Steroids speed recovery from septic shock despite lack of survival benefit
Use of hydrocortisone in patients with septic shock can speed up reversal of shock, shorten the time spent on mechanical ventilation in intensive care, and reduce the need for blood transfusion, although it does not improve survival of patients at 90 days compared with placebo, according to the ADRENAL* study, thus ending the debate over the role of steroids in septic shock therapy.
“Current clinical practice guidelines recommend the use of hydrocortisone in patients with septic shock if adequate fluid resuscitation and treatment with vasopressors have not restored haemodynamic stability; however, the guidelines classify the recommendation as weak, on the basis of the low quality of available evidence,” wrote the researchers, noting the conflicting results from existing literature, with no compelling evidence supporting or opposing the use of steroids for septic shock. [Intensive Care Med 2017;43:304-377]
At 90 days, the primary endpoint of all-cause mortality occurred at similar rates in both the hydrocortisone and the placebo groups (27.9 percent vs 28.8 percent, odds ratio [OR], 0.95; p=0.50). [N Engl J Med 2018;doi:10.1056/NEJMoa1705835]
The finding remained similar across prespecified subgroups, including those stratified according to sex, admission type (surgical vs medical), catecholamine dose (≤15 vs >15 µg/minute), sepsis site, APACHE** II score (≥25 vs <25), and time from shock onset to randomization.
Nonetheless, shock resolution was faster with hydrocortisone than with placebo (median, 3 vs 4 days, hazard ratio [HR], 1.32; p<0.001).
Hydrocortisone-treated patients also spent a shorter time on life support with mechanical ventilation during the initial episode vs the placebo group (median, 6 vs 7 days, HR, 1.13; p<0.001), although the differences were not significant after accounting for recurrent episodes of ventilation.
Additionally, fewer hydrocortisone-treated patients required a blood transfusion compared with those in the placebo group (37.0 percent vs 41.7 percent, OR, 0.82; p=0.004).
“Our trial provides evidence about the role of hydrocortisone as an adjunctive treatment in patients with septic shock,” said the researchers, alluding to the improvements with hydrocortisone in some secondary outcomes despite a lack of survival benefit at 90 days. “These haemodynamic effects may represent a beneficial role of hydrocortisone.”
Patients in the hydrocortisone group were discharged earlier from the intensive care unit (ICU) than those in the placebo group (median, 10 vs 12 days, HR, 1.14; p<0.001), although the number of days alive and out of the ICU was not significantly different after adjusting for multiple comparisons.
No significant differences were found between the two treatment groups in terms of 28-day mortality, shock recurrence, mechanical ventilation recurrence, the number of days alive and out of the hospital, need for renal replacement therapy, and new-onset bacteraemia or fungaemia.
“[W]e have finally shown what part steroids play in the treatment of these patients. If we can reduce the time spent in ICUs, that not only frees up space for other patients, it saves health systems worldwide a huge amount of money,” said lead author Professor Bala Venkatesh from The George Institute for Global Health in Sydney, Australia.
“A detailed cost–benefit assessment of these results was not done, but such an analysis may inform clinicians about the overall cost-effectiveness of hydrocortisone in patients with septic shock,” the researchers added.
The multinational, double-blind, parallel-group trial randomized 3,800 patients with septic shock undergoing mechanical ventilation to continuous intravenous infusion of hydrocortisone (200 mg/day) or placebo for 7 days or until discharge from the ICU or death, whichever came first.
“[We] specifically targeted a population of patients who had high requirements for vital organ support [use of mechanical ventilation and ≥4 hours of vasopressor therapy before randomization] and a substantial risk of death,” pointed out Venkatesh and co-authors.