New England Journal of Medicine March 01, 2018

Adjunctive Glucocorticoid Therapy in Patients with Septic Shock

Venkatesh B, Finfer S, Cohen J, et al. (ADRENAL Trial Investigators)

Bottom Line

A large randomized controlled trial demonstrating that a continuous infusion of hydrocortisone does not reduce 90-day mortality in patients with mechanically ventilated septic shock, despite accelerating shock resolution and shortening the initial duration of mechanical ventilation.

Key Findings

1. There was no significant difference in the primary outcome of 90-day mortality, which occurred in 511 of 1832 patients (27.9%) in the hydrocortisone group and 526 of 1826 (28.8%) in the placebo group (OR, 0.95; 95% CI, 0.82 to 1.10; P=0.50).

2. Hydrocortisone led to a significantly faster resolution of shock compared to placebo (median duration, 3 days vs. 4 days; HR, 1.32; 95% CI, 1.23 to 1.41; P<0.001).

3. Patients receiving hydrocortisone had a shorter duration of the initial episode of mechanical ventilation (median, 6 days vs. 7 days; HR, 1.13; 95% CI, 1.05 to 1.22; P<0.001), though there was no difference in the total days alive and free from mechanical ventilation.

4. The hydrocortisone group required significantly fewer blood transfusions than the placebo group (37.0% vs. 41.7%; OR, 0.82; 95% CI, 0.72 to 0.94; P=0.004).

5. There were no significant between-group differences in 28-day mortality, recurrence of shock, requirement for renal-replacement therapy, or incidence of new-onset bacteremia or fungemia.

Study Design

Design

RCT

Double-Blind

Sample

3,800

Patients

Duration

90 days

Median

Setting

Multicenter, multinational

Population Adults with septic shock undergoing mechanical ventilation.

Intervention Continuous intravenous infusion of hydrocortisone at a dose of 200 mg per day for up to 7 days (or until death or ICU discharge).

Comparator Matching placebo continuous infusion.

Outcome Death from any cause at 90 days.

Study Limitations

• The strict inclusion criteria requiring both septic shock and mechanical ventilation may limit the generalizability of the findings to less severely ill patients.

• The study design utilized continuous infusion of hydrocortisone, meaning results might not directly extrapolate to bolus dosing regimens.

• The trial lacked concurrent administration of fludrocortisone, which was evaluated in the contemporary APROCCHSS trial and complicates generalized conclusions about all corticosteroid regimens.

• There is the potential that specific unmeasured sub-phenotypes of septic shock might derive a survival benefit that is masked in the overall heterogeneous population.

Clinical Significance

The ADRENAL trial provided high-quality evidence that routine administration of hydrocortisone does not confer a mortality benefit for mechanically ventilated patients with septic shock. However, it confirmed the physiological benefits of steroids—namely, reducing vasopressor duration and time on the ventilator. Consequently, modern guidelines suggest using corticosteroids not as a universal upfront therapy, but as an adjunctive measure in patients with refractory septic shock who require escalating doses of vasopressors to maintain blood pressure.

Historical Context

The use of corticosteroids in sepsis has been one of the most debated topics in critical care for decades. Early trials in the 1980s using high-dose steroids showed harm. In 2002, the Annane trial suggested a mortality benefit with low-dose steroids specifically in patients failing a corticotropin stimulation test, but the subsequent CORTICUS trial (2008) failed to show a survival benefit, leaving the medical community in equipoise. The ADRENAL trial, as the largest critical care trial of its kind at the time, definitively established that hydrocortisone alone does not improve survival in a broad cohort of mechanically ventilated septic shock patients, though its simultaneous publication alongside the APROCCHSS trial (which found a benefit using hydrocortisone plus fludrocortisone) ensured that nuanced debate regarding specific steroid formulations would continue.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the pathophysiological rationale for administering glucocorticoids to patients in septic shock, and by what cellular mechanisms do they theoretically restore hemodynamic stability?

Key Response

This question explores the foundational concept of critical illness-related corticosteroid insufficiency (CIRCI). It highlights how exogenous steroids theoretically improve hemodynamics by upregulating alpha-1 adrenergic receptors, increasing vascular sensitivity to catecholamines, and inhibiting inducible nitric oxide synthase (iNOS), thereby reversing pathological vasodilation.

