New England Journal of Medicine MARCH 01, 2018

Adjunctive Glucocorticoid Therapy in Patients with Septic Shock

Venkatesh B, Finfer S, Cohen J, et al.

Bottom Line

In mechanically ventilated adults with septic shock, a 7-day continuous infusion of low-dose hydrocortisone failed to reduce 90-day all-cause mortality compared to placebo.

Key Findings

1. The primary outcome of 90-day all-cause mortality occurred in 27.9% of the hydrocortisone group compared to 28.8% in the placebo group (odds ratio, 0.95; 95% CI, 0.82 to 1.10; P=0.50).

2. Hydrocortisone treatment was associated with more rapid shock resolution (median time 3 days vs. 4 days; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001).

3. Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation (median 6 days vs. 7 days; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001) and fewer days spent in the ICU.

4. Regimen-attributed adverse events were more common in the hydrocortisone group (1.1% vs. 0.3%), though the overall incidence of serious adverse events remained low and comparable between groups.

5. Rates of new-onset bloodstream infections were identical between the study arms (14.1% in both groups).

Study Design

Design

RCT

Double-Blind

Sample

3,658

Patients

Duration

90 days

Median

Setting

Multicenter, international

Population Adults with septic shock undergoing mechanical ventilation who had received vasopressors or inotropes for at least 4 hours.

Intervention Continuous intravenous hydrocortisone infusion at 200 mg per day for up to 7 days.

Comparator Placebo infusion.

Outcome Death from any cause at 90 days.

Study Limitations

• The study specifically enrolled mechanically ventilated patients, potentially limiting the generalizability of these findings to patients with septic shock not requiring mechanical ventilation.

• The 95% confidence interval for the primary outcome (0.82 to 1.10) does not exclude the possibility of a small clinical benefit or a small clinical harm, leaving the absolute mortality effect uncertain.

• The trial excluded patients receiving etomidate, a common induction agent in emergency settings that can cause adrenal suppression, which may impact the applicability of the results to real-world trauma or emergency ICU populations.

• The study design used a continuous infusion rather than bolus dosing, which differs from some historical clinical practices and the protocol used in the concurrent APROCCHSS trial.

Clinical Significance

The ADRENAL trial provides robust evidence that low-dose hydrocortisone does not provide a survival benefit in septic shock. However, it supports the use of corticosteroids as a recovery-accelerating adjunct, as demonstrated by faster vasopressor weaning and shorter ICU stays. This has shifted clinical focus toward viewing steroids as a tool for physiological stabilization rather than a mortality-reducing intervention.

Historical Context

The use of corticosteroids for septic shock has been debated for decades, stemming from conflicting results in earlier trials like CORTICUS and meta-analyses. Before the ADRENAL trial, clinical practice was highly heterogeneous, often relying on weak evidence for the benefit of 'stress-dose' steroids in reversing refractory vasoplegia.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What are the primary physiological mechanisms by which exogenous glucocorticoids such as hydrocortisone increase mean arterial pressure in a patient experiencing septic shock?

Key Response

Hydrocortisone increases vascular sensitivity to endogenous catecholamines by upregulating alpha-1 adrenergic receptors and inhibiting the extraneuronal uptake of norepinephrine. Furthermore, it modulates the inflammatory response by inhibiting the synthesis of inducible nitric oxide synthase (iNOS), thereby reducing the production of nitric oxide, a potent vasodilator.

Resident

The ADRENAL trial showed no significant difference in 90-day mortality. In this context, what secondary clinical benefits might justify the use of hydrocortisone in a patient with vasopressor-refractory septic shock?

Key Response

Although 90-day mortality was unchanged, the ADRENAL trial demonstrated that patients receiving hydrocortisone had a significantly faster resolution of shock (median 3 vs 4 days), fewer days on mechanical ventilation, and a reduced need for blood transfusions. These outcomes are clinically relevant for ICU throughput and reducing complications associated with prolonged organ support.

Fellow

The ADRENAL trial utilized a continuous infusion of hydrocortisone (200mg/day), whereas the APROCCHS trial used intermittent boluses plus fludrocortisone. How might these differences in administration and mineralocorticoid coverage explain the discordant mortality findings between these two major trials?

Key Response

APROCCHS found a mortality benefit while ADRENAL did not. This may be attributed to the addition of fludrocortisone in APROCCHS, the higher baseline mortality risk in the APROCCHS cohort (indicating a sicker population more likely to benefit), or the pharmacokinetic differences between continuous infusion (ADRENAL) and bolus dosing, the latter of which may produce different peaks in genomic and non-genomic steroid activity.

Attending

Given the results of ADRENAL, should the clinical focus shift from survival as the primary endpoint to 'days alive and free of vasopressors' when discussing adjunctive steroid therapy with surrogate decision-makers?

Key Response

Since mortality benefit remains elusive or marginal in heterogeneous septic shock populations, the value proposition of steroids lies in 'morbidity modulation.' Shortening the duration of shock and mechanical ventilation can reduce the risk of ICU-acquired weakness and delirium, which are critical components of the post-intensive care syndrome (PICS) that affect long-term quality of life.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ADRENAL trial was powered to detect a 5% absolute difference in mortality. Considering the heterogeneity of treatment effect (HTE) in sepsis, how might a Bayesian re-analysis of this data provide more utility for precision medicine than the reported frequentist p-value?

Key Response

Sepsis is a syndrome, not a single disease. A frequentist approach averages the effect across all participants, potentially masking benefits in specific sub-phenotypes (e.g., hyper-inflammatory vs. hypo-inflammatory). Bayesian modeling allows for the calculation of the probability of benefit across various thresholds, facilitating a more nuanced understanding of which patient subsets are most likely to respond to corticosteroids.

Journal Editor

As a reviewer, what concerns would you raise regarding the 24-hour enrollment window in the ADRENAL trial and its impact on the study's ability to capture the peak 'window of opportunity' for steroid intervention?

Key Response

The 24-hour window from the start of mechanical ventilation is relatively broad. If the survival benefit of steroids is dependent on early intervention during the initial 'cytokine storm' or the immediate onset of vasopressor-refractory shock, including patients later in their course may dilute the observable therapeutic effect, leading to a type II error regarding mortality.

Guideline Committee

How do the findings of the ADRENAL trial reconcile with the 2021 Surviving Sepsis Campaign (SSC) recommendations regarding the threshold for initiating hydrocortisone?

Key Response

The 2021 SSC guidelines issue a 'weak recommendation' with 'moderate-quality evidence' suggesting the use of IV hydrocortisone at a dose of 200mg/day for patients with septic shock and an ongoing requirement for vasopressor therapy at a dose of ≥0.25 mcg/kg/min for at least 4 hours. ADRENAL reinforces the 'weak' nature of the recommendation by confirming that while steroids accelerate shock resolution, they do not provide a robust, universal survival benefit, suggesting use should be individualized based on vasopressor requirements.

Clinical Landscape

Noteworthy Related Trials

2002

Annane et al. Trial

n = 300 · JAMA

Tested

Hydrocortisone 50mg every 6 hours and fludrocortisone 50ug daily

Population

Patients with septic shock and relative adrenal insufficiency

Comparator

Placebo

Endpoint

28-day mortality

Key result: Corticosteroid therapy significantly reduced 28-day mortality in patients who were non-responders to the corticotropin test.

2008

CORTICUS Trial

n = 499 · NEJM

Tested

Hydrocortisone 50mg every 6 hours

Population

Patients with septic shock

Comparator

Placebo

Endpoint

Death at 28 days

Key result: Hydrocortisone therapy did not improve survival in patients with septic shock, regardless of their response to corticotropin.

2018

APROCCHSS Trial

n = 1241 · NEJM

Tested

Hydrocortisone 200mg/day plus fludrocortisone 50ug/day

Population

Patients with septic shock

Comparator

Placebo

Endpoint

90-day mortality

Key result: Treatment with hydrocortisone plus fludrocortisone resulted in lower 90-day mortality compared to placebo.

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