Adjunctive glucocorticoid therapy does not lower mortality in septic shock

1. Patients with septic shock in the intensive care unit (ICU) undergoing mechanical ventilation and managed with adjunctive continuous hydrocortisone infusion, did not have a lower 90-day mortality compared to placebo.

2. There was no difference between the placebo and hydrocortisone groups in secondary outcomes of mortality at 28 days, rate of recurrent shock, or number of days alive and out of the ICU or hospital.

Evidence Rating Level: 1 (Excellent)    

Study Rundown: Management of sepsis and septic shock typically involves antibiotics, fluids, and vasopressors, though evidence for adjuvant glucocorticoid therapy is controversial.  Prior studies using high-dose methylprednisolone were associated with high morbidity and mortality, and later trials with lower dose hydrocortisone did not provide conclusive results. Current guidelines for use of low dose hydrocortisone when fluid resuscitation and vasopressors fail to restore hemodynamic stability weakly supported.  This randomized controlled trial (RTC) assessed if hydrocortisone resulted in lower mortality compared to placebo in mechanically ventilated patients with septic shock. No difference in rate of death at 90 days was found between the two groups. Small improvements were seen in faster resolution of shock and shorter duration of initial mechanical ventilation in the hydrocortisone group. There was no significant difference in secondary outcomes of mortality at 28 days, rate of recurrent shock, number of days alive and out of the ICU or hospital, recurrent mechanical ventilation, rate of renal replacement therapy, or incidence of new-onset bacteremia or fungemia.

Strengths of this study were the RTC method, inclusion of international institutions, and a large number of patients providing sufficient power to detect a difference in the primary outcome. Limitations included no standardized adverse event recording, lack of data collection for all possible secondary infections beyond bacteremia and fungemia, no adjudication of appropriate antibiotic use, and not measuring long-term neuromuscular weakness.

Click to read the study, published in NEJM

Relevant Reading: Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review.

In-Depth [randomized controlled trial]: This study aimed to demonstrate whether using a hydrocortisone intravenous infusion reduced mortality among patients with septic shock who were mechanically ventilated.  Patients were randomly assigned to either receiving hydrocortisone (200 mg per day) or placebo for 7 days, or until death or discharge from the ICU (whichever came first).  The primary outcome was death from any cause at 90 days.

Between March 2013 and April 2017, patients (n = 3800) undergoing mechanical ventilation, with suspicion for infection, meeting more than 2 systemic inflammatory response syndrome criteria, and previously treated with vasopressors or inotropic agents were enrolled at 69 medical-surgical ICUs in 5 countries (Australia, United Kingdom, New Zealand, Saudi Arabia, Denmark).  Of those patients, 1832 were randomized to the hydrocortisone group, and 1826 to the placebo group.  At 90 days post-randomization 27.9% of hydrocortisone treated patients died, as did 28.8% in the placebo group (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.82 to 1.10; p = 0.50). Time to ICU discharge was shorter in the hydrocortisone group than in the placebo group (10 days vs 12 days; hazard ratio [HR], 1.14; 95% CI, 1.06 to 1.23, p < 0.001), as was the duration of mechanical ventilation (6 days vs 7 days; HR, 1.13; 95% CI, 1.05 to 1.22; p < 0.001).  There was no significant difference between the groups with respect to 28-day mortality (OR, 0.89, 95% CI, 0.76 to 1.03; p = 0.13), rate of recurrent shock (OR, 1.07; 95% CI, 0.94 to 1.22; p = 0.32), or median time to discharge from the hospital (HR, 1.06; 95% CI, 0.98 to 1.15; p = 0.13).

Image: PD

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