Resident

Given that the ADRENAL trial demonstrated no 90-day mortality benefit but did show faster resolution of shock and a shorter initial duration of mechanical ventilation, in which specific clinical scenarios should you consider initiating a continuous hydrocortisone infusion in the ICU?

Key Response

Tests clinical application and risk-benefit analysis. Residents should recognize that while steroids are not a mortality-reducing 'magic bullet' in sepsis, their vasopressor-sparing effects make them useful in refractory shock (escalating or high-dose vasopressor requirements), provided the clinician monitors for adverse effects like hyperglycemia.

Fellow

The ADRENAL trial and the APROCCHSS trial were published simultaneously but reported conflicting results regarding mortality in septic shock. What were the key methodological, pharmacological, and population differences between these two trials that might explain the divergent outcomes?

Key Response

Requires nuanced literature synthesis. Fellows must contrast the ADRENAL trial (continuous hydrocortisone, broader population, no mortality benefit) with APROCCHSS (bolus hydrocortisone plus fludrocortisone, higher severity of illness, significant mortality benefit) to understand how trial design and drug regimens influence critical care outcomes.

Attending

The ADRENAL trial treated 'septic shock' as a homogeneous clinical syndrome and failed to show a mortality benefit. How does this trial highlight the limitations of syndromic enrollment criteria in ICU trials, and how might precision medicine better target steroid-responsive phenotypes?

Key Response

Provokes high-level discussion on critical care research paradigms. Attendings should discuss how Sepsis-3 criteria lump together diverse biological endotypes (e.g., hyper-inflammatory vs. hypo-inflammatory), and how future practice may rely on biomarkers to identify specific patients who genuinely benefit from immunomodulation rather than applying a 'one-size-fits-all' approach.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ADRENAL trial was powered to detect a 4.1 percentage point absolute reduction in 90-day mortality. How does the reliance on a binary, long-term outcome like 90-day mortality impact statistical power in ICU trials compared to utilizing hierarchical composite endpoints or ordinal scales?

Key Response

Critiques traditional trial methodology. PhDs and researchers should discuss how 90-day mortality is subject to noise and competing risks from post-ICU events, and debate whether statistical efficiency could be improved using continuous or ordinal endpoints like 'days alive and free of organ support' or the win ratio.

Journal Editor

Considering the known and predictable physiological side effects of hydrocortisone, such as hyperglycemia and hypernatremia, what concerns would you raise regarding the potential unblinding of bedside clinicians, and how might this bias the trial's secondary outcomes?

Key Response

Evaluates threats to internal validity. A seasoned editor would flag that because hydrocortisone alters metabolic panels and rapidly reduces vasopressor requirements, clinicians might easily guess the treatment arm. This functional unblinding could bias subjective secondary endpoints, such as the clinical decision of when to extubate or cease pressors.

Guideline Committee

The current Surviving Sepsis Campaign (SSC) guidelines issue a weak recommendation to use IV corticosteroids only if fluid resuscitation and vasopressor therapy fail to restore hemodynamic stability. How does the ADRENAL trial's evidence profile solidify both the 'weak' strength of this recommendation and the specific clinical criteria for its use?

Key Response

Addresses evidence integration for policy. The ADRENAL trial's lack of a mortality benefit justifies withholding a 'strong' recommendation for routine use, while its definitive demonstration of faster shock reversal perfectly supports the guideline's specific niche: using steroids purely as a rescue, vasopressor-sparing adjunct in refractory shock.

Clinical Landscape

Noteworthy Related Trials

2002

Annane et al. Trial

n = 299 · JAMA

Tested

Hydrocortisone plus fludrocortisone

Population

Patients with septic shock and relative adrenal insufficiency

Comparator

Placebo

Endpoint

28-day survival

Key result: Significant reduction in the risk of death and improved shock reversal in patients receiving the corticosteroid combination.

2008

CORTICUS Trial

n = 499 · NEJM

Tested

Hydrocortisone 50 mg every 6 hours

Population

Patients with septic shock

Comparator

Placebo

Endpoint

28-day mortality in patients non-responsive to corticotropin

Key result: Hydrocortisone did not improve survival in patients with septic shock, though it did reverse shock more quickly.

2018

APROCCHSS Trial

n = 1,241 · NEJM

Tested

Hydrocortisone plus fludrocortisone

Population

Patients with septic shock

Comparator

Placebo

Endpoint

90-day all-cause mortality

Key result: 90-day mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group compared to the placebo group.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis