality was 43.0% in the hydrocortisone-plus-fludrocortisone group and 49.1% in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04), but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure–free days (14 vs. 12 days, P=0.003). The rate of serious adverse events did not differ significantly between the two groups.

In conclusion, 7-day treatment with a 50-mg intravenous bolus of hydrocortisone every 6 hours and a daily dose of 50 μg of oral fludrocortisone resulted in lower mortality at day 90 and at ICU and hospital discharge than placebo among adults with septic shock.

In this most recent attempt to revive the adjunctive therapy with glucocorticoids in septic shock, authors bring us magnificent results, which serves many believers who were waiting for data to justify the routine use of this therapy in cases of septic shock without response to vasopressors – and for the skeptics, a new approach to consider in these circumstances. The fact that these results seem to be so strong, is probably related to the greater benefit of this therapy in more severe patients, compared with those of other trials such as ADRENAL_[2], and CORTICUS_[4]. Furthermore, together with the ADRENAL_[2], trial results, this trial showed us that this therapy appears to be safe, leaving aside many of the false beliefs that to date made us doubt their benefit over any risk.

If the results of this trial will change our clinical practice remains to be seen, nevertheless these data will be a mayor contribution in subsequent meta-analysis to determine how to best treat patients with septic shock.

Article review prepared and submitted by EJRC member Aaron Blandino Ortiz, Department of Intensive Care Medicine, Vall d’Hebron University Hospital, Barcelona, Spain.

References.

1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017;43:304-377.
2. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 2018;378:797-808.
3. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Eng J Med 2018;378:809-818.
4. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358:111-24.