From the Journals

Hydrocortisone-fludrocortisone cuts deaths in septic shock

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Corticosteroids: What’s their place in treating septic shock?

The results of the Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial and the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL), both reported in the latest issue of NEJM, are landmark studies detailing the largest analyses of hydrocortisone use in patients with septic shock.

Both of these trials were massive, with over 5,000 patients combined, which is much larger than all previous studies according to Anthony Suffredini, MD, of the National Institutes of Health. An additional useful feature of these trials was that they had clear criteria for entry into the study. These criteria included: “vasopressor-dependent shock and respiratory failure leading to the use of mechanical ventilation, details of antimicrobial therapy, assessment of survival at 90 days, and well-defined secondary outcomes and analyses of adverse events.”

The ADRENAL and APROCCHSS had vastly different 90-day mortality rates: ADRENAL had mortality rates of 27.9% with hydrocortisone and 28.8% with placebo (P = .50), while APROACCHSS had mortality rates of 43.0% with hydrocortisone plus fludrocortisone and 49.1% with placebo (P = .03). Despite this, they both display the beneficial effect anti-inflammatory therapies, such as hydrocortisone, have on secondary outcomes of shock reversal and the reduction in duration of mechanical ventilation. “It is unlikely that in the near future sufficiently powered trials will provide us with better data” than the ADRENAL and APROCCHSS trials, Dr. Suffredini wrote.

Dr. Suffredini made these comments in an editorial accompanying this study in the New England Journal of Medicine. He is the deputy chief of the critical care medicine department at the National Institutes of Health Clinical Center, and he has served on the executive committee of the Department of Veteran Affairs Cooperative Studies Program. He has no other relevant financial disclosures to report.



Hydrocortisone in combination with fludrocortisone significantly reduced 90-day mortality in septic shock patients in a double-blind, randomized, controlled trial.

Prior to this study, two large trials had displayed that corticosteroids were beneficial in improving hemodynamic status and organ function, but little was known about corticosteroids’ ability to increase survival in sepsis patients.

a scene from an emergency dept., with people rushing and a patient on a stretcher DigitalVision/Thinkstock
“[Corticosteroids] improve cardiovascular function by restoring effective blood volume through increased mineralocorticoid activity and by increasing systemic vascular resistance, an effect that is partly related to endothelial glucocorticoid receptors,” wrote Djillali Annane, MD, of the University of Paris and his colleagues in the New England Journal of Medicine.“This might explain why in our trial there was less need for vasopressors with hydrocortisone plus fludrocortisone than with placebo.”

The study, named the Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, was designed to assess the benefit/risk ratio of using activated protein C – drotrecogin alfa (activated) – and corticosteroids together or separately in septic shock patients. The original design of the study included Xigris (drotrecogin alfa) and was composed of four parallel groups, but Xigris was removed from the market in October of 2011, so the study continued with only two parallel groups.

A total of 1,241 patients experiencing chronic septic shock were recruited into the two double-blind, parallel groups, with patients in one group receiving hydrocortisone plus fludrocortisone and the other receiving placebos. The placebos used in this study were similar in appearance to the actual treatment drugs. The placebos for hydrocortisone and fludrocortisone were either parenteral mannitol (133.6 mg), disodium phosphate (8.73 mg), and sodium phosphate (0.92 mg) or tablets of microcrystalline cellulose (59.098 mg), respectively.

Hydrocortisone was given intravenously every 6 hours as a 50-mg intravenous bolus, and fludrocortisone was given once a day as a 50-mcg tablet through a nasogastric tube. Patients in ICUs who had septic shock for less than 24 hours were included in the study. Septic shock was identified by the presence of a clinically or microbiologically documented infection, a Sequential Organ Failure Assessment score of 3 or 4 for at least two organs and for at least 6 hours, and receipt of vasopressor therapy for at least 6 hours.

After 90 days, 264 of 614 of the patients (43%) in the hydrocortisone/fludrocortisone group and almost half (49.1%) of 627 patients in the placebo group had died (P = .03). The relative risk of death was 0.88 (95% confidence interval, 0.78-0.99), which favored the hydrocortisone/fludrocortisone group. The researchers also observed that death was significantly lower in the hydrocortisone/fludrocortisone group, compared with the placebo group, at time of ICU discharge (35.4% vs. 41.0%, respectively; P = .04).

While mortality was reduced, patients still experienced adverse events. 326 of 614 (53.1%) patients in the hydrocortisone/fludrocortisone group and 363 of 626 patients (58.0%) in the placebo group experienced at least one serious adverse event by day 180 (P = 0.08).

“Seven-day treatment with a 50-mg intravenous bolus of hydrocortisone every 6 hours and a daily dose of 50 mcg of oral fludrocortisone resulted in lower mortality at day 90 and at ICU and hospital discharge than placebo among adults with septic shock,” concluded Dr. Annane and his coauthors.

The majority of researchers had no relevant financial disclosures to report, while some doctors received grants and personal fees unrelated to this study. This study was funded in part by public grants from the French Ministry of Health.

SOURCE: Annana A et al. NEJM. 2018 Feb 28. doi: 10.1056/NEJMoa1705716.

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